Skin and Soft Tissue Substitutes

Number: 0244

(Replaces CPB 311)

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses skin and soft tissue substitutes. 

  1. Medical Necessity

    Aetna considers the following skin and soft tissue substitute products medically necessary (unless otherwise specified) for wound care according to the criteria indicated below.

    1. Alloderm and Alloderm-RTU acellular dermal tissue matrix

      1. For breast reconstructive surgery (see CPB 0185 - Breast Reconstruction Surgery);
      2. For use in surgical repair of complex abdominal wall wounds (e.g., due to infection, fascial defect, etc.);
      3. For ear drum augmentation (tympanoplasty), repair of skull base defect, and temporal bone lining.

      Aetna considers the use of Alloderm experimental and investigational for all other indications  (e.g., hernia repair, reduction of incidence of Frey's syndrome following parotidectomy, repair of trans-sphincteric rectal fistula, and for use in reconstruction of the upper extremity) because its effectiveness for indications other than the one listed above has not been established.

    2. Allogeneic Human, Cadaver-Derived Skin Graft

      For the management of traumatic skin wounds and burn wounds if the wound is too large for autograft.

    3. AlloPatch

      For the treatment of partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care.

    4. AlloSkin

      As an allogeneic human, cadaver-derived skin graft for the management of traumatic skin wounds and burn wounds if the wound is too large for autograft. (Note: not AlloSkin AC or AlloSkin RT, which are different products).

    5. AmnioBand

      For the treatment of: 

      1. Difficult-to-heal chronic venous partial and full-thickness ulcers of the lower extremity that have failed standard wound therapy of at least 4-weeks duration;
      2. Partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care.
    6. Apligraf (graftskin), a culture-derived human skin equivalent (HSE)

      For any of the following indications:

      1. For use with standard diabetic foot ulcer care for the treatment of full-thickness neuropathic diabetic foot ulcers of greater than 6-weeks duration that have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure; or
      2. In conjunction with standard therapy to promote effective wound healing of chronic, non-infected, partial and full-thickness venous stasis ulcers that have failed conservative measures of greater than 4 weeks duration using regular dressing changes and standard therapeutic compression.

      Aetna considers Apligraft experimental and investigational for all other indications (e.g., traumatic wounds) because its effectiveness for indications other than the ones listed above has not been established.

    7. Artiss fibrin sealant

      For the treatment of individuals with severe burns.

      Aetna considers Artiss fibrin sealant experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

    8. Biobrane Biosynthetic Dressing

      For temporary covering of a superficial partial-thickness burn wound.

      Aetna considers Biobrane biosynthetic dressing experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

    9. DermACELL

      For treatment of:

      1. Partial and full-thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care;
      2. Oro-nasal fistula following cleft palate repair.

      For DermACELL for breast reconstruction, see CPB 0185 - Breast Reconstruction Surgery).

      Aetna considers DermACELL experimental and investigational for all other indications.

    10. Dermagraft

      For use in the treatment of:

      1. Full-thickness diabetic foot ulcers greater than 6-week duration that extend through the dermis, but without tendon, muscle, joint capsule or bone exposure; or
      2. Wounds related to dystrophic epidermolysis bullosa.

      Note: Consistent with the Food and Drug Administration (FDA)-approved labeling of Dermagraft, the product should be used in conjunction with standard wound care regimens. In addition, the product is not considered medically necessary in persons with an inadequate blood supply to the involved foot.

      Aetna considers Dermagraft experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

      Dermagraft is contraindicated and has no proven value in infected ulcers and ulcers with sinus tracts.

    11. Epicel cultured epidermal autograft

      For members who have deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30%.

      Note: Epicel may be used in conjunction with split-thickness autografts, or alone in persons for whom split-thickness autografts may not be an option due to the severity and extent of their burns.

      Aetna considers Epicel cultured epidermal autograft experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

    12. Epicord

      For treatment of partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care.

      Aetna considers Epicord experimental and investigational for all other indications.

    13. EpiFix

      For treatment of:

      1. Partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care;
      2. Difficult-to-heal chronic venous or diabetic partial and full-thickness ulcers of the lower extremity that have failed standard wound therapy of at least 4-weeks duration.

      Aetna considers EpiFix experimental and investigational for all other indications (e.g., Stevens-Johnson syndrome / toxic epidermal necrolysis syndrome). For amnioticc membrane for ocular surface disorders, see CPB 0293 - Corneal Graft and Amniotic Membrane Transplantation, Limbal Stem Cell Transplantation, or Sural Nerve Grafting for Ocular Indications.

    14. Grafix (Grafix Core and Grafix Prime)

      For treatment of partial and full-thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care.

      Aetna considers Grafix Core, Grafix PL Core, Grafix Prime and Grafix PL Prime experimental and investigational for all other indications.

    15. Graftjacket Regenerative Tissue Matrix

      For treatment of:

      1. Full-thickness diabetic foot ulcers greater than 6-weeks duration that extend through the dermis, but without tendon, muscle, joint capsule or bone exposure;
      2. Oro-nasal fistula following cleft palate repair.

      Aetna considers Graftjacket Regenerative Tissue Matrix experimental and investigational for all other indications (e.g., carpometacarpal joint repair, and rotator cuff repair); because its effectiveness for indications other than the one listed above has not been established.

    16. Integra Dermal Regeneration Template and Integra Bilayer Wound Matrix

      1. Integra Dermal Regeneration Template, Integra Bilayer Matrix Wound Dressing, and Integra Meshed Bilayer Wound Matrix (collagen-glycosaminoglycan copolymers) for the treatment of individuals with severe burns where there is a limited amount of their own skin to use for autografts or they are too ill to have more wound sites created;
      2. Integra Dermal Regeneration Template and Integra Omnigraft Dermal Regeneration Template for the treatment of partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care.

      Aetna considers Integra Dermal Regeneration Template and Integra Bilayer Wound Matrix experimental and investigational for all other indications (e.g., following excision of malignant melanoma) because its effectiveness for indications other than the ones listed above has not been established.

    17. Oasis Wound Matrix

      For treatment of:

      1. Partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care;
      2. Difficult-to-heal chronic venous partial and full-thickness ulcers of the lower extremity that have failed standard wound therapy of at least 4-weeks duration.

      Aetna considers Oasis Wound Matrix experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

    18. Orcel (bilayered cellular matrix)

      For healing donor site wounds in burn victims, and for use in persons with dystrophic epidermolysis bullosa undergoing hand reconstruction surgery to close and heal wounds created by the surgery, including those at donor sites.

      Aetna considers Orcel experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

    19. Strattice Reconstructive Tissue Matrix

      For use in surgical repair of complex abdominal wall wounds (e.g., due to infection, fascial defect, etc.).

    20. TheraSkin

      1. For the treatment of partial and full‐thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care; or
      2. As an allogeneic human, cadaver-derived skin graft for the management of traumatic skin wounds and burn wounds if the wound is too large for autograft. 
    21. TransCyte (allogeneic human dermal fibroblasts), a biosynthetic dressing

      1. For the temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in persons who require such a covering before autograft placement; or
      2. For the treatment of mid-dermal to indeterminate depth burn wounds that typically require debridement and that may be expected to heal without autografting.

      Aetna considers TransCyte experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

  2. Experimental and Investigational

    The following skin and soft tissue substitute products are considered experimental and investigational because there is inadequate evidence in the peer-reviewed medical literature to support their clinical effectiveness:

    1. ACM Surgical Collagen
    2. ACM Surgical Extra Advanced Collagen
    3. ACM Surgical Extra Advanced Collagen Powder
    4. ActiGraft
    5. AC5 Advanced Wound System (AC5)
    6. Adherus Dural Sealant
    7. Affinity Human Amniotic Allograft
    8. AlloAid amniotic liquid / amniotic patch
    9. AlloDerm for protection of the carotid artery following radical neck dissection
    10. AlloGen
    11. AlloGen Liquid
    12. AlloMax for indications other than breast reconstruction; for AlloMax for breast reconstruction (see CPB 0185 - Breast Reconstruction Surgery)
    13. AlloSkin AC Acellular Dermal Matrix
    14. Alloskin RT
    15. AlloWrap
    16. AlphaGems amniotic tissue allograft
    17. AltiPlast
    18. AltiPly
    19. Ambio Choice amniotic membrane
    20. Amnioamp-mp
    21. AmnioArmor
    22. AmnioCare
    23. AmnioCord
    24. AmnioCyte Plus
    25. AmnioExCel
    26. AmnioFill Human Placental Tissue Allograft
    27. AmnioFix Amnion/Chorion Membrane Allograft
    28. Amnio FRT
    29. AmnioGenix
    30. AmnioHeal amniotic membrane
    31. Amniomatrix Human Amniotic Suspension Allograft
    32. Amnio-Maxx or Amnio-Maxx Lite
    33. AmnioMTM
    34. Amnion allograft ASG
    35. Amnion Bio
    36. Amniorepair
    37. Amnios' acellular liquid amnion
    38. AmnioShield
    39. AmnioStrip
    40. Amniotext (suspenion or patch)
    41. Amnio Wound
    42. AmnioWrap2
    43. Amniotic fluid injection for wound healing (including corneal wound healing) and for prevention of adhesions after orthopedic surgery
    44. Amniox (human embryonic membrane) for tarsel tunnel repair and all other indications
    45. Amniply
    46. AmnyoFactor
    47. AmnyoFluid
    48. Apis
    49. Apligraf for necrotizing lesions
    50. Architect ECM
    51. Architect PX
    52. Artacent Cord
    53. Artacent Wound
    54. Artelon (poly[urethane urea] elastomer) for anterior cruciate ligament reconstruction, rotator cuff repair, trapezio-metacarpal joint osteoarthritis and all other indications
    55. Arthres GraftRope for acromio-clavicular joint separation reconstruction
    56. Arthrex Amnion matrix
    57. Arthrex Amnion viscous
    58. Arthroflex (FlexGraft)
    59. Ascent (injectable derived from human amniotic fluid)
    60. Autologous blood-derived products (e.g., autologous platelet-rich plasma, autologous platelet gel, and autologous platelet-derived growth factors (e.g., Autologel, Procuren, SafeBlood)
    61. Autologous fat for the treatment of scars
    62. Avotermin for improvement of skin scarring
    63. AxoBioMembrane
    64. Axolotl Ambient
    65. Axolotl Cryo
    66. Axolotl DualGraft
    67. Axolotl Graft
    68. Barrera SL, Barrera DL
    69. BellaCell HD
    70. BioDexcel
    71. BioDfactor Viable Tissue Matrix
    72. BioDfence human amniotic allograft
    73. BioDfence Dryflex
    74. BioDmatrix
    75. BioDRestore Elemental Tissue Matrix
    76. Bio-ConneKt
    77. BioFix Amniotic Membrane Allograft
    78. BioFix Flow Placental Tissue Matrix Allograft
    79. Bioinductive implant Regeneten
    80. Bionect
    81. BioSkin Flow
    82. Biostat Biologx fibrin sealant for wound healing and all other indications
    83. Biotape reinforcement matrix for soft tissue augmentation and all other indications
    84. Biovance Amniotic Membrane Allograft
    85. Biovance Tri-layer, Biovance 3L
    86. BioWound Membrane
    87. BioWound Plus Membrane
    88. BioWound XPlus Membrane
    89. carePATCH
    90. celera Dual Membrane
    91. celera Dual Layer
    92. CellECT (human amnion and amniotic fluid allograft)
    93. CellerateRX
    94. Cellesta Cord
    95. Cellesta Duo
    96. Cellesta Flowable Amnion
    97. Cellgenuity amniotic fluid
    98. Clarix 100
    99. Clarix Cord 1K
    100. Clarix Flo
    101. Cocoon Membrane
    102. Cogenex amniotic membrane
    103. Cogenex Flowable Amnion
    104. CollaFix
    105. Colla-Pad
    106. CollaSorb collagen dressing
    107. CollaWound collagen sponge
    108. Coll-e-Derm
    109. Collexa
    110. Complete FT
    111. Complete SL
    112. Conexa reconstructive tissue matrix
    113. Cook Medical anal fistula plug
    114. CoreCyte
    115. CoreText
    116. CorMatrix ECM Patch for cardiac tissue repair and all other indications
    117. Corplex or Corplex P
    118. Cortiva Allograft Dermis (for use in breast reconstructive surgery see CPB 0185 - Breast Reconstructive Surgery)
    119. C-QUR biosynthetic mesh
    120. CRXa
    121. Cryo-Cord
    122. CryoText
    123. CYGNUS Amnion Patch Allografts
    124. Cygnus Dual
    125. CYGNUS Matrix
    126. Cymetra injectable allograft for wound healing (see also CPB 0253 - Vocal Cord Paralysis/Insufficiency Treatments)
    127. Cytal Burn Matrix
    128. Cytal Multilayer Wound Matrix
    129. Cytal Wound Matrix
    130. Dehydrated human amniotic membrane allograft (e.g., AmnioPro, BioFix and FlowerPatch)
    131. DermaBind SL
    132. DermACELL, DermACELL AWM, and DermACELL AWM Porous for indications other than diabetic foot ulcers
    133. DermaClose RC continuous external tissue expander for facilitation of wound closure and all other indications
    134. Dermacyte
    135. Derma-Gide
    136. Dermagraft for chronic foot ulcer secondary to necrotizing fasciitis
    137. DermaMatrix (formerly InteXen) Porcine Dermal Matrix for wound healing and other indications other than breast reconstruction; for DermaMatrix for breast reconstruction (see CPB 0185 - Breast Reconstruction Surgery)
    138. DermaPure
    139. DermaSpan Acellular Dermal Matrix
    140. Dermavest Human Placental Connective Tissue Matrix
    141. Derm-Maxx
    142. Dermis on Demand (DOD) allografts
    143. DryFlex (human amnion allograft) for shoulder repair and all other indications
    144. Dual Layer Impax Membrane
    145. DuraGen Plus dural regeneration matrix for surgical repair of soft tissue deficiencies and all other indications
    146. DuraMatrix
    147. Durepair Regeneration Matrix
    148. Endoform Dermal Template
    149. ENDURAGen
    150. Enverse
    151. TransCu O2 (E02 Concepts, San Antonio, TX) continuous diffusion of oxygen (CDO) therapy for wound healing
    152. EpiBurn
    153. Epidex
    154. Epieffect
    155. EPIFLO transdermal continuous oxygen therapy for wound healing
    156. Equine-derived decellularized collagen products (e.g., OrthADAPT, Unite, and Unite Biomatrix)
    157. Esano A
    158. Esano AA
    159. Esano AC
    160. Esano ACA
    161. EZ Derm for wound healing and all other indications
    162. Evicel fibrin sealant for repair of cerebrospinal fluid leakage and all other indications
    163. Excellagen
    164. FlexHD acellular dermal matrix for wound healing (for FlexHD for breast reconstruction, see CPB 0185 - Breast Reconstruction Surgery)
    165. FloGraft Amniotic Fluid-Derived Allograft
    166. FlowerDerm
    167. FlowerFlo (FlowerAmnioFlo)
    168. FlowerPatch (FlowerAMINOPatch)
    169. Fluid Flow
    170. Fluid GF
    171. Fortaderm
    172. Fortaderm Antimicrobial
    173. Fortiva Porcine Dermis
    174. Gammagraft skin substitute
    175. Genesis Amniotic Membrane
    176. GORE BIO-A Fistula Plug
    177. Grafix cryo-preserved placental membrane
    178. GraftJacket Xpress injectable allograft for wound healing and all other indications
    179. Guardian
    180. Helicoll
    181. Human Health Factor 10 Amniotic Patch (HHF10-P)
    182. Hyalomatrix (hMatrix ADM) Tissue Reconstruction Matrix
    183. HydroFix
    184. Inforce
    185. InnovaBurn, InnovaMatrix XL
    186. InnovaMatrix AC, InnovaMatrix FS, InnovaMatrix PD
    187. Integra Wound Matrix and Integra Flowable Wound Matrix for the management of osteoradionecrosis of the jaw, wounds including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (e.g., abrasions, lacerations, second-degree burns, skin tears) and draining wounds and all other indications
    188. InteguPly
    189. Interfyl Human Connective Tissue Matrix
    190. Jacob's Ladder external closure device for wound closure
    191. Keramatrix
    192. Kerasorb Wound Matrix
    193. Keroxx Flowable Wound Matrix
    194. LiquidGen
    195. Matriderm
    196. Matrion
    197. MatriStem Burn Matrix
    198. MatriStem Micro Matrix
    199. MatriStem UBM (Urinary Bladder Matrix)
    200. MatriStem Wound Matrix
    201. Matrix HD Allograft
    202. Matrix PSM
    203. MediHoney
    204. Mediskin
    205. Medeor
    206. Membrane Graft
    207. Membrane Wrap
    208. MemoDerm
    209. Menaflex Collagen Meniscus Implant (see CPB 0786 - Menaflex)
    210. Meso BioMatrix
    211. MiAmnion for the treatment of burns
    212. Microlyte Matrix
    213. MicroMatrix
    214. Miro3D wound matrix
    215. MIRODERM
    216. Mirragen Advanced Wound Matrix
    217. MLG Complete
    218. MyOwn Skin
    219. Myriad Morcells
    220. Neoform Dermis for wound healing (for NeoForm for breast reconstruction, see CPB 0185 - Breast Reconstruction Surgery)
    221. NeoMatriX Wound Matrix
    222. NeoPatch chorioamniotic membrane allograft
    223. NeoStim DL
    224. NeoStim Membrane
    225. NeoStim TL
    226. Neox Cord 1K
    227. Neox 100
    228. Neox Flo
    229. Neuragen
    230. Neuroflex
    231. Novachor
    232. Novafix
    233. Novafix DL
    234. NovoSorb SynPath dermal matrix
    235. NuCel liquid wound covering
    236. NuDyn, NuDYN DL, NuDYN DL MESH, NuDYN SL, NuDYN SLW
    237. NuShield, NuShield Orthopaedics, and NuShield Spine
    238. Oasis burn matrix for wound healing and all other indications
    239. Oasis Tri-Layer Matrix
    240. Ologen Collagen Matrix
    241. Omega3 MariGen, Omega3 MariGen Shield, Omega3 Wound ECM, Omega3 Wound Matrix (Kerecis fish skin graft)
    242. Omeza Collagen Matrix
    243. Orion
    244. OrthADAPT Bioimplant (type I collagen scaffold) for tendon repair and all other indications
    245. OrthoFlo
    246. OsseoGuard
    247. Ovation
    248. OviTex (reinforced tissue matrix) for ventral hernia repair
    249. PalinGen Flow
    250. PalinGen Hydromembrane
    251. PalinGen Membrane
    252. Palingen SportFlow
    253. PalinGen XPlus Hydromembrane
    254. PalinGen XPlus Membrane
    255. ParaDerm dermal matrix
    256. Parietex Composite (PCO) Mesh for the treatment of genito-urinary (e.g., uterine or vaginal vault) prolapse
    257. Peri-Guard Repair Patch
    258. Peri-Strips Dry, and Peri-Strips Dry with Veritas Collagen Matrix
    259. Permacol Biologic Implant for soft tissue surgical repairs, including hernia repair, muscle flap reinforcement, rectal prolapse (including intussusception), rectocele repair, abdominal wall defects, plastic and reconstructive surgery, complex abdominal wall repair and all other indications
    260. PermeaDerm B
    261. PermeaDerm C
    262. PermeaDerm Glove
    263. Phoenix Wound Matrix
    264. Placental tissue matrix allograft
    265. Plurivest Human Placental Connective Tissue Matrix
    266. PolyCyte
    267. Porcine-derived decellularized collagen products (e.g., Collamend, Cuffpatch, Pelvicol, and Pelvisoft)
    268. Porcine-derived decellularized fetal skin products (e.g., Mediskin)
    269. Porcine-derived polypropylene composite wound dressing (e.g., Avaulta Plus)
    270. PriMatrix Dermal Repair Scaffold
    271. PRISMA matrix wound dressing for pressure ulcer
    272. Pro3-C amniotic membrane
    273. Procenta
    274. ProgenaMatrix
    275. ProLayer human allograft acellular dermal matrix
    276. ProMatrX ACF
    277. Promogran Matrix
    278. ProText
    279. PTFE felt
    280. Puracol Collagen Wound Dressing
    281. Puracol Plus Collagen Wound Dressing
    282. PuraPly Antimicrobial Wound Matrix (PuraPly AM)
    283. PuraPly Wound Matrix (PuraPly)
    284. Puros Dermis
    285. Radiofrequency stimulation devices (e.g., Provant Wound Closure System, MicroVas Vascular Treatment System) for wound healing
    286. RECELL Autologous Cell Harvesting Device (RECELL)
    287. Reguard
    288. Relese
    289. ReNu (amniotic membrane and fluid allograft)
    290. Renuva
    291. Repliform
    292. Repriza
    293. Resolve Matrix
    294. Restorigin Amnion Patch
    295. Restorigin Amniotic Fluid Therapy (AFT)
    296. Restrata
    297. Revita
    298. Revitalon
    299. RHEO (BioStem Life Sciences, Inc.)
    300. Seamguard
    301. Signature APatch
    302. SkinTE for the treatment of burns
    303. Silver-coated wound dressings (e.g., Acticoat, Actisorb, Aquacel Ag, Granufoam silver VAC dressing, Mepitel Ag, and Silversorb) for wound healing and all other indications
    304. Solana allograft
    305. Sonafine wound dressing
    306. SportMatrix
    307. SportMesh
    308. SteriShield II dual layer amnion patch
    309. Strattice Reconstructive Tissue Matrix for wound healing (for Strattice for breast reconstruction see CPB 0185 - Breast Reconstruction Surgery)
    310. StrataGraft
    311. Stravix
    312. Stravix PL
    313. Supra SDRM
    314. Suprathel
    315. SureDerm
    316. SurFactor
    317. SurgiCORD
    318. surgiGRAFT
    319. SurgiGRAFT-DUAL
    320. SurGraft FT
    321. SurGraft TL
    322. SurGraft XT
    323. SurgiMend for plastic and reconstructive surgery, muscle flap reinforcement, hernia repair, reinforcement of soft tissues repaired by sutures or suture anchors, during tendon repair surgery (including reinforcement of the rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons), and all other wound care indications (for SurgiMend for breast reconstruction, see CPB 0185 - Breast Reconstruction Surgery)
    324. Surgisis (including Surgisis AFP Anal Fistula Plug, Surgisis Gold Hernia Repair Grafts, and Surgisis Biodesign) (see CPB 0411 - Bone and Tendon Graft Substitutes and Adjuncts)
    325. SurGraft
    326. Symphony
    327. TAG
    328. Talymed
    329. TenoGlide tendon protector sheet (Tendon WrapTM tendon protector) for the management and protection of tendon injuries and all other indications
    330. TenSIX Acellular Dermal Matrix for tendon repair and all other indications
    331. TheraForm Standard/Sheet Absorbable Collagen Membrane
    332. TheraGenesis
    333. TissueMend for the repair or reinforcement of soft tissues repaired by sutures or suture anchors during tendon repair surgery, including reinforcement of the rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons, and all other indications. Note: Use of TissueMend is considered integral to the surgery and not separately reimbursed;
    334. Tornier BioFiber Absorbable Biological Scaffold, and Tornier Collagen Coated BioFiber Scaffold
    335. Truskin
    336. Unite Biomatrix
    337. Vaso Shield
    338. Veritas Collagen Matrix for use as an implant in the surgical repair of soft tissue deficiencies and all other indications
    339. VersaWrap Tendon Protector for the management and protection of tendon injuries and all other indications
    340. Viaflow / Viaflow C flowable placental tissue matrices
    341. Vitagel surgical hemostat for wound healing and all other indications
    342. Vendaje
    343. Vendaje AC (BioStem Life Sciences, Inc.)
    344. VIM Human Amniotic Membrane
    345. WoundEx Flow
    346. WoundEx Membrane
    347. WoundFix Membrane
    348. WoundFix Plus Membrane
    349. WoundFix XPlus Membrane
    350. WoundPlus Membrane or E-graft
    351. Xcell Amino Matrix
    352. XCellerate
    353. XCM Biologic Tissue Matrix
    354. Xelma
    355. XcelliStem
    356. XenMatrix
    357. X-Repair
    358. Xwrap Amniotic Membrane-Derived Allograft
    359. XWrap Dry or Hydro Plus
    360. Zenith Amniotic Membrane.

    Note: The use of Tisseel is considered integral to the surgery and is not separately reimbursed. 

    DuraSeal is considered integral to dural repair during spinal surgery and is not separately reimbursed.

    For nerve wraps or cuffs (e.g., Avance nerve graft, Axogen,2 nerve wrap, Integra Neural Wrap, NeuroMatrix collagen nerve cuff, and NeuroMend collagen nerve wrap), see CPB 0416 - Nerve Grafting: Selected Indications.

    For Aetna’s policy on systemic and topical hyperbaric oxygen, see CPB 0172 - Hyperbaric Oxygen Therapy (HBOT).

  3. Related Policies


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:

15271 - 15278 Application of skin substitute grafts
96574 Debridement of premalignant hyperkeratotic lesion(s) (ie, targeted curettage, abrasion) followed with photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care

Other HCPCS codes related to the CPB:

C5271 - C5274 Application of low cost skin substitute graft to trunk, arms, legs
C5275 - C5278 Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits
C7500 Debridement, bone including epidermis, dermis, subcutaneous tissue, muscle and/or fascia, if performed, first 20 sq cm or less with manual preparation and insertion of deep (eg, subfacial) drug-delivery device(s)

Medically necessary wound care treatments:

Other CPT codes related to the CPB:

11042 , 11045 Debridement; subcutaneous tissue
11043, 11046 Debridement; muscle and/or fascia
11044, 11047 Debridement; bone
11047     bone, each additional 20 sq cm, or part thereof
15002 - 15005 Surgical preparation or creation of recipient site
15777 Implantation of biologic implant (eg, acellular dermal matrix) for soft tissue reinforcement (eg, breast, trunk) (List separately in addition to code for primary procedure)
97597 Debridement (eg, high pressure waterjet with/without suction, sharp selective debridement with scissors, scalpel and forceps), open wound, (eg, fibrin, devitalized epidermis and/or dermis, exudate, devris, biofilm), including topical application(s), wound assessment, use of a whirlpool, when performed and instructions (s) for ongoing care, per session, total wound(s) surface area; first 20 sq cm or less
97598     each additional 20 sq cm, or part thereof (List separately in addition to code for primary procedure)

Apligraf (graftskin):

HCPCS codes covered if selection criteria are met:

Q4101 Apligraf, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
I83.001 - I83.029 Varicose veins of lower extremities with ulcer
I83.201 - I83.229 Varicose veins of lower extremities with ulcer and inflammation
I87.311 - I87.319 Chronic venous hypertension (idiopathic) with ulcer
I87.331 - I87.339 Chronic venous hypertension (idiopathic) with ulcer and inflammation

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A49.01 - A49.8 Bacterial infection of unspecified site
B78.1 Cutaneous strongyloidiasis
B95.0 - B95.8, B96.0 - B96.89 Streptococcus, staphylococcus, enterococcus and other bacterial agents as the cause of diseases classified elsewhere
E83.2 Disorders of zinc metabolism
I96 Gangrene
L08.82 - L08.9 Other and unspecified local infections of skin and subcutaneous tissue
M72.6 Necrotizing fasciitis
M86.00 - M86.86.9 Osteomyelitis
M87.00 - M87.9 Osteonecrosis
Numerous options Open wounds [Codes not listed due to expanded specificity]

Dermagraft:

HCPCS codes covered if selection criteria are met:

Q4106 Dermagraft, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
Q81.2 Epidermolysis bullosa dystrophica

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A49.0 - A49.8 Bacterial infection of unspecified site
B95.0 - B95.8, B96.0 - B96.89 Streptococcus, staphylococcus, enterococcus and other bacterial agents as the cause of diseases classified elsewhere
I70.261 - I70.269 Atherosclerosis of the extremities with gangrene
I83.201 - I83.229 Varicose veins of lower extremities with ulcer and inflammation
I96 Gangrene
L08.82 - L08.9 Other and unspecified local infection of skin and subcutaneous tissue
M72.6 Necrotizing fasciitis
M86.00 - M86.9 Osteomyelitis
M87.00 - M87.9 Osteonecrosis

Transcyte:

HCPCS codes covered if selection criteria are met:

Q4182 Transcyte, per square centimeter

ICD-10 codes covered if selection criteria are met:

T20.011A - T25.799S Burns

Orcel:

No specific code

HCPCS codes covered if selection criteria are met:

Q4100 Skin substitute, not otherwise specified

ICD-10 codes covered if selection criteria are met:

Q81.2 Epidermolysis bullosa dystrophica
T20.011A - T25.799S Burns

Biobrane biosynthetic dressing:

HCPCS codes covered if selection criteria are met:

Q4100 Skin substitute, not otherwise specified

CPT codes covered if selection criteria are met:

15050 - 15261 Autograft/tissue cultured autograft

ICD-10 codes covered if selection criteria are met:

T20.011A - T25.799S Burns

Integra Dermal Regeneration Template:

HCPCS codes covered if selection criteria are met:

Q4105 Integra Dermal Regeneration Template (DRT), per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
T20.00XA - T32.99S Burns

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

C43.0 - C43.9 Malignant melanoma of skin

Integra Bilayer Matrix Wound Dressing, and Integra Meshed Bilayer Wound Matrix:

HCPCS codes covered if selection criteria are met:

C9363 Skin substitute, Integra Meshed Bilayer Wound Matrix, per square centimeter
Q4104 Integra Bilayer Matrix Wound Dressing (BMWD), per sq sm

ICD-10 codes covered if selection criteria are met:

T20.00XA - T32.99S Burns

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

C43.0 - C43.9 Malignant melanoma of skin

Alloderm:

Other CPT codes related to the CPB:

19357 - 19369 Breast reconstruction
23420 Reconstruction of complete shoulder (rotator) cuff avulsion, chronic (includes acromioplasty)
23470 - 23472 Arthroplasty, glenohumeral joint
23473 - 23474 Revision of total shoulder arthroplasty, including allograft when performed
24344 Reconstruction lateral collateral ligament, elbow, with tendon graft (includes harvesting of graft)
24345 Repair medical collateral ligament, elbow, with local tissue
24346 Reconstruction medial collateral ligament, elbow, with tendon graft (includes harvesting of graft)
24360 - 24363 Arthroplasty, elbow
24365 - 24366 Arthroplasty, radial head
24370 - 24371 Revision of total elbow arthroplasty, including allograft when performed
25320 Capsulorrhaphy or reconstruction, wrist, open (eg, capsulodesis, ligament repair, tendon transfer or graft) (includes synovectomy, capsulotomy and open reduction) for carpal instability
25337 Reconstruction for stabilization of unstable distal ulna or distal radioulnar joint, secondary by soft tissue stabilization (eg, tendon transfer, tendon graft or weave, or tenodesis) with or without open reduction of distal
25390 - 25393 Osteoplasty, radius and/or ulna
25441 - 25442 Arthroplasty, with prosthetic replacement; distal radius and distal ulna
25446 Arthroplasty, with prosthetic replacement; distal radius and partial or entire carpus (total wrist)
26135 Synovectomy, metacarpophalangeal joint including intrinsic release and extensor hood reconstruction, each digit
26140 Synovectomy, proximal interphalangeal joint, including extensor reconstruction, each interphalangeal joint
26390 Excision flexor tendon, with implantation of synthetic rod for delayed tendon graft, hand or finger, each rod
26490 - 26496 Opponensplasty
26500 - 26502 Reconstruction of tendon pulley, each tendon
26530 - 26531 Arthroplasty, metacarpophalangeal joint
26535 - 26536 Arthroplasty interphalangeal joint
26541 - 26542 Reconstruction, collateral ligament, metacarpophalangeal joint, single
26545 Reconstruction, collateral ligament, interphalangeal joint, single, including graft, each joint
26548 Repair and reconstruction, finger, volar plate, interphalangeal joint
26550 Pollicization of a digit
26551 - 26554 Transfer, toe-to-hand with microvascular anastomosis
26555 Transfer, finger to another position without microvascular anastomosis
26556 Transfer, free toe joint, with microvascular anastomosis
26587 Reconstruction of polydactylous digit, soft tissue and bone
38724 Cervical lymphadenectomy (modified radical neck dissection)
42410 - 42426 Excision of parotid tumor or parotid gland

HCPCS codes covered if selection criteria are met:

Q4116 Alloderm, per square centimeter

ICD-10 codes covered if selection criteria are met:

C50.011 - C50.929 Malignant neoplasm of breast
C79.81 Secondary malignant neoplasm of breast
D05.00 - D05.92 Carcinoma in situ of breast
H65.00 - H67.9 Otitis media
H72.00 - H72.93 Perforation of tympanic membrane
N60.11 – N60.19 Diffuse cystic mastopathy
Q75.8 Other congenital malformations of skull and face bones
Q75.9 Congenital malformation of skull and face bones, unspecified
S02.101A – S02.19xS Fracture of base of skull
Z15.01 Genetic susceptibility to malignant neoplasm of breast
Z15.02 Genetic susceptibility to malignant neoplasm of ovary
Z80.3 Family history of malignant neoplasm of breast
Z80.41 Family history of malignant neoplasm of ovary
Z85.3 Personal history of malignant neoplasm of breast
Z90.10 - Z90.13 Acquired absence of breast and nipple
Z92.3 Personal history of irradiation

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

C44.42 Squamous cell carcinoma of skin of scalp and neck
K40.00 - K46.9 Hernia
K60.4 Rectal fistula [trans-sphincteric rectal fistula]
L74.52 Secondary focal hyperhidrosis [Frey's syndrome]

Artiss:

HCPCS codes covered if selection criteria are met:

C9250 Human plasma fibrin sealant, vapor-heated, solvent-detergent (Artiss), 2ml

ICD-10 codes covered if selection criteria are met:

T20.011A - T25.799S Burns

Oasis Wound Matrix:

HCPCS codes covered if selection criteria are met:

Q4102 Oasis Wound Matrix, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type I diabetes mellitus with foot ulcer
E11.621 Type II diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
I83.001 - I83.029 Varicose veins of lower extremities with ulcer
I83.201 - I83.229 Varicose veins of lower extremities with ulcer and inflammation
I87.311 - I87.319 Chronic venous hypertension with ulcer
I87.331 - I87.339 Chronic venous hypertension with ulcer and inflammation

Graftjacket Regenerative Tissue Matrix:

HCPCS codes covered if selection criteria are met:

Q4107 Graftjacket, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621, E09.621, E10.621, E11.621, E13.621 Diabetes mellitus
J34.89 Other specified disorders of nose and nasal sinuses [oro-nasal fistula]
Z87.730 Personal history of (corrected) cleft lip and palate [oro-nasal fistula]

Epicel:

No specific code

CPT codes covered if selection criteria are met:

15150 - 15157 Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits

ICD-10 codes covered if selection criteria are met:

T20.311A- T20.39XS, T20.711A – T20.79XS Burn and corrosion of third degree of face, head, and neck
T21.30XA – T21.39XS, T21.70XA – T21.79XS Burn and corrosion of third degree of trunk
T22.301A – T22.399A, T22.711A – T22.799S Burn and corrosion of third degree of shoulder and upper limb
T23.301A – T23.399S, T23.701A – T23.799S Burn and corrosion of third degree of wrist and hand
T24.301A – T24.399S, T24.701A - T24.799S Burn and corrosion of third degree of lower limb, except ankle and foot
T25.311A – T25.399S, T25.711A – T25.799S Burn and corrosion of third degree of ankle and foot
T31.30 - T31.99, T32.30 - T32.99 Burn [any degree] 30 to 90 percent or more of body surface

Epifix:

HCPCS codes covered if selection criteria are met:

Q4186 Epifix, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621, E09.621, E10.621, E11.621, E13.621 Diabetes mellitus with foot ulcer
I87.311 - I87.319 Chronic venous hypertension (idiopathic) with ulcer
L97.101 - L97.929 Non-pressure chronic ulcer of lower limb, not elsewhere classified

Grafix:

HCPCS codes covered if selection criteria are met:

Q4132 Grafix core, per sq cm
Q4133 Grafix prime, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621, E09.621, E10.621, E11.621, E13.621 Diabetes mellitus with foot ulcer

Epicord:

HCPCS codes covered if selection criteria are met:

Q4187 Epicord, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer

DermACELL:

HCPCS codes covered if selection criteria are met:

Q4122 DermACELL, DermACELL AWM or DermACELL AWM Porous, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
Q35.1 - Q37.9 Cleft lip and cleft palate
Z87.730 Personal history of (corrected) cleft lip and palate

Strattice:

HCPCS codes covered if selection criteria are met:

Q4130 Strattice TM, per sq cm)

ICD-10 codes covered if selection criteria are met:

S31.100A – S31.839S Open wounds of the abdomen

AmnioBand:

HCPCS codes covered if selection criteria are met:

Q4151 Amnioband or guardian, per sq cm
Q4168 Amnioband, 1 mg

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
I83.001 – I83.029 Varicose veins of lower extremity with ulcer [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]
I83.201 – I83.229 Varicose veins of lower extremity with both ulcer and inflammation [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]
I87.011 – I87.019 Postthrombotic syndrome with ulcer of lower extremity [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]
I87.031 – I87.039 Postthrombotic syndrome with ulcer and inflammation [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]
I87.311 – I87.319 Chronic venous hypertension (idiopathic) with ulcer [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]
I87.331 – I87.339 Chronic venous hypertension (idiopathic) with ulcer and inflammation [difficult to heal chronic venous partial and full thickness ulcers of the lower extremity]

AlloPatch:

HCPCS codes covered if selection criteria are met:

Q4128 FlexHD, AllopatchHD, or Matrix HD, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer

TheraSkin:

HCPCS codes covered if selection criteria are met:

Q4121 TheraSkin, per sq cm

ICD-10 codes covered if selection criteria are met:

E08.621 Diabetes mellitus due to underlying condition with foot ulcer
E09.621 Drug or chemical induced diabetes mellitus with foot ulcer
E10.621 Type 1 diabetes mellitus with foot ulcer
E11.621 Type 2 diabetes mellitus with foot ulcer
E13.621 Other specified diabetes mellitus with foot ulcer
Numerous options Open wounds [Codes not listed due to expanded specificity]
T20.011A - T25.799S Burn

Allogeneic human, cadaver-derived skin graft (e.g., Allosource PureSkin):

HCPCS codes covered if selection criteria are met:

Allogeneic human, cadaver-derived skin graft (e.g., Allosource PureSkin)- no specific code

ICD-10 codes covered if selection criteria are met:

T20.011A - T25.799S Burns
Numerous options Open wounds [Codes not listed due to expanded specificity]

AlloSkin:

HCPCS codes covered if selection criteria are met:

Q4115 AlloSkin, per square centimeter

ICD-10 codes covered if selection criteria are met:

T20.011A - T25.799S Burns
Numerous options Open wounds [Codes not listed due to expanded specificity]

Experimental and investigational wound care treatments - No specific code:

Actigraft, Adherus Dural Sealant, AlloAid amniotic liquid / amniotic patch, AlloMax, AlloSource cryopreserved human cadaver skin, Amnio FRT, AmnyoFactor, AmnioHeal amniotic membrane, Amnion allograft ASG, Cook Medical anal fistula plug, AmnioMTM, AmnioShield, AmnioStrip, Amniox (human embryonic membrane), BioDfactor, BioDRestore Elemental Tissue Matrix, Bionect, Biostat Biologx Fibrin Sealant, PTFE felt, Biotape Reinforcement Matrix, CellECT (human amnion and amniotic fluid allograft), CellerateRX, CollaFix, CollaMend, Connexa reconstruction tissue matrix, CorMatrix Patch, Cortiva Allograft Dermis, C-Qur biosynthetic mesh, CRXa, Cuffpatch, dehydrated human amniotic membrane allograft (e.g., AmnioPro, BioFix), Dermamatrix, DuraGen Plus Dural Regeneration Matrix, DuraMatrix, DuraSeal, Durepair Regeneration Matrix, Endoform, ENDURAgeN, EPIFLO transdermal continuous oxygen therapy, Epiburn, Epidex, FloGraft, Fortiva Porcine Dermis, GORE BIO-A Fistula Plug, Graftjacket regenerative tissue matrix for rotator cuff repair and carpometacarpal (CMC) joint repair, Granufoam silver VAC dressing, HydroFix, Inforce, Jacob’s Ladder external closure device, LiquidGen, Matriderm, Matrix PSM, MediHoney, Medeor, Mepitel Ag, Meso BioMatrix, MiAmnion, Neuroflex, NeuroForm Dermis, NuCel liquid wound covering, OrthADAPT Bioimplant (type I collagen scaffold), OrthoFlo, OsseoGuard, Ovation, Pelvico, Pelvisoft, Peri-Guard Repair Patch, Peri-Strips Dry, Peri-Strips Dry with Veritas Collagen Matrix, placental tissue matrix allograft. Porcine-derived polypropylene composite wound dressing (eg, Avaulta Plus™), PRISMA matrix wound dressing, Pro3-C amniotic membrane, Promogran, Puracol, Puros Dermis, ReNu (amniotic membrane and fluid allograft), RHEO (BioStem Life Sciences, Inc.), Repliform, Seamguard, Solana allograft, Sonafine wound dressing, SportMatrix, SportMesh, Sterishield II Dual Layer Amnion Patch, Stravix, Viaflow Placental Tissue Matrix, StrataGraft, Surgisis (including Surgisis AFP Anal Fistula Plug, Surgisis Gold Hernia Repair Grafts, and Surgisis Biodesign), TissueMend, Tornier BioFiber Absorbable Biological Scaffold, Tornier Collagen Coated BioFiber Scaffold, Vaso Shield, Viaflow C Flowable Placental Tissue Matrix, Vitagel Surgical Heomstat, Xelma, X-Repair, XenMatrix, ACM Surgical Collagen, ACM Surgical Extra Advanced Collagen, ACM Surgical Extra Advanced Collagen Powder, AlphaGems, AltiPlast, Ambio Choice, AmnioCord, AmnioFill, Amnios, AmnyoFluid, Aquacel Ag, Arthrex Amnion Matrix, Arthrex Amnion Viscous, BioFix Flow Placental Tissue Matrix Allograft, Colla-Pad, CollaSorb, CollaWound, Collexa, Fluid GF, Grafix cryo-preserved placental membrane, GraftJacket RTM, InteguPly, Kerasorb Wound Matrix, Merigen, Ologen, Omega3 Wound, Omega3 Wound Matrix, Puracol Plus, Renuva, Restrata, Stravix PL, TheraForm and VersaWrap Tendon Protector, Bioinductive implant regeneten, Cellgenuity amniotic fluid, Cryotext and Dermis on demand (DOD) allografts, Myriad morcells, Paraderm dermal matrix

HCPCS codes not covered for indications listed in the CPB:

A2001 InnovaMatrix AC, per sq cm
A2002 Mirragen Advanced Wound Matrix, per sq cm
A2003 Bio-connekt wound matrix, per square centimeter
A2004 XCelliStem, per sq cm
A2005 Microlyte Matrix, per sq cm
A2006 NovoSorb SynPath dermal matrix, per sq cm
A2007 Restrata, per square centimeter
A2008 TheraGenesis, per sq cm
A2009 Symphony, per sq cm
A2010 Apis, per sq cm
A2011 Supra sdrm, per square centimeter
A2012 Suprathel, per square centimeter
A2013 Innovamatrix fs, per square centimeter
A2014 Omeza collagen matrix, per 100 mg
A2015 Phoenix wound matrix, per square centimeter
A2016 Permeaderm b, per square centimeter
A2017 Permeaderm glove, each
A2018 Permeaderm c, per square centimeter
A2019 Kerecis omega3 marigen shield, per square centimeter
A2020 Ac5 advanced wound system (ac5)
A2021 Neomatrix, per square centimeter
A2022 Innovaburn or innovamatrix xl, per square centimeter
A2023 Innovamatrix pd, 1 mg
A2024 Resolve matrix, per square centimeter
A2025 Miro3d, per cubic centimeter
A4100 Skin substitute, fda cleared as a device, not otherwise specified
A4575 Topical hyperbaric oxygen chamber, disposable [TransCu O2] [EO2 Concepts]
A6196 - A6199 Alginate or other fiber gelling dressing, wound cover, sterile
A6206 - A6208 Contact layer, sterile, each dressing
A6209 - A6211 Foam dressing, wound cover, sterile, each dressing
C1781 Mesh (implantable)
C1832 Autograft suspension, including cell processing and application, and all system components [RECELL Autologous Cell Harvesting Device (RECELL)]
C9352 Microporous collagen implantable tube (NeuraGen Nerve Guide), per cm length
C9353 Microporous collagen implantable slit tube (NeuraWrap Nerve Protector), per cm length
C9354 Acellular pericardial tissue matrix of nonhuman origin (Veritas), per sq cm
G0428 Collagen meniscus implant procedure for filling meniscal defects (e.g., CMI, collagen scaffold, Menaflex)
Q4100 Skin substitute, not otherwise specified
Q4110 PriMatrix, per sq cm
Q4111 GammaGraft, per sq cm
Q4113 GRAFTJACKET XPRESS, injectable, 1cc
Q4117 HYALOMATRIX, per sq cm
Q4118 Matristem micromatrix, 1 mg
Q4123 AlloSkin RT, per square centimeter
Q4124 OASIS ultra tri-layer wound matrix, per sq cm
Q4125 Arthroflex, per sq cm
Q4126 MemoDerm, DermaSpan, TranZgraft or InteguPly, per square centimeter
Q4127 Talymed, per sq cm
Q4134 hMatrix, per sq cm
Q4135 Mediskin, per sq cm
Q4136 E-Z Derm, per sq cm
Q4137 Amnioexcel or biodexcel, per sq cm
Q4138 Biodfence dryflex, per sq cm
Q4139 Amniomatrix or biodmatrix, injectable, 1 cc
Q4140 Biodfence, per sq cm
Q4141 AlloSkin AC, per square centimeter
Q4142 XCM biologic tissue matrix, per sq cm
Q4143 Repriza, per sq cm
Q4145 Epifix, injectable, 1 mg
Q4146 Tensix, per sq cm
Q4147 Architect, architect PX, or architect FX, extracellular matrix, per sq cm
Q4148 Neox Cord 1K, Neox Cord RT, or Clarix Cord 1K, per sq cm
Q4149 Excellagen, 0.1 cc
Q4150 Allowrap DS or dry, per sq cm
Q4152 Dermapure, per sq cm
Q4153 Dermavest and Plurivest, per sq cm
Q4154 Biovance, per sq cm
Q4155 Neoxflo or clarixflo 1 mg
Q4156 Neox 100, per sq cm
Q4157 Revitalon, per sq cm
Q4158 Kerecis omega3, per square centimeter
Q4159 Affinity, per sq cm
Q4160 Nushield, per square centimeter
Q4161 Bio-connekt wound matrix, per per sq cm
Q4162 Woundex flow, bioskin flow, 0.5 cc
Q4163 WoundEx, BioSkin, per sq cm
Q4164 Helicoll, per sq cm
Q4165 Keramatrix or Kerasorb, per sq cm
Q4166 Cytal, per square centimeter[Cytal Burn Matrix, Cytal Wound Matrix]
Q4167 Truskin, per square centimeter
Q4169 Artacent wound, per square centimeter
Q4170 Cygnus, per square centimeter
Q4171 Interfyl, 1 mg
Q4173 Palingen or palingen xplus, per square centimeter
Q4174 Palingen or promatrx, 0.36 mg per 0.25 cc
Q4175 Miroderm, per square centimeter
Q4176 Neopatch, per square centimeter
Q4177 Floweramnioflo, 0.1 cc
Q4178 Floweramniopatch, per square centimeter
Q4179 Flowerderm, per square centimeter
Q4180 Revita, per square centimeter
Q4181 Amnio wound, per square centimeter
Q4183 Surgigraft, per sq cm
Q4184 Cellesta or Cellesta Duo, per sq cm
Q4185 Cellesta Flowable Amnion (25 mg per cc); per 0.5 cc
Q4188 AmnioArmor, per sq cm
Q4189 - Q4190 Artacent AC
Q4191 Restorigin, per sq cm
Q4192 Restorigin, 1 cc
Q4193 Coll-e-Derm, per sq cm
Q4194 Novachor, per sq cm
Q4195 - Q4197 Puraply
Q4198 Genesis Amniotic Membrane, per sq cm
Q4199 Cygnus matrix, per square centimeter
Q4200 SkinTE, per sq cm
Q4201 Matrion, per sq cm
Q4202 Keroxx (2.5 g/cc), 1 cc
Q4203 Derma-Gide, per sq cm
Q4204 XWRAP, per sq cm
Q4205 Membrane Graft or Membrane Wrap, per sq cm
Q4206 Fluid flow or fluid GF, 1 cc
Q4208 Novafix, per sq cm
Q4209 SurGraft, per sq cm
Q4210 Axolotl Graft or Axolotl DualGraft, per sq cm
Q4211 Amnion Bio or AxoBioMembrane, per sq cm
Q4212 AlloGen, per cc
Q4213 Ascent, 0.5 mg
Q4214 Cellesta Cord, per sq cm
Q4215 Axolotl Ambient or Axolotl Cryo, 0.1 mg
Q4216 Artacent Cord, per sq cm
Q4217 WoundFix, BioWound, WoundFix Plus, BioWound Plus, WoundFix Xplus or BioWound Xplus, per sq cm
Q4218 SurgiCORD, per sq cm
Q4219 SurgiGRAFT-DUAL, per sq cm
Q4220 BellaCell HD or Surederm, per sq cm
Q4221 Amnio Wrap2, per sq cm
Q4222 ProgenaMatrix, per sq cm
Q4224 Human health factor 10 amniotic patch (hhf10-p), per square centimeter
Q4225 Amniobind, per square centimeter
Q4226 MyOwn Skin, includes harvesting and preparation procedures, per sq cm
Q4227 AmnioCoreTM, per sq cm
Q4229 Cogenex Amniotic Membrane, per sq cm
Q4230 Cogenex Flowable Amnion, per 0.5 cc
Q4231 Corplex P, per cc
Q4232 Corplex, per sq cm
Q4233 SurFactor or NuDyn, per 0.5 cc
Q4234 XCellerate, per sq cm
Q4235 AMNIOREPAIR or AltiPly, per sq cm
Q4236 Carepatch, per square centimeter
Q4237 Cryo-Cord, per sq cm
Q4238 Derm-Maxx, per sq cm
Q4239 Amnio-Maxx or Amnio-Maxx Lite, per sq cm
Q4240 CoreCyte, for topical use only, per 0.5 cc
Q4241 PolyCyte, for topical use only, per 0.5 cc
Q4242 AmnioCyte Plus, per 0.5 cc
Q4244 Procenta, per 200 mg
Q4245 AmnioText, per cc
Q4246 CoreText or ProText, per cc
Q4247 Amniotext patch, per sq cm
Q4248 Dermacyte Amniotic Membrane Allograft
Q4249 AMNIPLY, for topical use only, per sq cm
Q4250 AmnioAmp-MP, per sq cm
Q4251 Vim, per sq cm
Q4252 Vendaje, per sq cm
Q4253 Zenith Amniotic Membrane, per sq cm
Q4254 Novafix dl, per square centimeter
Q4255 REGUaRD, for topical use only, per sq cm
Q4256 Mlg-complete, per square centimeter
Q4257 Relese, per square centimeter
Q4258 Enverse, per square centimeter
Q4259 Celera dual layer or celera dual membrane, per square centimeter
Q4260 Signature apatch, per square centimeter
Q4261 Tag, per square centimeter
Q4262 Dual layer impax membrane, per square centimeter
Q4263 Surgraft tl, per square centimeter
Q4264 Cocoon membrane, per square centimeter
Q4265 Neostim tl, per square centimeter
Q4266 Neostim membrane, per square centimeter
Q4267 Neostim dl, per square centimeter
Q4268 Surgraft ft, per square centimeter
Q4269 Surgraft xt, per square centimeter
Q4270 Complete sl, per square centimeter
Q4271 Complete ft, per square centimeter
Q4273 Esano aaa, per square centimeter
Q4274 Esano ac, per square centimeter
Q4275 Esano aca, per square centimeter
Q4276 Orion, per square centimeter
Q4277 Woundplus membrane or e-graft, per square centimeter
Q4278 Epieffect, per square centimeter
Q4279 Vendaje ac, per square centimeter
Q4280 Xcell amnio matrix, per square centimeter
Q4281 Barrera sl or barrera dl, per square centimeter
Q4282 Cygnus dual, per square centimeter
Q4283 Biovance tri-layer or biovance 3l, per square centimeter
Q4284 Dermabind sl, per square centimeter
Q4285 Nudyn dl or nudyn dl mesh, per square centimeter
Q4286 Nudyn sl or nudyn slw, per square centimeter

Artelon (poly[urethane urea] elastomer):

No specific code

HCPCS codes not covered for indications listed in the CPB:

L8658 Interphalangeal joint spacer, silicone or equal, each

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

L89.000 - L89.95 Pressure ulcer
M18.0 - M18.12 Bilateral and unilateral primary osteoarthritis of first carpometacarpal [trapezio-metacrpal joint osteoarthritis]
M18.2 - M18.52 Bilateral and unilateral post-traumatic osteoarthritis and other bilateral and unilateral secondary osteoarthritis of first carpometacarpal [trapezio-metacrpal joint osteoarthritis]
M19.041 - M19.049 Primary osteoarthritis [trapezio-metacarpal joint osteoarthritis]
M19.141 - M19.149 Post-traumatic osteoarthritis, hand [trapezio-metacarpal joint osteoarthritis]
M19.241 - M19.249 Secondary osteoarthritis, hand [trapezio-metacarpal joint osteoarthritis]
M23.50 - M23.52 Chronic instability of knee
M66.211 - M66.219, M66.811 - M66.819 Spontaneous rupture of extensor tendons, upper arm and shoulder
M75.100 - M75.122 Complete rupture of rotator cuff
M75.50 - M75.52 Bursitis of shoulder
S43.421A – S43.429S Sprain and strain of rotator cuff (capsule)
S83.501A – S83.529S Sprain of cruciate ligament of knee

Amniotic Fluid Injection (e.g., AmniFix™):

No specific code

CPT codes not covered for indications listed in the CPB:

20100 - 29999 Musculoskeletal system [not covered for prevention of adhesions after orthopedic surgery]

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

H18.821 - H18.829 Corneal disorder due to contact lens [corneal wound]
S05.00XA – S05.02XS Injury of conjunctiva and corneal abrasion without foreign body [corneal wound]
S05.8X1A – S05.92XS Other injuries of eye and orbit [corneal wound]

Arthres GraftRope:

No specific code

Other CPT codes related to the CPB:

29806 - 29828 Arthroscopy, shoulder, surgical

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

M24.811 - M4.819, M25.211 - M25.219, M25.311 - M25.310 Other joint derangement, NEC, involving shoulder region
S41.001A – S41.009S Unspecified open wounds of shoulder [open dislocation]
S43.101A – S43.101S Subluxation and dislocation of acromioclavicular (joint)

Autologous Fat:

CPT not covered for indications listed in the CPB:

11950 - 11954 Subcutaenous injection of filling material (e.g., collagen)
15769 Grafting of autologous soft tissue, other, harvested by direct excision (eg, fat, dermis, fascia)
15770 Graft; derma-fat-fascia
15771 Grafting of autologous fat harvested by liposuction technique to trunk, breasts, scalp, arms, and/or legs 50 cc or less injectate
+15772     each additional 50 cc injectate, or part there of (List separately in addition to code for primary procedure)
15773 Grafting of autologous fat harvested by liposuction technique to face, eyelids, mouth, neck, ears, orbits, genitalia, hands, and/or feet; 25 cc or less injectate
+15774     each additional 25 cc injectate, or part thereof (List separately in addition to code for primary procedure)
15877 Suction assisted lipectomy; trunk

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

L90.5 Scar conditions and fibrosis of skin
L91.0 Keloid scar

Autologous platelet-rich plasma, autologous platelet gel, and autologous platelet-derived growth factors (e.g., Autogel, Procuren, and Safeblood):

CPT not covered for indications listed in the CPB:

0232T Injection(s), platelet rich plasma, any tissue, including image guidance, harvesting and preparation when performed
0481T Injection(s), autologous white blood cell concentrate (autologous protein solution), any site, including image guidance, harvesting and preparation, when performed

HCPCS codes not covered for indications listed in the CPB:

S9055 Procuren or other growth factor preparation to promote wound healing

Other HCPCs codes related to the CPB:

P9020 Platelet rich plasma, each unit
P9022 Red blood cells, washed, each unit

Axogen Nerve Wrap:

No specific code

Other CPT codes related to the CPB:

64912 Nerve repair; with nerve allograft, each nerve, first strand (cable)
64913 Nerve repair; with nerve allograft, each additional strand (List separately in addition to code for primary procedure)

Avotermin:

No specific code

Other CPT codes related to the CPB:

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

L90.5 Scar conditions and fibrosis of skin

Cymetra Injectable Allograft:

HCPCS codes not covered for indications listed in the CPB:

Q4112 Cymetra, injectable, 1 cc [for vocal cord paralysis - see CPB 253]

DermaClose RC Continuous External Tissue Expander:

No specific code

CPT codes not covered for indications listed in the CPB:

11960 Insertion of tissue expander(s) for other than breast, including subsequent expansion

Evical Fibrin Sealant:

No specific code

ICD-10 codes not covered for indications listed in the CPB:

G96.0 Cerebrospinal fluid leak

Integra Neural Wrap, NeuroMatrix Collagen Nerve Cuff, and NeuroMend Collagen Nerve Wrap:

CPT codes not covered for indications listed in the CPB:

64912 Nerve repair; with nerve allograft, each nerve, first strand (cable)
64913 Nerve repair; with nerve allograft, each additional strand (List separately in addition to code for primary procedure)

HCPCS codes not covered for indications listed in the CPB:

C9355 Collagen nerve cuff (neuromatrix), per 0.5 centimeter length
C9361 Collagen matrix nerve wrap (neuromend collagen nerve wrap), per 0.5 centimeter length

Integra Matrix Wound Dressing and Flowable Wound Matrix:

CPT codes not covered for indications listed in the CPB (not all-inclusive):

10040 - 19499 Surgery, integumentary system

HCPCS codes not covered for indications listed in the CPB:

Q4108 Integra Matrix, per sq cm
Q4114 Integra Flowable Wound Matrix, injectable, 1 cc

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

M27.2 Inflammatory conditions of jaws

Oasis Burn Matrix:

HCPCS codes not covered for indications listed in the CPB:

Q4103 Oasis Burn Matrix, per sq cm

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

T20.011A – T25.799S Burns

Parietex™Composite (PCO) Mesh:

HCPCS codes not covered for the indications listed in the CPB:

C1781 Mesh (implantable)

ICD-10 codes not covered for indications listing in the CPB (not all inclusive):

N81.0 - N81.9 Female genital prolapse

Permacol Biologic Implant:

HCPCS codes not covered for indications listed in the CPB:

C9364 Porcine implant, Permacol, per square centimeter

ICD-10 codes not covered for indications listed in the CPB:

K56.1 Intussusception [rectum]
K62.3 Rectal prolapse
N81.6 Rectocele

Radiofrequency stimulation:

CPT codes not covered for indications listed in the CPB:

97032 Application of a modality to one or more areas; electrical stimulation, (manual), each 15 minutes

HCPCS codes not covered for indications listed in the CPB:

G0281 Electrical stimulation, (unattended), to one or more areas, for chronic Stage III and Stage IV pressure ulcers, arterial ulcers, diabetic ulcers, and venous stasis ulcers not demonstrating measurable signs of healing after 30 days of conventional care, as part of a therapy plan of care [if billed for Provant or MicroVas]
G0282 Electrical stimulation, (unattended), to one or more areas, for wound care other than described in G0281 [if billed for Provant or MicroVas]

SurgiMend:

HCPCS codes not covered for indications listed in the CPB:

C9358 Dermal substitute, native, non-denatured collagen (SurgiMend Collagen Matrix), per 0.5 square centimeters
C9360 Dermal substitute, native, non-denatured collagen, neonatal bovine origin (SurgiMend Collagen Matrix), per 0.5 square centimeters

TenoGlide Tendon Protector Sheet:

CPT codes not covered for indications listed in the CPB (not all-inclusive):

20924 Tendon graft
23405 - 23406, 24300 - 24342, 25260 - 25316, 26350 - 26502, 26510, 27097 - 27098, 27380 - 27400, 27650 - 27692, 28200 - 28262 Repair, revision, and/or reconstruction, tendon
25109, 26170, 26180 Excision of tendon
24357 - 24359, 26060, 27000 - 27006, 27306 - 27307, 27605 - 27606, 28010 - 28011 Tenotomy

HCPCS codes not covered for indications listed in the CPB:

C9356 Tendon, porous matrix of cross-linked collagen and glycosaminoglycan matrix (Tenoglide Tendon Protector Sheet), per square centimeter

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

Numerous options Injury to nerves and spinal cord [Codes not listed due to expanded specificity]

OviTex:

HCPCS codes not covered for indications listed in the CPB:

OviTex- no specific code

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

K43.0 – K43.9 Ventral Hernia

Background

Bioengineered skin and soft tissue substitutes are cellular or acellular matrices and can be derived from human tissue (autologous or allogeneic), nonhuman tissue (xenographic), synthetic materials or a composite of these materials. Specific manufacturing process vary by company, but generally involve seeding selected cells onto a matrix, where they receive proteins and growth factors necessary for them to multiply and develop into the desired tissue. The tissue may be used for a variety of conditions and procedures including breast reconstruction, treatment of severe burns, surgical wounds and healing of lower extremity ulcers, such as diabetic and/or venous ulcers.

A technology assessment prepared for the Agency for Healthcare Research and Quality (AHRQ) describes the various products commercially available in the United States that may be considered skin substitutes, and identifies and assesses the clinical literature evaluating skin substitutes published since the 2012 AHRQ report "Skin Substitutes for Treating Chronic Wounds". Synder et al. (2020) conducted a systematic review of the published literature, grey literature and scientific packets received from manufacturers. The authors searched for systematic reviews/meta-analyses, randomized controlled trials (RCTs), and prospective nonrandomized comparative studies examining commercially available skin substitutes. The authors identified 76 commercially available skin substitutes and categorized them based on the Davison-Kotler classification system. Sixty-eight (89%) were categorized as acellular dermal substitutes, mostly replacements from human placental membranes and animal tissue sources. Three systematic reviews and 22 RCTs examined use of 16 distinct skin substitutes, including acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes in diabetic foot ulcers, pressure ulcers, and venous leg ulcers. Of the 22 included RCTs, 16 studies compared a skin substitute with standard of care (e.g., debridement, glucose control, compression bandages for venous leg ulcers, daily dressing changes with moisture-retentive dressing, such as an alginate or hydrocolloid). Twenty-one ongoing clinical trials (all RCTs) examined an additional nine skin substitutes with similar classifications. The authors found that the studies rarely reported clinical outcomes, such as amputation, wound recurrence at least 2 weeks after treatment ended, or patient-related outcomes, such as return to function, pain, exudate, and odor. The authors concluded that there is a lack of studies examining the efficacy of most skin substitute products and the need for better-designed and -reported studies providing more clinically relevant data. Before findings can be relied upon, more data are needed on hospitalization, pain reduction, need for amputation, exudate and odor control, and return to baseline activities of daily living and function.

ACM Surgical Collagen and ACM Surgical Extra Advanced Collagen

According to the manufacturer, Human Biosciences, Inc., ACM Surgical Collagen and ACM Surgical Extra Advanced Collagen are 100 percent native freeze-dried, type-1 bovine collagen matrix, provided in a collagen sheet configuration.(CMS, 2019). The products are indicated for use as a scaffold in the "management of partial and full-thickness wounds [i.e. surgical wounds, donor sites, graft sites, second degree burns, traumatic wounds (pressure, venous, mixed vascular etiologies, diabetic ulcers)] to support healing." ACM Surgical Collagen and ACM Surgical Extra Advanced Collagen are administered by applying each individual matrix directly to the wound surface after preparation of the wound site to remove necrotic debris, bioflim, and non-viable tissue, using the clinician's choice of fixation. Each matrix provides the same amount of collagen per square centimeter of product. Usually one tissue is applied per application. Additional applications may be required, based on physician choice. These products are packaged in sterile, single-use pouches and available in sheet sizes: 2"x2", 4"x4", 4"x5", 7x7", 8"x12".

ACM Surgical Extra Advanced Collagen Powder

According to the manufacturer, Human Biosciences, ACM Surgical Extra Advanced Collagen Powder "is indicated for wound management of partial and full-thickness wounds such as second degree burns, ulcers (pressure, venous, mixed vascular etiologies, diabetic ulcers) and other wounds (e.g. surgical wounds, scrapes, traumatic wounds)" (CMS, 2019). The product is applied directly to the wound surface after preparation of the wound site to remove necrotic debris, biofilm, and non variable tissue. It is supplied as sterile, single-use 1gm pouch, 1gm vial, 5gm vial and 10gm bottle.

ActiGraft

ActiGraft is a FDA-cleared regenerative wound care solution.  It enables health care providers to produce in-vitro blood clots from a patient's whole blood.  Once applied, the blood clot tissue serves as a protective covering, biologic scaffold and wound microenvironment to promote the natural wound healing processes of the body.  There is a clinical trial on “Safety and Efficacy of ActiGraft Compared to Standard of Care in DFUs” that is still recruiting participants.  Estimated primary completion date will be December 2021;and estimated study completion date will be June 2022  (Last updated: October 6, 2020).  Safety and Efficacy of ActiGraft

There is a lack of evidence to support the use of ActiGraft for the treatment of chronic diabetic foot ulcer or any other indications.

AC5 Advanced Wound System

The AC5 Advanced Wound System is composed of biocompatible and resorbable peptides that self-assemble into a nanofiber network that is similar in appearance to an extracellular matrix. AC5 is a self-assembling wound care matrix that provides clinicians with multi-modal support and utility across all phases of wound healing. Its composition creates a physical barrier to mitigate contamination and help modulate inflammation. The extracellular-like scaffold creates an environment enabling cellular migration and soft tissue regeneration within the wound bed. AC5 Advanced Wound System is available as a powder that is hydrated at the point of care to create a 3-dimensional wound conforming matrix that enables full wound contact. This product is supplied in a kit that includes: 1 x 3 mL syringe with Luer-Lok tip, 1 x vial of lyophilized peptide, 1 x vial of Sterile Water for Injection, USP 2 x 18-gauge, 1.5 inch needles, 1 x 18-gauge 1.5 inch blunt fill needles, 2 x Alcohol Prep pad wipes. Each kit is for single patient use only and may be used on wounds between 20-25 square centimeters (2022b).

Adherus

Adherus is made of 2 components that form a gel when they are combined.  The gel is applied after the surgeonn closes a dural incision.  The gel acts as a thin, elastic barrier intended to prevent CSF from leaking until the dura tissue has properly healed on its own.  The gel is then absorbed by the body over several months and excreted or removed from the body through the urine.

Affinity

Affinity, amniotic fluid membrane allograft, is minimally processed for clinical use in wound repair and healing (CMS, 2014). Affinity is comprised of the amniotic epithelial layer, the amniotic basement membrane, and the amniotic stroma. This membrane contains (1) collagen types III, IV, laminin and proteglycans; (2) cross-linked hyaluronic acid; (3) trophic proteins; (4) growth factors; (5) Tissue Inhibitors of Matrix metallo-proteinases (TIMPs); and (6) multipotential cells. Affinity is intended to be applied as an on-lay graft for acute and chronic wounds, including, but not limited to, neuropathic ulcers, venous stasis ulcers, pressure ulcers, burns, post-traumatic wounds and post-surgical wounds. The product will be sterilely packaged for single-use and available in the following size: 2.5 x 2.5 cm. 

McQuilling et al (2017) stated that chronic wounds require extensive healing time and place patients at risk of infection and amputation.  Recently, a fresh hypothermically stored amniotic membrane (HSAM) was developed and has subsequently shown promise in its ability to effectively heal chronic wounds.  These investigators examined the mechanisms of action that contribute to wound-healing responses observed with HSAM.  A proteomic analysis was conducted on HSAM, measuring 25 growth factors specific to wound healing within the grafts.  The rate of release of these cytokines from HSAMs was also measured.  To model the effect of these cytokines and their role in wound healing, proliferation and migration assays with human fibroblasts and keratinocytes were conducted, along with tube formation assays measuring angiogenesis using media conditioned from HSAM.  Furthermore, the cell-matrix interactions between fibroblasts and HSAM were examined.  Conditioned media from HSAM significantly increased both fibroblast and keratinocyte proliferation and migration and induced more robust tube formation in angiogenesis assays.  Fibroblasts cultured on HSAMs were found to migrate into and deposit matrix molecules within the HSAM graft.  The authors concluded that these collective results suggested that HSAM positively affected various critical pathways in chronic wound healing, lending further support to promising qualitative results observed clinically and providing further validation for ongoing clinical trials.  This was an in-vitro study. 

Mowry et al (2017) noted that chronic and recalcitrant wounds present a significant therapeutic challenge.  Amniotic tissues contain many regenerative cytokines, growth factors, and extracellular matrix molecules including proteoglycans, hyaluronic acid, and collagens I, III, and IV.  Dehydrated amnion/chorion grafts are currently used to treat a variety of wounds such as diabetic foot ulcers (DFUs) and burns.  These investigators hypothesized that processing methodologies, dehydration, and hypothermic processing and storage of amniotic tissues would affect overall quality of wound healing; they compared dehydrated amnion/chorion (dHACM) grafts to a novel HSAM graft in a full-thickness rat wound model.  Sprague-Dawley rats were anesthetized and prepped for surgery; 4 1.5-cm diameter full-thickness wounds were created and treated with either:
  1. dHACM,
  2. dHACM meshed,
  3. HSAM, or
  4. wound left ungrafted (sham).  

After 9 or 21 days, wounds and surrounding areas were collected and stained with hematoxylin and eosin.  Blinded quantitative analysis of quality of wound healing was completed by evaluating hair follicle/gland formation, dense/scar-like matrix, and basket-weave matrix.  At varying time-points following placement of the grafts into full-thickness defects, these researchers found that all amniotic-derived tissue grafts appeared to stimulate improved healing over sham wounds, evidenced by more normal-appearing dermal matrix architecture, epidermal structure, and maturity.  Furthermore, the HSAM grafts promoted greater tissue regeneration than the dHACM meshed grafts, as measured by the presence of basket-weave collagen matrix and formation of follicles and glands.  The authors concluded that this study built on the amassing literature supporting amniotic tissues for wound repair and demonstrated the importance of tissue processing on the quality of wound healing.  This was a study with a small animal wound model. 

Sabo et al (2018) noted that amniotic membranes have been used for a variety of surgical applications since the 1900s.  Recent developments in the field of chronic wound care have accelerated and expanded their use.  To-date, there are over 70 amniotic products available, including dehydrated human amnion/chorion and cryopreserved human amnion.  The integrity of these grafts, however, may be compromised during processing.  Fresh HSAM may improve healing rates by preserving growth factors and living cells, including stem cells, as well as retaining the membrane’s native structure.  In a prospective case-series study, healing outcomes were evaluated in patients receiving HSAM for the treatment of chronic non-healing ulcers.  Relevant medical history was captured in addition to data on wound characteristics and measurements.  Two venous leg ulcers and 1 post-surgical wound were treated with HSAM.  A significant reduction in wound size was observed for patients treated with HSAM.  Overall, HSAM demonstrated a wound size reduction of 93.94 % in 42 days.  These results provided evidence that HSAM may reduce the long-term costs associated with the care of chronic ulcers by increasing the healing rate and lowering the risk of infection and complications.  The authors stated that the findings of this pilot case series (n = 3) was subsequently used to inform larger DFUs and venous leg ulcers (VLUs) trials that are ongoing at the time of this writing. 

In a randomized controlled trial (RCT), Serena et al (2020) examined the effectiveness of HSAM versus standard of care (SOC) in DFUs.  This study was carried out on 76 DFUs analyzed digitally.  Cox wound closure for HSAM (38 wounds) was significantly greater (p = 0.04) at weeks 12 (60 versus 38 %), and 16 (63 versus 38 %).  The probability of wound closure increased by 75 % (hazard ratio [HR] = 1.75; 95 % confidence interval [CI]: 1.16 to 2.70).  HSAM showed greater than 60 % reductions in area (82 versus 58 %; p = 0.02) and depth (65 versus 39 %; p = 0.04) versus SOC.  The authors concluded that HSAM increased frequency and probability of wound closure in DFUs versus SOC.  These researchers stated that although this was the 1st RCT of HSAM and the study was properly powered for expected treatment effect size based on real-life use of the product, further prospective effectiveness and cost-effectiveness studies, including studies analyzing patient reported outcomes and recurrence rates are needed.  Comparative effectiveness research studies in a real-world setting that include larger numbers of patients and centers, as well as longer follow-up times hold promise to better define the effectiveness of HSAM compared with other amniotic membrane allografts.

AlloDerm

AlloDerm (Life Cell Corp., The Woodlands, TX), an acellular dermal matrix processed from human allograft skin. AlloDerm is processed from human cadaver skin with the cells responsible for immune response and graft rejection removed. The remainder is a matrix or framework of natural biological components, ready to enable the body to mount its own tissue regeneration process. AlloDerm is indicated for use in association with breast reconstruction procedures.

The product has been promoted from the manufacturer for hernia and breast reconstruction. Alloderm has been used in the treatment of burn injury.  According to the product labeling, "AlloDerm is to be used for repair or replacement of damaged or inadequate integumental tissue or for other homologous uses of human integument." Donated human sikin tissue is supplied by tissue banks and processed into the dermis product. During the processing, cells are removed and the product is freeze-dried (Snyder, et al., 2012). However, there is currently limited evidence to support the use of AlloDerm for wound healing.

Lattari et al (1997) described the use of AlloDerm dermal grafts on 3 patients with full-thickness burns of the distal extremities.  Grafts were applied to the hand in 2 cases and the dorsum of the foot in the 3rd case.  Range of motion, grip strength, fine motor coordination, and functional performance were quantitatively evaluated.  As shown by these patients, cosmetic and functional results were considered good to excellent after the use of AlloDerm grafts with thin autografts.

Tsai et al (1999) presented 12 cases of clinical application of a composite grafting technique in which AlloDerm provided source of dermis, and an ultra-thin autograft (0.004  to 0.006 inch in thickness) provided epidermis.  In these patients, the composite grafts were applied to full-thickness burn wounds over various articular skin surfaces.  The average skin graft take rate was 91.5 %.  These ultra-thin autografts allow the donor sites to heal faster.  The mean time of donor site re-epithelization was 6 days.  All patients had a nearly normal range of joint motion (average 95 % of normal) after 1 year's follow-up.  Wound assessment over time has shown supple skin that has been resistant to trauma and infection.  The cosmetic results were judged to be fair to good by surgeons and patients after 1 year's follow-up.

Gore (2005) stated that because skin thins with advancing age, traditional thickness skin grafts cannot always be obtained in very elderly burn patients without creating a new full-thickness wound at the skin graft donor site.  In an attempt to circumvent this problem, AlloDerm and thin autograft (depth 0.005 inches) were used in skin grafting 10 elderly burn patients (age of 78 years +/- 2, TBSA burn 17 % +/- 2; mean +/- SEM) over a 1-year period.  The outcome of patients receiving AlloDerm was compared retrospectively to a similar group of 18 elderly patients admitted over the prior year, 8 of whom underwent operative wound excision and autografting (depth 0.014 inches) without AlloDerm.  Length of hospital stay was significantly reduced in patients treated with AlloDerm compared to the total group of elderly in whom selective use of operative debridement and skin grafting was used.  Functional outcome was improved in those patients who underwent skin grafting regardless of operative technique.  Donor site healing time was significantly reduced with AlloDerm (12 days +/- 1 versus 18 days +/- 2), while graft take was similar to conventional autografting.  Unfortunately, 3-month mortality remained poor regardless of operative skin grafting or technique used.  The authors concluded that these findings suggested that use of AlloDerm may allow more elderly burn patients to undergo operative wound closure, thus improving functional outcome and reducing hospitalization.  Unfortunately, long-term survival for very elderly burn patients remains poor.

A number of papers have examined the use of AlloDerm as a tissue graft for contaminated abdominal wall defects and hernia repair.  Wound infection and infection of the mesh can be grave complications of hernia repair, often necessitating removal of the mesh and application of a tissue graft. In breast reconstruction, AlloDerm has been used in conjunction with a subpectoral (major) placement of breast implants to achieve more complete implant coverage without the use of other muscles.  Although these indications are promising, evidence is limited to small retrospective case series with limited follow-up.

Ventral hernia repair in potentially contaminated or potentially infected fields limit the use of synthetic mesh products.  In this scenario, biosynthetic mesh products that are absorbed and/or replaced with the body's own tissue are intended to reduce the incidence of post-operative chronic wound complications.  Rapid re-vascularization, re-population, and remodeling of the matrix occur on contact with the patient's own tissue.  Only limited, and mostly preliminary data, is available on the use of these types of mesh and concerning the potential complications associated with the use of these types of meshes.

In one of the few published comparative studies of AlloDerm in hernia repair, Gupta et al (2006) compared the efficacy and the complications associated with the use AlloDerm and Surgisis bioactive mesh (Cook Surgical, Bloomington, IN), a product obtained by the processing of porcine small intestine submucosa, for ventral herniorrhaphy.  The investigators reported on the outcomes of 74 patients who underwent ventral hernia repair using these products between June 2002 and March 2005.  The first 41 procedures were performed using Surgisis bioactive mesh, and the remaining 33 patients had ventral hernia repair with AlloDerm.  The investigators reported that the use of the AlloDerm mesh resulted in 8 hernia recurrences.  Fifteen of the 33 patients treated with AlloDerm developed a diastasis or bulging at the repair site.  Seroma formation was only a problem in 2 patients.  The investigators reported that the Surgisis bioactive mesh resulted in significant seroma formation in over 25 % of patients.  Explanted material revealed separated layers of unincorporated middle layers of the Surgisis mesh.  The investigators reported that 3 of the patients had the mesh placed in a contaminated field with no resultant sequela, and there were no hernia recurrences.  Patients also had a significant degree of discomfort and pain during the immediate post-operative period.  The investigators concluded that post-operative diastasis and hernia recurrence were a major problem with the AlloDerm mesh.  On the other hand, seroma formation was a major problem with the Surgisis mesh repair, as was the post-operative pain.  The investigators recommended further design improvements in both forms of these new mesh products.

In another comparative study, Espinosa-de-los-Monteros et al (2007) retrospectively reviewed 39 abdominal wall reconstructions with AlloDerm in 37 patients and compared them with 39 randomly selected abdominal wall reconstructions without AlloDerm.  The investigators reported a significant decrease in recurrence rates when AlloDerm was added as an overlay to primary closure plus rectus muscle advancement and imbrication in patients with medium-sized hernias.  On the other hand, no differences were observed when adding AlloDerm as an overlay to patients with large-size hernias treated with underlay mesh. 

Jin et al (2007) compared 2 techniques of fascial bridging versus fascial re-inforcement repair with regard to their long-term recurrence rates using Alloderm in patients with abdominal wall defects, and concluded that, because of high recurrence rates with fascial bridging, Alloderm should be used only as a re-inforcement after primary fascial re-appoximation.  The investigators retrospectively studied the outcomes of 37 patients with abdominal defects repaired with Alloderm.  Eleven patients underwent bridged fascial repair, and 26 patients had reinforced fascial repair.  Mean follow-up was 21.4 months (range of 15 to 36 months).  In the bridged group, 1 patient died on post-operative day 20.  Of the remaining 10 patients, 8 patients (80 %) developed recurrences; 7 patients required re-operation, but 1 patient refused repair.  In the re-inforced group, 4 patients were lost to follow-up and 2 patients died.  Four of the remaining 20 patients (20 %) developed recurrences that required repair; this was significantly different from the recurrence rate in the bridged group (p = 0.009).

Bluebond-Lagner et al (2008) reported on recurrent laxity requiring secondary intervention in a series of patients who were repaired with interpositional Alloderm.  The investigators reviewed all patients who underwent repair of massive ventral hernias and identified 7 patients who presented with abdominal wall laxity following component separation with interpositional Alloderm alone.  The investigators reported that all patients developed laxity within 12 months and required a secondary procedure.  At the time of re-exploration, severe attenuation in the Alloderm was noted.  The segment was excised, the edges closed primarily, and prolene mesh was placed as an onlay.

Vetrees et al (2008) reported on a retrospective review of outcomes of surgical repair of 83 patients with open abdomen that were treated at Walter Reed Army Medical Center.  Surgical management included early definitive abdominal closure (EDAC) (serial abdominal closure with prosthetic Gore-Tex Dualmesh and final closure supplemented with polypropylene mesh or Alloderm in 56 patients, primary fascial closure in 15 patients, planned ventral hernia (PVH) in 9 patients, and vacuum-assisted closure with Alloderm in 3 patients).  Complications included removal of infected prosthetic mesh in 4 EDAC closure patients; the investigators noted that mesh-related complications had decreased over time.  The investigators reported that rates of infection, abdominal wall hematoma, deep venous thrombosis, and pulmonary embolism did not differ between groups.  In the EDAC group, infections complicated final polypropylene mesh closure in 3 of 28 patients closed with prosthetic mesh; 1 of 14 patients closed with biologic mesh (Alloderm) noted increased laxity at the repair site.  Of 56 patients treated with EDAC, 2 patients had recurrent ventral hernia.  Of the 3 patients closed with Alloderm and vacuum assisted closure, 1 patient had recurrent ventral hernia.  The investigators reported that no final Alloderm closures required removal after placement, but "long-term results have been disappointing ... The excessive cost of biologic material requires better results than those documented in previous studies."  Limitations of this study include its lack of randomization, variation in the described closure methods, its retrospective nature, and limitations of some data points.  The investigators concluded that "polypropylene mesh final EDAC closure risks infection and subsequent fistula formation, and long-term follow-up are needed.  Use of biologic mesh as either final EDAC closure or with vacuum-assisted closure also requires long-term follow-up to justify its increased cost and increased risk of abdominal wall laxity."

Available published evidence regarding the use of Alloderm in breast reconstructive surgery consists primarily of several small case series (e.g., Salzberg, 2006; Breuing and Colwell, 2007; Zienowicz and Karacaoglu, 2007; Garramone and Lam, 2007; Spear et al, 2008).  There are no comparative studies to determine whether the use of Alloderm improves aesthetic outcomes. In addition, the duration of follow-up in published studies is limited so the impact on longer-term complications such as severe contractures cannot be determined.

The only published comparative study of Alloderm (Preminger et al, 2008) in breast reconstructive surgery found that Alloderm did not increase the rate of tissue expansion after tissue expander placement.  This matched, retrospective cohort study compared expansion rates in patients who underwent tissue expander/implant reconstruction with Alloderm (n = 45) versus persons who underwent standard tissue expander/implant reconstruction (n = 45).  Median number of expansions performed was 5 and 6 in the Alloderm and non-Alloderm cohorts (p = 0.117).  The study found no difference in the mean rate of post-operative tissue expansion (Alloderm: 97 ml/injection versus non-Alloderm: 95 ml/injection [p = 0.907]).

Randomized clinical studies are ongoing of Alloderm for tissue expander implant reconstruction and for other indications (MSKCC, 2009). 

Hiles and colleagues (2009) noted that biologic grafts for hernia repair are a relatively new development in the world of surgery.  A thorough search of the Medline database for uses of various biologic grafts in hernia shows that the evidence behind their application is plentiful in some areas (ventral, inguinal) and nearly absent in others (para-stomal).  The assumption that these materials are only suited for contaminated or potentially contaminated surgical fields is not borne out in the literature, with more than 4 times the experience being reported in clean fields and the average success rates being higher (93 % versus 87 %).  Outcomes prove to be dependent on material source, processing methods and implant scenarios with failure rates ranging from zero to more than 30 %.  Small intestinal submucosa (SIS) grafts have an aggregate failure rate of 6.7 % at 19 months whereas acellular human dermis (AHD) grafts have a failure rate of 13.6 % at 12 months.  Chemically cross-linked grafts have much less published data than the non-cross-linked materials.  In particular, the search found 33 articles for SIS, 32 for AHD, and 13 for cross-linked porcine dermis.  Furthermore, the cumulative level of evidence for each graft material was fairly low (2.6 to 2.9), and only 1 material (SIS) had level 1 evidence reported in any hernia type (inguinal and hiatal). 

Kissane and Itani (2012) studied the experience and outcomes of patients who underwent repair of a ventral incisional hernia with biologic mesh.  Online database and detailed reference searches were conducted.  Studies chosen for review had a sample size of at least 40 patients, level IV evidence at most, and a Methodological Index for Nonrandomized Studies index of at least 10.  Indications for use of biologic mesh, type of mesh, patient comorbidities, and surgical techniques were also noted.  A total of 8 studies fulfilled the search criteria and included 635 patients using AlloDerm, Surgisis, and Strattice biologic tissue matrices.  In one study, indications and surgical techniques were standardized, and follow-up was prospective.  In the other 7 studies, indications, surgical techniques, and follow-up were assessed retrospectively.  The mean patient age, when reported, was 55.7 years.  Body mass index ranged from 30 to 35 kg/m2 in 44 % of the reported patients.  In 7 of the 8 studies [565 patients (89 %)], the mean follow-up was 25.8 months and the mean hernia recurrence rate was 21 %.  Complication rate exceeded 20 % in most studies.  The authors concluded that biologic tissue matrices are mostly used in contaminated fields, which has allowed for a 1-stage repair with no or little subsequent mesh removal.  Ventral incisional hernia repair with these matrices continues to be plagued by a high recurrence rate and complications.  They stated that prospective, randomized trials are needed to properly direct practice in the use of these meshes and evaluate their ultimate value.

Zeng et al (2012) evaluated the precise effectiveness of AlloDerm implants for preventing Frey syndrome after parotidectomy, using a systematic review and meta-analysis.  These investigators searched randomized and quasi-randomized controlled trials in which AlloDerm implants were compared to blank controls for preventing Frey syndrome after parotidectomy, from the PubMed, Embase, the Cochrane Library and the ISI Web of Knowledge databases, without any language restriction.  Two reviewers independently searched, identified, extracted data and assessed methodological quality.  Relative risks with 95 % confidence intervals (CIs) were calculated and pooled.  Five articles involving 409 patients met the inclusion criteria.  Meta-analyses showed a significant 85 % relative risk reduction in objective incidence (RR = 0.15, 95 % CI: 0.08 to 0.30; p < 0.00001) and 68 % in subjective incidence (RR = 0.32, 95 % CI: 0.19 to 0.57; p < 0.00001) of Frey syndrome with AlloDerm implants; there was a significant 91 % relative risk reduction in salivary fistula (RR = 0.09, 95 % CI: 0.01 to 0.66; p = 0.02); there was no statistical significance for the incidence of facial nerve paralysis (RR = 0.96, 95 % CI: 0.84 to 1.09; p = 0.51); there was no statistical significance for the incidence of seroma/sialocele (RR = 1.36, 95 % CI: 0.66 to 2.80; p = 0.40); there was a trend for a small effect in improving facial contour.  Adverse events related to AlloDerm implants were not found.  There is evidence that AlloDerm reduces the incidence of Frey syndrome effectively and safely, and also has the potential to improve facial contour and decrease salivary fistula.  However, the authors concluded that it is unclear whether AlloDerm implants improve facial contour and decrease other complications; they stated that further controlled evaluative studies incorporating more precise measures are required.  Also, an UpToDate review on "Salivary gland tumors: Treatment of locoregional disease" (Lydiatt and Quivey, 2012) does not mention the use of AlloDerm.

In a systematic review and meta-analysis, Li et al (2013) examined the safety and effectiveness of different types of grafts for the prevention of Frey syndrome after parotidectomy.  The following data bases were searched electronically: MEDLINE (using OVID, from 1948 to July 2011), Cochrane Central Register of Controlled Trials (CENTRAL, issue 2, 2011), EMBASE (1984 to July 2011), World Health Organization International Clinical Trials Registry Platform (July 2011), Chinese BioMedical Literature Database (1978 to July 2011), and the China National Knowledge Infrastructure (1994 to July 2011).  The relevant journals and reference lists of the included studies were manually searched for randomized controlled trials (RCTs) studying the effect and safety of different types of grafts for preventing Frey syndrome after parotidectomy.  The risk of bias assessment using Cochrane Collaboration's tool and data extraction was independently performed by 2 reviewers.  The meta-analysis was performed using Review Manager, version 5.1.  A total of 14 RCTs and 1,098 participants were included.  All had an unclear risk of bias.  The meta-analysis results showed that the use of an acellular dermis matrix can reduce by 82 % the risk of Frey syndrome compared with the no-graft group using an objective assessment (relative risk [RR] 0.18, 95 % confidence interval [CI]: 0.12 to 0.26; p < 0.00001; Grading of Recommendations, Assessment, Development, and Evaluation [GRADE] quality of evidence: high).  The acellular dermis matrix can also reduce by 90 % the risk of Frey syndrome compared with the no-graft group using a subjective assessment (RR 0.10, 95 % CI: 0.05 to 0.22; p < 0.00001; GRADE quality of evidence: high).  The muscle flaps can reduce by 81 % the risk of Frey syndrome compared with the no-graft group (RR 0.19, 95 % CI: 0.13 to 0.27; p < 0.00001; GRADE quality of evidence: high).  No statistically significant difference was found between the acellular dermal matrix and muscle flap groups (RR 0.73, 95 % CI: 0.15 to 3.53, p = 0.70; GRADE quality of evidence: low).  No serious adverse events were reported.  The authors concluded that the present clinical evidence suggests that grafts are effective in preventing Frey syndrome after parotidectomy.  Moreover, they stated that further RCTs are needed to confirm this conclusion and prove the safety of the grafts.

Lee and colleagues (2018) noted that acellular human dermal allografts have been shown to be effective for soft-tissue implantation.  In a prospective RCT, these researchers compared outcomes of tympanoplasty using tragal perichondrium and acellular human dermal allograft (MegaDerm).  A total of 60 patients scheduled to undergo tympanoplasty were randomly assigned to the autologous tragal perichondrium group (n = 33) or acellular human dermal allograft group (n = 27).  Post-operative hearing gain, graft success rate at 1 and 6 months and operation times were compared between groups.  Graft success rate, defined as the complete closure of tympanic membrane perforation, did not show any significant inter-group difference (75.8 % versus 85.2 %, p = 0.519).  Air conduction thresholds and air-bone gaps showed significant improvements in both groups; from 38.7 ± 15.9 dB to 30.2 ± 15.6 dB (p < 0.001) and from 17.8 ± 7.3 dB to 11.5 ± 7.0 (p = 0.001) in the autologous tragal perichondrium group, and from 30.4 ± 12.2 dB to 24.5 ± 13.0 dB (p = 0.006) and from 14.3 ± 5.1 dB to 7.6 ± 4.6 dB (p < 0.001) in the acellular human dermal allograft group.  The amount of hearing gain (p = 0.31) and closure of air-bone gap (p = 0.863) were not meaningfully different between groups.  The mean operation time was significantly lower in the acellular human dermal allograft group (35.2 mins versus 27.4 mins, p = 0.039).  The authors concluded that acellular human dermal allograft was shown to be an effective alternative to tragal perichondrium, with similar graft success rates and post-operative hearing results, but with reduced operation times.

Alloderm and Strattice for Surgical Repair of Complex Abdominal Wall Wounds

Booth et al (2013) stated that many surgeons believe that primary fascial closure with mesh reinforcement should be the goal of abdominal wall reconstruction (AWR), yet others have reported acceptable outcomes when mesh is used to bridge the fascial edges.  It has not been clearly shown how the outcomes for these techniques differ.  These investigators hypothesized that bridged repairs result in higher hernia recurrence rates than mesh-reinforced repairs that achieve fascial coaptation.  They retrospectively reviewed prospectively collected data from consecutive patients with 1 year or more of follow-up, who underwent mid-line AWR between 2000 and 2011 at a single center.  These researchers compared surgical outcomes between patients with bridged and mesh-reinforced fascial repairs.  The primary outcomes measure was hernia recurrence; multi-variate logistic regression analysis was used to identify factors predictive of or protective for complications.  This study included 222 patients (195 mesh-reinforced and 27 bridged repairs) with a mean follow-up of 31.1 ± 14.2 months.  The bridged repairs were associated with a significantly higher risk of hernia recurrence (56 % versus 8 %; hazard ratio [HR] 9.5; p < 0.001) and a higher overall complication rate (74 % versus 32 %; odds ratio [OR] 3.9; p < 0.001).  The interval to recurrence was more than 9 times shorter in the bridged group (HR 9.5; p < 0.001).  Multi-variate Cox proportional hazard regression analysis identified bridged repair and defect width greater than 15 cm to be independent predictors of hernia recurrence (HR 7.3; p < 0.001 and HR 2.5; p = 0.028, respectively).  The authors concluded that mesh-reinforced AWRs with primary fascial coaptation resulted in fewer hernia recurrences and fewer overall complications than bridged repairs; and surgeons should make every effort to achieve primary fascial coaptation to reduce complications.

Sbitany et al (2015) stated that repair of grade 3 and grade 4 ventral hernias is a distinct challenge, given the potential for infection, and the co-morbid nature of the patient population.  These investigators evaluated their institutional outcomes when performing single-stage repair of these hernias, with biologic mesh for abdominal wall reinforcement.  A prospectively maintained database was reviewed for all patients undergoing repair of grade 3 (potentially contaminated) or grade 4 (infected) hernias, as classified by the Ventral Hernia Working Group.  All those patients undergoing repair with component separation techniques and biologic mesh reinforcement were included.  Patient demographics, co-morbidities, and post-operative complications were analyzed.  Uni-variate analysis was performed to define factors predictive of hernia recurrence and wound complications.  A total of 41 patients underwent single-stage repair of grade 3 and grade 4 hernias during a 4-year period.  The overall post-operative wound infection rate was 15 %, and hernia recurrence rate was 12 %.  Almost all recurrences were seen in grade 4 hernia repairs, and in those patients undergoing bridging repair of the hernia; 1 patient required removal of the biologic mesh.  Those factors predicting hernia recurrence were smoking (p = 0.023), increasing body mass index (p = 0.012), increasing defect size (p = 0.010), and bridging repair (p = 0.042).  No mesh was removed due to peri-operative infection.  Mean follow-up time for this patient population was 25 months.  The authors concluded that single-stage repair of grade 3 hernias performed with component separation and biologic mesh reinforcement was effective and offered a low recurrence rate.  Furthermore, the use of biologic mesh allows for avoidance of mesh explantation in instances of wound breakdown or infection.  Bridging repairs were associated with a high recurrence rate, as is single-stage repair of grade 4 hernias.

Romain et al (2016) noted that different types of biologic mesh have been introduced as an alternative to synthetic mesh for use in repairing contaminated ventral hernias because of their biocompatible nature.  These researchers compared the clinical outcomes of patients who underwent complex ventral hernia repairs with either non cross-linked or cross-linked porcine dermal meshes.  This was retrospective analysis from a prospectively maintained database from January 2010 to May 2013.  Patients undergoing open incisional hernia repair with a biologic mesh in the presence of a clean-contaminated, contaminated or dirty wound were reviewed.  There were 39 patients who underwent single-staged abdominal wall reconstruction for a contaminated ventral hernia with a biologic mesh.  In 15 cases, non-crosslinked mesh was used (Strattice, n = 8; Protexa, n = 1; XenMatrix, n = 6); a cross-linked mesh was used in the remaining 24 cases (Permacol n = 21; CollaMend n = 3).  The median follow-up was 11.9 ± 10.6 months.  The overall morbidity was 71.8 % (n = 28), with 15.4 % (n = 6) for grade I, 23.1 % (n = 9) for grade II, 23.1 % (n = 9) for grade III (n = 3 grade IIIA, n = 6 grade IIIB), 7.7 % (n = 3) for grade IV and 2.6 % (n = 1) for grade V.  In the cross-linked group, there were 6 complications directly linked to the biologic mesh, compared with 3 in the non-cross-linked group.  Overall wound morbidity was 41.0 % (n = 16).  There were 13 hernia recurrences (33.3 %), and recurrence rate was not significantly different for both groups.  The authors concluded that despite the high rate of wound morbidity associated with the single-staged reconstruction of contaminated fields, it could be safely performed with biologic mesh reinforcement.  Recurrence rate was not significantly different between cross-linked and non-crosslinked porcine meshes.

Giordano et al (2017a) noted that previous studies suggested that bridged mesh repair for abdominal wall reconstruction may result in worse outcomes than mesh-reinforced, primary fascial closure, particularly when ADM was used.  In a retrospective study, these researchers compared their outcomes of bridged versus reinforced repair using ADM in abdominal wall reconstruction procedures.  This trial included 535 consecutive patients at the authors’ cancer center who underwent abdominal wall reconstruction either for an incisional hernia or for abdominal wall defects left after excision of malignancies involving the abdominal wall with underlay mesh.  A total of 484 (90 %) patients underwent mesh-reinforced abdominal wall reconstruction and 51 (10 %) underwent bridged repair abdominal wall reconstruction; ADM was used, respectively, in 98 % of bridged and 96 % of reinforced repairs.  These investigators compared outcomes between these 2 groups using propensity score analysis for risk-adjustment in multi-variate analysis and for 1-to-1 matching.  Bridged repairs had a greater hernia recurrence rate (33.3 % versus 6.2 %, p < 0.001), a greater overall complication rate (59 % versus 30 %, p = 0.001), and worse freedom from hernia recurrence (log-rank p < 0.001) than reinforced repairs.  Bridged repairs also had a greater rate of wound dehiscence (26 % versus 14 %, p = 0.034) and mesh exposure (10 % versus 1 %, p = 0.003) than mesh-reinforced abdominal wall reconstruction.  When the treatment method was adjusted for propensity score in the propensity-score-matched pairs (n = 100), these researchers found that the rates of hernia recurrence (32 % versus 6 %, p = 0.002), overall complications (32 % versus 6 %, p = 0.002), and freedom from hernia recurrence (68 % versus 32 %, p = 0.001) rates were worse after bridged repair.  They did not observe differences in wound healing and mesh complications between the 2 groups.  The authors concluded that in their population of primarily cancer patients at MD Anderson Cancer Center bridged repair for abdominal wall reconstruction was associated with worse outcomes than mesh-reinforced abdominal wall reconstruction; especially when employing ADM, reinforced repairs with biologic mesh should be used for abdominal wall reconstruction whenever possible.

Giordano et al (2017b) hypothesized that elderly patients (greater than or equal to 65 years) experience worse outcomes following AWR for hernia or oncologic resection.  These researchers included all consecutive patients who underwent complex AWR using ADM between 2005 and 2015.  Propensity score analysis was performed for risk adjustment in multi-variable analysis and for 1-to-1 matching.  The primary outcome was hernia recurrence; the secondary outcomes included surgical site occurrence (SSO) and bulging.  Mean follow-up for the 511 patients was 31.4 months; 184 (36 %) patients were elderly.  The elderly and non-elderly groups had similar rates of hernia recurrence (7.6 % versus 10.1 %, respectively; p = 0.43) and SSO (24.5 % versus 23.5 %, respectively; p = 0.82).  Bulging occurred significantly more often in elderly patients (6.5 % versus 2.8 %, respectively; p = 0.04).  After adjustment through the propensity score, which included 130 pairs, these results persisted.  The authors concluded that contrary to their hypothesis, elderly patients did not have worse outcomes in AWR with ADM; and surgeons should not deny elderly patients AWR solely because of their age.

Garvey et al (2017) stated that long-term outcomes data for hernia recurrence rates after AWR with ADM are lacking.  These investigators evaluated the long-term durability of AWR using ADM.  They studied patients who underwent AWR with ADM at a single center in 2005 to 2015 with a minimum follow-up of 36 months.  Hernia recurrence was the primary end-point and SSO was a secondary end-point.  The recurrence-free survival curves were estimated by Kaplan-Meier product limit method.  Uni-variate and multi-variable Cox proportional hazards regression models and logistic regression models were used to evaluate the associations of risk factors at surgery with subsequent risks for hernia recurrence and SSO, respectively.  A total of 512 patients underwent AWR with ADM.  After excluding those with follow-up less than 36 months, 191 patients were included, with a median follow-up of 52.9 months (range of 36 to 104 months); 26 of 191 patients had a hernia recurrence documented in the study.  The cumulative recurrence rates were 11.5 % at 3 years and 14.6 % by 5 years.  Factors significantly predictive of hernia recurrence developing included bridged repair, wound skin dehiscence, use of human cadaveric ADM, and coronary disease; component separation was protective.  In a subset analysis excluding bridged repairs and human cadaveric ADM patients, cumulative hernia recurrence rates were 6.4 % by 3 years and 8.3 % by 5 years.  The crude rate of SSO was 25.1 % (48 of 191).  Factors significantly predictive of the incidence of SSO included at least 1 co-morbidity, BMI greater than or equal to 30 kg/m2, and defect width of greater than 15 cm.  The authors concluded that the use of ADM for AWR was associated with 11.5 % and 14.6 % hernia recurrence rates at 3- and 5-years follow-up, respectively; a voiding bridged repairs and human cadaveric ADM could improve long-term AWR outcomes using ADM.

Mericli et al (2017) stated that the optimal strategy for AWR in the presence of a stomal-site hernia is unclear.  These investigators hypothesized that the rate of ventral hernia recurrence in patients undergoing a combined ventral hernia repair and stomal-site herniorraphy would not differ clinically from the ventral hernia recurrence rate in patients undergoing an isolated ventral hernia repair.  They also hypothesized that bridged ventral hernia repairs result in worse outcomes compared with reinforced repairs, regardless of stomal hernia.  These researchers retrospectively reviewed prospectively collected data from consecutive AWR performed with ADM at a single center between 2000 and 2015.  They compared patients who underwent a ventral hernia repair alone (AWR) and those who underwent both a ventral hernia repair and ostomy-associated herniorraphy (AWR+O).  These investigators conducted a propensity score matched analysis to compare the outcomes between the 2 groups.  Multi-variable Cox proportional hazards and logistic regression models were used to study associations between potential predictive or protective reconstructive strategies and surgical outcomes.  The authors included 499 patients (median follow-up of 27.2 months; inter-quartile range [IQR] 12.4 to 46.6 months), 118 AWR+O and 381 AWR.  After propensity score matching, 91 pairs were obtained.  Ventral hernia recurrence was not statistically associated with ostomy-associated herniorraphy (adjusted HR 0.7; 95 % CI: 0.3 to 1.5; p = 0.34).  However, the AWR+O group experienced a significantly higher percentage of SSO (34.1 %) than the AWR group (18.7 %; adjusted odds ratio [OR] 2.3; 95 % CI: 1.4 to 3.7; p < 0.001).  In the AWR group, there were significantly fewer ventral hernia recurrences when the repair was reinforced compared with bridged (5.3 % versus 38.5 %; p < 0.001).  The authors concluded that there was no statistically significant difference in ventral hernia recurrence between the AWR and AWR+O groups’ bridging was associated with an increased rate of hernia recurrence and should be avoided if possible.

Lombardi et al (2023) compared the in-vitro/benchtop and in-vivo mechanical properties and host biologic response to ovine rumen-derived/polymer mesh hybrid OviTex with porcine-derived acellular dermal matrix Strattice Firm.  OviTex 2S Resorbable (OviTex 2S-R) and Strattice morphology were examined in-vitro using histology and scanning electron microscopy; mechanical properties were assessed via tensile test; in-vivo host biologic response and explant mechanics were examined in a rodent subcutaneous model.  Separately, OviTex 1S Permanent (OviTex 1S-P) and Strattice were evaluated in a primate abdominal wall repair model.  OviTex 2S-R showed layer separation, whereas Strattice retained its structural integrity and demonstrated higher maximum load than OviTex 2S-R out-of-package (124.8 ± 11.1 N/cm versus 37.9 ± 5.5 N/cm, p < 0.001), 24 hours (55.7 ± 7.4 N/cm versus 5.6 ± 3.8 N/cm, p < 0.001), 48 hours (45.3 ± 14.8 N/cm versus 2.8 ± 2.6 N/cm, p = 0.003), and 72 hours (29.2 ± 10.5 N/cm versus 3.2 ± 3.1 N/cm, p = 0.006) following collagenase digestion.  In rodents, inflammatory cell infiltration was observed between OviTex 2S-R layers, while Strattice induced a minimal inflammatory response.  Strattice retained higher maximum load at 3 weeks (46.3 ± 27.4 N/cm versus 9.5 ± 3.2 N/cm, p = 0.041) and 6 weeks (28.6 ± 14.1 N/cm versus 7.0 ± 3.0 N/cm, p = 0.029).  In primates, OviTex 1S-P exhibited loss of composite mesh integrity whereas Strattice integrated into host tissue with minimal inflammation and retained higher maximum load at 1 month than OviTex 1S-P (66.8 ± 43.4 N/cm versus 9.6 ± 4.4 N/cm; p = 0.151).  The authors concluded that Strattice retained greater mechanical strength as shown by lower susceptibility to collagenase degradation than OviTex 2S-R in-vitro, as well as higher maximum load and improved host biologic response than OviTex 2S-R in rodents and OviTex 1S-P in primates.

The authors stated that the rodent subcutaneous implant model had several drawbacks that may have affected the level of observed inflammatory response.  Studies have reported that mesh-mediated inflammation is partly linked to mechanical forces exerted by the host physiology, and that re-modeling of biological materials is influenced by host-dependent mechanical tension that is usually limited in small animal models.  With this limitation in mind and to generate supplemental data in a more functional, mechanically loaded model, the 2 meshes were also implanted in a well-established non-human primate abdominal wall repair model, which has been extensively used to evaluate host biologic responses to surgical meshes.  Another drawback of the study was the use of animal models under healthy conditions.  In the future, comparative studies involving functional, or stress conditions (e.g., infection/contamination) may be more clinically relevant.

AlloDerm for Repair of Skull Base Defect

In a retrospective analysis, Weber et al (2002) examined if acellular dermal allograft AlloDerm (Life Cell Corporation, Woodlands, TX) can be used to cover canal wall down mastoid defects, and repair dural defects from trans-labyrinthine and trans-petrosal approaches to the skull base.  A total of 18 patients were operated on with canal wall down mastoidectomies, and Alloderm was used to reconstruct the tympanic membrane and line the mastoid cavity; 11 patients had dural defects reconstructed after skull base approach surgery.  These researchers examined if the Alloderm graft healed in canal wall down mastoidectomy procedures with good epithelialization.  For the skull base approaches, they determined whether a cerebrospinal fluid (CSF) leak had occurred.  The 18 patients who were reconstructed with an Alloderm graft after a canal wall down mastoidectomy all had good epithelialization.  As with fascia reconstruction, some granulation tissue occurred, but this was easily controlled in the office-setting.  Of the 11 patients who underwent reconstruction for skull base surgery approaches, none developed a CSF leak.  The authors concluded that AlloDerm may provide a suitable grafting material when fascia was either not readily available, or the size of the defect precluded the use of fascia.

In a retrospective chart review, Lorenz et al (2003) reported their experience in reconstructing defects of the anterior and middle cranial fossa skull base using endoscopic placement of AlloDerm.  In all cases, the skull base repair was completed with a similar technique.  After identification of the defect boundaries, endoscopic trans-nasal repair was performed through placement of a layered reconstruction of acellular dermal allograft, septal bone/cartilage, and acellular dermal allograft, which were all placed on the intra-cranial side of the defect.  A mucosal free graft was draped over the reconstruction.  Fibrin glue was used to hold the mucosal graft in place, and the reconstruction was supported by both absorbable and non-absorbable nasal packing.  A total of 8 patients with 9 skull base defects underwent the procedure for repair of CSF rhinorrhea.  All defects were successfully repaired; 1 patient underwent successful reconstruction of bilateral ethmoid roof defects that resulted from endoscopic resection of ethmoid adenocarcinoma; 24 patients underwent primary resection of hypophyseal adenomas; 23 patients had macroadenomas, and intra-operative CSF leaks were noted in 11 patients.  Sellar repairs after trans-sphenoidal hypophysectomy were successful in 22 of 24 patients; 1 patient with hypophysectomy required re-operation (1 of 24 [4 %]) for secondary closure of a CSF leak.  Serious complications were avoided in all patients.  Patients were followed for a period ranging from 5 to 57 months (mean period, of 34 months).  The authors concluded that acellular dermal allograft can be successfully used for the reconstruction of anterior and middle cranial fossa skull base defects.  This allograft, which is easy to manipulate endoscopically, provided an effective seal and barrier in skull base reconstruction and avoided the need for a donor site.

Germani et al (2007) noted that endoscopic repair of small- to medium-sized anterior skull base (ASB) defects using bone, cartilage, fascia, fibrin glue, lipolized dura, and, more recently, acellular dermal allograft had all been described with equal efficacy.  These researchers reviewed their experience with the use of acellular dermis as the sole graft material in endoscopic reconstruction of large ASB defects.  A retrospective chart review of all patients who underwent endoscopic repair of ASB defects at the University of Miami between the years of 2001 and 2006 was conducted.  A total of 56 patients were identified who met these criteria.  All repairs were performed by a trans-nasal, endoscopic approach.  Outcome measures included success of graft take and incidence of major and minor complications.  Dural defect size was defined as small (less than 0.4 cm), intermediate (0.4 to 2.0 cm), and large (greater than 2.0 cm).  AlloDerm was used as the primary graft material in 30/55 (55 %) cases; 16/55 (29 %) of the repaired defects were classified as large.  Graft success was 97 % in the AlloDerm group and 92 % in the non-AlloDerm group.  The incidence of major and minor complications in the AlloDerm group was 0 % and 3.3 %, respectively.  In the non-AlloDerm group, the incidence of major and minor complications was 4 % and 12 %, respectively.  There were no statistical differences in the complication rates based on the type of repair or defect size.  The authors concluded that AlloDerm can be used successfully to repair ASB defects, including large defects that were greater than 2 cm in size with little or no morbidity.

Patel et al (2010) stated that “Even though AlloDerm inlay is a successful option for reconstruction of some skull base defects, it is now used as an adjunct (if the flap is too small, etc.) or as last line option after vascular options have been exhausted in our practices”.

AlloDerm for Repair of Trans-Sphincteric Rectal Fistula

An UpToDate on “Operative management of anorectal fistulas” (Champagne, 2021) does not mention Alloderm or acellular cadaveric dermis as a management/therapeutic option.

AlloGen

According to Vivex Biomedical, Inc., "AlloGen is composed of 100% human liquid amnion" (CMS, 2019). It is "an amniotic fluid product derived from donated birth tissue... processed using aseptic techniques..." The allograft is exposed to electron beam radiation... to ensure terminal sterilization. "AlloGen is intended for treatment of non-healing wounds and burn injuries." The manufacturer claims that use of AlloGen liquid for the treatment of non-healing wounds and burn injuries is a homologous use in that "Just as amniotic fluid protects and nourishes the fetus during development, AllGen provides the same protection to injured or traumatized tissue." The dosage of AlloGen is per cubic centimeter (cc). It is intended for external application. It is supplied in single use vials ranging from 0.25 to 2.0 ml.

Allomax

AlloMax is an allograft made from donated human skin consisting of epidermal and dermal layers. AlloMax is a dry sheet of sterile, human dermis for use in repairing abdominal wall wounds, hernia repair, multi-layer surgical wounds/openings and other damaged tissue. It has also been used for repair of chest wall defects and breast reconstruction. According to the manufacturer, when hydrated and placed in contact with healthy well vascularized tissue, the graft supports cell in-growth and revascularization, allowing the body to remodel the graft and over time close the wound. In breast reconstruction, it closes the space between the pectoralis muscle and the chest wall. For hernia repair, AlloMax is used to repair complex abdominal wall wounds. Often multiple pieces of AlloMax are sutured together to repair an abdominal wall wound or defect. AlloMax is supplied in an individualized sterile pouch in a variety of sizes. According to the manufacturer, there are significant differences in product attributes even among similar products.

A 2012 review was conducted on the history of use of acellular dermal matrices in breast reconstructive surgery (Cheng and St. Cyr, 2012).  The authors stated that a paucity of data exists to directly compare AlloDerm®, DermaMatrix®, Strattice™, Permacol™, DermACELL, FlexHD®, SurgiMend®, and AlloMax™ for use in breast reconstruction.  They found that most studies related to hernia repair and concluded that an ideal acellular dermal matrix product is still unavailable.

AlloPatch

AlloPatchHD is an acellular human dermis derived from human allograft skin minimally processed to remove epidermal and dermal cells.  It is processed using proprietary procedures developed by Musculoskeletal Transplant Foundation (MTF, Edison, NJ) to preserve and maintain the natural biomechanical, biochemical and matrix properties of the dermal graft.  AlloPatchHD is used to support cellular repopulation and vascularizaton in applications at the surgical site.  According to the manufacturer, this unique product is indicated for use to replace damaged or inadequate integumental tissue.  Allopatch HD is designed to provide an extracellular matrix (ECM) scaffold for tendon augmentation (Snyder et al, 2012).

AlloPatch Pliable (MTF, Edison, NJ) is a preparation of a reticular cut of human dermis aseptically processed to preserve the native tissue and retain the standard amount of collagens and elastins normally present. It requires no rehydration or refrigeration prior to use and can be stored at ambient temperature. This dermis differs from many of the other human dermal matrices available that are derived from a more superficial cut of the dermis, which contains both papillary and reticular portions of the dermis. The HR-ADM comes in size-specific grafts as small as 1·5 cm × 1·5 cm to minimize wastage and can be trimmed to fit the wound. 

Zelen et al (2017a) compared clinical outcomes of AlloPatch Pliable, a novel, open-structure human reticular acellular dermis matrix (HR-ADM), to facilitate wound closure in non-healing diabetic foot ulcers (DFUs) versus DFUs treated with standard of care (SOC). Following a 2-week screening period in which DFUs were treated with offloading and moist wound care, patients were randomised to either SOC alone or HR-ADM plus SOC applied weekly for up to 12 weeks. At 6 weeks, the primary outcome time, 65% of the HR-ADM-treated DFUs healed (13/20) compared with 5% (1/20) of DFUs that received SOC alone. At 12 weeks, the proportions of DFUs healed were 80% and 20%, respectively. Mean time to heal within 12 weeks was 40 days for the HR-ADM group compared with 77 days for the SOC group. There was no incidence of increased adverse or serious adverse events between groups or any adverse events related to the graft. Mean and median graft costs to closure per healed wound in the HR-ADM group were $1475 and $963, respectively. The authors stated that strengths of the study include comprehensive SOC, satisfactory allocation concealment, an ITT analysis, adequate statistical power based on sample size and appropriate adjustment for multiple statistical testing and reporting according to CONSORT guidelines. Limitations of this investigation include lack of blinding from the patient's and investigator's perspective, an absence of exact tissue-level exposure measurement and reporting for each wound (e.g. Wagner grading), although each wound was evaluated to ensure that no wound reached greater then Wagner 2. There is also extensive right censoring for analyses at 12 weeks because of the decision to exit patients from the study whose wounds did not reduce in area by at least 50% after 6 weeks of either treatment regimen. 

Zelen et al (2017b) retrospectively reviewed healing in patients with DFUs that failed the standard of care (SOC) treatment from a previous prospective randomized, controlled trial (RCT). That trial compared the efficacy of AlloPatch Pliable human reticular acellular dermal matrices (HR-ADMs) with the SOC. Of the 16 out of 20 patients who did not heal in the SOC group, 12 were eligible for crossover treatment with the HR-ADM. The authors studied the rate of complete healing in that specific cohort after 12 weeks of crossover treatment. Of the 12 patients who were eligible for the HR-ADM, 10 (83%) achieved complete wound healing, with a mean healing time of 21 days to  closure. The corresponding wound area reduction was from 1.7 cm2 to 0.6 cm2. The mean product cost to closure was $800/patient. 

The relatively small sample of this study and its extension raise questions about the generalizability of the findings. In addition to the limitations mentioned by the authors, the method of blinding in the randomized controlled trial also introduced the potential for bias. Adjudicators were blinded to patient study group assignments, but the protocol does not say that the adjudicators were blinded to the investigators assessment of healing.

Dasgupta and colleagues (2016) hypothesized that a novel human reticular ADM (HR-ADM; AlloPatch Pliable) when aseptically processed would have a more open uniform structure with retention of biological components known to facilitate wound healing.  The reticular and papillary layers were compared through histology and scanning electron microscopy.  Biomechanical properties were assessed through tensile testing.  The impact of aseptic processing was evaluated by comparing unprocessed with processed reticular grafts.  In-vitro cell culture on fibroblasts and endothelial cells were performed to showcase functional cell activities on HR-ADMs.  Aseptically processed HR-ADMs have an open, interconnected uniform scaffold with preserved collagens, elastin, glycosaminoglycans, and hyaluronic acid.  HR-ADMs had significantly lowered ultimate tensile strength and Young's modulus versus the papillary layer, with a higher percentage elongation at break, providing graft flexibility.  These preserved biological components facilitated fibroblast and endothelial cell attachment, cell infiltration, and new matrix synthesis (collagen IV, fibronectin, von Willebrand factor), which support granulation and angiogenic activities.  The authors concluded that the novel HR-ADMs provided an open, interconnected scaffold with native dermal mechanical and biological properties.  Furthermore, aseptic processing retained key extracellular matrix elements in an organized framework and supported functional activities of fibroblasts and endothelial cells.  Moreover, they stated that further in-vitro studies are needed to characterize the cell behavior and functionality of these biologically and mechanically stable novel reticular dermal grafts in a chronic setting.

Zelen et al (2018) noted that aseptically processed human reticular acellular dermal matrix (HR-ADM) has been previously shown to improve wound closure in 40 diabetic patients with non-healing foot ulcers.  The study was extended to 40 additional patients (80 in total) to validate and extend the original findings.  The entire cohort of 80 patients underwent appropriate off-loading and SOC during a 2-week screening period and, after meeting eligibility criteria, were randomized to receive weekly applications of HR-ADM plus SOC or SOC alone for up to 12 weeks.  The primary outcome was the proportion of wounds closed at 6 weeks; 68 % (27/40) in the HR-ADM group were completely healed at 6 weeks compared with 15 % (6/40) in the SOC group.  The proportions of wounds healed at 12 weeks were 80 % (34/40) and 30 % (12/40), respectively.  The mean time to heal within 12 weeks was 38 days for the HR-ADM group and 72 days for the SOC group.  There was no incidence of increased adverse or serious adverse events (AEs) between groups or any graft-related AEs.  The mean and median HR-ADM product costs at 12 weeks were $1,200 and $680, respectively.  The authors concluded that HR-ADM was clinically superior to SOC, was cost-effective relative to other comparable treatment modalities, and was an effective treatment for chronic non-healing DFUs.

The authors stated that drawbacks of this study included the fact that it was an open study that did not blind the patient or the investigator to the intervention allocated because blinding was not feasible (although reviewers were blinded to the type of treatment in their evaluation of wound closure).  It was also limited in ulcer size and depth, in that there was no tendon, capsule, muscle, or bone exposure, which is frequently observed in complex ulcers presenting to the wound clinic.  These investigators stated that future trials may assess the use of HR‐ADM on deeper wounds and more medically complex patient populations as frequently seen in the "real‐world" population.

A draft assessment of wound care products prepared for AHRQ judged this randomized controlled study by Zelen, et al. (2018) to be at moderate risk of bias.

Agrawal and colleagues (2012) presented a retrospective, case-series study of the clinical and structural outcomes (1.5 T MRI) of arthroscopic rotator cuff repair with acellular human dermal graft reinforcement performed by a single surgeon in patients with large, massive, and previously repaired rotator cuff tears.  A total of 14 patients with mean anterior to posterior tear size 3.87 ± 0.99 cm (median of 4 cm, range of 2.5 to 6 cm) were enrolled in the study and were evaluated for structural integrity using a high-field (1.5 T) MRI at an average of 16.8 months after surgery.  The Constant-Murley scores, the Flexilevel Scale of Shoulder Function (Flex SF), scapular plane abduction, and strength were analyzed.  MRI results showed that the rotator cuff repair was intact in 85.7 % (12/14) of the patients studied; 2 patients had a Sugaya Type IV recurrent tear (2 of 14; 14.3 %), which were both less than 1 cm.  The Constant score increased from a pre-operative mean of 49.72 (range of 13 to 74) to a post-operative mean of 81.07 (range of 45 to 92) (p = 0.009).  Flexilevel Scale of Shoulder Function (Flex SF) Score normalized to a 100-point scale improved from a pre-operative mean of 53.69 to a post-operative mean of 79.71 (p = 0.003).  The Pain Score improved from a pre-operative mean of 7.73 to a post-operative mean of 13.57 (p = 0.008).  Scapular plane abduction improved from a pre-operative mean of 113.64° to a post-operative mean of 166.43° (p = 0.010).  The strength subset score improved from a pre-operative mean of 1.73 kg to a post-operative mean of 7.52 kg (p = 0.006).  The authors concluded that this study presented a safe and effective technique that may help improve the healing rates of large, massive, and revision rotator cuff tears with the use of an acellular human dermal allograft.  This technique demonstrated favorable structural healing rates and statistically improved functional outcomes in the near-term.  Level of Evidence: IV.

Alloskin/ AlloSkin RT

Alloskin is allograft derived from epidermal and dermal human cadaver skin that has been preserved. It is regulated by the FDA as human tissue for transplantation (CMS, 2010). It is used in acute and chronic wound therapy.

Alloskin / AlloSource

Alloskin (Allosource, Centennial, OH) is a specialty allograft derived from epidermal and dermal cadaveric tissue and designed for wound care (Snyder, et al., 2012). Alloskin is a 1:1 meshed, biological cadaveric dermis, which is decellularized and further processed to provide an acellular tissue allograft (CMS, 2013). These products have been used in acute and chronic wound therapy.

Alloskin AC allograft is a natural skin replacement that can be used as a scaffold for regeneration of tissue through revascularization and remodeling into the host tissue to achieve wound closure of partial or full-thickness wounds due to tissue loss from burns, trauma and chronic wounds, such as venous and arterial ulcers, diabetic foot ulcers and pressure ulcers (CMS, 2013). Alloskin AC tissue allograft is surgically applied and secured to the skin by the anchoring method chosen by the surgeon (sutures, staples, adhesive glue, etc.). Alloskin AC is supplied 4cmx4cm/16cm2 and 5cmx5cm/25cm2. There is a similar human cadaver acellular product, Graftjacket.. Alloskin AC is processed differently than Graftjacket. After epidermal layer is removed by chemical delamination, the resulting dermal product is low-dose, e-beam irradiated to preserve the graft in a shelf-stable format. E-beam sterilization is considered a gentler method of sterilization than gamma irradiation for delicate collagen matrices. 

AlloSkin RT human allograft is a meshed, biologic wound covering comprised of human cadaveric dermis. It is low-dose, e-beam irradiated, allowing its use in clinical settings where there is no access to a cryo-rated freezer. AlloSkin RT is for homologous use and is used clinically as a temporary skin replacement for closure of partial or full-thickness wounds due to burns, trauma or chronic wounds, such as venous and arterial ulcers, neuropathic diabetic ulcers and pressure ulcers. AlloSkin is surgically applied and secured to the skin by anchoring method chosen by the surgeon (sutures, staples, adhesive glue, etc.). The allograft sloughs in 7-14 days as granulation of the wound bed proceeds, and might be reapplied to provide a skin replacement that is intended to help promote wound healing by protection of the injured tissues and supporting final closure of the wound. The manufacturer states that Alloskin is processed differently than similar products.

Moravveg et al (2012) reported on 14 patients with severe third-degree burns treated with Alloskin from June 2009 until December 2010 as the sample for this study.  After debridement and wound excision, meshed split thickness skin graft was used to cover the entire wound.  Alloskin (allofibroblasts cultured on a combination of silicone and glycosaminoglycan) was applied on one side and petroleum jelly-impregnated gauze (Iran Polymer and Petrochemical Institute) was applied on the other.  The healing time, scar formation, and pigmentation score were assessed for the patients.  All analyses were undertaken with SPSS 17 software.  The authors stated that Alloskin demonstrated good properties compared to petroleum jelly-impregnated gauze.  The average healing time and hypertrophic scar formation were significantly different between the two groups.  In addition, the skin pigmentation score in the alloskin group was closer to normal.  The authors stated that Alloskin grafting may be a useful method to reduce healing time and scar size and may require less autologous split thickness skin grafts in extensive burns where a high percentage of skin is burned and there is a lack of available donor sites.

Fagotti and colleagues (2019) compared the clinical outcomes between 2 groups of patients who underwent arthroscopic hip capsular reconstruction with the same surgical technique with an ilio-tibial band (ITB) allograft versus dermal allograft tissue.  From March 2013 to October 2015, patients who were 18 years of age or older and who underwent revision arthroscopic hip surgery with capsular reconstruction by the senior author were identified.  Patients who were younger than 18 years old, had a lateral center-edge angle  of less than 20° or Tonnis osteoarthritis grade 2 or 3, or refused to participate were excluded.  Patients were assigned to 2 groups based on whether an ITB (ITB group) or a dermal allograft (dermal group) was used to reconstruct the capsule.  The ITB graft was used initially, then the dermal graft was used when it was available.  The dimensions were based on the intra-operative measurement of the capsular defect, and the thickness was 3 mm.  Other treatments included labral debridement, repair, or reconstruction; treatment of residual femoro-acetabular impingement (FAI); and treatment of cartilage damage.  Clinical outcome scores including the Hip Outcome Score (HOS)-Activity of Daily Living scale (primary outcome measure), modified Harris Hip Score, HOS-Sports scale, SF-12, and Western Ontario & McMaster Universities Osteoarthritis Index were compared between the groups in addition to the failure rate (conversion to total hip arthroplasty {THA], revision hip arthroscopy) and patient satisfaction rate with the outcome (range of 1 to 10).  A total of 36 patients (9 men and 27 women) met the inclusion criteria.  Each group consisted of 18 patients (18 hips) with a mean age of 30.9 ± 9.4 years in the ITB group and a mean age of 29.8 ± 9.4 years in the dermal group (p = 0.718).  There were no differences in patient demographics, physical examination findings, or imaging characteristics.  The procedure failed for 8 patients (4 in the ITB group and 4 in the dermal group), and another surgery was required (p = 1.0).  Additional surgeries included 3 THAs, 1 periarticular osteotomy, and 4 revision arthroscopies.  The mean follow-up time was 25 months (range of 18 to 38 months) in both groups (p = 0.881).  At follow-up, the HOS-Activity of Daily Living scale, SF-12, modified Harris Hip Score, and HOS-Sports scale measures were significantly higher in the ITB group than in the dermal group (p < 0.05).  A greater percentage of patients reached minimum clinically important difference in the ITB group for Western Ontario & McMaster Universities Osteoarthritis Index and HOS scales with the minimum clinically important difference for HOS-Sports scale being significantly higher in the ITB group (p = 0.04).  Patient satisfaction scores were 8 and 6 in the ITB and dermal groups, respectively.  The authors concluded that at a mean follow-up time of 25 months, hip capsular reconstruction with an ITB allograft results in improved clinical outcomes compared with the dermal allograft.  A similar failure rate was noted in both groups, but a greater percentage of patients in the ITB group achieved clinical improvement.

The authors stated that this study had several drawbacks including the small sample size (n = 36).  This may limit the ability to determine whether differences were significant because of lack of power.  This procedure was limited to patients with large capsular defects that could not be repaired.  Although more of these defects are being seen, these researchers still see a limited number of cases in their practice.  Another limitation was the lack of specific selection criteria during pre-operative patient evaluation.  The effectiveness of MRI in identifying a capsule requiring a reconstruction has not been studied, and clinical symptoms did not define when a capsule defect was large enough to require a reconstruction.  In this study, the ITB graft reconstructions were performed before the dermal graft reconstructions.  This may have influenced the outcomes, based on the learning curve of the senior surgeon, in favor of the dermal group.  Another limitation was the presence of concomitant procedures.  It was unclear whether the capsular reconstruction resulted in improved outcomes after adequate treatment of other hip pathologies.  Availability of enough human tissue to prepare an allograft is not a reality for many health care facilities worldwide.  This is an advanced procedure, and it may be difficult to perform future studies because of its technical complexity and questionable clinical benefit.

PureSkin is an allograft that is available in fresh configuration or cryo-preserved from (meshed and non-meshed).  It is used in burn patients to advance wound healing when autografting is not feasible.  The International Society for Burn Injury (ISBI) practice guidelines for burn care (ISBI, 2016) noted that “A wound too large to be safely repaired with autograft should be repaired with allograft or skin substitute”.

Allowrap

Allowrap DS or Dry are a double-sided epithelial layer human amniotic membrane. It has been used as an onlay and/or wrapping tissue applications following surgical repair.

AlloWrap DS and AlloWrap Dry consist of human amniotic membrane that has been processed using a proprietary technology, and is designed with two layers of amniotic tissue with the epithelial layers facing outward (CMS, 2014).  AlloWrap DS tissue allograft is surgically applied to the skin.  Most wounds respond with one application of AlloWrap DS; however it can be reapplied if needed.  AlloWrap DS is supplied in the following sizes: 2cm x 2cm; 2cm x 4cm; 4cm x 4cm; and 4cm x 8cm.  AlloWrap Dry tissue is surgically applied to the skin and is supplied in a range of sizes: 1 x 1cm; 1 x 2cm; 1.5 x 2cm; 1 x 4cm; 2 x2cm; 2 x 4cm; 4 x 4cm; 6 x 6cm; and 4 x 8cm. It can be used in a variety of procedures as a wound cover or barrier. 

AmnioAMP-MP

AmnioAMP-MP (Stratus BioSystems), a decellularized dehydrated human amniotic membrane (DDHAM) which is derived from the placental amnion and includes epithelial and stromal components that provide a collagen-rich extracellular matrix, cytokines, and growth factors. The allograft, which is chorion free, provides a physical platform for infiltrating cells as well as extracellular proteins such as elastin, fibronectin, proteoglycans, glycosaminoglycans, and laminins, important in extracellular matrix strength, cell attraction, and migration. AmnioAMP-MP human amniotic extracellular matrix provides the scaffold for cell attachment and proliferation needed for granulation tissue development, vascularization, and epithelization for tissue repair with minimized inflammation and scarring. AmnioAMP-MP is E-Beam sterilized and provided in a dry sheet form that is ready to use and is stored at ambient temperature. Indications include, but not limited to, application to partial and full-thickness acute and chronic wound (such as burns, diabetic wounds, venous wounds, arterial wounds, pressure wounds), including wounds with exposed tendon, muscle, and bone. AmnioAMP-MP delivers a natural collagen rich (Type 1,11) extracellular matrix with extracellular proteins, including fibronectin and laminins, as well as cytokines and growth factors to damaged soft tissues. AmnioAMP-MP serves as a barrier to microbes and adhesions and as the structural platform to support appropriate cellular growth resulting in efficient healing with minimal inflammation and scarring. The AmnioAMP-MP allograft is supplied sterile as single use products available in multiple sizes. The actual size of the amniotic allograft that is applied is determined by the health care provider based on wound size.

AmnioArmor

AmnioArmor (Bone Bank Allografts, a subsidiary of Globus Medical, Inc.) is a dehydrated human amniotic membrane allograft derived from placental tissue submucosa. It is intended for topical application as a wound covering for acute and chronic wounds. It contains dual collagen layers and growth factors including epidermal growth factor, (EFG) basic fibroblast growth factor (BFGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), transforming growth factors (TGFs), nerve growth factor (NGF), and many chemokines/cytokines. There are no peer-reviewed published studies evaluating the safety and efficacy of AminoArmor. Once applied to the surgical site, AmnioArmor can be hydrated with sterile saline or other sterile solution, if needed. Suture material or tissue adhesives may be used to apply the graft to the surgical site. AmnioArmor is available in several sizes for optimal coverage and placement, including 1 cm x 1 cm, 2 cm x 2 cm, 2 cm x 3 cm, 4 cm x 4 cm, 4 cm x 6 cm, 4 cm x 8 cm, and 16 mm diameter.

AmnioBand and Guardian

AmnioBand and Guardian are human tissue allografts made of donated placental membrane (CMS, 2014).  The allograft is comprised of native human amnion and chorion.  The amnion and the chorion together create a membrane in which the amnion serves as a covering epithelium.  The membrane is hydrophilic and can be used in a hydrated or dehydrated state.  Although marketed under two different brand names, the products are identical.  Amniobrand and Guardian are allograft membrane coverings intended for interior or exterior wounds including use as a covering for the surgical site.  Usage includes various wounds and ulcers and other soft tissue defects.  Both AmnioBrand and Guardian are processed and packaged under aseptic conditions, and are available in the same 5 sizes: 2x2 cm, 3x4 cm, 3x8 cm, 4x4 cm, and 4x6 cm. 

According to the manufacturer Musculoskeletal Transplant Foundation, AmnioBand Viable is a placental matrix derived from human donated amnion membranes originating from the inner lining of the placenta. AmnioBand Viable is intended for internal and external tissue defects, including acute, chronic, and surgically-created wounds. It is used as a natural wound scaffold to support the body’s inherent ability to restore and remodel tissue through components that have been preserved in the native tissue. AmnioBand Viable contains biological extracellular matrix proteins, cytokines, growth factors, and viable endogenous cells that work to support host tissue remodeling. This provides a barrier to infections and helps to maintain a moist wound environment for healing. AmnioBand Viable is supplied in 2 cm x 2 cm and 5 cm x 5 cm sizes.

According to the manufacturer, AmnioBand SL is a dehydrated single amnion layer matrix derived from human donated amnion membranes originating from the inner lining of the placenta. It is indicated for patients who present with chronic wounds caused by diabetes, obesity, COPD, obstructed blood flow and other underlying conditions. AmnioBand SL is a minimally processed human allograft which retains the structural properties of the amnion extracellular matrix. The resulting dehydrated allograft serves as a wound scaffold. AmnioBand SL contains growth factors and cytokines that support the membrane’s native function to promote cell proliferation and tissue remodeling during the wound healing phase. AmnioBand SL is available in rectangular and circular shapes ranging from 0.79 square centimeter to 49 square centimeters.

According to the Musculoskeletal Transplant Foundation, AmnioBand Particulate is derived from human donated amnion membrane originating from the inner lining of the placenta. AmnioBand Particulate is an allograft membrane scaffold for wounds, including use as a scaffold for a surgical site. It is a lyophilized placental matrix in particulate form, aseptically processed to preserve the tissue’s natural cytokines and tissue matrix. AmnioBand Particulate is intended to be used as a wound care scaffold for the replacement of damaged or inadequate integumental tissue, such as diabetic foot ulcers venous leg ulcers, pressure ulcers, or for other homologous use, particularly irregularly-shaped or crevassing wounds. AmnioBand Particulate is available in a variety of masses, ranging from 40mg to 160mg.

Didomenico et al (2016) compared AmnioBand (MTF, Edison, NJ) aseptically processed dehydrated human amnion and chorion allograft (dHACA) versus standard of care (SOC) in facilitating wound closure in  nonhealing DFUs. Patients with DFUs treated with SOC (off-loading, appropriate debridement, and moist wound care) after a 2-week screening period were randomized to either SOC or wound-size-specific dHACA applied weekly for up to 12 weeks plus SOC. Primary endpoint was the percentage of wounds healed at 6 weeks between groups. At 6 weeks, 70% (14/20) of the dHACA-treated DFUs healed compared with 15% (3/20) treated with SOC alone. Furthermore, at 12 weeks, 85% (17/20) of theDFUs in the dHACA group healed compared with 25% (5/20) in the SOC group, with a corresponding mean time to heal of 36 and 70 days, respectively. At 12 weeks, the mean number of grafts used per healed wound for the dHACA group was 3.8 (median 3.0), and mean cost of the tissue to heal a DFU was $1400. The mean wastage at 12 weeks was 40%. One adverse event and 1 serious adverse event occurred in the dHACA group; neither was graft related. Three adverse events and 1 serious adverse event occurred in the SOC group.

The drawbacks of this study included the lack of blinding (patient and investigator) and lack of a soft-tissue matrices comparator.  Future studies may consider comparing different amniotic tissue forms and allowing wounds of greater severity or depth.  In addition, withdrawal of patients whose wounds did not reduce in area by at least 50 % after 6 weeks of either treatment regimen – done to ensure patient safety – resulted in high right censoring for analyses at 12 weeks.  Another issue in regard to inclusion/exclusion criteria was the use of ABI as one means of evaluating distal perfusion.  Diabetic patients’ calcification of lower extremity arteries can falsely elevate readings, with values often exceeding 1.3.  In most instances, such high readings would have automatically caused a screen failure, and this might have resulted in a more biased population, which was why Doppler studies were performed on the entire cohort for evaluation of biphasic flow in the study extremities.  Finally, although the cost analysis was based upon publically available data (mean sales price per cm2 and published studies), a preferred, full health economic analysis of dHACA was beyond the scope of this trial.

A draft assessment of wound care products prepared for AHRQ judged this randomized controlled study by DiDomenico, et al. (2016) to be at moderate risk of bias.

DiDomenico and associates (2017) noted that in a published, prospective RCT comparing aseptically processed dHACA to SOC, 85 % wound closure rates were reported in the dHACA-arm while only 25 % of patients in the SOC-arm healed.  In a retrospective cross-over study, these researchers evaluated the effectiveness of dHACA in those patients that failed to respond to the SOC treatments and who exited the original study after failing up to 12 weeks of SOC treatment.  Patients with non-healing wounds from the SOC-arm after exit from the original study were offered weekly adjunctive applications of dHACA (AmnioBand) for up to 12 weeks.  The primary end-point was the proportion of wounds completely healed at 12 weeks; secondary end-points included the difference in wound area from baseline to the end of study and the percentage area reduction (PAR).  A total of 11 patients were eligible to participate; wounds for 9 of the 11 patients healed (82 %).  The mean wound area decreased from 1.7 cm² to 0.2 cm² (p = 0.0005), with a corresponding mean PAR of 92 %.  Of the 2 wounds that failed to heal, 1 DFU decreased in area by 91 % and the other by 26 %.  The authors concluded that the results of this cross-over study supported the conclusions of the original RCT, which determined that aseptically processed dHACA was an effective means to treat recalcitrant DFUs.  Moreover, they stated that further comparative investigations and studies of more complex wounds will further clarify which patients will most benefit from this technology.

The main drawbacks of this study were its retrospective nature, small sample size (n = 11), and the fact that patients were not required to follow-up since they were seen as regular wound patients in the clinic and were under no obligation to return and receive the complimentary graft.  In addition, a comprehensive economic analysis was also beyond the scope of this study.

DiDomenico et al (2018) stated that amnion and chorion allografts have shown great promise in healing diabetic foot ulcers (DFUs).  Results from an interim analysis of 40 patients have demonstrated the accelerated healing ability of a novel aseptically processed, dehydrated human amnion and chorion allograft (dHACA).  These investigators reported on the full trial results of 80 patients where dHACA was compared with standard of care (SOC) in achieving wound closure in non-healing DFUs.  After a 2-week screening period, during which patients with DFUs were unsuccessfully treated with SOC, patients were randomized to either SOC alone or SOC with dHACA applied weekly for up to 12 weeks.  At 12 weeks, 85 % (34/40) of the dHACA-treated DFUs healed, compared with 33 % (13/40) treated with SOC alone.  Mean time to heal within 12 weeks was significantly faster for the dHACA-treated group compared with SOC, 37 days versus 67 days in the SOC group (p = 0.000006).  Mean number of grafts used per healed wound during the same time period was 4.0, and mean cost of the tissue to heal a DFU was $1,771.  The authors concluded that aseptically processed dHACA healed DFUs significantly faster than SOC at 12 weeks.  These researchers stated that future trials of dHACA should consider a comparative arm using an advanced skin substitute for greater evidence and may even permit wounds of greater severity or depth.  Patients with a higher proportion of serious co-morbidities may also be considered in order to enhance representation of a more "real‐world" scenario.

The authors noted that the main drawback of this study was withdrawing patients at 6 weeks rather than continuing through 12 weeks of treatment if clinicians judged that their wounds were not sufficiently responding to treatment in order to ensure patient safety and permit other treatment pathways. 

Additional clinical studies involving larger numbers of patients from a variety of clinical settings are necessary to establish the effectiveness and safety of AmnioBand.

Glat et al (2019) noted that aseptically processed dHACA (AmnioBand) has shown great promise in the treatment of recalcitrant DFUs when compared with standard wound care but has not yet been compared to any other tissue forms used in treating DFUs.  The hypothesis was to conduct a randomized controlled trial (RCT) in which dHACA was compared to one of the earliest and most commonly accepted tissue-engineered skin substitutes (TESS) (Apligraf) in the treatment of non-healing DFUs over a period of 12 weeks to assess the superiority of healing.  Following a 2-week screening period during which subjects with DFUs were treated with collagen alginate dressing, 60 subjects were randomized at 5 sites to receive either dHACA or TESS applied weekly, with weekly follow-up for up to 12 weeks.  The mean time to heal within 6-week time period for the dHACA group was 24 days (95 % confidence interval [CI]: 18.9 to 29.2) versus 39 days (95 % CI: 36.4 to 41.9) for the TESS group; the mean time to heal at 12 weeks was 32 days (95 % CI: 22.3 to 41.0) for dHACA-treated wounds versus 63 days (95 % CI: 54.1 to 72.6) for TESS-treated wounds.  The proportion of wounds healed at study completion (12 weeks) was 90 % (27/30) for the dHACA group versus 40 % (12/30) for the TESS group.  The mean product cost for the dHACA group was significantly lower than that for the TESS group [dHACA: $2,200 (median of $1,300); TESS: $7,900 (median of $6,500)].  The mean wastage (%) at 12 weeks was also significantly lower for the dHACA group than that for the TESS group (36 % versus 95 %).  The authors concluded that aseptically processed dHACA healed diabetic foot wounds more reliably, statistically significantly faster than and at significantly lower cost than TESS.

The authors stated that study limitations included lack of principal investigator blinding, which was not possible due to visual dissimilarity of the tissues.  Also, measuring the time to application was not performed.  In addition, the recalcitrant nature of the wound in the location that the graft was applied was not looked at.  Finally, withdrawing patients at 6 weeks rather than continuing through 12 weeks of treatment if their wounds were not sufficiently responding to treatment to ensure patient safety and permit other treatment pathways could be considered a limitation as well.  These researchers stated that future studies may consider looking at even more treatment algorithms that will further help enhance wound-healing technique in diabetic patients.

Serena, et al. (2022) reported on a randomized controlled trial evaluating the safety and effectiveness of weekly and biweekly applications of AmnioBand dehydrated human amnion and chorion allograft (dHACA) plus standard of care compared to standard of care alone on chronic venous leg ulcers. This open-label randomized controlled trial included patients with chronic venous leg ulcers at eight wound care centers across the United States. The primary endpoint was the proportion of healed ulcers at 12 weeks. Secondary endpoints included the proportion of ulcers achieving 40 percent closure at 4 weeks and the incidence of adverse events.  Among 101 patients screened for eligibility, 60 were eligible and enrolled. At 12 weeks, significantly more venous leg ulcers healed in the two dHACA-treated groups (75 percent) than in the standard-of-care group (30 percent) ( p = 0.001) even after adjustment for wound area ( p = 0.002), with an odds ratio of 8.7 (95 percent CI, 2.2 to 33.6). There were no significant differences in the proportion of wounds with percentage area reduction greater than or equal to 40 percent at 4 weeks among all groups. The adverse event rate was 63.5 percent. Among the 38 adverse events, none were graft or procedure related, and all were resolved with appropriate treatment.  The investigators concluded that AmnioBand dHACA and standard of care, either applied weekly or biweekly, significantly healed more venous leg ulcers than standard of care alone, suggesting that the use of aseptically processed dHACA is advantageous and a safe and effective treatment option in the healing of chronic venous leg ulcers.

AmnioBind

AmnioBind (Predictive Biotechnology) is a terminally sterilized, dehydrated, full thickness placental membrane (PM) allograft tissue intended for homologous use for the repair, reconstruction, and replacement of the recipient’s tissue at the discretion of a physician.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of AmnioBind.

AmnioCyte Plus

AmnioCyte Plus (Predictive Biotech) is a minimally manipulated human tissue allograft derived from the extracellular matrix of the amniotic membrane. It is processed to preserve the cytokines, growth factors and scaffolding proteins from within the amniotic membrane matrix for homologous use. AmnioCyte Plus is intended for use in repair, reconstruction, replacement or supplementation of a recipient's cells or tissue by performing the same basic functions of amniotic membrane matrix in the recipient as it would in the donor. The amount and administration (injected or topical) of the allograft is determined by the clinician based on the intended use in each patient. The product is distributed as a liquid allograft contained in a vial that is shipped frozen for preservation (-80C on dry ice) and is intended to be stored in that frozen state (-60C to -80C or colder) until used or expiration date is reached. It can be ordered in 3 vial sizes: 0.5 mL, 1 mL or 2 mL. The product is simply drawn up after proper thawing using a 21G-23G needle to syringe and then prepared and applied.

There is a lack of evidence regarding the effectiveness of the AmnioCyte Plus allograft.

AmnioExCel and BioDExCel 

AmnioExCel (also marketed under trade name BioDExCel) is a sterile, resorbable, noncrosslinked dehydrated human amnion membrane allograft composed of an epithelial layer and a stromal layer specifically processed for repair or replacement of lost or damaged dermal tissue (CMS, 2013). The product contains collagen and extracellular substrates to include growth factors, connective proteins, and cytokines that support and promote angiogenesis, tissue granulation and epithelialization for the repair and replacement of injured tissue. The collagen in the allograft provides an extracellular matrix which acts as a natural scaffold for cellular attachment and a structural tissue matrix that facilitates cell migration and proliferation for tissue repair and regeneration. The natural composition of the amniotic membrane extracellular matrix is preserved without cross-linkage, thereby providing improved graft incorporation by the body. Usage includes, but is not limited to, allograft application to wounds including traumatic injuries, burns or surgical wounds; complex, chronic and acute wounds, such as diabetic ulcers, venous and arterial ulcers, pressure ulcers or cutaneous ulcers; wounds with exposed tendon, muscle, bone or other vital structures and other soft tissue defects. Both AmnioExCel and BioDExCel are sterilely packaged for single use and each product is available in the same 5 sizes: 1.5 x 2 cm; 2 x 3 cm; 2 x 6 cm; 4 x 4 cm; and 4 x 8 cm.

In a prospective, open-label, randomized, parallel group clinical trial, Snyder et al (2016) evaluated dehydrated amniotic membrane allograft (DAMA) (AmnioExCel, Derma Sciences Inc., Princeton, NJ) plus SOC compared to SOC alone for the closure of chronic DFUs. This study was implemented at 8 clinical sites in the U.S.  Eligibility criteria included adults with type 1 or type 2 diabetes mellitus who have 1 or more ulcers with a Wagner classification of grade 1 or superficial 2 measuring between 1 cm2 and 25 cm2 in area, presenting for more than 1 month with no signs of infection/osteomyelitis; ankle-brachial index (ABI) greater than 0.7; HbA1c Less than 12 %; and serum creatinine less than 3.0 mg/dL.  Eligible subjects were randomized (1:1) to receive either SOC alone (n = 14) or DAMA+SOC (n = 15) until wound closure or 6 weeks, whichever occurred first.  The end-point was the proportion of subjects with complete wound closure (defined as complete re-epithelialization without drainage or need for dressings).  A total of 35 % of subjects in the DAMA+SOC cohort achieved complete wound closure at or before week 6, compared with 0 % of the SOC alone cohort (intent-to-treat population, p = 0.017).  There was a more robust response noted in the per protocol population, with 45.5 % of subjects in the DAMA+SOC cohort achieving complete wound closure, while 0 % of SOC-alone subjects achieved complete closure (p = 0.0083).  No treatment-related adverse events were reported.  The authors concluded that these findings suggested DAMA is safe and effective in the management of DFUs, but additional research is needed.

A draft assessment of wound care products prepared for AHRQ judged this randomized controlled study by Snyder, et al. (2016) to be at moderate risk of bias.

AmnioMatrix and BioDMatrix

AmnioMatrix and BioDMatrix are a viable human multipotential placental cryopreserved allografts composed of morselized amniotic membrane and amniotic fluid components recovered from the same human donor (CMS, 2013). The amniotic membrane is separated from the placenta and morselized into particulate form, then combined with amniotic fluid components to form the allograft. The processing method is intended to preserve the structural properties of the collagen; growth factors; inherent cellular materials and matrix present in the tissue to create a micro-scaffold to be used to aid in the wound healing process. AmnioMatrix (also to be marketed under the trade name BioDMatrix) is intended for the treatment of wounds, including but not limited to surgical wounds, burns or traumatic injury; and chronic and acute wound conditions. The allograft is also used to augment the local treatment of soft tissue defects for the supportive treatment of wound-associated bone defects. The product may be mixed with normal saline for application to surgical sites and open, complex or chronic wounds or mixed with the recipient’s blood to fill soft tissue defects and wound-associated bone defects. AmnoMatrix is cryopreserved and supplied in injectable form in sterile vials. It is available in 4 sizes: small (0.25 cc); medium (0.50 cc); large (1.0 cc); and extra-large (3.0 cc). 

Amnio-Maxx and Amnio-Maxx Lite

Amnio-Maxx (Royal Biologics) is a dual layered, dehydrated, amniotic tissue membrane graft derived from Cesarean Section donors. The Amnio-Maxx Lite version (Royal Biologics) is a single layer. The product is for wound covering, applied directly to the wound bed. Both products are used for chronic, non-healing wounds such as diabetic foot ulcers and venous leg ulcers or soft tissue defects. Amniotic tissue consists primarily of fibrillary and membranous collagens, elastin, and a mix cytokines and growth factors that provide the properties unique to placental tissues. There are various sizes of each product; the provider uses the size that most closely matches the wound size. Once the graft has been applied, it is covered with a bandage. Amnio-Maxx and Amnio-Maxx-Lite both come in sterile pouches.

There is a lack of evidence regarding the effectiveness of the Amnio-Maxx or Amnio-Maxx Lite allograft.

AmnioPro Flow

AmnioPro Flow (Human Regenerative Technologies, LLC) is a human placental tissue matrix consisting of decellularized particulate placental connective tissue matrix intended to replace or supplement damaged or inadequate integument. AmnioPro Flow is ideal for use in difficult to reach, irregularly shaped or tunneled wounds. Typically one application is applied per wound; however it may be reapplied if necessary. AmnioPro Flow is supplied in the following sizes: 0.5cc, 1.0cc, 1.5cc, and 2.0cc vials.

AmnioPro Membrane

AmnioPro Membrane (Human Regenerative Technologies, LLC) is a human amniotic tissue allograft consisting of dehydrated and decellularized human amniotic membrane that has been processed with proprietary HydraTek technology. AmnioPro thin membrane is designed as a single layer wound covering for common wounds, and AmnioPro thick membrane is designed as a thicker single layer wound covering for deeper wounds where tissue bulk is required. It is intended to be used as a wound covering and is surgically applied to the skin in the treatment of chronic acute and surgical wounds. Both products are available in the following sizes: 1x1cm, 1x2cm, 2x2cm, 2x4cm, 4x4cm, 4x6cm, and 4x8cm.

Amniorepair and AltiPly

Amniorepair and AltiPly (Zimmer Biomet) are human cellular and tissue-based products. Each allograft is restricted to homologous use for use in procedures on a single occasion by a licensed physician. The products are lyophilized placental membrane allografts that are aseptically processed to preserve the native extracellular matrix and endogenous proteins of the tissue. They are indicated for homologous use as a biological barrier or wound cover, forming a protective cover for a variety of acute and chronic wounds. The products are enclosed in a sterile wrap then sealed in a sterile inner and secondary outer pouch. The outer pouch is contained in a labeled box. Allograft size is indicated on the package label. Using sterile forceps, the physician applies the graft directly onto the prepared wound bed with the stromal side directly against the wound bed. The graft absorbs the moisture directly from the wound bed; however, a few drops of sterile saline may be added to the graft after it has been applied to the wound if all areas are not rehydrated. The treated wound is covered with a non-adherent dressing followed by saline moistened gauze to fill but not pack the wound.

There is a lack of evidence regarding the effectiveness of the Amniorepair or AltiPly allograft.

AmnioShield Amniotic Tissue Barrier

AmnioShield amniotic tissue barrier (Alphatec Spine, Carlsbad, CA) is a amniotic membrane-based implantable barrier to prevent/reduce scar tissue formation.   There is a lack of evidence regarding the effectiveness of the AmnioShield amniotic tissue barrier.

AmnioStrip

AmnioStrip is comprised of placental tissue designed for use in protecting a wide variety of wounds, while simultaneously creating an environment conducive to the regeneration of healthy tissue. This tissue supposedly improves outcome in would management.  However, there is a lack of evidence regarding its clinical effectiveness.

Amniotext

Amniotext (Regenative Labs) is a minimally manipulated, amniotic membrane derived, human tissue allograft suspension product. The product serves to provide a barrier/support function and to aid in healing of defect. It is intended to provide the extracellular matrix needed for the infiltration, attachment and proliferation of cells required for the repair of damaged tissue. Amniotic membrane human tissue-based products have shown to reduce scarring, fibrosis and adhesions in surgical and wound sites. It is administered through a syringe to the defect and the amount is determined by the clinician based on the size of the defect. Each human tissue-based product distributed by Regenative Labs is identified by its own unique serial number. The product is packaged in a transport protective pouch. The product is contained in a cryogenic primary tissue container, which contains a product label that includes the product details such as unique product number, storage requirements and volumes. Contents are aseptically processed and are not considered sterile.

There is a lack of evidence regarding the effectiveness of the Amniotext allograft.

Amniotext patches (Regenative Labs) are minimally manipulated, amniotic membrane-derived, human tissue allografts. The product serves as wound covering. It is typically used for chronic non-healing wounds such as diabetic foot ulcers and venous leg ulcers. It provides the extracellular matrix needed for the infiltration, attachment and proliferation of cells required for repair of damaged tissue. The graft is applied directly to the wound bed and is available in various sizes, the size used matches the wound defect. Each human tissue-based product distributed by Regenative Labs is identified by its own unique serial number. The product is packaged in a transport protective pouch. The product is contained in a dual package tissue container system, in which the outermost ploy-foil pouch contains a product label that includes the product details such as unique product number, storage requirements and size. Contents are aseptically processed and sterilized, and are considered sterile.

There is a lack of evidence regarding the effectiveness of the Amniotext patch.

Amniotic Fluid Injection (e.g., Amniofix)

Amniofix (MiMedx Group, Inc.) is a solubilized amniotic membrane for the purpose of growth factors. Amniotic fluid contains fibrinolytic agents, and there is evidence from animal models of the potential for amniotic fluid injection for corneal wound healing and for prevention of adhesion formation following orthopedic surgery.  However, there is insufficient evidence (from human studies) to support the use of amniotic fluid injection for these indications. A controlled study is currently ongoing to evaluate the clinical effectiveness of AmnioFix in the reduction of the tenacity and frequency of soft tissue adhesions during the removal of segmental posterior lumbar instrumentation. In addition, a randomized controlled study of Amniofix in the treatment of recalcitrant plantar fasciitis is currently ongoing.

Amnio Wound

Amnio Wound is a lyophilized human amniotic membrane allograft comprised of an epithelial layer and 2 fibrous connective tissue layers specifically processed to be used for the repair and replacement of lost or damaged dermal tissue (CMS, 2017).  Amnio Wound is intended for use in the following conditions: neuropathic ulcers, venous stasis ulcers, post-traumatic wounds, pre-and post-surgical wounds and pressure ulcers, diabetic wounds, burn wounds, scar tissue, scarring, adhesion barrier.  The graft is administered by placing the stromal side onto the external wound area followed by the clinician's standard closing procedures.  It is stored at ambient temperature.  There is a lack of evidence regarding the effectiveness of Amnio Wound allograft.

AmnioWrap2

According to RegenTX Partners, LLC., AmnioWrap2 is an amniotic/chorionic tissue allograft intended for the treatment of wounds, including lower extremity ulceration caused by diabetes, chronic venous disease, and other chronic conditions (CMS, 2019). Acute wounds involving the dermal tissue layer may be appropriate for treatment with AnmioWrap2. AmnioWrap2 is provided dry in a double foil sterile pouch. It is available in various sizes, from 1 x 1 cm to 10 x 12 cm.

Amniply

Amniply (International Tissue Inc.) is an amniotic membrane graft. It comes in both a single and dual layer option. Amniply is a collagenous membrane derived from the submucosa of the placenta. The product serves multiple functions. It can be used in surgical procedures such as tendon repairs and spinal fusions. It can also be utilized as a wound covering for chronic, non-healing wounds such as diabetic foot ulcers, venous leg ulcer, and pressure ulcers. The graft is either placed into the wound bed or to the affected area. It is then covered using the physician’s choice of a dressing to keep the graft in place. There are numerous sizes of Amniply. The provider should always use the size that most closely matches the defect or wound. Each graft is individually packaged and can be stored in ambient temperature. Refrigeration is not required.

AmnyoFluid

AmnyoFluid is a natural amniotic fluid product acquired through fluid donation at the time of a normal full-term cesarean section. All donors are screened and tested to meet FDA standards for tissue donations.  The amniotic fluid is filtered and a cryo-preservative agent is added to stabilize fluid for safe storage and use.

Riboh et al (2016) stated that AM-derived products have been successfully used in ophthalmology, plastic surgery, and wound care, but little is known about their potential applications in orthopedic sports medicine.  These researchers provided an updated review of the basic science and pre-clinical and clinical data supporting the use of AM-derived products and reviewed their current applications in sports medicine.  A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases.  The search term amniotic membrane was used alone and in conjunction with stem cell, orthopedic, tissue engineering, scaffold, and sports medicine.  The search identified 6,870 articles, 80 of which, after screening of the titles and abstracts, were considered relevant to this study; 55 articles described the anatomy, basic science, and non-orthopedic applications of AM-derived products; 25 articles described pre-clinical and clinical trials of AM-derived products for orthopedic sports medicine.  Because the level of evidence obtained from this search was not adequate for systematic review or meta-analysis, a current concepts review on the anatomy, physiology, and clinical uses of AM-derived products was presented.  The authors concluded that AM have many promising applications in sports medicine.  They are a source of pluripotent cells, highly organized collagen, anti-fibrotic and anti-inflammatory cytokines, immuno-modulators, and matrix proteins.  These properties may make it beneficial when applied as tissue engineering scaffolds, improving tissue organization in healing, and treatment of the arthritic joint.  The current body of evidence in sports medicine is heavily biased on in-vitro and animal studies, with little to no human clinical data.  Nonetheless, 14 companies or distributors offer commercial AM products.  The preparation and formulation of these products alter their biological and mechanical properties, and a thorough understanding of these differences will help guide the use of AM-derived products in sports medicine research.

Muttini et al (2018) reported a study of amniotic epithelial cells, which form the innermost layer of the AM.  These cells can be easily isolated and display peculiar and unique properties, such as plasticity and differentiation potential toward the 3 germinal layers, that may aid regeneration and/or repair of damaged or diseased tissues and organs.  A robust literature based on in-vitro, experimental, and clinical studies in large animals demonstrated that these cells can enhance the regeneration of tendons, bone, and articular cartilage.  The  authors stated that on the basis of these considerations, allo-transplantation of human amniotic epithelial cells could be proposed for clinical trials in human orthopedic conditions.

Sultan et al (2018) evaluated the use of placental and amniotic tissue-based products as an adjuvant treatment to the operative management of orthopedic sports injuries.  A comprehensive literature search was performed on PubMed, EBSCO Host, Embase, and SCOPUS.  Studies published between January 1, 2000 and June 1, 2018 were reviewed.  Inclusion criteria were that studies should have reported on:
  1. operative uses of placental tissue matrix therapy in tendons and ligaments injuries;
  2. clinical outcomes; and
  3. human subjects.  

In addition, the following studies were excluded:

  1. animal studies;
  2. basic science studies;
  3. non-English language studies;
  4. review studies; and
  5. duplicate studies across databases.  

Additionally, to determine the various product compositions and indications for use, these investigators searched publicly available manufacturer's website content, marketing literature, FDA registration documents, and Center for Medicare and Medicaid Services (CMS) submissions to assess the key differences for each of the products.  Current evidence has led to investigation of various placental and AM products used as an adjuvant treatment to surgical reconstruction of various types of tendon injuries, with a demonstrated effectiveness found mostly in the short-term, with follow-up ranging between 5 weeks and 2 years.  In addition, their safety and minimal complication profile have been demonstrated.  Marked differences exist among the currently available products due to variations in their formulations, tissue source, processing methodology, sterilization method, preservation and storage methods, indications for use, and FDA regulation.  The authors concluded that operative uses of placental and AM-derived tissues appeared to be safe when utilized as an adjuvant or augmentation option along with surgical reconstruction.  However, several factors may come into play when considering the diversity of commercially available products.  These researchers stated that future clinical trials are needed to confirm the safety and demonstrate clearer indications and specific guidelines for use in each clinical scenario involving operative management of tendon injuries.

Duerr et al (2019) stated that in orthopedic sports medicine, amniotic-derived products have demonstrated promising pre-clinical and early clinical results for the treatment of tendon/ligament injuries, cartilage defects, and OA.  The AM is a metabolically active tissue that has demonstrated anti-inflammatory, antimicrobial, anti-fibrotic, and epithelialization-promoting features that make it uniquely suited for several clinical applications.  The authors stated that although the existing clinical literature is limited, there are several ongoing clinical trials aiming to elucidate the specific applications and benefits of these products.

Hannon et al (2019) noted that the use of intra-articular therapies as sources of growth factors, anti-inflammatory mediators, and medicinal signaling cells for osteo-arthritis (OA) is rapidly evolving.  Amnion, chorion, amniotic fluid, and the umbilical cord are distinct placental tissues that have been investigated for use in OA.  Amniotic membrane (AM) synthesizes a variety of growth factors, cytokines, and vasoactive peptides that modulate inflammation.  In addition, they contain amniotic epithelial cells and amniotic mononuclear undifferentiated stromal cells, which have chondrogenic and osteogenic differentiation capacity.  AMs are also rich sources of hyaluronic acid and proteoglycans, which could play a role in the potential therapeutic relief of OA.  Currently, there are several commercially available formulations of AM that differ based on content as well as how they were preserved.  Understanding the processing of amniotic tissue is important because of their distinct mechanical and biologic effects of preservation on AM grafts.  To-date, there have been 2 pre-clinical and only 1 clinical study on the use of AM for OA, which showed promising results.  The authors concluded that many high level of evidence clinical trials are currently underway investigating the use of AM of OA.  They stated that future basic science and clinical research is needed to better understand the anti-inflammatory and chondro-regenerative properties of amniotic tissue and to determine clinically what amniotic tissue product is most effective for symptomatic OA.

Apis

Apis received Food and Drug Administration (FDA) 510(k) clearance as a skin and soft-tissue skin substitute medical device. Apis consists primarily of gelatin, a porcine collagen derivative, in addition to Manuka honey and hydroxyapatite. It is fully absorbable and biodegradable and indicated in the management of wounds, including: full and partial thickness wounds, pressure ulcers (stages I-IV), venous stasis ulcers, diabetic ulcers, abrasions, surface wounds, traumatic wounds (healing by secondary intention), donor site wounds, and surgical wounds.

Apligraf (Graftskin)

In recent years, skin grafting has evolved from the initial autograft and allograft preparations to biosynthetic and tissue-engineered human skin equivalents (HSE).  Apligraf (graftskin) (Organogenesis, Canton, MA), also referred to human skin equivalent, is a living, cell-based, bilayered skin construct.  Like human skin, Apligraf has 2 primary layers, including an outer, epidermal layer made of living human keratinocytes, the most common cell type of the human epidermis, to replicate the structure of the human epidermis.  The human  keratinocytes and fibrobasts are derived from neonatal forsekins. The dermal layer of Apligraf consists of living human fibroblasts and bovine type 1 collagen, the most common cell type in the human dermis, to create a dermis-like structure that produces additional matrix proteins. Proponents state that Apligraf stimulates the patient's own cells to regenerate tissue and heal the wound through mechanisms that include the secretion of growth factors, cytokines, and matrix proteins (Snyder, et al., 2012). Apligraf does not contain melanocytes, Landgerhans' cells, macrophages, lymphocytes, or tissue structures such as blood vessels, hair follicles, and sweat glands.  

Apligraf has has received a premarket approval (PMA) by the U.S. Food and Drug Administration (FDA) in 1998 for treatment of venous leg ulcers and in 2001 for treatment of diabetic ulcers.  Apligraft has been approved for marketing under a premarket approval for "use with standard therapeutic compression for the treatment of noninfected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1 month duration and which have not adequately responded to conventional ulcer therapy." Multiple supplemental approvals have been added since the first approval, including an indication for treating diabetic foot ulcers. Several of the supplements involve approval of the use of new human keratinocyte or fibroblast cell strains in the manufacture of Apligraf (Snyder, et al., 2012). Venous ulceration, a relatively common manifestation of venous hypertension, is often refractory to conservative treatment and difficult to treat.  Human skin equivalents appeared to promote wound healing in 3 ways:
  1. apparent graft "take";
  2. temporary wound closure (persistence of HSE with subsequent wound re-epithelialization from wound margins); and
  3. stimulation of host healing without temporary persistence by acting as a biologic dressing.

Rice et al (2015) used Medicare claims data to assess the real-world medical services utilization and associated costs of Medicare patients with diabetic foot ulcers (DFUs) treated with Apligraf or Dermagraft (human fibroblast-derived dermal substitute (HFDS)) compared with those receiving conventional care (CC). DFU patients were selected from Medicare de-identified administrative claims using ICD-9-CM codes. The analysis followed an 'intent-to-treat' design, with cohorts assigned based on use of (1) BLCC, (2) HFDS, or (3) CC (i.e., ≥1 claim for a DFU-related treatment procedure or podiatrist visit and no evidence of skin substitute use) for treatment of DFU in 2006-2012. Propensity score models were used to separately match BLCC and HFDS patients to CC patients with similar baseline demographics, wound severity, and physician experience measures. Medical resource use, lower-limb amputation rates, and total healthcare costs (2012 USD; from payer perspective) during the 18 months following treatment initiation were compared among the resulting matched samples. Data for 502 matched BLCC-CC patient pairs and 222 matched HFDS-CC patient pairs were analyzed. Increased costs associated with outpatient service utilization relative to matched CC patients were offset by lower amputation rates (-27.6% BLCC, -22.2% HFDS), fewer days hospitalized (-33.3% BLCC, -42.4% HFDS), and fewer emergency department visits (-32.3% BLCC, -25.7% HFDS) among BLCC/HFDS patients. Consequently, BLCC and HFDS patients had per-patient average healthcare costs during the 18-month follow-up period that were lower than their respective matched CC counterparts (-$5253 BLCC, -$6991 HFDS). This study is limited by the fact that it is based upon administrative claims data. The authors stated that its findings relied on accuracy of diagnosis and procedure codes contained in the claims data, and did not account for outcomes and costs beyond 18 months after treatment initiation.

Apligraf was shown in clinical trials to heal even longstanding (greater than 1 year's duration) venous leg ulcers more effectively and faster than compression therapy alone.  The results of controlled, multi-center studies indicate that HSE interacts with the patient's own cells, responds to individual wound characteristics, and promotes healing.  Further studies are underway to investigate its use for the treatment of pressure sores, dermatological surgery wounds and burns.  At this time, there is insufficient information to extend coverage for the use of Apligraf in the treatment of these conditions.

Architect ECM and Architect PX

Architect Extracellular Matrix (ECM) is a medical device comprised almost entirely of type I collagen that has been stabilized and sterilized for ease of use and enhance durability as a wound dressing. It is made from equine pericardium and utilized a patented collagen stabilizing technology called "BriDGE" that supports rapid healing by: not promoting an inflammatory response; serving as a temporary matrix that provides a platform for cell migration; helping to optimize the wound-healing environment; and facilitating cellular activity. The manufacturers of Architect state that it is "the only equine pericardium sourced ECM wound dressing available on the US market since the withdrawal of Synovis’ Unite Biomatrix in June, 2012." It is used for partial or full-thickness wounds such as diabetic foot ulcers, second-degree burns and venous leg ulcers.

Architect PX is a partially stabilized extracellular matrix (ECM) comprised of equine pericardium that is indicated for the local management of moderately to heavy exuding wounds (CMS, 2014). By partially stabilizing its equine pericardium ECM, Architect PX can maintain its natural ECM tissue regeneration properties longer on the wound. The manufacturer claims that "this "partially" stabilized extracellular matrix more quickly adheres to the wound bed than Architect, thereby fitting more closely into established wound care protocol". Products that adhere more slowly may require more provider training to achieve optimal results. Architect PX can limit the inflammatory response, thereby enabling the ECM components to support tissue regeneration longer during the healing process. Architect PX is also engineered to provide structural and functional proteins which can stimulate and support tissue regeneration for a longer duration than non-stabilized products.

Artacent

According to the manufacturer Tides Medical, Artacent Wound is a dual-layer human amniotic membrane graft used for acute and chronic wound applications (CMS, 2019). It is derived from the submucosa of donated human placenta. It consists of collagen layers, including basement membrane and stromal matrix. Its dual layer and bilateral application improves handling, while its unique design permits easy manipulation and placement onto the wound bed. The manufacturer claims that Artacent Wound contains essential growth factors "shown to stimulate wound healing". Artacent Wound is "intended for treatment of acute and chronic wounds such as diabetic ulcers, venous stasis ulcers, burns, and additional wounds that are refractory to more conservative care." Artacent Wound is applied to the wound bed following wound preparation. Absorbable/non-absorbable suture material and/or tissue adhesives may be used to apply the graft to the site, if necessary. Artacent Artacent Wound is supplied in the following sizes: 1 cm x 1 cm, 2 cm x 2 cm, 2 cm x 3 cm, 4 cm x 4 cm, 4 cm x 6 cm, 4 cm x 8 cm, 10 mm disk, and 16 mm disk.

Artacent Cord

According to Tides Medical, Artacent Cord human umbilical cord is "a wound healing patch that is comprised of the umbilical cord." "It is intended for the treatment of acute and chronic wounds such as diabetic ulcers, venous stasis ulcers, burns, and additional wounds that are refractory to more conservative care." Artacent Cord is applied to the wound bed following wound preparation. Absorbable/non-absorbable suture material and /or tissue adhesives may be used to apply the graft to the site, if necessary. Once applied the allograft can hydrated with sterile saline or other sterile solution, if needed.

Artelon

Artelon (poly[urethane urea] elastomer) is a degradable biomaterial that serves as a scaffold for tissue ingrowth and provides temporary support for healing tissue.  Gisselfält et al (2002) described the synthesis, wet spinning, mechanical testing, and degradation of poly(urethane urea)s (PUURs) intended for clinical use in anterior cruciate ligament (ACL) reconstruction.  The effects of soft segment chemical composition and molar mass and the kind of diamine chain extender on the material properties were investigated.  It was found that the fibers made of PUUR with polycaprolactone diol (PCL530) as soft segment and MDI/1,3-DAP as hard segment (PCL530-3) have high tensile strength and high modulus and when degraded keep their tensile strength for the time demanded for the application.  The authors concluded that from a chemical and mechanical point of view PUUR fibers of PCL530-3, Artelon, are suitable for designing a degradable ACL device.

Nilsson et al (2005) stated that a new spacer for the trapezio-metacarpal joint (TMC) based on a biological and tissue-preserving concept for the treatment of TMC osteoarthritis (OA) has been evaluated.  The purpose was to combine a spacing effect with stabilization of the TMC joint.  Artelon (Artimplant AB, Sweden) TMC Spacer is synthesized of a degradable polyurethaneurea (Artelon), which has been shown to be biocompatible over time and currently is used in ligament augmentation procedures.  Fibers of the polymer were woven into a T-shaped device in which the vertical portion separates the bone edges of the TMC joint and the horizontal portion stabilizes the joint.  A total of 15 patients with disabling pain and isolated TMC OA were included in the study; 10 patients received the spacer device and the remaining 5 (control group) were treated with a trapezium resection arthroplasty with abductor pollicis longus (APL) stabilization.  The median ages of the 2 groups were 60 and 59 years, respectively.  Pain, strength, stability, and range of motion were measured before and after surgery.  Radiographical examination was performed in all patients before and after surgery.  At follow-up evaluation 3 years after surgery, an unbiased observer evaluated all patients.  Biopsy specimens were obtained from 1 patient 6 months after surgery.  All patients were stable clinically without signs of synovitis.  In both groups all patients were pain-free.  The median values for both key pinch and tripod pinch increased compared with before surgery in the spacer group but not in the APL group.  The biopsy examinations showed incorporation of the device in the surface of the adjacent bone and the surrounding connective tissue.  No signs of foreign-body reaction were seen.  The authors concluded that the findings in this study showed significantly better pinch strength after Artelon TMC Spacer implantation into the TMC joint compared with APL arthroplasty.  This was a small retrospective study; its findings need to be validated.

Huss et al (2008) stated that full thickness skin wounds in humans heal with scars, but without regeneration of the dermis.  A degradable PUUR, Artelon is already used to reinforce soft tissues in orthopedics, and for the treatment of osteoarthritis of the hand, wrist, and foot.  These researchers performed in vitro experiments followed by in vivo studies to examine if the PUUR is biocompatible and usable as a template for dermal regeneration.  Human dermal fibroblasts were cultured on discs of PUUR, with different macrostructures (fibrous and porous).  They adhered to and migrated into the scaffolds, and produced collagen.  The porous scaffold was judged more suitable for clinical applications and 4 mm Artelon, 2 mm-thick discs of porous scaffold (12 % w/w or 9 % w/w polymer solution) were inserted intradermally in 4 healthy human volunteers.  The implants were well-tolerated and increasing ingrowth of fibroblasts was seen over time in all subjects.  The fibroblasts stained immunohistochemically for procollagen and von Willebrand factor, indicating neocollagenesis and angiogenesis within the scaffolds.  The authors concluded that PURR scaffold may be a suitable material to use as a template for dermal regeneration. 

Wojan et al (2015) conducted a Cochrane review to assess the effects of different surgical techniques, including Artelon joint resurfacing, for trapeziometacarpal (thumb) osteoarthritis. The authors searched the following sources up to August 2013: CENTRAL (The Cochrane Library 2013, Issue 8), MEDLINE (1950 to August 2013), EMBASE (1974 to August 2013), CINAHL (1982 to August 2013), Clinicaltrials.gov (to August 2013) and World Health Organization (WHO) Clinical Trials Portal (to August 2013). The authors selected randomized controlled trials (RCTs) or quasi-RCTs where the intervention was surgery for people with thumb osteoarthritis. Outcomes were pain, physical function, quality of life, patient global assessment, adverse events, treatment failure or trapeziometacarpal joint imaging. We excluded trials that compared non-surgical interventions with surgery. The authors used standard methodological procedures expected by the Cochrane Collaboration. Two review authors independently screened and included studies according to the inclusion criteria, assessed the risk of bias and extracted data, including adverse events. The authors included 11 studies with 670 participants. Seven surgical procedures were identified (Artelon joint resurfacing, trapeziectomy with ligament reconstruction and tendon interposition (LRTI), trapeziectomy, trapeziectomy with ligament reconstruction, trapeziectomy with interpositional arthroplasty (IA), arthrodesis and Swanson joint replacement). Most included studies had an unclear risk of most biases which raises doubt about the results. No procedure demonstrated any superiority over another in terms of pain, physical function, quality of life, patient global assessment, adverse events, treatment failure (re-operation) or trapeziometacarpal joint imaging. One study demonstrated a difference in adverse events (mild-moderate swelling) between Artelon joint replacement and trapeziectomy with tendon interposition. However, the quality of evidence was very low due to a high risk of bias and imprecision of results. Low quality evidence suggests trapeziectomy with LRTI may not provide additional benefits or result in more adverse events over trapeziectomy alone. Mean pain (three studies, 162 participants) was 26 mm on a 0 to 100 mm VAS (0 is no pain) for trapeziectomy alone, trapeziectomy with LRTI reduced pain by a mean of 2.8 mm (95% confidence interval (CI) -9.8 to 4.2) or an absolute reduction of 3% (-10% to 4%). Mean physical function (three studies, 211 participants) was 31.1 points on a 0 to 100 point scale (0 is best physical function, or no disability) with trapeziectomy alone, trapeziectomy with LRTI resulted in sightly lower function scores (standardized mean difference 0.1, 95% CI -0.30 to 0.32), an equivalent to a worsening of 0.2 points (95% CI -5.8 to 6.1) on a 0 to 100 point scale (absolute decrease in function 0.03% (-0.83% to 0.88%)). Low quality evidence from four studies (328 participants) indicates that the mean number of adverse events was 10 per 100 participants for trapeziectomy alone, and 19 events per 100 participants for trapeziectomy with LRTI (RR 1.89, 95% CI 0.96 to 3.73) or an absolute risk increase of 9% (95% CI 0% to 28%). Low quality evidence from one study (42 participants) indicates that the mean scapho-metacarpal distance was 2.3 mm for the trapeziectomy alone group, trapeziectomy with LRTI resulted in a mean of 0.1 mm less distance (95% CI -0.81 to 0.61). None of the included trials reported global assessment, quality of life, and revision or re-operation rates. Low-quality evidence from two small studies (51 participants) indicated that trapeziectomy with LRTI may not improve function or slow joint degeneration, or produce additional adverse events over trapeziectomy and ligament reconstruction. The authors stated that they are uncertain of the benefits or harms of other surgical techniques due to the mostly low quality evidence from single studies and the low reporting rates of key outcomes. There was insufficient evidence to assess if trapeziectomy with LRTI had additional benefit over arthrodesis or trapeziectomy with IA. There was also insufficient evidence to assess if trapeziectomy with IA had any additional benefit over the Artelon joint implant, the Swanson joint replacement or trapeziectomy alone. The authors did not find any studies that compared any other combination of the other techniques mentioned above or any other techniques including a sham procedure. The authors concluded that they did not identify any studies that compared surgery to sham surgery and they excluded studies that compared surgery to non-operative treatments. They were unable to demonstrate that any technique confers a benefit over another technique in terms of pain and physical function. Furthermore, the included studies were not of high enough quality to provide conclusive evidence that the compared techniques provided equivalent outcomes.

Currently, there is insufficient evidence to support the use of Artelon for ACL reconstruction, rotator cuff repair, TMC osteoarthritis, and other indications.

Arthroflex 

According to the manufacturer, ArthroFlex (FlexGraft) is a unique decellularized human skin allograft product indicated for the treatment of chronic wounds, such as diabetic foot ulcers and large surgical wounds. Arthroflex contains both collagen and elastin which provide structural support for resilience, a compliment of growth factors to assist healing, as well as multiple cytokines that assist in epithelialization and modulate the proliferation and differentiation of epithelium, and finally fully developed extracellular matrix which allows for infiltration of recipient cells. The extracellular matrix stimulates epithelialization from the wound periphery and from remnant epidermal appendages when placed in contact with the wound. The manufacturer states that Arthroflex provides a physiological barrier that decreases water loss, electrolytes, proteins and heat from the wound bed and creates a mechanical barrier that reduces environmental microbiological contamination. Arthroflex is applied directly to the wound or ulcer and secured to the site in one of several ways, including the use of sutures, staples, or skin adhesive strips. It is currently provided with a thickness of 1.26 mm to 1.75 mm and two scaffold sizes: 35 mm x 35 mm and 40 mm x 70 mm. The manufacturer states that they are likely to provide additional product sizes and thicknesses in the future. Arthroflex decellularized dermis patch has also been used in Achilles tendon repair and shoulder reconstruciton. Available peer-reviewed published medical literature on Arthroflex has focused on its biomechanical properties (Ehsan et al, 2012; Beitzel et al, 2012).

Mihata et al (2013) examined the clinical outcome and radiographic findings after arthroscopic superior capsule reconstruction (ASCR) for symptomatic irreparable rotator cuff tears.  From 2007 to 2009, a total of 24 shoulders in 23 consecutive patients (mean age of 65.1 years) with irreparable rotator cuff tears (11 large, 13 massive) underwent ASCR using fascia lata (FL).  These researchers used suture anchors to attach the graft medially to the glenoid superior tubercle and laterally to the greater tuberosity.  They added side-to-side sutures between the graft and infraspinatus tendon and between the graft and residual anterior supraspinatus/subscapularis tendon to improve force coupling.  Physical examination, radiography, and magnetic resonance imaging (MRI) were performed before surgery; at 3, 6, and 12 months after surgery; and yearly thereafter.  Average follow-up was 34.1 months (24 to 51 months) after surgery.  Mean active elevation increased significantly from 84° to 148° (p < 0.001) and external rotation increased from 26° to 40° (p < 0.01).  Acromio-humeral distance (AHD) increased from 4.6 ± 2.2 mm pre-operatively to 8.7 ± 2.6 mm post-operatively (p < 0.0001).  There were no cases of progression of osteoarthritis (OA) or rotator cuff muscle atrophy; 20 patients (83.3 %) had no graft tear or tendon re-tear during follow-up (24 to 51 months).  The American Shoulder and Elbow Surgeons (ASES) score improved from 23.5 to 92.9 points (p < 0.0001).  The authors concluded that ASCR restored superior gleno-humeral stability and function of the shoulder joint with irreparable rotator cuff tears.  These researchers stated that these findings suggested that this reconstruction technique was a reliable and useful alternative treatment for irreparable rotator cuff tears.  Level of Evidence = IV.

Tokish and Beicker (2015) noted that chronic, massive, irreparable rotator cuff tears remain one of the most challenging pathologies in shoulder surgery to treat.  Because of this, many treatment options exist for the management of chronic retracted rotator cuff tears; and SCR is one option that provides the potential to restore and rebalance the force couples necessary for dynamic shoulder function.  These investigators described an all-arthroscopic technique using an acellular dermal allograft for SCR indicated for patients with a deficient superior rotator cuff.  This technique provided an option for patients with an irreparable rotator cuff tear without compromising future therapeutic options.  The authors concluded that although this is a relatively new and unproven method for treating chronic irreparable rotator cuff tears, their short-term results were promising.  Nevertheless, these researchers stated that larger studies with long-term follow-up are needed to fully evaluate the success of this technique.

In a prospective, blinded, non-randomized, single-center, study, Gilot and colleagues (2015) compared the results of arthroscopic repair of large to massive rotator cuff tears (RCTs) with or without augmentation using an extracellular matrix (ECM) graft and to present ECM graft augmentation as a valuable surgical alternative used for biomechanical reinforcement in any RCT repair.  Subjects included patients who underwent arthroscopic repair of a large to massive RCT with or without augmentation with ECM graft.  The primary outcome was assessed by the presence or absence of a re-tear of the previously repaired rotator cuff, as noted on ultrasound examination.  The secondary outcomes were patient satisfaction evaluated pre-operatively and post-operatively using the 12-item Short Form Health Survey, the American Shoulder and Elbow Surgeons shoulder outcome score, a VAS score, the Western Ontario Rotator Cuff index, and a shoulder activity level survey.  These researchers enrolled 35 patients in the study: 20 in the ECM-augmented rotator cuff repair group and 15 in the control group.  The follow-up period ranged from 22 to 26 months, with a mean of 24.9 months.  There was a significant difference between the groups in terms of the incidence of re-tears: 26 % (4 re-tears) in the control group and 10 % (2 re-tears) in the ECM graft group (p = 0.0483).  The mean pain level decreased from 6.9 to 4.1 in the control group and from 6.8 to 0.9 in the ECM graft group (p = 0.024).  The American Shoulder and Elbow Surgeons score improved from 62.1 to 72.6 points in the control group and from 63.8 to 88.9 points (p = 0.02) in the treatment group.  The mean Short Form 12 scores improved in the 2 groups, with a statistically significant difference favoring graft augmentation (p = 0.031), and correspondingly, the Western Ontario Rotator Cuff index scores improved in both arms, favoring the treatment group (p = 0.0412).  The authors concluded that the use of ECM for augmentation of arthroscopic repairs of large to massive RCTs reduced the incidence of re-tears, improves patient outcome scores, and is a viable option during complicated cases in which a significant failure rate was anticipated.  Level of Evidence = III.  This study had several drawbacks.  One such limitation was the study design; this was not a randomized study and included only 1 facility and 1 surgeon.  Moreover, these researchers did not comment on pre-operative MRI findings of fatty infiltration or atrophy.  Finally, surgically, a non-controlled graft size could also be viewed as a limitation.

Morris and colleagues (2018) noted that massive cuff tears can prove especially challenging to treat.  Although these types of tears are often considered inoperable, augmented repair using an acellular dermal matrix may improve success rates.  One acellular dermal matrix, AF-ADM, has shown encouraging results in an earlier case series which prompted this prospective study in an older population.  After screening and evaluation for repair using traditional arthroscopic techniques, a total of 13 subjects with irreparable rotator cuff tears underwent a mini-open approach with AF-ADM augmentation.  An MRI was performed for each subject preoperatively, at 3 months post-operative, and at 12 months post-operative.  Clinical outcomes were assessed at 3 months, 12 months, and 24 months post-operative using the Constant-Murley Shoulder Scoring Scale, the Modified ASES, and patient satisfaction scores.  At 24 months follow-up, subjects demonstrated a significant 32.3 (64.4 %) mean improvement in the Constant-Murley score (p = 0.0001), a significant 32.5 (60.4 %) mean improvement in the ASES score (p = 0.0009), and a significant 31.8 mean in VAS (p = 0.0011) with scores of 82.5, 86.3, and 7.4, respectively.  Patient satisfaction was high at 24 months with a reported mean score of 3.4 and a median of 4.0 (out of 4).  There were no complications related to graft use.  Only 2 subjects exhibited radiographic graft failures with MRIs revealing tears in the native tissue but fully intact graft material.  However, these subjects also showed excellent clinical outcome scores.  The authors concluded that the assessments and patient satisfaction scores indicated that significant improvements can be achieved as early as 3 months with AF-ADM augmentation, despite the severity of these tears and age of the patients.  The high success rate was especially notable as the subject group was older patients, who may have greater difficulty healing.  The results presented here showed that AF-ADM can be used successfully to treat massive and recurrent rotator cuff tears.

The authors stated that one limitation of this study was the lack of a control group.  Given the abundance of historical data from other studies using older or alternative techniques, these researchers felt that the documented radiographic and functional outcomes scores could be used by clinicians for comparison.  Another limitation was the small subject population (n = 13).  However, this study does have the strength of a prospective study, and the subject population was similar enough to that of other studies to be comparable, yet different enough to add to the literature.  Finally, in support of transparency, some authors were affiliated with LifeNet Health, the non-profit organization that processes AF-ADM.  However, potential bias was minimized by permitting only the clinician investigators to decide whether augmentation was necessary as well as to determine if repairs were successful.

In a multi-center study, Denard et al (2018) evaluated the short-term outcomes of arthroscopic SCR with dermal allograft for the treatment of irreparable massive rotator cuff tears (MRCTs).  This trial was performed on patients undergoing arthroscopic SCR for irreparable MRCTs.  The minimum follow-up was 1 year.  Range of motion (ROM) and functional outcome according to VAS pain, ASES score, and subjective shoulder value (SSV) score were assessed pre-operatively and at final follow-up.  Radiographs were used to evaluate the acromio-humeral interval (AHI).  A total of 59 patients with a mean age of 62.0 years had a minimum follow-up of 1 year; 25 patients (42.4 %) had a prior rotator cuff repair.  Forward flexion improved from 130° pre-operative to 158° post-operative, and external rotation improved from 36° to 45°, respectively (p < 0.001).  Compared with pre-operative values, the VAS decreased from 5.8 to 1.7, the ASES score improved from 43.6 to 77.5, and the SSV score improved from 35.0 to 76.3 (p < 0.001).  The AHI was 6.6 mm at baseline and improved to 7.6 mm at 2 weeks post-operatively but decreased to 6.7 mm at final follow-up.  Based on post-operative magnetic resonance imaging, 45 % (9 of 20) of the grafts demonstrated complete healing; 46 (74.6 %) cases were considered a success; 11 patients (18.6 %) underwent a revision procedure including 7 reverse shoulder arthroplasties.  The authors concluded that arthroscopic SCR using dermal allograft provided a successful outcome in about 70 % of cases in an initial experience.  These researchers stated that these preliminary results were encouraging in this difficult to manage patient population, but precise indications are important and graft healing is low in their initial experience.  Level of Evidence =  IV.

Pennington et al (2018) presented the concept of superior capsular distance to quantitatively measure the decreased distance present upon restoration of superior capsular integrity.  These investigators carried out a retrospective review of patients treated with arthroscopic SCR with a minimum 12-month follow-up.  Outcome analysis was performed via an internet-based outcome-tracking system to evaluate VAS and ASES scores.  Radiographic analysis of antero-posterior radiographs analyzed AHI and superior capsular distance.  Digital dynamometric strength and functional ROM assessments were also obtained.  The main inclusion criteria for patients in this analysis was all patients who underwent SCR during the time period of this report.  A total of 86 patients with an average age of 59.4 years presented with massive rotator cuff tears (Cofield greater than 5 cm).  Outcome data revealed improvement in VAS (4.0 to 1.5), and ASES (52 to 82) scores at 1 year (p = 0.005).  Radiographic analysis showed increase in AHI (mean 7.1 mm pre-operatively to mean 9.7 mm at 1 year) (p = 0.049) and superior capsular distance (mean 52.9 mm pre-operatively to mean 46.2 mm at 1 year) (p = 0.011).  Strength improved significantly (forward flexion/abduction/external rotation of 4.8/4.1/7.7 lb pre-operatively to 9.8/9.2/12.3 lb at 1 year) as well as ROM (forward flexion/abduction of 120°/103° pre-operatively to 160°/159° at 1 year) (p = 0.044/p = 0.007/p = 0.02).  At follow-up, 90 % of patients were satisfied.  The authors concluded that this analysis revealed that arthroscopic SCR with acellular dermal allograft has been successful in decreasing pain and improving function in this patient subset.  Radiographic analysis has also shown a consistent and lasting decrease in superior capsular distance and increase in AHI, indicating maintenance of superior capsular stability.  Level of Evidence = IV.

Dimock et al (2019) stated that the short-term clinical results of SCR are promising, however, there is need for further long-term studies, as well as randomized controlled trials (RCTs) comparing SCR to other treatment modalities for irreparable rotator cuff tears.  These researchers stated that further imaging studies looking at graft healing rates are also needed as the healing rates published so far are variable.  Additionally, the mechanism of action by which SCR delivered good short-term functional outcomes needs further clarification, as does the importance of the choice of graft type and thickness.

Zastrow et al (2019) stated that preliminary results of SCR showed consistent improvement in shoulder functionality and pain reduction.  However, a decrease in post-operative AHIs indicated dermal allograft elongation and persistent superior migration of the humerus, potentially contributing to later graft failure.  The authors stated that studies with longer follow-up are needed to evaluate the long-term utility of SCR in the treatment of irreparable rotator cuff tears.

Makovicka et al (2020) stated that SCR is emerging as a viable surgical option to address the irreparable rotator cuff tear.  Biomechanical studies suggested that the humeral head-stabilizing effect of SCR appeared to translate into improved clinical outcomes.  The authors stated that future research should focus on further defining the indications, limitations, and optimal technique.

Artiss

Artiss (Baxter Healthcare Corp., Deerfield, IL), a slow-setting fibrin sealant consisting of human fibrinogen and low concentration human thrombin, received FDA approval in March, 2008 for use in attaching skin grafts onto burn patients without the use of staples or sutures.  Artiss sets in approximately 60 seconds as opposed to rapid-setting fibrin sealants, which set in 5 to 10 seconds.  This gives the physician additional time to position the skin graft over a burn before the graft starts to adhere to the skin.  The sealant is available in a pre-filled syringe (frozen) formulation and a lyophilized form.  Both dosage forms, once prepared and ready to use, can be sprayed, thus enabling application in a thin and even layer.

The FDA approved Artiss based on the results of a phase III study.  The multi-center, prospective, randomized, controlled study (Foster et al, 2008) compared the use of Artiss to staples in 138 burn patients requiring skin grafting.  Patients had burn wounds measuring less than or equal to 40 % of total body surface area with 2 comparable test sites measuring between 1 and 4 % total body surface area each.  Wound closure at day 28 was assessed using test site planimetry and review of day 28 photographs by 3 independent blinded evaluators (primary endpoint analysis).  Secondary efficacy measures included hematoma/seroma on day 1, engraftment on day 5, and wound closure on day 14.  Investigator and patient-reported outcomes were also assessed.  The proportion of test sites with complete wound closure at day 28 was 70.3 % in Artiss treated sites and 65.8 % in stapled sites, as assessed by planimetry.  Blinded review of day 28 photographs confirmed that the rate of complete wound closure was similar between the 2 treatments, although the overall assessed rates of closure were lower than those determined by planimetry: Artiss (43.3 %) and staples (37.0 %).  The lower limit of the 97.5 % CI of the difference between Artiss and staples was -0.029, which is above the pre-defined non-inferiority margin of -0.1.  Therefore, Artiss is at least as efficacious as staples at the 97.5 % 1-sided level for complete wound closure by day 28.  Hematoma/seroma on day 1 occurred at significantly (p < 0.0001) fewer Artiss-treated sites (29.7 % [95 % CI: 22.2 to 38.1 %]) compared with stapled sites (62.3 % [95 % CI: 53.7 to 70.4 %]).  Engraftment on day 5 was deemed to be 100 % in 62.3 % (95 % CI: 53.7 to 70.4 %) of the Artiss-treated sites and 55.1 % (95 % CI: 46.4 to 63.5 %) of the stapled sites (p = 0.0890).  Complete wound closure by day 14 occurred in 48.8 % (95 % CI: 39.9 to 57.8 %) of the Artiss-treated sites and 42.6 % (95 % CI: 34.0 to 51.6 %) of the stapled sites (p = 0.2299).  Artiss scored better than staples for all investigator-assessed outcomes (e.g., quality of graft adherence, preference for method of fixation, satisfaction with graft fixation, and overall quality of healing).  Likewise, Artiss scored significantly better than staples for all patient-assessed outcomes (e.g., anxiety about pain and treatment preference).  The safety profile of Artiss was excellent as indicated by the lack of any related serious adverse experiences.  The authors concluded that Artiss is safe and effective for attachment of skin grafts with outcomes at least as good as or better than staple fixation.

Ascent

Ascent (StimLabs, LLC.) is a dehydrated cell and protein concentrate (dCPC) injectable derived from human amniotic fluid. According to the manufacturer, Ascent combines a selected set of cells from amniotic fluid and their components, including TIMPs, growing factors, interleukins and hyaluronic acid. Through complex interactions, these components work together to provide protecting, cushioning, lubrication, and inflammation reduction at the site of injury. Ascent is intended for the treatment of non-healing wounds and burn injuries. Ascent is offered in 7.5 mg, 15 mg, and 30 mg powdered weight. The suggested reconstitution volumes are 0.5 cc, 1 cc, and 2 cc respectively giving a 0.75%, 1.5% and 3% dose. Ascent is reconstituted using sterile saline based on recommended reconstitution amounts.

Autologous Blood Derived Products: Autologous Platelet-Rich Plasma, Autologous Platelet Gel, and Autologous Platelet-Derived Growth Factors (e.g., Procuren)

Growth factors that are derived from platelets assist in the process of blood vessel formation (angiogenesis) and can be obtained either by using recombinant DNA technology or through centrifuged autologous blood. Autologous growth factors, including autologous platelet-derived growth factors (PDGF), autologous platelet concentrate (APC) and autologous platelet gel (APG), also known as platelet-rich plasma (PRP) or "buffy coat," are harvested from a patient’s own (autologous) blood. APC and APG are topically applied to wounds or systemically administered to purportedly accelerate healing and reduce complications of chronic nonhealing wounds that fail to respond to conventional methods of wound treatment or used as an adjunct (addition) to surgery to promote hemostasis and reduce wound complications. Examples of autologous blood derived products include, but may not be limited to: Autologel; Procuren; SafeBlood; and Vitagel.

Procuren is a platelet-derived growth factor suggested for use in the management of chronic non-healing wounds.  The Agency for Health Care Policy and Research's Clinical Practice Guideline Treatment of Pressure Ulcers concluded that the effectiveness of growth factors for this indication has not been sufficiently established to warrant recommendation for use.  In 1992, the Centers for Medicare and Medicaid Services (CMS) issued a national non-coverage determination for platelet-derived wound healing formulas intended to treat patients with chronic, non-healing wounds.  This decision was based on a lack of sufficient published data to determine safety and efficacy, and a Public Health Service technology assessment.  A CMS Decision Memorandum (2003) concluded that there is insufficient evidence of the effectiveness of autologous platelet rich plasma (PRP) or autologous platelet-derived growth factor (PDGF) in improving healing in chronic non-healing cutaneous wounds.  In a second reconsideration, CMS concluded there is insufficient evidence of effectiveness of autologous PRP for the treatment of chronic non-healing cutaneous wounds or for acute surgical wounds when the autologous PRP is applied directly to the closed incision or dehiscent wounds (CMS, 2007).

Avance Nerve Garaft

Avance Nerve Graft is a processed, decedecellularized nerve allograft, used as an alternative to nerve conduits for nerve repair procedures.

Avomentin

Ferguson et al (2009) assessed scar improvement with avotermin (recombinant, active, human TGFbeta3).  In 3 double-blind, placebo-controlled studies, intra-dermal avotermin (concentrations ranging from 0.25 to 500 ng/100 microL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 hrs later, in healthy men and women.  Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomization scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone.  Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in 2 studies, and from week 6 to month 7 after wounding in the 3rd.  Investigators, participants, and scar assessors were blinded to treatment.  Efficacy analyses were intention-to-treat.  In 2 studies, avotermin 50 ng/100 microL per linear cm significantly improved median score on a 100 mm visual analog scale (VAS) by 5 mm (range of -2 to 14; p = 0.001) at month 6 and 8 mm (-29 to 18; p = 0.0230) at month 12.  In the 3rd study, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI: 5.5 to 24.2] at 5 ng/100 microL per linear cm to 64.25 mm [49.4 to 79.1] at 500 ng/100 microL per linear cm).  Nine [60 %] scars treated with avotermin 50 ng/100 microL per linear cm showed 25 % or less abnormal orientation of collagen fibres in the reticular dermis versus 5 [33 %] placebo scars.  After only 6 weeks from wounding, avotermin 500 ng/100 microL per linear cm improved VAS score by 16.12 mm (95 % CI: 10.61 to 21.63).  Adverse events at wound sites were similar for avotermin and controls.  Erythema and edema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing.  The authors concluded that avotermin has potential to provide an accelerated and permanent improvement in scarring.

AxioBioMembrane

According to the manufacturer, AxoBioMembrane (Axoloti Biologix, Inc.) is indicated for full and partial-thickness, chronic, acute, wounds and hard to heal wounds (CMS, 2019). After preparation of the wound site, the human amnion allograft is surgically applied to the wound surface by the physician, extended beyond the wound margin and secured in place using the clinician's choice of fixation. AxoBioMembrane is available in 3 sizes; 1cm x 2cm, 2cm x 3cm, and 4cm x 4cm.

Axolotl Ambient and Axolotl Cryo

According to the manufacturer, Axoloti Biologix, INc., Axolotl Ambient and Axololt Cryo are intended for homologous use and to support the repair of soft tissue injury (CMS, 2019). The products are applied to the wound surface and/or injected into the wound margins. The products are available in 0.5 ml, 1 ml, and 2 ml dose sizes.

Axolotl Graft and Axolotl DualGraft

According to the manufacturer Axoloti Biologix, Inc., Axoloti Graft and Axoloti DualGraft are "human amniotic allograft, decellularized, dehydrated placental membrane used as a wound barrier, nerve wrap, and serves as a selective membrane to allow for the repair or regeneration of damaged or diseased tissues" (CMS, 2019). Axolotl DualGraft is a thicker version of the allograft for wound areas that are more vulnerable to damage. The product is available in four sizes; 1 x 2cm, 2 x 3cm, 4 x 4cm, and 4 x 6cm.

Barrera SL and Barrera DL

Barrera SL and Barrera DL are dehydrated amniotic membrane allograft. These allograft products are designed to act as a protective wound cover or barrier and function as a protective coverage from the surrounding environment in wounds, including surgically created wounds. Barrera SL and Barrera DL are supplied in a single layer or dual layer form, respectively, available in various sizes for single patient use topical application.as a per square centimeter dosage. Product packaging consists of an outer pouch and a sealed inner pouch with a sterile heat sealed peel back seal for each pouch. The allograft products require storage at room temperature (CMS, 2023a).

BellaCell HD

According to HansBiomed Corp., BellaCell HD is a human acellular dehydrated dermis regenerative tissue matrix indicated "for use in skin reconstruction to repair skin loss from burn injuries, congenital diseases, abdominal wall repair, hiatal hernia repair, breast reconstruction, and ulcers or malformation" (CMS, 2019). BellCell HD is supplied as 1.0-1.39mm, 1.4-1.79mm, 1.8-2.29mm, 2.3-2.99mm and 3.0-3.49mm.

BioBrane

Biobrane (Mylan Laboratories, Inc., Canonsburg, PA) is a biosynthetic wound dressing constructed of a silicon film with a nylon fabric partially imbedded into the film.  The fabric presents to the wound bed a complex 3-dimensional structure of tri-filament thread to which collagen has been chemically bound.  Blood/sera clot in the nylon matrix, thus, firmly adhering the dressing to the wound until epithelialization occurs. 

Phillips et al (1989) reviewed 851 applications of Biobrane on partial skin thickness burn wounds awaiting epithelialization.  After the patients had been evaluated and resuscitated as needed, the burn wounds were cleansed and debrided.  Those evaluated as shallow were treated with Biobrane application.  Joint surfaces were splinted for immobilization.  The wound was inspected at 24 and 48 hours and if any fluid had accumulated it was aspirated and the wound was redressed.  When the Biobrane was adherent, the wound was covered with a light dressing and joint immobilization was discontinued.  Treatment with Biobrane dressing provided certain advantages over other topical wound care.  As the dressing changes were performed less frequently outpatient care was possible, with a resultant decrease in both the length of hospital stay and the ultimate cost of burn care.  Wound desiccation is prevented and pain is decreased.  Accurate diagnosis of wound depth is crucial if Biobrane is to be used.  Very deep wounds will not allow Biobrane adherence, neither will it occur if the wound has a high bacterial count.  If joint surfaces are not splinted, the Biobrane will shear and not adhere to the wound.  Convex and concave surfaces can be treated with Biobrane, which may need to be meshed.

Bishop (1995) noted that Biobrane offers a number of advantages as a wound dressing for children.  It does not require the use of surgical instruments, noisy distractions, painful manipulation of the wound, or regimented daily dressing changes.  Biobrane does offer the pediatric patient with burns immediate comfort and protection, and enhances patient compliance and parental satisfaction.  This is corroborated by the findings of Cassidy et al (2005).  These researchers compared the effectiveness of Biobrane and Duoderm for the treatment of small intermediate thickness burns in children in a prospective, randomized fashion to determine their relative impact on wound healing, pain scores, and cost.  Patients under 18 years of age with intermediate thickness burns on a surface area less than 10 % were enrolled and treated with one of the two dressing systems.  Data collected included mechanism of injury, time to complete healing, pain scores, and institutional cost of materials until healing was complete.  No significant difference in time to healing or pain scores was detected between the 2 groups.  The cost of each treatment was statistically more expensive in the Biobrane group.  The results of this study showed that Duoderm and Biobrane provide equally effective treatment of partial thickness burns among in the pediatric population. 

Barret et al (2000) stated that partial-thickness burns in children have been treated for many years by daily, painful tubbing, washing, and cleansing of the burn wound, followed by topical application of anti-microbial creams.  Pain and impaired wound healing are the main problems.  These investigators hypothesized that the treatment of 2nd-degree burns with Biobrane is superior to topical treatment.  A total of 20 pediatric patients were prospectively randomized into 2 groups to compare the effectiveness of Biobrane versus 1 % silver sulfadiazine.  The rest of the routine clinical protocols were followed in both groups.  Demographic data, wound healing time, length of hospital stay, pain assessments and pain medication requirements, and infection were analyzed and compared.  Main outcome measures included pain, pain medication requirements, wound healing time, length of hospital stay, and infection.  The application of Biobrane to partial-thickness burns proved to be superior to the topical treatment.  Patients included in the biosynthetic temporary cover group presented with less pain and required less pain medication.  Length of hospital stay and wound healing time were also significantly shorter in the Biobrane group.  None of the patients in either group presented with wound infection or needed skin autografting.  The authors concluded that the treatment of partial-thickness burns with Biobrane is superior to topical therapy with 1 % silver sulfadiazine.  Pain, pain medication requirements, wound healing time, and length of hospital stay are significantly reduced.  Furthermore, in a review on tissue-engineered temporary wound coverings, Ehrenreich and Ruszczak (2006) stated that "[b]oth Biobrane and TransCyte have a strong body of evidence supporting their use in acute wounds.  The most important clinical advantages of both products are prevention of wound desiccation, reduction in pain, reduced dressing changes, and in most reported studies, an acceleration in healing….TransCyte may be justified in full thickness and deep partial thickness injuries, whereas Biobrane is more appropriate for more superficial wounds".

Vloemans et al (2014) performed a systematic review of wound management and dressing materials to select the best treatment option for children with burns. A search in Medline and Embase revealed 51 articles for a critical appraisal. The articles were divided into randomized controlled trials, cohort studies and a group of case-reports. Total appraisal did not differ much among the groups; the level of evidence was highest in the randomized controlled trials and lowest in the case-reports. In 16 out of 34 comparative studies, silver sulfadiazine or a silver sulfadiazine/chlorhexidine-gluconate combination was the standard of wound care treatment. The competitor dressing was Biobrane in six studies and amnion membrane in three. Tulle gauze, or tulle gauze impregnated with an antibacterial addition were the standard of care treatment in seven studies. The authors concluded that, in general, membranous dressings like Biobrane and amnion membrane performed better than the standard of care on epithelialization rate, length of hospital stay and pain for treatment of partial thickness burns in children. However, hardly any of the studies investigated long-term results like scar formation. 

Austin et al (2015) reported on a five year retrospective cohort study evaluating upper extremity burns treated with temporary wound coverage (Biobrane or cadaveric allograft). The primary outcome was to determine the impact choice of wound coverage had on operative time and cost. The secondary outcome was the need for revision of upper extremity debridement prior to definitive autografting. The investigators included 45 patients in this study: 15 treated with cadaveric allograft and 30 treated with Biobrane skin substitute. The investigators found that Biobrane had a significantly lower procedure time (21.12 vs. 54.78 min per %TBSA excised, p=0.02) and cost (1.30 vs. 2.35 dollars per minute per %TBSA excised, p=0.002). Both techniques resulted in 2 revisions due to complications. The investigators concluded that Biobrane is superior to cadaveric allograft as a temporizing skin substitute in the acute burn wound, both in terms of procedure time and associated cost. The investigators stated that they believe that this is largely due to the relative ease of application of Biobrane.

Krezdorn et al (2017) conducted a retrospective cohort study of adult patients that have been admitted with scalds in one center between 2011 and 2014. The investigators assessed two groups, group 1 with Biobrane as initial treatment and group 2 with topical treatment using polyhexanid hydrogel and fatty gauze. Primary outcome variables were rate of secondary deepening, surgery, infection (defined as positive microbiological swabs and antibiotic treatment) and length of stay. Total body surface area (TBSA) as well as diabetes mellitus (DM), hypertension, smoking and alcohol consumption as potential confounders were included. The study included 52 patients; 36 patients received treatment with Biobrane and 16 with ointment and fatty gauze. No significant differences were found for age and TBSA whereas gender ratio was different (25/11 male/female in group 1 vs 4/12 in group 2, p=0.003). Rate of secondary deepening, surgery, infection as well as days of hospital stay (DOHS) were comparable. Logistic and multilinear regression showed TBSA to be a predictive factor for infection (p=0.041), and TBSA and age for length of stay (age p=0.036; TBSA p=0.042) in group 1. The investigators concluded that the use of Biobrane in adult scald lesions is safe and non-inferior to topical treatment options. In elder patients and larger TBSA Biobrane may increase the risk of infection or a prolonged stay in hospital.

BioCleanse

BioCleanse processed human allograft tendons are used in various areas of the body to repair, replace or reconstruct the native tendon or ligament.  The tendon is surgically implanted into the body to recreate the normal anatomy and restore basic function.  It can be used to repair anterior cruciate ligaments, posterior cruciate ligaments, medial collateral ligaments, lateral collateral ligaments, posterior lateral corner, medial patella femoral ligament, Achilles tendons, biceps, acromioclavicular joints, lateral ankle stabilizations, lunar collateral ligaments and any soft tissue repair augmentation. By using BioCleanse tendons instead of an autograft, the surgeon may minimize operating time and eliminate second-site donor morbidity. BioCleanse tendons are restricted to homologous use for the repair, replacement or reconstruction of musculoskeletal defects by a qualified healthcare professional.

Bio-ConneKt Wound Matrix

Bio-ConneKt Wound Matrix (MLM Biologics) is a bioengineered skin substitute derived from equine Type I collagen (CMS, 2015). Bio-ConneKt is intended for management of moderately to heavily exuding wounds, including partial and full thickness wounds, draining & tunneling wounds, pressure sores/ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds, and surgical wounds. The product is placed directly into the wound site and incorporates into the wound, as the wound heals.

Bio-ConneKt is supplied in 4 different sizes: 6 cm x 7 cm, 5 cm x 5 cm, 3 cm x 3 cm, and 2 cm x 2 cm. It comes in a double pouch package and in a final outer cardboard envelope. The product is trimmed to a size slightly larger than the outline of the wound, then affixed to the wound and covered with a standard, non-adherent surgical dressing.

BioDfactor Human Amnion Allograft

BioDfactor human amnion allograft was developed as a liquid wound-covering product for use in-vivo to fill soft tissue defects or bone voids.  It can be applied directly to the surgical site or mixed with patients’ own blood to provide an easy to use wound- covering.

Koike et al (2011) stated that human amniotic cells are a valuable source of functional cells that can be used in various fields, including regenerative medicine and tissue engineering.  These researchers investigated the utility of human amniotic epithelial (hAE) cells as a new cell source for culturing stratified epithelium sheets for intra-oral grafting.  Enzymatically isolated hAE cells were submerged in a serum-free, low-calcium-supplemented MCDB 153 medium without a feeder layer.  The hAE cells were seeded onto a Millicell cell culture plate insert and cultured while submerged in a high-calcium medium for 4 days.  Then, they were cultured at an air-liquid interface for 3 weeks.  Cultures of hAE cells proliferated at the air-liquid interface.  After 3 weeks, the hAE cells cultivated using the air-liquid interface method lead to almost 10 continuous layers of stratified epithelium without para-keratinization or keratinization.  It confirmed immunohistochemically that the presence of CK10/13 and Ki-67 positive cells were spread throughout almost all the epithelial layer, and that CK19 positive cells were expressed throughout the entire epithelial layer in the cultured hAE cell sheets.  Cultured hAE cells sheets showed a staining pattern similar to that of uncultured oral mucosa: ZO-1 and occludin were located in the intercellular junctions throughout all the epithelial layers.  It was suggested that the hAE sheets consisted of highly-active proliferating cells and undifferentiated cells, and had a barrier function.  The authors concluded that these findings suggested that hAE cells may be a promising cell source for the development of stratified epithelium allograft sheets using a human cell strain.

Gutierrez-Moreno et al (2011) analyzed the literature on the safety and effectiveness of amniotic membrane grafting and compared the cost of currently available grafts (autografts, amniotic membrane grafts, and biocompatible skin substitutes) to promote tissue repair in venous ulcers.  A systematic review of the literature on the use of amniotic membrane grafts for the treatment of venous ulcers was performed up to 2010.  A cost-minimization analysis of direct healthcare costs was then performed (at 3 and 6 months).  A sensitivity analysis was performed to confirm the stability of the results.  Only 1 study addressing safety and effectiveness was identified.  The cost-minimization analysis showed that autografts are always the least-expensive option (€ 1,053 compared with € 1,825 for amniotic membrane grafts and € 5,767 for biocompatible skin grafts).  At 6 months, however, amniotic membrane grafts would have cost € 6,765 less than the use of biocompatible skin substitutes.  The authors concluded that despite having excellent therapeutic potential for the re-epithelialization of venous ulcers that do not respond to conventional treatment, amniotic membrane transplant remains an experimental therapy.  Autograft is the most efficient treatment but amniotic membrane graft is less expensive than the use of biocompatible skin substitutes.

BioDfence

BioDfence is a sterile human placental-derived amniotic tissue based allograft that is procured from live, healthy donors during childbirth. BioDfence is composed of an epithelial layer and a stromal layer specifically processed for the repair and replacement of lost or damaged dermal tissue or the prohibition of adhesion formation (CMS, 2013). This allograft contains collagens and extracellular substrates to include growth factors, connective proteins, and cytokines that preserve planes of tissue while inhibiting incorporation of the vital structure(s) into the overlying developing tissue. The collagen acts as a scaffold for cellular attachment and a structural tissue matrix that facilitates cell migration and proliferation. Thes product was initially used in the acute care inpatient setting in connection with neurosurgical, orthopedic and spine surgical procedures. BioDfence is also being used in individual wound care cases. The dehydrated (and the hydrated) human amnion allografts are intended for the repair or replacement of lost or damaged dermal tissue. Usage includes, but is not limited to, allograft application to wounds including: traumatic injuries, burns, Mohs procedures or surgical wounds; complex chronic and acute wounds, such as diabetic ulcers venous and arterial leg ulcers, pressure ulcers or cutaneous ulcers; wounds with exposed vital structures, e.g., tendon, bone, blood vessels; and other soft tissue defects. The product also provides adhesion barrier properties when necessary. In neurosurgery, it provided a structural barrier between the dura and surrounding soft tissue using a sutureless technique. BioDfence is packaged for single use in 7 sizes: 1.5 x 2cm; 2 x 3 cm; 2 x 6 cm; 4 x 4 cm; 4 x 8 cm; 10 x 10 cm; and 15 x 15 cm. According to the manufacturer, the differences between BioDfence and BioDfence Dryflex (see below) are as follows: BioDfence DryFlex is dehydrated, making it less sticky, and a better choice for use with instrumentation. BioDfence is hydrated, which makes it a bit sticky and glue may not be needed, which may make it easier to use for procedures such as on corneal defects. Both BioDfence DryFlex and BioDfence have a cross-linked basement membrane which is not penetrable and becomes a biologic barrier. It is placed over exposed vital structures, such as nerves, blood vessels or other tissues to protect them and keep them intact.

BioDfence DryFlex 

BioDfence DryFlex is a sterile allograft derived from amniotic membrane that is procured fropm live, healthy donors during child birth and comes fully hydrated or dehydrated.. It is sused a s a structural barrier between the dura and surrounding soft tissue using a suture-less tehnicque.

BioDfence DryFlex is a human placental-derived amniotic tissue based allograft composed of an epithelial layer and a stromal layer specifically processed for the repair and replacement of lost or damaged dermal tissue or the prohibition of adhesion formation (CMS, 2013). This allograft contains collagens and extracellular substrates to include growth factors, connective proteins, and cytokines that preserve planes of tissue while inhibiting incorporation of the vital structure(s) into the overlying developing tissue. The collagen acts as a scaffold for cellular attachment and a structural tissue matrix that facilitates cell migration and proliferation. While this product was initially used in the acute care inpatient setting in connection with neurosurgical, orthopedic and spine surgical procedures, physicians and surgeons are now using it in individual wound care cases. The dehydrated (and the hydrated) human amnion allografts are intended for the repair or replacement of lost or damaged dermal tissue. Usage includes, but is not limited to, allograft application to wounds including: traumatic injuries, burns Mohs procedures or surgical wounds; complex chronic and acute wounds, such as diabetic ulcers venous and arterial leg ulcers, pressure ulcers or cutaneous ulcers; wounds with exposed vital structures, e.g., tendon, bone, blood vessels; and other soft tissue defects. The product also provides adhesion barrier properties when necessary. BioDfence DryFlex is packaged for single use in 5 sizes: 1.5 x 2cm; 2 x 3 cm; 2 x 6 cm; 4 x 4 cm; and 4 x 8 cm. The differences between BioDfence Dryflex and BioDfence are as follows: BioDfence DryFlex is dehydrated, making it a better choice for use with instrumentation. BioDfence is hydrated, which may not be needed, which may make it easier to use for procedures such as on corneal defects. Both products have a cross-linked basement membrane which is not penetrable and becomes a biologic barrier. It is placed over exposed vital structures, such as nerves, blood vessels or other tissues to protect them and keep them intact.

BioDRestore Elemental Tissue Matrix

The BioDRestore Elemental Tissue Matrix is a moralized, flowable tissue allograft derived from amniotic tissues.

BioFix

The BioFix Allograft Membrane and Allograft Membrane-Plus are dehydrated, decellularized amniotic membranes, intended for homologous use as a wound covering. The BioFix Allograft Flow is intended for homologous use as a wound covering or connective tissue matrix.  The BioFix Membrane is about 45 µm thick.  The BioFix Membrane-Plus is about 200 µm thick.  Each membrane is offered in the following sizes: 2x4 cm, 4x4 cm, 4x6 cm, and 4x8 cm.  The BioFix Flow is offered in 0.5 cc, 1.0 cc, and 2.0 cc. 

Bioinductive Implant Regeneten

Washburn et al (2017) noted that symptomatic partial-thickness rotator cuff tears and full-thickness tears with poor tissue quality often pose a dilemma for orthopedic surgeons.  Despite advances in repair techniques and fixation devices, re-tear rates remain high.  Progression of partial-thickness tears has been noted to be over 50 %, with remaining fibers seeing increased strain.  Patch augmentation that induces a healing response while decreasing peak strain of adjacent tissue is becoming more popular among orthopedic surgeons.  The authors presented an all-arthroscopic technique guide for application of a Food and Drug Administration (FDA)-approved bovine bioinductive patch (Rotation Medical, Plymouth, MN).  The risks associated with bovine bioinductive patch augmentation procedure include infection, dislodgement of implants, immune response, and structural failure.  The limitations associated with bovine bioinductive patch augmentation procedure include previous bovine scaffolds have had limited success, and the technique has not been proved in a human model.

Thon et al (2019) noted that failure of repair of large and massive rotator cuff tears is a challenging problem within orthopedics.  Poor tendon tissue and vascularity are known causes for failure of rotator cuff repairs.  In a case-series study, these researchers examined the safety, outcomes, and healing rates when large and massive rotator cuff repairs are augmented with a bioinductive collagen scaffold patch in a proof-of-principle design.  A total of 23 patients undergoing repair of full-thickness large (2-tendon) or massive (3-tendon) rotator cuff tears augmented with a bioinductive collagen patch were enrolled in a prospective, single-arm, proof-of-principle study.  No partial repairs were performed, and a complete rotator cuff repair was successfully achieved in each case; 16 patients underwent revision rotator cuff repairs versus 7 primary repairs.  Safety was determined by any implant-related adverse event (AE).  A single magnetic resonance imaging (MRI) scan was utilized to confirm tendon healing and thickness at a minimum of 6 months post-operatively.  Post-operative ultrasound (US) was used in office by the treating surgeon to evaluate tendon thickness at 3-, 6-, 12-, and 24-month intervals.  American Shoulder and Elbow Surgeons (ASES) scores were collected at final follow-up.  Overall, a 96 % (22 of 23) healing rate was confirmed on US and MRI.  However, incidence of treatment clinical failure was 9 % (2 of 23), as 1 patient's tendon healed but eventually underwent additional surgery.  There were no AEs attributed to the implant reported.  Final US rotator cuff thickness was 7.28 ± 0.85 mm (mean ± SD), and final MRI rotator cuff thickness was 5.13 ± 1.06 mm.  The mean ASES score at final follow-up was 82.87 ± 16.68 (range of 53.33 to 100).  The authors concluded that no complications attributed to the implant were reported, and new tendon formation was apparent on US and MRI, with relatively high healing rates at 2-year follow-up.  Arthroscopic application of this bioinductive collagen scaffold when combined with rotator cuff repair is a safe and effective treatment for healing of large and massive rotator cuff repairs.  Level of Evidence = IV.

Bionect

Bionect (Innocutis Holdings, LLC., Charleston, SC) is a topical hyaluronic acid sodium salt, 0.2%. According to the manufacturer, the sodium hyaluronate (Hyalastine®) is derived from a natural fermentation process. Hyaluronic acid is a biological polysaccharide (glycosaminoglycan) and is a major component of the extracellular matrix of connective tissues. Bionect Cream was cleared for marketing under the 510(k) process in February 1997. Bionect is now available in cream, gel, spray and foam formulations for "the dressing and management of partial to full thickness dermal ulcers (pressure sores, venous stasis ulcers, arterial ulcers, and diabetic ulcers), wounds including cuts, abrasions, donor sites, and post-operative incisions, irritations of the skin, and first and second degree burns. The dressing is intended to cover a wound or burn on a patient’s skin, and protect against abrasion, friction, and desiccation."

Shaharudin et al (2016) stated that hyaluronic acid (HA) and its derivatives are used for chronic wounds, but evidence of their effectiveness remains unclear. The aim of this study was to provide more updated evidence for the effectiveness of HA (or its derivatives) compared with placebo or other agents for promoting healing in chronic wounds. The Cochrane Central Register of Controlled Trials, MEDLINE via Ovid Online, CINAHL and the EMBASE via EBSCO host databases were searched. Drug companies and experts in wounds were also contacted. Randomised controlled trials of HA (or its derivatives) compared with control were eligible for inclusion. The authors identified nine randomised controlled trials involving 865 participants with chronic wounds were included in the review. The reporting for mixed arterial and venous ulcers seems to be better quality than that for venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). Studies provided little evidence regarding the claimed effects of HA or its derivatives on healing of chronic wounds. However, there is some evidence on their effectiveness for reducing pain intensity for mixed arterial and venous ulcers, which involved 255 patients (MD=-6.78 [95% CI: -11.10 to -2.46]). Evidence to guide decisions regarding the use of HA or its derivatives to promote wound healing is still limited. More good-quality randomised controlled trials are warranted.

Brown et al (1999) stated hyaluronan has been introduced as a vehicle for topical application of drugs to the skin. We sought to determine whether hyaluronan acts solely as a hydrophilic reservoir on the surface of intact skin or might partly penetrate it. Drug-free hyaluronan gels were applied to the intact skin of hairless mice and human forearm in situ, with and without [3H] hyaluronan. [3H]hyaluronan was shown by autoradiography to disseminate through all layers of intact skin in mouse and human, reaching the dermis within 30 min of application in mice. Cellular uptake of [3H]hyaluronan was observed in the deeper layers of epidermis, dermis, and in lymphatic endothelium. Absorption through skin was confirmed in mice by chromatographic analysis of blood, urine, and extracts from skin and liver, which identified 3H as intact hyaluronan and its metabolites, free acetate and water. Hyaluronan absorption was similarly demonstrated without polyethylene glycol, which is usually included in the topical formulation. [3H]hyaluronan absorption was not restricted to its smaller polymers as demonstrated by the recovery of polymers of (360-400 kDa) from both blood and skin. This finding suggests that its passage through epidermis does not rely on passive diffusion but may be facilitated by active transport. This study establishes that hyaluronan is absorbed from the surface of the skin and passes rapidly through epidermis, which may allow associated drugs to be carried in relatively high concentration at least as far as the deeper layers of the dermis. This was a study in mice and human skin to establish that hyaluronic acid does permeate the normal epidermis to accumulate in the dermis. The primary limitation of this study was that it does not discuss clinical outcomes in a wound care setting.

Schlesinger et al (2014) stated that hyaluronic acid sodium salt gel 0.2% is a topical device effective in reducing skin inflammation. Facial seborrheic dermatitis, characterized by erythema and or flaking/scaling in areas of high sebaceous activity, affects up to five percent of the United States population. Despite ongoing study, the cause of the condition is yet unknown, but has been associated with yeast colonization and resultant immune derived inflammation. First-line management typically is with keratolytics, topical steroids, and topical antifungals as well as the targeted immunosuppressant agents pimecrolimus and tacrolimus. The objective of this study was to evaluate the efficacy and safety of a novel topical antiinflammatory containing low molecular weight hyaluronic acid. This was a prospective, observational, non-blinded safety and efficacy study in an outpatient setting. Individuals 18 to 75 years of age with facial seborrheic dermatitis were included. Outcome measures included scale, erythema, pruritus, and the provider global assessment, all measured on a five-point scale. Subjects were assessed at baseline, Week 2, Week 4, and Week 8. Final data with 13 of 17 subjects are presented. Hyaluronic acid sodium salt gel 0.2% was shown through visual grading assessments to improve the provider global assessment by 65.48 percent from baseline to Week 4. Reductions in scale, erythema, and pruritus were 76.9, 64.3, and 50 percent, respectively, at Week 4. At Week 8, the provider global assessment was improved from baseline in 92.3 percent of subjects. Treatment with topical low molecular weight hyaluronic acid resulted in improvement in the measured endpoints. Final data reveal continued improvement from that seen in the interim data shown previously. Topical low molecular weight hyaluronic acid is another option that may be considered for the treatment of facial seborrheic dermatitis in the adult population. Compliance and tolerance were excellent. Limitations of this study include a small sample size, lack of blinding, a short follow-up period, and the studied indication was seborrheic dermatitis, not wound care.

Gariboldi et al (2008) stated that in sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. The authors found that LMW-HA induces activation of keratinocytes, which respond by producing beta-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-alpha, IL-1beta, or IL-6 was observed. Ex vivo and in vivo treatments of murine skin with LMW-HA showed a release of mouse beta-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release beta-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, the authors’ observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of beta-defensins by keratinocytes, thus ameliorating the self-defense of the skin for the protection of cutaneous tissue from infection by microorganisms. The authors concede their observations that LMW-HA may clarify a physiological mechanism that is probably present in the skin to avoid eventual bacterial infection is "only speculative at the moment".

Weindl et al (2004) stated that glycosaminoglycan hyaluronic acid (HA), or hyaluronan, is a major component of the extracellular matrix of skin, joints, eye and many other tissues and organs. In spite of its simple structure, HA demonstrates remarkable rheological, viscoelastic and hygroscopic properties which are relevant for dermal tissue function. Biological activities in skin, however, are also due to its interaction with various binding proteins (hyaladherins). Due to an influence on signaling pathways, HA is involved in the wound-healing process and scarless fetal healing. Increased HA concentrations have been associated with inflammatory skin diseases. In clinical trials, topical application of HA improved wound healing; in particular, acute radioepithelitis, venous leg ulcers or diabetic foot lesions responded to HA treatment. Moreover, as a topical drug delivery system for diclofenac, an HA gel has recently been approved for the treatment of actinic keratoses. Finally, chemical modifications led to new HA derivates and biomaterials, which may be introduced into therapy in the future. Therefore, ongoing research offers new horizons for the therapeutic use of this glycosaminoglycan which has been regarded as an inert structural component until recently.

Greco et al (1998) stated that human dermal fibroblasts suspended in a collagen matrix exhibit a 4-day delay in cell division, while the same cells in monolayer divided by day 1. The initial rates of 3H-thymidine incorporation by cells in monolayer or suspended in collagen were not significantly different. When suspended in collagen, there was a threefold increase in the proportion of cells in a tetraploidal (4N) DNA state compared to the same cells in monolayer. Flow cytometry analysis and 3H-thymidine incorporation studies identified the delay of cell division as a consequence of a block in the G2/M of the cell cycle and not an inhibition of DNA synthesis. The inclusion of 150 microg/ml of hyaluronic acid (HA) in the manufacture of fibroblast populated collagen lattices (FPCL) caused a stimulation of cell division, as determined by cell counting; increased the expression of tubulin, as determined by Western blot analysis; and reduced the proportion of cells in a 4N state, as determined by flow cytometry. HA added to the same cells growing in monolayer produced a minimal increase in the rate of cell division or DNA synthesis. HA supplementation of FPCLs stimulated cell division as well as tubulin concentrations, but it did not enhance lattice contraction. The introduction of tubulin isolated from pig brain or purchased tubulin into fibroblasts by electroporation prior to their transfer into collagen lattices promoted cell division in the first 24 hours and enhanced FPCL contraction. It is proposed that tubulin protein, the building blocks of microtubules, is limited in human fibroblasts residing within a collagen matrix. When human fibroblasts are suspended in collagen, one effect of added HA may be to stimulate the synthesis of tubulin which assists cells through the cell cycle. The primary limitation of this study was that it does not discuss clinical outcomes in a wound care setting.

Biovance

Biovance is a decellularized dehydrated human amniotic membrane (DDHAM) used in the repair or replacement of damaged or lost soft tissue (CMS, 2014).  This allograft is derived from the placental amnion and includes epithelial and stromal components that provide a collagen-rich extracellular matrix.  In addition to the natural scaffold being a physical conduit for infiltrating cells, Biovance contains extracellular proteins such as elastin, fibronectin, proteoglycans, glycosaminoglycans, and laminins important in extracellular matrix strength, cell attraction, and migration.  Biovance is sterilized and available in 4 sizes: 1x2 cm, 2x3 cm, 4x4 cm and 6x6 cm.

Biovance Tri-Layer or Biovance 3L

Biovance Tri-Layer or Biovance 3L is a triple-layer decellularized, dehydrated human amniotic membrane and sterilized via e-beam irradiation. This product is designed to act as a cover or to function as a protective coverage from the surrounding environment in wound and surgical repair and reconstruction procedures. Biovance Tri-Layer or Biovance 3L units are measured based on the dimension of the wound area and sheets can be trimmed and customized for the shape of the wound. This amniotic membrane product is supplied as a sterile and sealed single-use pouches with availability in multiple sizes from 10 mm disk to 10 cm x 12 cm sheets (CMS, 2023a).

carePATCH

carePATCH (Extremity Care, LLC) is dehydrated amniotic membrane allograft used for the treatment of non-healing wounds and burn injuries. CarePATCH amniotic membrane allograft delivers cytokines, proteins and growth factors to help regenerate soft tissue. Human amniotic membrane is a thin collagenous membrane that consists of collagen layers including the basement membrane and stromal matrix. The extracellular matrix (ECM) components of the amniotic tissue include collagens, growth factors fibronectin, laminins, integrins and hyaluronans. Additionally, amniotic membrane allograft is immune privileged and possesses little or no risk of foreign body reaction which can lead to fibrosis and graft failure. CarePatch is designed to function as a protective wound cover or barrier to offer protection from the surrounding environment in wounds, including surgically created wounds such as ocular repair and reconstruction and only for homologous use. The dosage for carePATCH amniotic membrane allograft is per square centimeter. carePATCH is available in the following wound preparation. Absorbable/ non-absorbable suture material and/or tissue adhesives may be used to apply the graft to the site if necessary. CarePATCH is supplied in the following allograft sizes: 2 cm x 2 cm, 2cm X 4cm, 4 cm x 4 cm, 4 cm x 6 cm, 5 cm x 5 cm, 4 cm x 8 cm (CMS, 2023b).

There is a lack of evidence regarding the effectiveness of the carePATCH allograft.

Celera Dual Layer and Celera Dual Membrane

Both celera Dual Membrane and celera Dual Layer are minimally manipulated human amniotic and/or chorionic membrane products extracted from placental tissues that maintain the structural and functional property of the tissues. The end product is dehydrated, packaged, and terminally sterilized by irradiation. These products mainly consist of extracellular matrix proteins which function as a natural, biologic barrier. These products are intended to serve as a wound cover or skin substitute in patients with cutaneous wounds. Dosage is per centimeter square (cm2) and dependent size of injury or site of application. Celera Dual Membrane and celera Dual Layer products are available in various size and configuration sheets with a total of 1 to 49 cm2 and stored at ambient temperature (CMS, 2022c).

There is a lack of evidence regarding the effectiveness of celera Dual Membrane and celera Dual Layer products.

CellECT

Lee and Goodman (2009) described a novel treatment of secondary osteonecrosis (ON) of the femoral condyles that is relatively simple, has low morbidity, and does not preclude the patient from other more extensive treatments in the event of failure.  A total of 3 patients with extensive secondary ON of the femoral condyles were treated with decompression and debridement of the area of ON and grafting with the Cellect DBM System (Depuy Spine, Inc., Raynham, MA), which provided a graft matrix enriched with a 3-fold to 4-fold increase in osteo-progenitor cells.  At 2 years, all 3 patients had no complications and had excellent results with near-normal function and activity levels.  The authors concluded that these preliminary results demonstrated that this technique is a viable option, at least in the short-term, especially in patients with extensive, multifocal lesions

Englund et al (2010) summarized their efforts in deriving, characterizing and banking of 20 different human embryonic stem cell lines.  These researchers derived a large number of human embryonic stem cell lines between 2001 and 2005.  One of these cell lines was established under totally xeno-free culture conditions.  In addition, several subclones have been established, including a karyoptypical normal clone from a trisomic mother line.  A master cell banking system has been utilized in concert with an extensive characterization program, ensuring a supply of high quality pluripotent stem cells for further research and development.  In this report, these investigators also presented the first data on a proprietary novel antibody, hES-Cellect, that exhibits high specificity for undifferentiated hES cells.  In addition to the traditional manual dissection approach of propagating hES cells, the authors also reported on the successful approaches of feeder-free cultures as well as single cell cultures based on enzymatic digestion.  All culture systems used as reported here have maintained the hES cells in a karyotypical normal and pluripotent state.  These systems also have the advantage of being the principal springboards for further scale up of cultures for industrial or clinical applications that would require vastly more cells that can be produced by mechanical means.

Delibaltov et al (2016) introduced an interactive cell analysis application, called CellECT, for 3D+t microscopy datasets.  The core segmentation tool is watershed-based and allowed the user to add, remove or modify existing segments by means of manipulating guidance markers.  A confidence metric learns from the user interaction and highlights regions of uncertainty in the segmentation for the user's attention.  User corrected segmentations are then propagated to neighboring time points.  The analysis tool computes local and global statistics for various cell measurements over the time sequence.  Detailed results on 2 large datasets containing membrane and nuclei data were presented:
  1. a 3D+t confocal microscopy dataset of the ascidian Phallusia mammillata consisting of 18 time-points, and
  2. a 3D+t single plane illumination microscopy (SPIM) dataset consisting of 192 time-points. 

Additionally, CellECT was used to segment a large population of jigsaw-puzzle shaped epidermal cells from Arabidopsis thaliana leaves.  The cell coordinates obtained using CellECT are compared to those of manually segmented cells.  The authors concluded that CellECT provided tools for convenient segmentation and analysis of 3D+t membrane datasets by incorporating human interaction into automated algorithms.  Users can modify segmentation results through the help of guidance markers, and an adaptive confidence metric highlights problematic regions.  Segmentations can be propagated to multiple time-points, and once a segmentation is available for a time sequence cells can be analyzed to observe trends.  The segmentation and analysis tools presented here generalize well to membrane or cell wall volumetric time series datasets.

CellerateRx

CellerateRX activated type 1 collagen powder is composed of collagen fragments approximately 1/100th the size of the native collagen molecule. The product is intended to deliver the benefits of collagen immediately to the wound site in a variety of types of wounds. Newman, et al. (2008) reported on their experience with CellerateRx activated type I collagen in the treatment of recalcitrant wounds in the diabetic population resulting from minor trauma and/or venous stasis disease. The authors reported on two middle-aged diabetic male patients with lower extremity wounds refractory to conservative wound care who were treated with CellerateRx (activated, fragmented, and nonintact type I collagen) in a gel and powder form. The authors stated that both patients had complete resolution of recalcitrant wounds in 6 to 7 weeks. The authors concluded that wound resolution was evident when using the authors' practice protocol, which includes the application of activated collagen. The authors stated that the inherent properties of type I collagen may contribute to a more rapid healing process.

Cellesta Amniotic Membrane

Cellesta Amniotic Membrane (Ventris Medical, LLC) is a minimally manipulated, single-layered, amniotic membrane allograft which is affixed to a poly mesh backing which can be sutured, glued, or laid over tissue. It is intended for homologous use only, and is available in various sizes in dry or hydrated forms. Cellesta Amniotic Membrane is primarily used as a biological covering or protective barrier in reconstructive procedures, such as for chronic wound healing. There are no peer-reviewed published studies evaluating the safety and efficacy of Cellesta.

Cellesta™ Flowable Amnion

Cellesta™ Flowable Amnion (Ventris Medical, LLC) is a minimally manipulated chorion-free, human amniotic membrane, suspended in a saline solution, intended for use as a regenerative wound filler for the treatment of acute, chronic and surgically-created wounds. It is available as a pre-filled syringe for direct application (not for injection) for homologous use only. It is specifically designed for treatment of deep dermal wounds, irregularly-shaped crevassing and tunneling wounds, augmentation of deficient/inadequate soft tissue, and other complex wound cases where a patch form of amniotic membrane may not provide complete wound coverage. There are no peer-reviewed published studies evaluating the safety and efficacy of Cellesta.

Cellesta Cord

According to the manufacturer, Ventris Medical, LLC., Cellesta Cord is an umbilical cord allograft product intended for use as a regenerative wound covering for the treatment of acute, chronic and surgically created wounds. Cellesta Cord can be sutured, or glued, or laid over the desired tissue. It is available in 8 sizes: 3 circular and 5 rectangular: 12 mm, 15 mm, 18 mm, 1.5 x 1.5 cm, 3 x 2 cm, 3 x 4 cm, 3 x 6 cm, and 3 x 8 cm.

Cellesta Duo

Cellesta Duo (Ventris Medical, LLC.), is a dual human amniotic membrane allograft. Cellesta Duo is intended for use as a regenerative wound covering for the treatment of acute, chronic and surgically created wounds (CMS, 2019). Cellesta Duo is available wet or dry in 5 different sizes: 2 x 2 cm, 2 x 4 cm, 2 x 6 cm, 3 x 3 cm, 4 x 4 cm, and 4 x 8 cm. Cellesta Duo is a dual allograft affixed to a layer of poly mesh. This can be sutured, or glued, or laid over the affected tissue.

Cellgenuity Amniotic Fluid

Vines et al (2016) noted that there are few therapeutic options for symptomatic knee osteoarthritis (OA).  Human amniotic suspension allografts (ASA) have anti-inflammatory and chondro-regenerative potential; thus, representing a promising treatment strategy.  In anticipation of a large, placebo-controlled trial of intra-articular ASA for symptomatic knee OA, a prospective, open-label, feasibility study was carried out.  A total of 6 patients with Kellgren-Lawrence grade-3 and grade-4 tibio-femoral knee OA were administered a single intra-articular ASA injection containing cryopreserved particulated human amnion and amniotic fluid cells.  Patients were followed for 12 months after treatment; no significant injection reactions were noted.  Compared with baseline there were (i) no significant effect of the ASA injection on blood cell counts, lymphocyte subsets, or inflammatory markers; and (ii) a small, but statistically significant increase in serum IgG and IgE levels.  Patient-reported outcomes (PROs) including International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome, and Single Assessment Numeric Evaluation scores were collected throughout the study and examined for up to 12 months.  The authors concluded that the findings of this study demonstrated the feasibility of a single intra-articular injection of ASA for the treatment of knee OA and provided the foundation for a large, placebo-controlled trial of intra-articular ASA for symptomatic knee OA.

Farr et al (2019) stated that placental-derived tissues are a known source of anti-inflammatory and immune modulating factors.  Published pilot data on ASA for the treatment of knee OA demonstrated safety and trends for improved pain and function.  In a multi-center, single-blinded, randomized controlled trial (RCT), these researchers examined the efficacy of symptom modulation with ASA compared with saline and hyaluronic acid (HA) in subjects with knee OA.  A total of 200 subjects were randomized 1:1:1 to ASA, HA, or saline, with subjects blinded to their allocation.  Changes from baseline of PROs -- EQ-5D-5L, Knee Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS), Tegner, and Single Assessment Numerical Evaluation (SANE) -- were compared between groups.  Patients reporting unacceptable pain at 3 months were considered treatment failures and withdrawn from the study.  Statistical analysis was completed by comparing changes in PROs from baseline to 3 and 6 months for all groups.  Comparison of demographics between treatment groups showed no significant differences between groups.  Patients reporting unacceptable pain at 3 months in each group were ASA (13.2 %), HA (68.8 %), and saline (75 %).  Patients receiving ASA demonstrated significantly greater improvements from baseline for overall pain (VAS), KOOS pain, and KOOS-activities of daily living scores compared with those in the HA group (3 months) and both groups (6 months).  ASA patients had significantly greater improvements in KOOS symptom scores compared with HA and saline at 3 and 6 months, respectively.  OMERACT-OARSI responder rates for ASA, HA, and saline groups were 69.1, 39.1, and 42.6 %, respectively (p = 0.0007).  Subjects receiving ASA treatment showed greater improvements in PROs and fewer patients reported unacceptable pain compared with HA and saline.  The authors concluded that the findings of this RCT suggested that ASA injection was an effective treatment for the non-operative management of symptomatic knee OA.

The authors stated that this study had several drawbacks.  The design was single-blinded, rather than double-blinded.  While the initial double-blinded design was abandoned due to the obvious differences in viscosity between the injectates (saline, HA, ASA) that made blinding of the injector impossible; however, the primary outcome parameters were patient-reported; thus, reducing or eliminating the influence of an unblinded investigator.  Due to ethical concerns of requiring patients reporting unacceptable pain control to continue with the study, withdrawal was allowed at 3 months, limiting subsequent data recording.  However, using the last observation carried forward (LOCF) technique, an accepted method in similar trials, in this setting carried forward a poor result that was unlikely to improve over time.  Due to varying HA formulations (molecular weight, cross-linking, etc.), results and conclusions of this study may not be applicable to other HA products. 

It should be noted that this study was supported by Organogenesis, Inc.  Conflict of Interest: Dr. Farr reported grants and personal fees from Organogenesis during the conduct of the study and personal fees from Organogenesis outside the submitted work.  Dr. Gomoll reported grants and personal fees from Organogenesis, grants and personal fees from Vericel, personal fees from Moximed, and grants and personal fees from Joint Restoration Foundation (JRF), outside the submitted work.  Dr. Yanke reported grants from Organogenesis, during the conduct of the study; grants and other from Arthrex, Inc.; grants and other from JRF Ortho, outside the submitted work.  Dr. Strauss reported grants from Organogenesis during the conduct of the study and personal fees from Organogenesis outside the submitted work, personal fees from Vericel, and personal fees from JRF, outside the submitted work. Dr. Mowry reported that she is an employee of Organogenesis Inc.

ClarixFlo

ClarixFlo is a cryopreserved biological particulate amniotic membrane and umbilical cord product derived from human placental tissue (CMS, 2014).  It is intended to facilitate replacement or supplement damaged or inadequate integumental tissue.  ClarixFlo is supplied in a single-use vial in three different doses: 25 mg, 50 mg and 100 mg.  It is prepared by the physician as a suspension with normal saline for injection into the tissue.  The typical patient will receive 1 treatment of ClarixFlo to facilitate healing.  Dosing is dependent upon the size of the damaged or inadequate integumental tissue.

Cocoon Membrane

The Cocoon Membrane is a human-derived amnion allograft that is a minimally manipulated placental membrane used as a wound covering and barrier. The product is terminally sterilized. The Cocoon Membrane is designed to function as a covering and barrier for full and partial-thickness, chronic, and acute wounds. Following preparation of the wound site, the Cocoon Membrane is applied to the wound surface and extended beyond the wound margins with secure placement via the clinician’s selection of fixation. Reapplication is determined by the clinician if necessary (CMS, 2023b).

Cogenex

Cogenex Amniotic Membrane (Ventris Medical, LLC) is a minimally manipulated amniotic membrane allograft intended for homologous use and functions as a covering or barrier that offers protection from surrounding environment in reparative and reconstructive procedures. These procedures include but are not limited to chronic wound repair, urologic and gynecological surgeries, and burn wound reconstruction. Dosage depends on the size of the wound, injury and/or the scope of the surgery. Cogenex Amniotic Membrane is available wet or dry in 8 different sizes: 2 x 2 cm, 3 x 3 cm, 2 x 4 cm, 2 x 6 cm, 4 x 4 cm, 4 x 6 cm, 4 x 8 cm and 2 x 12 cm.

There is a lack of evidence regarding the effectiveness of the Cogenex amniotic membrane.

Cogenex Flowable Amnion (Ventris Medical, LLC) is a minimally manipulated amniotic membrane allograft. It is an amniotic membrane suspended in a saline solution, intended for homologous use only. It acts as a cushion in dynamic environments and is designed for treatment of deep dermal wounds, irregularly-shaped, crevassing and tunneling wounds, augmentation of deficient/ inadequate soft tissue, and other complex wound cases where a patch form of amniotic membrane may not provide complete wound coverage. Cogenex Flowable Amnion is a particulate powder pre-suspended for direct application and is stored on shelf at ambient temperature. The prescribed dosage depends on size of the wound, injury and/or scope of the surgery. It is available in 3 different volumes- 0.5 cc, 1.0 cc and 3.0 cc. It is provided in a prefilled syringe and can be administered into/onto the wound or injury. Cogenex Flowable Amnion is supplied by the donation of assenting, pre-screened women at the time of an elective, live, Caesarian birth.

There is a lack of evidence regarding the effectiveness of the Cogenex Flowable Amnion allograft.

Coll-e-Derm

Coll-e-Derm (Parametrics Medical) is a dermal allograft derived from human dermal tissue. It is intended to support wound and burn healing for wounds that have not healed with conventional treatment. The product is applied by placing over a wound, which may be sutured when warranted. It is indicated for replacement of damaged homologous tissue, repair of soft tissue defects, breast reconstruction, abdominal wall repair, soft tissue augmentation, tendon augmentation, and tendon lengthening. There are no peer-reviewed published studies evaluating the safety and efficacy of Coll-e-Derm.

Complete FT

Complete FT is a full thickness amnion-chorion sourced allograft that acts as a barrier and protective covering from the encompassing environment to acute and chronic wounds. This product is a sterile, individual use, dehydrated allograft sources from donated human amnion-chorion membrane. Complete FT is a fully resorbable graft, without requiring removal from the wound bed, that functions by providing a physical barrier to the wound. Complete FT is applied after standard wound preparation. It is applied directly without requiring fixation to the wound bed. The dosage is per square centimeters and dependent on the wound size. It is intended for external application and can be reapplied, as necessary (CMS,2023c).

Complete SL

Complete SL is a single layer amnion sourced allograft that acts as a barrier and protective covering from the encompassing environment to acute and chronic wounds. This product is a sterile, individual use, dehydrated allograft sourced from donated amniotic membrane. Complete SL is a fully resorbable graft, without requiring removal from the wound bed, that functions by providing a physical barrier to the wound. Complete SL is applied after standard wound preparation. It is applied directly without requiring fixation to the wound bed. The dosage is per square centimeters and dependent on the wound size. It is intended for external application and can be reapplied, as necessary (CMS,2023c).

Conexa Reconstructive Matrix

Conexa reconstructive matrix (Tornier, Inc., Edna, MN) is a porcine dermis tissue substitute that is cleared through the 510(k) process as LifeCell Tissue Matrix (LTM) Surgical Mesh (LifeCell Corporation, Branchburg, NJ).  According to the FDA (2008), the matrix is intended for the reinforcement of soft tissue repaired by sutures or suture anchors during tendon repair surgery including re-reinforcement of Achilles, biceps, patellar, quadriceps, rotator cuff, or other tendons.  Indications for use also include the repair of body wall defects that require the use of reinforcing or bridging material to obtain the desired surgical outcome.  The device is not intended to replace normal body structure or provide the full mechanical strength to support tendon repair of the Achilles, biceps, patellar, quadriceps, rotator cuff, or other tendons.  Sutures, used to repair the tear, and sutures or bone anchors used to attach the tissue to the bone, provide biomechanical strength for the tendon repair.  Based on the thickness of the matrix, this product is available as Conexa 100 and Conexa 200.

Conexa Reconstructive Tissue Matrix is an implantable orthopedic tissue graft used to reinforce orthopedic soft tissue repairs. It is made from porcine dermis processed to remove porcine cells and other cross-species contaminants, and sterilized. The Conexa Reconstructive Tissue Matrix is intended for the reinforcement of soft tissue repaired by sutures or suture anchors during tendon repair surgery and reinforcement for rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons. Other indications for use include the repair of body wall defects which require the use of reinforcing or bridging material to obtain the desired surgical outcome. The manufacturer claims that Conexa supports a regenerative mechanism of action, instead of a "repair" mechanism of action (i.e. scar tissue formation). With repair mechanisms of action, the body will attempt to repair the graft site with scar tissue, resulting in weaker, less functional surgical outcomes. By providing an intact, undamaged, sterile extracellular matrix, Conexa acts as a host-friendly biologic scaffold that supports attachment of the body’s natural tissue regeneration mechanism to produce new tendon tissue and rapid population of new capillaries to provide blood flow and needed nutrition. Conexa also provides mechanical load sharing and reduces the stress on the repair site thereby reducing the chance of a re-tear or sub-optimal repair outcome. Conexa is supplied in a range of sizes from 2x4 cm to 5x10 cm. The size is selected by the surgeon depending on the repair size to be reinforced and may be cut or shaped as needed. Conexa is supplied in a terminally sterile pouch contained in an outer box. There is one Conexa unit per box. According to the manufacturer, only GraftJacket and Conexa have been validated in primate animal models in published peer-review tissue engineering literature to support a regenerative mechanism of action.

However, there is insufficient evidence to support the safety and effectiveness of Conexa as studies have primarily been in the form of individual case reports (Stover et al, 2009).

Cook Medical Anal Fistula Plug

Filgate et al (2015) stated that enteric fistulas are a recognized complication of various diseases and surgical interventions.  Non-operative medical management will result in closure of 60 to 70 % of all fistulas over a 6- to 8-week period, those that fail non-operative management will require operative intervention if they are to close.  These investigators presented a series of upper gastro-intestinal (GI) fistula managed with endoscopic intervention and insertion of biological fistula plug over a 3-year period across 3 Hospitals, both public and private, in Western Australia.  Over a 3-year period, 14 patients were referred for treatment of acute or persistent fore-gut fistulas.  All fistulas were managed with endoscopic intervention and insertion of a porcine small intestine sub-mucosa plug (Biodesign Cook medical Inc., Bloomington, IN).  No patients with fistula were excluded.  Data were collected on patient demographics and underlying diagnosis.  The biological plugs were deployed using 3 different endoscopic techniques (direct deployment via the endoscope, catheter-assisted endoscopic deployment, or a pull through via a guide wire using a rendezvous technique).  Patients with fore-gut fistula were treated using biological plugs.  The age of the fistulas treated ranged from 14 days to 3 years.  The fistulas were predominantly gastric in origin (8 cases); 3 esophageal, 1 gastro-pleural-bronchial, and 2 jejunal fistulas were also managed using this technique.  Of the 14 fistulas treated using this method, 13 resolved following the treatment.  Median time to closure of the fistula was 2 days (range of 1 to 120 days); 3 patients required more than 1 intervention to complete closure.  The authors concluded that biological plugs offered a further option for management of the traditionally difficult foregut fistula, without major morbidity associated with other treatment modalities.  It is limited to the ability to deploy the plug endoscopically.  This was a small study (n = 14); and it did not entail the use of anal fistula plug.

CoreCyte

CoreCyte (Predictive Biotech) is a minimally manipulated human tissue allograft derived from the Wharton's jelly of the umbilical cord. CoreCyte is processed to preserve the cytokines, growth factors and proteins of Wharton's jelly for homologous use. It is intended for use in the repair, reconstruction, replacement or supplementation of a recipient's cells or tissues by performing the same basic function(s) of Wharton's jelly within the recipient as it would the donor. The amount and administration (injected or applied topically) of the allograft is determined by the clinician based on the intended use in each patient case. The product is distributed as a liquid allograft contained in a vial that is shipped frozen for preservation (-80C, on dry ice) and is intended to be stored in that frozen state (-60C to -80C or colder) until used or expiration date is reached. CoreCyte can be ordered in 3 different vial sizes: 0.5 mL, 1.0 mL OR 2.0 mL. The product is simply drawn up after proper thawing using a 21 G-23G needle to syringe and then prepared and applied as determined by a licensed clinician.

There is a lack of evidence regarding the effectiveness of the CoreCyte allograft.

CoreText and ProText

Regenative Labs offers the CoreText and ProText, which are very similar Wharton’s jelly-derived human tissue allografts. The difference between ProText and CoreText is that the cell sorter used in the preparation of Protext is 300 um mesh and for CoreText is 200um. Thus, the particle fiber size is larger for ProText. Both the products are intended to provide the extracellular matrix needed for the infiltration, attachment and proliferation of cells required for the repair of damaged tissue. They are typically used for muscle and cartilage tears and help to repair damaged tissue. The products are used for wounds and tissue defects and is applied directly to the defect using a syringe. The amount used depends on the size of the defect and the clinicians’ discretion. Each human tissue-based product distributed by Regenative Labs is identified by its own unique serial number. The product is packaged in a transport protective pouch. The product is contained in a cryogenic primary tissue container, which contains a product label that includes the product details such as unique product number, storage requirements and volumes. Contents are aseptically processed and are not considered sterile.

There is a lack of evidence regarding the effectiveness of the CoreText or ProText allograft.

CorMatrix ECM

CorMatrix ECM is an acellular biomaterial ((porcine small intestine submucosa processed to remove cells) the remaining ECM is composed of structural proteins such as collagen, elastinc, etc. It supports cardiac epairs and gradully replace tissue as it is remodeleed, leaving no foreighn material behind.

Corplex and Corplex P

Corplex, pre square centimeter (StimLabs, LLC) is a human umbilical cord allograft obtained from donated human birth tissue through the retention of both the epithelial layer and the Wharton's jelly. The sheet is processed using the Clearify process to maximize the retention of desired structural components. This process is designed to retain a thick structure optimized for use as a wound covering for deep and challenging wounds. Corplex retains key extracellular matrix components, including collagens and proteoglycans that provide a robust matrix. The product is then dehydrated, cut into various sheet sizes and presented in a dehydrated graft form and packaged as separate, individual units and terminally sterilized. The allograft only contains non-viable cells that were present at the time the tissue was donated. It is minimally manipulated and intended for homologous use only. The function of Corplex is for repair, reconstruction, replacement or supplementation of the recipient's tissue. The allograft is specifically intended to be used as a wound covering or barrier membrane over chronic and acute wounds. The route of administration is topical and is supplied as 15 mm, 2 x 2 cm, 2 x 3 cm and 3 x 5 cm sheets. Corplex is supplied in sheet form in a sterile inner pouch. The inner pouch is inside a non-permeable outer pouch contained in a carton. It should be maintained in its original packaging and stored at ambient temperature (0C to 38C) until ready for use. When stored properly Corplex allografts are shelf stable for up to 5 years.

Corplex P (StimLabs, LLC) is a sterile, Wharton's jelly allograft obtained from a single donated human umbilical cord, dehydrated into small pieces, and presented in a graft form. The allografts are then packaged as individual units to fill volumes of 1 cc, 2 cc and 4 cc in sterile glass vials and terminally sterilized. The allograft contains only non-viable cells that were present at the time the tissue was donated, with no supplementary viable or non-viable cells added during processing. It is minimally manipulated and intended for homologous use only. It is intended to supplement connective tissue voids in open wound environments to protect and cushion the surrounding tissue. The product must be rehydrated at the point of use and administered topically. Corplex P is to be packed into the wound environment. A dressing must be used following application as the product is not intended to be used as a wound covering or barrier membrane. The sterile Wharton's jelly allograft is presented in a dehydrated format in vials, available in three fill volumes: 1 cc, 2 cc and 4 cc. Corplex P allograft is supplied as small, sterile, lyophilized pieces packaged in a vial format. The allograft is freeze-dried and supplied in sterile vials presented in an outer pouch for easier use in aseptic environments. The outer pouch is contained in a carton. Corplex P is stored at ambient temperature (0C to 38C) until ready to use.

There is a lack of evidence regarding the effectiveness of the Corplex or Corplex P allograft.

Cortiva Allograft Dermis

Corrtiva Allograft Dermis is a noncrosslinked acellular porcine dermal matrix, used for soft tissue repair procedures such as hernia repair.

C-QUR™ Biosynthetic Mesh

C-QUR™ (Atrium Medical Corporation, Hudson, NH) biosynthetic mesh has been proposed for use in abdominal surgical repair procedures.  Currently, there are no peer-review published studies available describing this product or its use in human subjects.  Further investigation is needed to ascertain the clinical value of C-QUR™ biosynthetic mesh.

Cryo-Cord

Cryo-Cord (Royal Biologics) is an umbilical cord product that is applied directly to a non-healing wound. It is a cryopreserved product that serves as wound covering. Cryo-cord is minimally manipulated, semi-transparent, collagenous membrane allograft obtained with consent from healthy mothers during cesarean section delivery. Cryo-cord is derived from the umbilical cord. It is typically used for chronic non-healing wounds or affected area. There are multiple product sizes; the provider uses the size that most closely matches the wound. It comes in a pouch.

There is a lack of evidence regarding the effectiveness of the Cryo-cord allograft.

CryoText

CryoText denotes Wharton’s jelly or human umbilical cord product that is rich in cytokines, growth factors, and scaffolding proteins.  It is used as a replacement tissue that is intended to replace missing or damaged connective tissue. 

Cygnus

According to the manufacturer Vivex Biomedical, Inc., CYNGNUS is an amniotic tissue allograft with innate regenerative capability to support healing without adhesion or scar formation (CMS, 2016). It is used most often to treat acute wounds, chronic wounds, and burns, and it can serve as an adhesion barrier to keep potentially adherent surfaces apart. CYGNUS is a dried human amnion membrane allograft composed of a single layer of epithelial cells, a basement membrane, and an avascular connective tissue matrix. It is a minimally manipulated, dried non-viable cellular amniotic membrane allograft that preserves and delivers multiple extracellular matrix proteins, growth factors, cytokines, and other specialty proteins present in amniotic tissue to help regenerate soft tissue. CYGNUS is supplied in a variety of sizes, ranging from 1 cm x 2 cm to 7 cm x 7 cm.

Cygnus Dual

Cygnus Dual is a semi-transparent, collagenous membrane amnion allograft produced from the amnion layer of the fetal membrane via aseptic processing techniques. This allograft product is obtained with consent from healthy mothers during cesarean section delivery. Terminal product sterilization occurs via electron-beam irradiation. Cygnus Dual is supplied as a single use package and available in a variety of sizes. The allograft is stored at ambient conditions for up to 5 years (CMS, 2023a).

Cymetra

Cymetra (Life Cell Corp., Branchburg, NJ) is an injectable micronized particulate form of AlloDerm that contains the collagens, elastin, proteins and proteoglycans that are present in AlloDerm (Snyder, et al., 2012).  Like AlloDerm, Cymetra is made from human allograft skin.  Because of the small particle size, Cymetra can be delivered by injection as a minimally invasive tissue graft.  According to the manufacturer, Cymetra is ideally suited for the correction of soft-tissue defects requiring minimally invasive techniques, such as injection laryngoplasty.

Most of the published literature on Cymetra has focused on its use in injection laryngoplasty for vocal cord paralysis (see CPB 253 - Vocal Cord Paralysis / Insufficiency Treatments), and its use in cosmetic soft tissue augmentation (Hirsch and Cohen, 2006; Narins and Bowman, 2005; Sclafani et al, 2002), with the remainder of the literature addressing miscellaneous applications (Allam, 2007; Levy, et al, 2005; Banta et al, 2003). 

Cytal (formerly Matristem)

According to the manufacturer, MatriStem/Cytal matrix products are composed of a porcine-derived extracellular matrix, also known as urinary bladder matrix. The primary advantage of MatriStem/Cytal products is that they maintain their natural collagen structure and components that are gradually incorporated within the patients’ body while replacing the product with site-appropriate tissue. The result is constructively remodeled, site-specific tissue.

MatriStem/Cytal Burn Matrix, MatriStem/Cytal Micro Matrix, MatriStem/Cytal Surgical Matrix and MatriStem/Cytal Wound Matrix are made from a naturally occurring bioscaffold derived from porcine tissue, placed into a surgical site or wound. It is resorbed and replaced with new native tissue. The MatriStem/Cytal Surgical Matrix has been used for implantation to reinforce soft tissue where weakness exists (e.g., tissue and body wall Repair). The MatriStem/Cytal Wound Matrix comes in sheets or micronized particle forms, and has beeen used for chronic vascular ulcers, diabetic ulcers, draining wounds, partial and full-thickness wounds, podiatric pressure ulcers, surgical wounds (donor sites/grafts, post0chemosurgery, post-laser surgery, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears), tunneled/undermined wounds, and venous ulcers.

Cytal (formerly MatriStem) Wound Care Matrix is an extracellular matrix product derived from porcine urinary bladder tissue and designed to be replaced by native tissue in the wound (Snyder et al, 2012). MatriStem Wound Sheet (ACell, Inc., Columbia, MD) was cleared for marketing under the 510(k) process in October 2009  and "is intended for the management of wounds that including: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining wounds.  The device is intended for one-time use".  MatriStem Wound Care Matrix was cleared for marketing under the 510(k) process in August 2010 (K112409) with MatriStem Wound Sheet as the predicate device and with the same indications.

MatriStem/Cytal wound micromatrix powder (Medline Industries, Inc., Mundelein, IL) is made from the extracellular matrix (ECM) material that naturally occurs in porcine bladders (pigs tissue has a collagen structure that is nearly identical to that of human tissue); that is why MatriStem/Cytal wound powder is sometimes known as pig powder.  The powder keeps the wound from healing and as a result the body focuses on creating new cells.  Its main mechanism has to do with the fact that the body doesn’t have to regenerate so much extracellular matrix on its own.  Because the wound is covered in extracellular matrix there’s an increase of regenerative cells that are able to re-grow the tissue. MatriStem/Cytal MicroMatrix is a porcine-derived, naturally occurring non cross-linked, completely resorbable, acellular extracellular matrix derived from specific layers of porcine urinary bladder. MatriStem/Cytal MicroMatrix is made from the same material as the MartiStem/Cytal Wound Sheet, but in a micronized particle (powder) form. In this form, it is easier to apply when the wound has an irregular shape, under-mining edges or tunneling, or when shifting may cause the wound to lose contact with the dressing. The lyophilized micronized particles are applied topically to the surface of the wound to maintain and support a healing environment for wound management. MatriStem/Cytal contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue would normally be expected. It is indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. MatriStem/Cytal MicroMatrix is supplied as 20 mg (5 ea) per box; 30 mg (5 ea.) per box; 60 mg (5 ea.) per box; 100 mg (1 ea.) per box; and 200 mg (1 ea.) per box. According to the manufacturer, existing codes do not adequately describe this product because of its unique combination of bioactive properties, especially its bimodal characteristic: one surface consists of an intact basement membrane which is especially conducive to epithelial and endothelial cell attachment, proliferation, and differentiation and is ideal for epithelial cell growth in many applications, which results in a more natural regeneration with little, if any, scar tissue formation. However, there is a lack of evidence regarding the effectiveness of the Matristem/Cytal wound powder.

MatriStem/Cytal Wound Sheets are manufactured in multiple sizes of single layer lyophilized sheet configurations that are applied topically to the surface of the wound. MatriStem contains a unique epithelial basement membrane which is known to be composed of serveral types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal triggers abundant new blood vessel formation and recruits numberous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue would normally be expected. It is indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. MatriStem/Cytal wound sheets are supplies as: 3 cm x 3.5 cm (box of 5); 3 cm x 7 cm (box of 5); 7 cm x 10 cm (1 ea); 10 cm x 15 cm (box of 5); 10 cm x 15 cm (1 ea). The manufacturer states that this product has a unique combination of bioactive properties, especially its bimodal characteristic: one surface consists of an intact basement membrane which is especially conducive to epithelial and endothelial cell attachment, proliferation, and differentiation and is ideal for epithelial cell growth in many applications, which results in a more natural regeneration with little, if any, scar tissue formation.

MatriStem/Cytal Surgical Matrix is a porcine-derived, naturally occurring dehydrated extracellular matrix that maintains and supports a healing environment for wound management. MatriStem surgical devices are manufactured in various sizes of multi-layer dehydrated dry sheet configurations. When applied to a wound, these devices changes the healing response, resulting in remodeled, functional, site specific tissue. MatriStem contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue would normally be expected. It is indicated for implantation to reinforce soft tissues. MatriStem/Cytal Surgical Matrix products are supplied as follows: surgical Matrix RS as (box of 5) 1.5 cm discs, 1 ea. 2cm x 4 cm, 1 ea. 2cm x 4 cm, 1 ea. 5 cm x 5 cm, 1 ea. 7 cm x 10 cm, 1 ea. 6 cm x 15 cm, 1 ea. 10 cm x 15 cm; Plastic Surgery Matrix as (box of 5) 1.5 cm discs, 1 ea. 4 cm x 12 cm, 1 ea. 6 cm x 15 cm, 1 ea. 7 cm x 10 cm, 1 ea. 10 cm x 15 cm; Plastic Surgery Matrix XS as 1 ea. 4 cm x 12 cm, 1 ea. 6 cm x 15 cm, 1 ea. 7 cm x 10 cm and 1 ea. 10 cm x 15 cm. According to the manufacturer, this product has a unique combination of bioactive properties, especially its bimodal characteristic: one surface consists of an intact basement membrane which is especially conducive to epithelial and endothelial cell attachment, proliferation, and differentiation and is ideal for epithelial cell growth in many applications, which results in a more natural regeneration with little, if any, scar tissue formation.

Cytal Burn Matrix (formerly MatriStem Burn Matrix) is a porcine-derived, naturally occurring dehydrated extracellular matrix, also known as urinary bladder matrix, that maintains and supports a healing environment for wound management. Cytal Burn Matrix is manufactured in multi-layer lyophilized (freeze-dried) sheet configurations. When applied to a wound, these devices changes the healing response, resulting in remodeled, functional, site specific tissue. According to the manufacturer, Cytal contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. Cytal triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue would normally be expected. The manufacturer states that it is indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. Cytal Burn Matrix is supplied as: 7 cm x 10 cm fenestrated wound sheet, 1 ea; and 7 cm x 10 cm meshed wound sheet, 1 ea.; 3 cm x 3.5 cm (5/box) and (10/box); 3 cm x 7 cm (5/box and 10/box); 7 cm x 10 cm (1 ea. and 5/box); and 10 cm x 15 cm (1 ea. and 5/box). According to the requester, this product has a significant therapeutic distinction over similar products in that it offers the following characteristics:
  1. naturally occurring, non-cross-linked extracellular matrix; completely resorbable;
  2. acellular;
  3. contains multiple naturally occurring growth factors;
  4. bimodal surface characteristic;
  5. may reduce scar tissue formation;
  6. antimicrobial properties;
  7. lyophilized; and
  8. indicated in a complete range of wounds. 

MatriStem/Cytal PSMX is a porcine-derived, lyophilized acellular extracellular matrix that maintains and supports a healing environment for wound management. It is indicated for the management of partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. When applied to a wound, MatriStem/Cytal PSMX changes the healing response, resulting in remodeled, functional, site specific tissue. MatriStem/Cytal PSMX contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal PSMX triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue wound normally be expected. MatriStem/Cytal PSMX is supplied as follows: 5cm x 5cm, 4cm x 12 cm, 7cm x 10cm, 6cm x 15cm, 8cm x 16cm, and 10cm x 15cm. According to the manufacturer, MatriStem/Cytal PSMX is distinct from the other similar skin substitute products because it is naturally occurring, non-crosslinked, completely resorbable, acellular, and has bimodal surface characteristics and antibacterial properties.

MatriStem/Cytal Wound Matrix RS is a porcine-derived, lyophilized acellular extracellular matrix that maintains and supports a healing environment for wound management. It is indicated for the management of partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. When applied to a wound, MatriStem/Cytal Wound Matrix RS changes the healing response, resulting in remodeled, functional, site specific tissue. MatriStem/Cytal Wound Matrix RS contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal Wound Matrix RS triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue wound normally be expected. MatriStem/Cytal Wound Matrix RS is supplied as follows: 1.5 cm disc (box of 5 each), 2cm x 4cm, 5cm x 5cm, 7cm x 10cm, 6cm x 15cm, 8cm x 16cm, and 10cm x 15cm. According to the manufacturer, MatriStem/Cytal Wound Matrix RS is distinct from the other similar skin substitute products because it is naturally occurring, non-crosslinked, completely resorbable, acellular, and has bimodal surface characteristics and antibacterial properties.

MatriStem/Cytal PSM is a porcine-derived, extracellular matrix that maintains and supports a healing environment for wound management. It is indicated for the management of partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. When applied to a wound, MatriStem/Cytal PSM changes the healing response, resulting in remodeled, functional, site specific tissue. MatriStem/Cytal PSM contains a unique epithelial basement membrane which is known to be composed of several types of collagen, adhesion proteins, glycoproteins, and other elements of an extracellular matrix which all act synergistically in supporting natural tissue healing. MatriStem/Cytal PSM triggers abundant new blood vessel formation and recruits numerous cell types to the site of the injury or wound. During the healing process, the device is degraded and completely resorbed, leaving new tissue where scar tissue wound normally be expected. MatriStem/Cytal PSM is supplied as follows: 1.5cm disc (box of 5 each), 5cm x 5cm, 4cm x 12 cm, 7cm x 10cm, 6cm x 15cm, 7cm x 15cm, and 10cm x 15cm. According to the manufacturer, MatriStem/Cytal PSM is distinct from the other similar skin substitute products because it is naturally occurring, non-crosslinked, completely resorbable, acellular, and has bimodal surface characteristics and antibacterial properties.

Cytal Wound Matrix 3-Layer (Cytal 3L) and Cytal Wound Matrix 6-Layer (Cytal 6L) are generally intended for the management of wounds (both acute & chronic) including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor site/grafts, post-Mohs surgery, post laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining wounds (CMS, 2017). Cytal 3L and Cytal 6L are composed of animal derived, extracellular matrix, and are skin substitutes. They are comprised of naturally-occurring urinary bladder matrix (UBM), and maintain an intact epithelial basement membrane to maintain and support a healing environment through constructive remodeling. Cytal 3L and Cytal 6L are supplied in multi-layer single-use sheet configuration in sizes up to 10m x 15 cm. The devices are terminally sterilized using electron beam irradiation.

According to the manufacturer, Cytal 1 Layer; 2 Layer and burn products are intended for the management of wounds (both acute and chronic) (CMS, 2017). They are comprised of naturally-occurring urinary bladder matrix (UBM), and maintain an intact epithelial basement membrane to maintain and support a healing environment through constructive remodeling. These devices are cut to the desired size and applied directly to the wound bed by the treating clinician after removal of wound exudate and debris. They are intended for single use as they are applied and resorb into the patient's body. The manufacturer states that there is a significant functional therapeutic distinction between Cytal 1 Layer and 2 Layer and Cytal Burn products, and Cytal 3 and 6 Layer products, on the basis of different manufacturing processes, (Cytal1, Cytal 2 and Cytal Burn) are freeze dried and lyophilized; whereas Cytal 3L and Cytal 6L are vacuum-pressed and have a fenestration pattern to aid in suturing. According to the manufacturer, "these difference result in function al and therapeutic distinctions."

Martinson and Martinson (2016) used Medicare claims data from 2011 to 2014 to identify beneficiaries with diabetes and foot ulcers. Patients treated with one of four types of skin substitute (Apligraf, Dermagraft, OASIS, and MatriStem) were identified. The skin substitutes were compared on episode length; amputation rate; skin substitute utilisation; and skin substitute costs. There were 13,193 skin substitute treatment episodes: Apligraf (HML) was used in 4926 (37.3%), Dermagraft (HSL) in 5530 (41.9%), OASIS (SIS) in 2458 (18.6%) and MatriStem (UBM) in 279 (2.1%). The percentage of DFUs that healed at 90 days were: UBM 62%; SIS 63%; HML 58%; and HSL 58%. Over the entire time, UBM was non-inferior to SIS (p<0.001), and either was significantly better than HML or HSL (p<0.005 in all four tests). HML was marginally superior to HSL (p=0.025 unadjusted for multiple testing). Medicare reimbursements for skin substitutes per DFU episode for UBM ($1435 in skin substitutes per episode) and SIS ($1901) appeared to be equivalent to each other, although non-inferiority tests were not significant. Both were less than HML ($5364) or HSL ($14,424) (p<0.0005 in all four tests). HML was less costly than HSL (p<0.0005). The authors concluded that various types of skin substitutes appear to be able to confer important benefits to both patients with DFUs and payers. Analysis of the four skin-substitute types resulted in a demonstration that UBM and SIS were associated with both shorter DFU episode lengths and lower payer reimbursements than HML and HSL, while HML was less costly than HSL but equivalent in healing. Limitations of this study include the fact that it is a retrospective observational study using administrative claims data.

Frykberg et al (2016) reported on an interim analysis of a prospective, multicenter clinical study is to assess the application of MatriStem MicroMatrix (MSMM) and MatriStem Wound Matrix (MSWM) (porcine urinary bladder derived extracellular matrix) compared with Dermagraft (DG) (human fibroblast-derived dermal substitute) for the management of non-healing diabetic foot ulcers (DFUs). The investigators conducted a randomized, multicentrer study at thirteen centers throughout the US. It was designed to evaluate the incidence of ulcer closure, rate of ulcer healing, wound characteristics, patient quality of life, cost-effectiveness, and recurrence. Those subjects whose DFUs decreased in size by ≤30% or increased by ≤50% during the standard of care (SOC) phase were randomized into the treatment phase of the study. The study evaluated complete wound closure by eight weeks with weekly device application. A two-week post treatment SOC phase followed the treatment phase for any wounds that did not heal by the end of eight weeks, and wound closure was also evaluated at the end of that period. Ulcer recurrence at 6 months post-treatment was evaluated in the subjects that showed wound healing by the end of the post-treatment SOC phase. Standard adjunctive therapy, including debridement, saline irrigation and foot off-loading, was provided to both arms during the four-week screening period, after which eligible subjects were randomised in a 1:1 ratio, to either the MatriStem (MS) or DG treatment arm. This study was developed to evaluate the hypothesis that the wound outcomes observed after wound management with MS were non-inferior to those of DG after eight weeks. The investigators reported on a planned interim results of this study after one half of the projected enrolment was completed. There were 95 subjects consented and entered into the SOC four-week screening phase of the trial and 56 were randomized into the treatment phase. At the planned interim analysis, there was a significantly lower cost per subject and significant improvement in patient quality of life for the subjects treated with MS compared with those managed with DG. However, there was not a statistically significant difference found during the analysis of the interim data between the two study groups for rate of wound healing or number of subjects with complete wound closure. The investigators concluded that the data from this interim analysis show that MSMM and MSWM provide results for healing DFUs that are similar to the results obtained for DG at a significant quality of life and economic advantage.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Frykberg, et al. (2016) to be at moderate risk of bias.

Alvarez, et al. (2017) reported on a prospective, parallel, randomized, single-center study involving 17 subjects in an outpatient wound care center setting. Each subject with a DFU was randomized (2:1) to receive the Matristem urinary bladder wound matrix (UBM) plus offloading with a total contact cast (TCC) or standard care (nonadherent dressing plus TCC). All DFUs were on the plantar surface of the foot and all were Grade I-A according to the University of Texas Wound Classification System. A traditional TCC was used in all patients and consisted of a minimally padded, well-molded, and rigid (plaster plus fiberglass) construct that maintains contact with the entire plantar surface of the foot and lower leg. The endpoints of the study were wound healing at 12 and 16 weeks and ulcer recurrence at 1 year. Wound evaluations were performed weekly and wound surface area was measured by photo-digital planimetry. In the UBM group, the incidence of wound healing at 12 and 16 weeks was 90% and 100%, respectively, compared with 33% and 83.3% in the control (P = .062). The mean time to healing in the UBM-treated group was 62.4 days compared with 92.8 days in the control group (P = .031). The incidence of ulcer recurrence at 1 year was 10% (1/11) in the UBM-treated group and 50% (3/6) in the control. The authors concluded that the results of this interim analysis suggest treatment of DFUs with a UBM could significantly reduce the time to healing and improve the rate of recurrence.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Alvarez, et al. (2017) to be at moderate risk of bias.

DermaBind SL

DermaBind SL is a sterile, single use, dehydrated allograft produced from donated human amnion membrane. This allograft product is designed to act as a cover and barrier that functions as a protective coverage from the surrounding environment. DermaBind SL is indicated for the management of wounds, such as, partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds, trauma wounds, and draining wounds. It is for external application with dosage per square centimeter and dependent on wound size and can be reapplied if necessary. Subsequent to standard wound preparation, DermaBind SL is applied directly and adheres to the wound bed without requiring fixation. It is fully resorbable and does not require removal from the wound bed. DermaBind SL is supplied as a sterile single use package in a variety of sizes (CMS, 2023a).

DermACELL

DermACELL is an acellular regenerative human dermal allograft procured and processed from donated human tissue. DermACELL is used to provide a physiological and mechanical barrier that reduces environmental contamination and assists in promotion of granulation tissue and epithelialization for any topical or surgical wound. It is sutured topically to wounds, such as chronic non-healing wounds or partial and full thickness burns, and is sutured surgically to muscle flaps or other connective tissue for indications such as closing of complicated ventral/incisional hernias, breast reconstruction, temporal defects, tendon and ligament damage, and in guided tissue regeneration in oral applications. As an allograft collagen scaffold, DermACELL supports a patient's own cellular in-growth, resulting in tissue regeneration. DermACELL is supplied as one packaged allograft in various sizes, from 4 to 96 square centimeters and from 0.2-0.4 mm thick.

DermACELL, DermACELL AWM, DermACELL AWM Porous (LifeNet Health) "are decellularized human dermal allografts" indicated for use in "chronic non-healing wounds such as diabetic and venous leg ulcers, acute burns, breast reconstruction and other associated soft tissue injuries" (CMS, 2019). The grafts comes in various sizes, from 4 to 320 square centimeters and from 0.2 - 3.5 mm thick.

DermaCELL is provided by the Skin and Wound Allograft Institute, which is a wholly owned subsidiary of LifeNet Health (Virginia Beach, VA) (Snyder et al, 2012).  The company believes that its MatraCell processing technology creates a readily available, extracellular matrix that then provides a collagen scaffold to support cell ingrowth.

There is limited published evidence in the peer-reviewed medical literature on DermACELL (Chen et al, 2012; Capito et al, 2012).

Walters et al (2016) reported on an interim analysis of a multicenter study involving 168 patients who were randomized into DermACELL, conventional care, and Graftjacket treatment arms in a 2:2:1 ratio. Patients in the acellular dermal matrix groups received either 1 or 2 applications of the graft at the discretion of the investigator. Weekly follow-up visits were conducted until the ulcer healed or the endpoint was reached. At the primary endpoint of 12 weeks, there as a nonsignificant trend in the proportion of completely healing ulcers in the DermACELL arm than in the conventional care arm and the Graftjacket arm (52.8% versus 41.1% and 39.1%, respectively, NS). By 16 weeks, the DermACELL arm had a significantly higher proportion of completely healed ulcers than the conventional care arm (67.9% vs 48.1%; P = .0385) and a nonsignificant trend toward greater healing than in the Graftjacket arm (67.9% vs 47.8%; P = .1149). Contrary to prior studies of Graftjacket, in this study sponsored by the manufactuers of DermACELL, there was no evidence of efficacy of Graftjacket compared to conventional treatment; the rates of complete healing and mean percent reduction in wound area from baseline with Graftjacket was neither clinically or significantly different than with conventional treatment. The DermACELL arm also exhibited a nonsignificant greater reduction in wound area at 16 weeks than the conventional care arm (91.4% vs 80.3%; P = .0791) and the Graftjacket arm (91.4% vs 73.5%; P = .0762). There was a nonsignificant trend in reduction of wound area at 16 weeks in the conventional care arm than in the Graftjacket arm. There was no clinically or statistically significant difference in mean number of weeks to complete wound closure in the DermACELL arm (8.6 weeks) than in the conventional care arm (8.7 weeks) and the Graftjacket arm (8.6 weeks). The authors reported that the proportion of severe adverse events and the proportion of overall early withdrawals were similar among the 3 groups based on relative population size (P ≥ .05).  Limitations of the study include its open label nature and the lack of a run-in period. The study report did not specify whether the persons who were assigned to conventional care were treated according to widely accepted, evidence-based clinical guidelines. There were a significant number of dropouts (18 of 71 in the DermACELL group, 13 of 69 in the conventional care arm, and 5 of 28 in the Graftjacket arm, and intention to treat analysis was not reported.

In a prospective RCT, Cazzell and colleagues (2017) compared the safety and efficacy of a human acellular dermal matrix (ADM), D-ADM, with a conventional care arm and an active comparator human ADM arm, GJ-ADM, for the treatment of chronic diabetic foot ulcers.  The study enrolled 168 diabetic foot ulcer subjects in 13 centers across 9 states.  Subjects in the ADM arms received 1 application but could receive 1 additional application of ADM if deemed necessary.  Screen failures and early withdrawals left 53 subjects in the D-ADM arm, 56 in the conventional care arm, and 23 in the GJ-ADM arm (2:2:1 ratio).  Subjects were followed through 24 weeks with major end-points at weeks 12, 16, and 24.  Single application D-ADM subjects showed significantly greater wound closure rates than conventional care at all 3 end-points while all applications D-ADM displayed a significantly higher healing rate than conventional care at week 16 and week 24.  GJ-ADM did not show a significantly greater healing rate over conventional care at any of these time-points.  A blinded, 3rd party adjudicator analyzed healing at week 12 and expressed "strong" agreement (κ = 0.837).  Closed ulcers in the single application D-ADM arm remained healed at a significantly greater rate than the conventional care arm at 4 weeks post-termination (100 % versus 86.7 %; p = 0.0435).  There was no significant difference between GJ-ADM and conventional care for healed wounds remaining closed.  Single application D-ADM demonstrated significantly greater average percent wound area reduction than conventional care for weeks 2 to 24 while single application GJ-ADM showed significantly greater wound area reduction over conventional care for weeks 4 to 6, 9, and 11 to 12.  The authors concluded that D-ADM demonstrated significantly greater wound healing, larger wound area reduction, and a better capability of keeping healed wounds closed than conventional care in the treatment of chronic DFUs.

The authors stated that although this study utilized stringent criteria for evaluation, the lack of information surrounding additional applications of human ADMs in the literature proved challenging for study design.  This resulted in the study being erroneously powered using healing rates reported in other human ADM studies that reported only a single application of product with a 12 week follow-up period.  Although the single application wound healing rate shown in this study was significantly better than conventional care throughout, the healing rate for all subjects did not become statistically significant until week 15 even though the percent wound area reduction was statistically significant from week .  This study provided a very detailed analysis of healing rates and it should be noted that multiple probability tests were applied to this data set without correcting related probabilities.  While some may consider this a source of probability bias, more recent views have found this acceptable.  Elucidating the effect of a second application on the overall wound environment and its ability to heal was not considered during protocol development.  Furthermore, since additional applications of ADMs were allowed at investigator discretion and a few of these wounds healed quickly thereafter, more second applications may have occurred than were necessary.  Criteria for the timing of second applications for ADMs were not standardized and were an area of consideration for additional research.  The results of the logistic regression analysis indicated that baseline wound area size should be a focal point of further research.  Additionally, although wound depth was collected at each visit, these data were not used as the Silhouette System had difficultly reliably determining depth.  It appeared that the depth measurements may have changed depending on the angle or distance of the camera.  However, investigators used a ruler to measure wound depth to determine if a subject passed the inclusion criteria so there was no concern about the accuracy of the screening process.  It should be noted that in contrast to the unreliable depth measurements, the Silhouette system was extremely accurate in measuring the wound area.  Furthermore, the outlined area image was double-checked for every subject at each visit to ensure the wound area was accurately measured.  Another weakness of this study was that the investigators were not blinded to the treatment type when assessing wound closure.  However, this was mitigated by the use of the Aranz laser system which eliminated the bias in measuring wound area reduction.  Additionally, a blinded, third-party adjudicator assessed healed wounds and those close to healing by 12 weeks follow-up.  The adjudicator expressed "strong" agreement with investigator designations and found an additional 2 healed wounds for D-ADM, 1 healed wound for GJ-ADM, and no change for conventional care subjects.  These additional healed wounds were conservatively not included in the data analysis; but were evidence that there was no investigator bias in favor of D-ADM specifically or ADMs in general.  Another disadvantage mentioned previously was the possibility of an artificially lowered healing rate for as many as 9 D-ADM wounds due to the stricter definition of healing applied in this study.  The different definitions in healing should be taken into account when comparing this study with older literature, but this study may provide a benchmark for healed rates as more published studies transition to the new AHRQ guidelines for determining the healed status of wounds.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Cazzel, et al. (2017) to be at low risk of bias.

Cazzell (2019) stated that VLUs are often chronic and difficult to treat, which makes alternative options to conventional care necessary to improve ulcer healing rates.  While human ADMs have shown promise in treating DFUs, no comparative studies have been published regarding VLU treatment.  In a multi-center, randomized, controlled, open-label trial, these researchers evaluated the safety and efficacy of D-ADM compared with conventional wound care management in patients with chronic ulcers of the lower extremity.  Patients were randomly assigned to receive either D-ADM or standard of care (control) in a 2:1 ratio.  Treatment began at week 0 and wounds were evaluated on a weekly basis until wound closure was observed or the patient completed 24 weekly follow-up visits.  A total of 18 patients were included in the D-ADM arm and 10 patients in the control arm.  There was a strong trend of reduction in percent wound area for D-ADM patients with an average reduction of 59.6 % at 24 weeks versus 8.1 % at 24 weeks for control patients.  In addition, healed ulcers in the D-ADM arm remained closed at a substantially higher rate after termination than healed ulcers in the control.  The authors concluded that this exploratory study demonstrated D-ADM increased healing rates and reduction in wound size compared to conventional care.  The D-ADM also presented a favorable profile compared to the published literature on HSE, which can require several applications.  These researchers stated that these early results support the use of D-ADM for treating chronic VLUs; and further larger prospective, RCTs are needed to better assess its place in clinical practice.

The authors stated that this pilot study had several limitations.  The small patient population (n = 18 in the D-ADM group) and unbalanced proportion between the 2 groups (2:1) ensured a low probability of achieving statistical significance.  However, as a pilot study, the purpose was to explore the potential for therapeutic benefits from using D-ADM in patients with VLUs, an area with scarce information, and achieving statistical significance was not expected.  Accordingly, the larger proportion of D-ADM patients provided a better understanding of its therapeutic effects and safety profile, both of which are critical information for use in designing future trials.  Another limitation of this study was the lack of criteria for investigators to follow as to when a 2nd application would be appropriate.  Such formal guidelines do not exist with this new material and was left to individual clinician discretion.  Finally, although the lack of blinding for study investigators would be considered a limitation, an independent adjudicator blinded to treatment type evaluated the healing status of all wounds as a secondary check to prevent bias.  The kappa score of 0.923 indicated very good inter-rater reliability between the study investigators and the blinded, independent adjudicator.  Furthermore, the adjudicator scored 1 additional wound treated with D-ADM as healed that the study investigators scored as unhealed, suggesting investigator bias was not an issue despite the lack of blinding.

In a prospective, multi-center, single-arm trial, Cazzell and colleagues (2019) examined the safety and efficacy of an acellular dermal matrix allograft, DermACELL (D-ADM), in the treatment of large, complex diabetic foot ulcers (DFUs) that probed to tendon or bone.  Inclusion criteria were Wagner grade 3 or 4 DFUs between 4 weeks and 1 year in duration.  All subject received 1 application of D-ADM at baseline and could receive 1 additional application if wound healing arrested.  Ulcers were assessed weekly for 16 weeks using a laser measuring device.  A total of 61 subjects were enrolled, with an average wound area of 29.0 cm; 59 of these ulcers showed exposed bone.  The entire per-protocol population (n = 47) achieved 100 % granulation.  The mean time to 100 % granulation was 4.0 weeks with an average of 1.2 applications of D-ADM.  Mean percent wound area reduction was 80.3 % at 16 weeks.  Those DFUs 15 cm or smaller were substantially more likely to close than DFUs larger than 29 cm (p = 0.0008) over a 16-week duration.  No complications were associated with the use of the studied matrix.  The authors concluded that the D-ADM demonstrated the ability to rapidly reduce the size of large, complex DFUs with exposed bone.  Some wounds did not completely heal by 16 weeks; however, the significant reduction in size suggested that these large, complex wounds may heal if given more time.  These researchers stated that further study is needed.

The authors stated that a major limitation of this study was the lack of a control arm.  These researchers believed that the efficacy of the D-ADM was supported because of rapid granulation and wound area reduction.  Although it was not possible to make direct comparisons to results from standard-of-care, the outcomes using D-ADM can be compared with results reported in the literature.  For example, the product’s efficacy was supported by the average number of applications needed to induce granulation (1.2) and healing (1.0).  These averages were in sharp contrast to the 9.0 and 6.8 mean applications, respectively, reported for a viable cryopreserved human placental membrane (vCHPM).  Another major limitation was that the study follow-up terminated after 16 weeks, which provided an insufficient length of time for the extremely large ulcers to heal.  These investigators stated that future studies that include Wagner grades 3 and 4 DFUs would benefit from a longer study duration.  In addition, hemoglobin A1c levels were recorded for only 16 patients (mean hemoglobin A1c = 8.0 %) because that information was charted well before informed consent was obtained for the other subjects.  Because that information was not available, study authors collected concomitant medications and anti-diabetic regimens for those 59 subjects with a diagnosis of diabetes: 13 were treated with 1 or more oral agents, 20 with insulin, 23 with both insulin and oral agents, and 2 with diet and exercise.  The biases encountered for natural recovery or healing and use of adjunctive therapies were considered during protocol design.  The protocol required the target wounds to have shown little response to standard-of-care wound therapies for at least 4 weeks prior to the screening visit.  Criteria also dictated that the wounds required aggressive surgical debridement in addition to a documented need for the use of a cellular and/or tissue-based products (CTPs).  Hyperbaric oxygen treatments were not allowed as an adjunct treatment during the trial.  Those subjects who needed additional surgical intervention on the target limb during the treatment period were withdrawn from the trial.  An additional limitation was that the analyses primarily focused on per-protocol subjects.  The focus on per-protocol subjects was carried out to ensure fair and accurate comparisons with the previously published literature on DFUs with exposed bone.  However, the per-protocol population included all patients who completed the trial regardless of their compliance.  For example, 1 per-protocol patient was consistently non-adherent to off-loading, negative pressure wound therapy (NPWT), and dressing changes.  This not only hindered healing, but also resulted in the subject’s wound area increasing in size compared with baseline.  This patient’s outcome not only highlighted the importance of treatment adherence, but also represented an issue that clinicians encounter and was therefore included in the analyses.  The intent-to-treat (ITT) population included 9 subjects who withdrew from the study for non-graft-related events, of which 2 ulcers did not have a decrease in size over time.  One of these 2 patients was diagnosed at week 9 with osteomyelitis that required a resection impacting the target ulcer (change in area from 5.9 cm2 to 7.6 cm2 at exit).  The other subject was removed at week 2 for osteomyelitis in the target limb that required a first ray resection that impacted the target ulcer (change in area from 13.6 cm2 to 13.7 cm2 at exit).  The average decrease in ulcer area was 33.1 % during the time these 9 subjects were under treatment.  Study authors acknowledged that the wide confidence intervals for baseline wound size on healing indicated that a larger population is needed to calculate a more precise interval.  However, the lower ends of the ranges still suggested that ulcer size had a significant impact on healing.  Lastly, the study population had an unusually poor level of health for inclusion in a clinical trial; however, their pre-existing vascular and renal conditions were representative of patients observed in "real world" clinics, and the study authors believed that their outcomes were an important and beneficial addition to the literature.

DermaClose RC Continuous External Tissue Expander

The DermaClose RC Continuous External Tissue Expanders are sterile, single-patient use skin anchors that are made of 316L surgical stainless steel.  These skin anchors are placed about 1.5 cm from the edge of the wound, and they penetrate the skin to 4.5 mm into the subcutaneous tissue, and are held in place with 2 standard skin staples.  Once the anchors are in place, the line from the DermaClose tension controller is attached around each skin anchor and the knob of the tensioning device is rotated until a clutch mechanism provides an audible indication that full tension has been achieved.  The DermaClose now automatically maintains the proper amount of tension to gently stretch the skin on the subcutaneous planes around the wound until the edges of the wound are brought close enough together for final suturing and closure.  There is insufficient evidence regarding the effectiveness of DermaClose Continuous External Tissue Expander.

Santiago et al (2016) presented a series of 14 patients who suffered massive extremity soft tissue injuries and were treated with an external tissue expansion system (DermaClose RC). Outcome measurements included time to definitive closure and method of definitive wound closure. A 5-patient subset of this group was prospectively analyzed to determine measurements including initial wound surface area (WSA), percentage reduction in WSA, and related complications. Overall time to wound coverage ranged from 1 to 6 days, with mean time to wound coverage being 4.4 days. Of the 14 patients included in the series, 12 (85.7%) were able to undergo delayed primary closure, whereas 2 required split thickness skin grafting. In the 5-patient subgroup, WSA initially ranged from 20.25 to 1031.25 cm2. Mean wound size was 262.7 cm2. Decrease in WSA ranged from 44% to 93% of the initial WSA, with mean decrease being 74.3% (95% confidence interval, 57.33-91.3).

Reinard et al (2016) reviewed the medical records of patients with large cranial defects (> 5 cm) following multiple complicated craniotomies who had undergone reconstructive cranioplasty with preoperative tissue expansion using the DermaClose RC device. In addition to gathering data on patient age, sex, primary pathology, number of craniotomies and/or craniectomies, history of radiation therapy, and duration of external scalp tissue expansion, the authors screened patient charts for cerebrospinal fluid (CSF) leak, meningitis, intracranial abscess formation, dermatitis, and patient satisfaction rates. The 6 identified patients (5 female, 1 male) had an age range from 36 to 70 years. All patients had complicating factors such as recalcitrant scalp infections after multiple craniotomies or cranial radiation, which led to secondary scalp tissue scarring and retraction. All patients were deemed to be potential candidates for rotational flaps with or without skin grafts. All patients underwent the same preoperative tissue expansion followed by standard cranial bone reconstruction. None of the patients developed CSF leak, meningitis, intracranial abscess, dermatitis, or permanent cosmetic defects. None of the patients required a reoperation. Mean follow-up was 117 days. 

Dermacyte

Dermacyte (Merakris) is an amniotic membrane allograft. The function of the product, according to its indicated use, is to treat non-infected partial thickness skin ulcers (diabetic foot ulcer, venous stasis ulcer, decubitus ulcer) greater than 1-month duration and which have not adequately responded to conventional therapy, or as clinically indicated. It provides a protective extracellular matrix to cover wounds and support cell attachment and ingrowth during healing of chronic non-healing wounds. Following the preparation of the wound bed to ensure it is free from necrotic tissue, a clinician selects Dermacyte Matrix according to the wound size and applies the product to the wound using aseptic technique followed by compression wraps to secure the product in place. It may be used across a range of ages in male and female patient populations with chronic wounds refractory to conventional therapy or as clinically indicated. The mean patient age is approximately 60 years of age based on existing literature, and a range between 18 and 80 years of age.

There is a lack of evidence regarding the effectiveness of the Dermacyte amniotic membrane allograft.

Derma-Gide

Derma-Gide (Geistlich Pharma North America, Princeton, NJ) was previously called Geistlich wound matrix. The manufacturer added additional smaller rectangular sizes and added new round shapes and changed the name to Derma-Gide. Derma-Gide is intended to be used for the management of wounds including: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic venous ulcers, surgical wounds and trauma skin wounds. Derma-Gide is a porcine, porous and resorbable 3D collagen matrix, that is derived from non-crosslinked, porcine (skin and connective) tissue. The manufacturer states that the product consists of Types I and III collagen that have been specifically processed to support angiogenesis. Angiogenesis is vital to successful wound healing and in the formation of granulation tissue in the wound bed.

Armstrong et al (2020) stated that diabetic foot ulcers (DFUs) have significant clinical impact and carry a substantial economic burden.  Patients with DFUs that are refractory to standard wound care are at risk for major complications, including infection and amputation and have an increased risk of mortality.  In an observational pilot study, these researchers examined the safety and effectiveness of a novel decellularized purified reconstituted bilayer matrix (PRBM) in treating DFUs.  A total of 10 diabetic patients with refractory wounds that failed to heal after at least 4 weeks of standard wound care were studied in this Institutional Review Board (IRB)-approved trial; 10 consecutive wounds were treated weekly with the PRBM for up to 12 weeks.  At each weekly visit, the wound was evaluated, photographed, and cleaned, followed by application of new graft if not completely epithelialized.  Assessment included measurement of the wound area and inspection of the wound site for signs of complications.  The primary outcome measure was wound closure, as adjudicated by independent reviewers; and secondary outcomes included assessment of overall adverse events (AEs), time to closure, percent area reduction, and the cost of product(s) used; 9 of 10 patients achieved complete wound closure within 4 weeks, and 1 did not heal completely within 12 weeks.  The mean time to heal was 2.7 weeks.  The mean wound area reduction at 12 weeks was 99 %.  No AEs nor wound complications were observed.  The authors concluded that these early clinical findings suggested that the PRBM may be an effective tool in the treatment of DFUs.  These researchers stated that a larger, randomized trial would be valuable in examining whether the observed trends would be validated.

Armstrong et al (2021) noted that biomaterial engineering has produced many matrices for use in tissue repair, employing various materials and processing methods, which could impact the ability of the products to encourage wound healing.  Recently, these researchers reported favorable clinical outcomes, using a novel purified reconstituted bilayer matrix (PRBM; Geistlich Derma-Gide) for the treatment of chronic diabetic foot ulcers.  Evaluations of the structural and functional characteristics of PRBM in-vitro were carried out to examine how this biomaterial may affect the favorable clinical results observed by influencing the wound environment and key physiologic mechanisms necessary for the healing process.  Investigations included scanning electron microscopy, cell culture analyses, gene expression assays, matrix metalloproteinase (MMP) activity assessment, and pH measurement.  Cross-sectional scanning electron microscopy demonstrated a distinct bilayer structure with porous and compact layers.  The PRBM structure allowed cell types involved in wound healing to bind and proliferate.  Expression analysis of growth factor-responsive genes demonstrated binding and preservation of bioactive growth factors TGF-β1, bFGF, and VEGF by PRBM.  Boyden chamber migration assays revealed increased cellular migration compared with controls . In the presence of PRBM, the activity of MMP-1, MMP-2, and MMP-9 was significantly lower compared with control samples.  pH of the PRBM in solution was slightly acidic.  The authors concluded that based on in-vitro evaluations, it appeared that the PRBM processing without deleterious chemical cross-linking resulted in a suitable ECM possessing characteristics to aid natural wound healing, including cell attachment, migration, proliferation, differentiation, and angiogenesis.  These investigators stated that these in-vitro data support the promising healing rate observed clinically when chronic DFUs were treated with PRBM.  They noted that these findings along with encouraging preliminary clinical results support further investigation and clinical application of this PRBM.

Armstrong et al (2022) noted that diabetic foot infections continue to be a major challenge for health care delivery systems.  Following encouraging results from a pilot study using a novel PRBM to treat chronic DFUs, these researchers designed a prospective, randomized, multi-center trial comparing outcomes of PRBM at 12 weeks compared with a standard of care (SOC) using a collagen alginate dressing.  The primary endpoint was percentage of wounds closed after 12 weeks; and secondary outcomes included assessments of complications, healing time, quality of life (QOL), and cost to closure.  A total of 40 patients were included in an intent-to-treat (ITT) and per-protocol (PP) analysis, with 39 completing the study protocol (n = 19 PRBM, n = 20 SOC).  Wounds treated with PRBM were significantly more likely to close than wounds treated with SOC (ITT: 85 % versus 30 %, p = 0.0004, PP: 94 % versus 30 % p = 0.00008), healed significantly faster (mean 37 days versus 67 days for SOC, p = 0.002), and achieved a mean wound area reduction within 12 weeks of 96 % versus 8.9 % for SOC.  No AEs directly related to PRBM treatment were reported.  Mean PRBM cost of healing was $1,731.  The authors concluded that the use of PRBM was safe and effective for treatment of chronic DFUs. 

These researchers stated that the findings of this study were encouraging; however, as with all studies certain limitations were recognized.  These included: a small cohort of only 40 patients (n = 19 in the PRBM group) as well as a relatively small number of sites compared with large premarket trials; the inclusion of only full-thickness, non-infected, non-ischemic wounds; and the lack of longer-term follow-up (current follow- up of only 12 weeks).  These investigators also noted that a comprehensive assessment of advanced skin substitutes by the Agency for Healthcare Research and Quality (Synder et al, 2020) suggested a need for studies evaluating patients with more serious co-morbidities; thus, future trials should consider a "real-world" patient population with more complex wounds, including deeper wounds.  Furthermore, longer term studies reporting recurrence, hospitalizations, amputation, and mortality are recommended.

Dermagraft

Dermagraft is a wound care product manufactured from human fibroblast cells derived from newborn foreskin tissue. The fibroblasts are cultured on a bioarbsorbable polyglactin mesh. Proteins and growth factors are secreted during the culture period and generate a three dimensional human dermis. 

Dermagraft (Advanced BioHealing, Inc., La Jolla, CA) has been approved by the FDA for repair of diabetic foot ulcers. Dermagraft is composed of cryopreserved human-derived fibroblasts and collagen applied to a bioabsorbable mesh (similar to the material used in strong bioabsorbable sutures).  The fibroblasts are obtained from human newborn foreskin tissue. During the Dermagraft manufacturing process, the human fibroblasts are seeded onto a bioabsorbable polyglactin mesh scaffold.  The fibroblasts proliferate to fill the interstices of this scaffold and secrete human dermal collagen, matrix proteins, growth factors and cytokines, to create a 3-dimensional human dermal substitute containing metabolically active, living cells. Dermagraft does not contain macrophages, lymphocytes, blood vessels, or hair follicles. It comes frozen as a single sheet (2 by 3 inches) for a single application

In September 2001, FDA approved Dermagraft for marketing under the premarket approval (PMA) process for "use in the treatment of full-thickness diabetic foot ulcers greater than six weeks’ duration which extend through the dermis, but without tendon, muscle, joint capsule or bone exposure. Dermagraft should be used in conjunction with standard wound care regimens and in patients that have adequate blood supply to the involved foot."

In support of FDA approval, a 12-week multi-center clinical study was performed involving 314 patients with chronic diabetic ulcers who were randomized to Dermagraft or control.  Patients in the Dermagraft group received up to 8 applications of Dermagraft over the course of the 12-week study.  All patients received pressure-reducing footwear and were encouraged to stay off their study foot as much as possible.  By week 12, the median percent wound closure for the Dermagraft group was 91 % compared to 78 % for the control group.  The study also showed that ulcers treated with Dermagraft closed significantly faster than ulcers treated with conventional therapy.  Patients treated with Dermagraft were 1.7 times more likely to close than control patients at any given time during the study.  No serious adverse events were attributed to Dermagraft.  There was a lower rate of infection, cellulitis, and osteomyelitis in the Dermagraft treated group.  Of the patients enrolled, 10.4% of the Dermagraft patients developed an infection while 17.9 % of the Control patients developed ulcer infection.  Overall, 19 % of the Dermagraft group developed infection, cellulitis, or osteomyelitis.  In the control group, 32.5 % patients developed the same adverse events. 

Frykberg et al (2015) reported on a study aimed at evaluating the incidence of amputations/bone resections in a randomized controlled trial comparing human fibroblast-derived dermal substitute plus conventional care with conventional care alone for the treatment of patients with diabetic foot ulcers (DFUs) greater than 6 weeks duration. Ulcer-related amputation/bone resection data were extracted from data on all adverse events reported for the intent-to-treat population (N = 314), and amputations were categorized by type: below the knee, Syme, Chopart, transmetatarsal, ray, toe, or partial toe. Data were analyzed retrospectively for the incidence of amputation/bone resection by treatment. The incidence of amputation/bone resection in the study was 8.9% (28/314) overall, 5.5% (9/163) for patients receiving human fibroblast-derived dermal substitute, and 12.6% (19/151) for patients receiving conventional care (P = .031). Of the 28 cases of amputation/bone resection, 27 were preceded by ulcer-related infection. The investigators concluded that there were significantly fewer amputations/bone resections in patients who received human fibroblast-derived dermal substitute versus conventional care, likely related to the lower incidence of infection adverse events observed in the human fibroblast-derived dermal substitute treatment group.

Dermagraft has also been approved by the FDA for use in the treatment of wounds related to dystrophic epidermolysis bullosa. Dystrophic epidermolysis bullosa is a blistering, hereditary skin condition, in which the filaments that anchor the epidermis to the underlying dermis are either absent or do not function 

Harding, et al. (2013) reported on an open-label, prospective, multicenter, randomized controlled study to evaluate the efficacy and safety of human fibroblast-derived dermal substitute (HFDS) plus four-layer compression therapy compared with compression therapy alone in the treatment of venous leg ulcers. The primary outcome variable was the proportion of patients with completely healed study ulcers by 12 weeks. The number healed was further summarized by ulcer duration and baseline ulcer size. Sixty-four (34%) of 186 patients in the HFDS group experienced healing by week 12 compared with 56 (31%) of 180 patients in the control group (P = 0·235). For ulcers ≤ 12 months duration, 49 (52%) of 94 patients in the HFDS group versus 36 (37%) of 97 patients in the control group healed at 12 weeks (P = 0·029). For ulcers ≤ 10 cm(2), complete healing at week 12 was observed in 55 (47%) of 117 patients in the HFDS group compared with 47 (39%) of 120 patients in the control group (P = 0·223). The most common adverse events (AEs) were wound infection, cellulitis and skin ulcer. The frequency of AEs did not markedly differ between the treatment and control groups.

A draft assessment of wound care products prepared for AHRQ judged this randomized controlled study by Harding, et al. (2013) to be at low risk of bias.

In May 2006, Advanced BioHealing purchased the global rights to Dermagraft from Smith & Nephew.

DermaMatrix

DermaMatrix tissue is an allograft derived from donated human skin. To minimize inflammation or rejection at the surgical site, the epidermis and all viable dermal cells are removed while the original dermal collagen matrix is maintained. DermaMatrix Acellular Dermis is processed by the Musculoskeletal Transplant Foundation (MTF) and is available through Synthes CMF. Published peer-reviewed evidence for DermaMatrix has focused on its use in breast reconstruction. It is used for the replacement of damaged or inadequate integumental tissue or for the repair, reinforcement or supplemental support of soft tissue defects. According to the manufacturer, clinical applications include, but are not limited to the following: facial applications, including soft tissue defects, nasal reconstruction and septal perforation, parotidectomy; intraoral applications, including cleft palate repair, oral resurfacing, vestibuloplasty; radial forearm free flap repair; breast reconstruction postmastectomy; and abdominal wall repair. Peer-reviewed published evidence for DermaMatrix has focused primarily on its use in breast reconstruction. There is limited peer-reviewed published evidence supporting its use for other applications (Capito, et al., 2012; Athavale, et al., 2012; Kathju, et al., 2011; Lee, et al., 2010).

DermaMatrix (formerly InteXen) Porcine Dermal Matrix is pyrogen free, porcine dermis. It has been used in treatment of hernias where the connective tissue has ruptured or for implantation to reinforce soft tissues in urological, gynecological and gastroenterological anatomy.

Dermapure

DermaPure is a single layer decellularized dermal allograft derived from split thickness grafts harvested from human cadaver tissue donors,  DermaPure is used for the treatment of acute and chronic wounds such as diabetic foot ulcers, venous stasis ulcers, and additional wounds that are refractory to more conservative care (CMS, 2014). DermaPure is derived from split thickness grafts harvested from cadaveric human tissue donors. DermaPure is supplied in the following allograft sizes: 2x3cm, 3x4cm, and 4x6cm. 

Dermaspan

DermaSpan is an acellular dermal matrix derived from aseptically processed cadaveric human allograft skin tissue. It is used for the repair or replacement of damaged or inadequate integumental tissue or for other homologous uses of human integument. The allograft acts as a scaffold to facilitate angiogenesis and migration of growth factors that stimulate cell migration. The collagen scaffold of DermaSpan facilitates the recellularization and revascularization of the host tissue. DermaSpan is applied to the patient's surgical site and secured by suturing. It may be applied for up to two applications. According to the applicant, when applied to the wound, DermaSpan has been shown to become vascularized and incorporated into the wound bed and to provide an effective means for wound closure. DermaSpan is supplied freeze-dried, with one side covered by a layer of N-Terface membrane backing enclosed inside a Tyvek inner pouch. The allograft and inner pouch are then enclosed in a secondary outer Poly-foil pouch and sterilized. Approximate allograft dimensions, thicknesses and expiration date are indicated on the labeling. There is a lack of peer-reviewed published clinical evidence supporting the use of Dermaspan.

Dermavest

Dermavest is a particularized, decellularized human placental connective tissue extracellular matrix intended to replace or supplement damaged or inadequate integumental tissue (skin substitute) and re-stabilize a debrided wound (CMS, 2014).  Dermavest is comprised of a different source of human connective tissue than the other products.  It has up to 5 times more (mg) human connective tissue matrix per square cm.  It is supplied as a single dehydrated, 2x3cm sterile pad.

Dermis on Demand (DOD) Allograft

Dermis on Demand (DOD) allograft is a human cell-, tissues or cellular, or tissue-based product (HCT/P).  It is an allogeneic, processed acellular dermis intended for homologous use only, including the supplemental support, protection, reinforcement or covering of soft tissue.  This allograft is a 5-year shelf stable human dermis product that can be used to augment existing soft tissue directly in line with existing surgical procedures.

Derm-Maxx

Derm-Maxx (Royal Biologics) is a freeze-dried decellularized dermal matrix allograft that is provided from consenting donors. It is used for integumentary augmentation and serve as a covering for wounds and skin defects. The Derm-Maxx Allograft is produced using a process that reduces native nucleic acids, cells and other antigenic material while preserving the collagen matrix with vascular channels. The extracellular matrix supports cellular infiltration, attachment, and proliferation. The unique processing technique preserves the collagen and elastic tissue fibers while maintaining the open channels through which cells can migrate, proliferate and form new blood vessels. This biologic process is crucial to the integration and remodeling of the allograft by host cells. Derm-Maxx comes in various sizes; the provider uses the size that most closely matches the skin defect or the wound area. It is applied directly to the affected area. It comes in sterile pouches.

There is a lack of evidence regarding the effectiveness of the Derm-Maxx allograft.

Dual Layer Impax Membrane

Dual Layer Impax Membrane is a sterile dehydrated dual layered human amniotic membrane allograft. This product is designed to function as a barrier or cover for acute and chronic wounds and for use as a barrier to protect wounds from the surrounding environment. After standard wound preparation, Dual Layer Impax Membrane can be applied directly to the wound for single use in an individual patient. Dual Layer Impax is supplied in a primary foil pouch and secondary Tyvek pouch and adheres to sterilization requirements. The single sterile, double pouched membrane is available in various sizes with the smallest being 2 cm by 3 cm (CMS, 2023b).

Duragen Plus

DuraGen Plus Dural Regeneration Matrix is an absorbable implant for repair of dural defects. It is a soft, white, pliable, nonfriable porous collagen matrix. DuraGen Plus is supplied as sterile, non-pyrogenic, for single use.

DuraMatrix

DuraMatrix is a dura substitute matrix membrane engineered from purified type I collagen, used for onlay or sutured implantation.

Duraseal

DuraSeal Xact is a synthetic, absorbable hydrogel used for dural sealing to prevent cerebral spinal fluid (CSF) leaks of the dura mater. It is indicated as an adjunct to sutures for repair in spine surgery. DuraSeal Xact is sprayed onto a target tissue site as a two-component liquid system through an applicator attached to two syringes. During application, the two liquids mix and react to form a flexible, absorbable hydrogel suitable for sealing the dura mater. DuraSeal Xact is supplied as a kit containing two pre-filled syringes, a powder vial, and an applicator. The powder vial contains PEG, which is reconstituted by the first syringe to create a PEG ester solution. The second syringe contains a trilysine amine solution polymerization to form a biocompatible absorbable hydrogel.

Endoform

Endoform Dermal Template (Mesynthes, Ltd., North Attleboro, MA, and Wellington, New Zealand) is a non-reconstituted, acellular, collagen, single-use wound matrix dressing derived from ovine forestomach. It is indicated for in the treatment of partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds (Snyder, et al., 2012).

EndoForm Dermal Template is an extracellular matrix derived from ovine forestomach. According to the company Web site, "Endoform is a proprietary biomaterial containing a rich and complex mix of important biological extracellular matrix (ECM) molecules, including structural (collagens I, III, IV & elastin) and adhesive proteins (fibronectin and laminin), glycosaminoglycans (heparin sulfate and hyaluronic acid) and growth factors (FGF2 & TGFß)."

EndoForm Dermal Template was cleared for marketing under the 510(k) process in January 2010 for "single use in the treatment of the following wounds: partial and full-thickness wounds; pressure ulcers; venous ulcers; diabetic ulcers; chronic vascular ulcers; tunneled/undermined wounds; surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence); trauma wounds (abrasions, lacerations, second-degree burns, and skin tears); draining wounds."

Endoform Dermal Template is a wound dressing primarily composed of ovine collagen and is supplied as a sterile intact, perforated or meshed sheet ranging in size from 9 cm2 to 400 cm2. Endoform is supplied sterile and is intended for single use in the treatment of wounds. Endoform is cut to fit the shape of the wound, placed on the wound bed, rehydrated with sterile saline and covered. When rehydrated, Endoform transforms into a soft conforming sheet which is naturally incorporates into the wound over time. The dressing can be left in place for 5 - 7 days. Endoform is sold in boxes of 10 dressings each and has a 2 year shelf-life. Endoform does not require physician fixation. Because of its simplicity, a patient at home can perform a dressing change once a treatment plan has been established.

There is a lack of peer-reviewed published evidence on Endoform collagen wound dressing.

ENDURAGen

ENDURAGen Dermal Collagen implants are an acellular dermal matrix composed of cross-linked porcine dermal collagen.  ENDURAGen Collagen Implant is a biomaterial made of a patented collagen matrix that has a structural architecture similar to human tissue which provides a scaffold for fibroblast infiltration and vascularization. The enzymatic digestion and cross-linking manufacturing process is intended to make ENDURAGen Implants resistant to breakdown and absorption, allowing for a durable repair or reconstruction for soft tissue contouring and/or reinforcement procedures.

The ENDURAGen Collagen Implant was cleared as substantially equivalent to Permacol, originally approved by the U.S. Food and Drug Administration on January 17, 2002. ENDURAGen Collagen Implants are specifically indicated for soft tissue reinforcement, augmentation, and repair in plastic and reconstructive surgery of the head and face. The ENDURAGen Biomaterial is a sterile, off-white, moist, durable, flexible flat sheet of cross-linked porcine dermal collagen and elastin fibers. The flexible material is intended to conform to anatomical shapes. ENDURAGen Implants are prehydrated and supplied in sterile sealed packets.

Peer-reviewed published evidence for the use of ENDURAGen is limited to case reports, small case series, and evaluations of its biomechanical properties (Wu et al, 2011; McCord et al, 2008; Cillo et al, 2007; Vural et al, 2006; Ibrahim et al, 2013).

In 2008, McCord and group reported their experience using a new acellular porcine dermal graft (Enduragen) in 129 eyelids.  A retrospective chart review was performed that included every case in which Enduragen was used by the two primary authors in the upper or lower eyelid.  Patient demographics, type of procedure performed, and complications were reviewed.  A total of 69 patients and a total of 129 eyelids were included in the study.  Eight procedures were spacers in the upper lid, 104 were for spacers in the lower lid, and 17 were for lateral canthal reinforcement.  Twenty-two procedures were in primary cases and 47 were in eyelids for secondary reconstructions, for a total of 69 patients.  There were 13 eyelid complications, for a complication rate of 10 %.  Nine cases required surgical revision, and there were 4 cases of infection, all of which were successfully treated with oral and topical antibiotics.  According to the authors Enduragen has proved to be a very satisfactory substitute for ear cartilage and fascia in eyelid surgery in both reconstructive and primary eyelid cases.  It seems to be far superior to other commercially available tissue substitutes because of its predictability of structure and robust behavior.  All problems that were encountered in this series seemed to be related more to technical errors than to any deficiency in or reaction to the Enduragen.  The increased strength, rigidity, and durability give support to the lids comparable to that obtained with autogenous ear cartilage and fascia.

Enverse

Enverse (StimLabs, LLC) contains non-viable cells and is to be used as a wound covering or barrier membrane, over chronic and acute wounds, including dermal ulcers or defects. No viable or non-viable cells are added to the harvested amniotic membrane. The processed membrane is dehydrated and cut into various sizes, and presented in a sterilized, dehydrated sheet graft form.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of Enverse.

Epicel

Epicel (Genzyme Biosurgery, Cambridge, MA) is a cultured epidermal autograft intended to treat deep dermal or full-thickness burns (Snyder, et al., 2012). Skin cells are grown or cultured from a postage-stamp sized sample of the individual’s own healthy skin. Epicel is indicated to replace the epidermis on severely burned patients.

According to the product labeling, "Epicel® cultured epidermal autografts (CEA) is an aseptically processed wound dressing composed of the patient’s own (autologous) keratinocytes grown ex vivo in the presence of proliferation-arrested, murine (mouse) fibroblasts. Epicel® consists of sheets of proliferative, autologous keratinocytes, ranging from 2 to 8 cell layers thick and is referred to as a cultured epidermal autograft." Epicel is created by co-cultivation of the patient’s cells with murine cells and contains residual murine cells. Therefore, FDA considers Epicel a xenotransplantation product. Epicel was granted an humanitarian device exemption (HDE) by FDA in October 2007 and is "indicated for use in patients who have deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30 percent. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns." Epicel is not indicated for use in chronic wounds.

Epicel is indicated for use in a subgroup of the burn population that represents the most severely injured patients.  The FDA granted Epicel its humanitarian use device designation in 2007 for the treatment of life-threatening wounds resulting from severe burns.  Due to the small population for which Epicel is indicated, it is unlikely there will be sufficient evidence to demonstrate the effectiveness of Epicel for the treatment of burns.  The primary benefit of Epicel is that the total number of grafts required to treat a patient can be produced from a single biopsy of unburned skin.  Patients suffering burns over a significant body surface area can be completely covered regardless of the amount of unburned skin available for split thickness skin grafts.  This minimizes the time to wound closure and minimizes the time in which the patient is most susceptible to serious and potentially life threatening complications.  Munster (1992) reported on a series of patients (n = 10) treated with cultured epidermal autografts who had a significantly reduced mortality rate (14 %) when compared with control patients (48 %).  In a 5-year single-center series, Carsin et al (2000) treated 30 burn patients with cultured epithelial autografts (total body surface area of a mean of 37 %).  Cultured epithelial autografts achieved permanent coverage of a mean of 26 % of total body surface area, an area greater than that covered by conventional autografts and survival was 90 % in these severely burned and otherwise traumatized patients.  Final cultured epidermal autograft take was a mean of 69 %. 

Epicel is made from a patient's own skin cells and then grown on a layer of mouse cells to enhance growth.  It is indicated for use in patients who have deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30 %.  It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns.  Enough skin can be grown from a biopsy the size of a postage stamp to cover the entire body.  The process takes approximately 16 days and the skin graft integrates with surrounding tissue 3 to 4 weeks after surgery.

Epicord

EpiCord (Mimedx Group, Inc.) is a lyophilized, non-viable cellular umbilical cord allograft that provides a natural biological barrier and protective structure for wound healing environments. EpiCord is comprised of the protective elements of the umbilical cord with a thin amnion layer and a thicker Wharton Jelly mucopolysaccaride component. EpiCord provides an extracellular matrix (ECM) as a scaffold in the form of collagen types, fibronectin, laminins, and proteoglycans. This structure provides a natural wound covering and scaffold for cellular growth. According to the manufacturer, EpiCord is indicated for diabetic elderly patients who are affected by slow healing wounds. It is to be used in the treatment and management of chronic and acute wounds, burns as well as a natural biological barrier to protect tendons. EpiCord would be used in the treatment of a chronic leg ulcer that requires debridement, topical care and an allograft placement and dressing for proper management. EpiCord can be stored in ambient conditions.

In a prospective, multi-center, randomized-controlled, comparative parallel study, Tettelbach et al (2019b) examined the safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non-healing diabetic foot ulcers (DFU).  This trial was conducted at 11 centers in the U.S.  Individuals with a confirmed diagnosis of type 1 or type 2 diabetes presenting with a 1 to 15 cm2 ulcer located below the ankle that had been persisting for at least 30 days were eligible for the 14-day study run-in phase.  After 14 days of weekly debridement, moist wound therapy, and off-loading, those with less than or equal to 30 % wound area reduction post-debridement (n = 155) were randomized in a 2:1 ratio to receive a weekly application of EpiCord (n = 101) or standardized therapy with alginate wound dressing, non-adherent silicone dressing, absorbent non-adhesive hydro-polymer secondary dressing, and gauze bandage roll (n = 54).  All wounds continued to have appropriate off-loading during the treatment phase of the study.  Study visits were conducted for 12 weeks.  At each weekly visit, the DFU was cleaned and debrided as necessary, with the wound photographed pre- and post-debridement and measured before the application of treatment group-specific dressings.  A follow-up visit was performed at week 16.  The primary study end-point was the percentage of complete closure of the study ulcer within 12 weeks, as assessed by Silhouette camera.  Data for randomized subjects meeting study inclusion criteria were included in an ITT analysis.  Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40); ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70 %) versus 26 of 54 (48 %) for EpiCord and alginate dressings, respectively, p = 0.0089.  Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81 %) for EpiCord-treated and 26 of 48 (54 %) for alginate-treated DFUs, p = 0.0013.  For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96 %) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65 %) of adequately debrided alginate-treated ulcers, p < 0.0001; 75 subjects experienced at least 1 adverse event (AE), with a total of 160 AEs recorded.  There were no AEs related to either EpiCord or alginate dressings.  The authors concluded that the results of this 1st RCT on the use of EpiCord as a treatment for DFUs provided additional evidence of the safety and efficacy of dehydrated placental tissues.

The authors stated that although the study groups were well matched for traditional factors influencing healing, other circumstances, typically problematic in the diabetic population, that these researchers did not control for, such as nutrition, co-morbidities, and polypharmacy, may have also influenced healing rates in the current study population.  This was an industry-sponsored study; further studies with independent funding sources are needed to determine the clinical effectiveness of this novel therapy.

Epidex

Epidex (Euroderm AG, Baden-Dättwil, Switzerland) is a skin product generated from keratinocytes from the patient’s hair follicles.  Epidermal sheets are created with silicone membrane support. Euroderm AG seems to be strictly a European company (Snyder et al, 2012).  None of its skin products seem to be sold in the United States and it has no listing with FDA.

Epieffect

Epieffect is a minimally manipulated, lyophilized, non-viable cellular allograft derived from human amniotic membrane. This allograft product includes the amnion layer, intermediate layer, and chorion layers of the human placental tissue. Epieffect is designed to act as a barrier and function as a protective environment in acute and chronic wounds. This product is supplied as sterile 2 cm x 3 cm, 3 cm x 5 cm, 4 cm x 4 cm, 5 cm x 6 cm, and 7 cm x 7 cm sheets.in a carton that can be stored at room temperature with a 5 -year shelf life. Epieffect is for one-time use (CMS, 2023a).

EpiFix Amniotic Membrane Allograft

EpiFix amniotic membrane allograft (MiMedx Group, Inc., Kennesaw, GA) is a biologic human amniotic membrane processed through Surgical Biologic's proprietary Purion® process, which combines cleaning, dehydration and sterilization to produce a safe, technically sterilized tissue allowing for storage at room temperature.  It is used for the treatment of dermal wounds.

EpiFix is a multi-layer biologic dehydrated human amniotic membrane allograft comprised of an epithelial layer and two fibrous connective tissue layers specifically processed to be used for the repair or replacement of lost or damaged dermal tissue. It is prepared from human placenta. The processed allograft contains collagen types IV, V, and VII that promote cellular differentiation and adhesion. Usage includes on lay applications for, but not limited to, neuropathic ulcers, venous stasis ulcers, post-traumatic wounds and post-surgical wounds and pressure ulcers. According to the manufacturer, EpiFix provides a matrix for cellular migration/proliferation, provides a natural biological barrier, and is non-immunogenic. The manufacturer states that it also delivers well-known essential wound healing growth factors; delivers minimally manipulated extracellular matrix (ECM) proteins; provides unique anti-inflammatory cytokines, and contains tissue inhibitors of metallo-proteinases. Each allograft is packed in a hermetically sealed double peel pouch packaging in an outer box carton. According to the manufacturer, EpiFix differs from other products produced from human tissue based upon the derived source of the tissue allograft and allograft contents. Only EpiFix is composed of normal dehydrated human amniotic membrane (dHAM) and has no synthetic components. EpiFix has been used in burns, plastic surgery and wound care.

EpiFix Injectable is a minimally manipulated, dehydrated, non-viable cellular amniotic membrane allograft that preserves and delivers multiple extracellular matrix proteins, growth factors, cytokines and other specialty proteins present in amniotic tissue to help regenerate soft tissue (CMS, 2013). EpiFix Injectable is used in the treatment and management of chronic wounds. Usage includes injectable applications for neuropathic ulcers, venous stasis ulcers, post traumatic ulcers, post-surgical ulcers and pressure ulcers. It is particularly suited to deeply creviced, irregularly shaped or tunneling wounds. EpiFix Injectable is used for wound treatment, when it is necessary to replace or repair lost or damaged human collagen tissue. EpiFix Injectable can be injected in the wound site and hydrated as needed, or mixed with a fixed amount of normal saline solution to prepare a suspension for injection into the wound or areas of chronic inflammation. The size of the dosing used is determined based upon the size of the wound defect. EpiFix Injectable vials contain processed, dehydrated, sterilized amniotic membrane tissue grafts to be reconstituted to 0.5cc, 1.25cc and 2.0cc amounts.

There is limited evidence from well-controlled studies of the use of EpiFix amniotic membrane allograft in the treatment of wounds, with most of the evidence from a single investigator group, raising questions about the generalizability of findings. Although several studies have examined natural human amniotic membrane in wound healing, these studies would not be applicable to EpiFix, because the processing of the human amniotic membrane in preparation of the product may affect its performance. Thus, additional clinical outcome studies of EpiFix are needed to determine its performance in wound care. 

Zelen et al (2013) reported on a randomized controlled trial of dehydrated human amniotic membrane (DHAM) allografts in adults with a diabetic foot ulcers.  Subjects included 25 patients with diabetic foot ulcers of one month (4-weeks) duration or longer from a podiatry practice.  Patients were excluded if they had large ulcers (greater than 25 cm2), Charcot foot, ulcer extending to the bone, clinical signs of infection, or inadequate circulation to the foot.  Patients were randomized to receive "standard of care" (SOC) alone or standard care with the addition of DHAM.  Standard care included the use of a silver containing dressing (Silvasorb gel and Aqacel AG) at the discretion of the attending clinician and a compression dressing.  Wound size reduction and rates of complete healing after 4 and 6 weeks were evaluated.  Mean wound size reduction in the 12 patients in the SOC group was 20 percent at week 1, compared to a mean reduction in wound size of over 80 % in the 13 patients in the DHAM group.  At 4 weeks, none of the subjects from the SOC group (0 %) was healed, whereas 10 of the 13 subjects in the DHAM group (77 %) had healed (p < 0.001).  At 6 weeks, 1 of the 12 subjects from the SOC group (8 %) was healed and 12 of the 13 subjects in the DHAM group (92 %) were healed (p < 0.001).  At 6 weeks, wounds were reduced by a mean of 1.8 % in the SOC group versus 98.4 % in the DHAM group (p < 0.001).  No infections were reported in the DHAM group whereas 17 % of the SOC group had infections.  Commenting on the results of this study, Lavery and Weir (2014) stated "[i]t has the best results that have ever been reported in any DFU study for the treatment group and probably the worst for the control group …".

Limitations of the study by Zelen et al (2013) included the lack of blinding of the investigators gathering data on wound size and other outcomes (such as through use of photographs).  Other limitations include omission of certain important baseline variables and outcomes, and the lack of a guideline-supported protocol for standard of care that was sufficiently detailed to minimize variability.  Other clinical studies of Epifix suffer from similar limitations.

A draft assessment of wound care products prepared for AHRQ judged this randomized controlled study by Zelen, et al. (2013) to be at moderate risk of bias.

Zelen et al (2013) reported on study of the micronized dehydrated amniotic membrane (mDHAM) where 45 patients were randomized to receive injection of 2 cc 0.5 % Marcaine plain, then either 1.25 cc saline (controls), 0.5 cc micronized dehydrated human amniotic membrane mDHAM, or 1.25 cc mDHAM.  Follow-up visits occurred over 8 weeks to measure function, pain, and functional health and well-being.  Zelen et al reported that significant improvement in plantar fasciitis symptoms was observed in patients receiving 0.5 cc or 1.25 cc mDHAM versus controls within 1 week of treatment and throughout the study period.  At 1 week, AOFAS Hindfoot scores increased by a mean of 2.2 ± 17.4 points for controls versus 38.7 ± 11.4 points for those receiving 0.5 cc mDHAM (p < .001) and 33.7 ± 14.0 points for those receiving 1.25 cc mDHAM (p < .001).  By week 8 AOFAS Hindfoot scores increased by a mean of 12.9 ± 16.9 points for controls versus 51.6 ± 10.1 and 53.3 ± 9.4 for those receiving 0.5 cc and 1.25 cc mDHAM, respectively (both p < .001).  No significant difference in treatment response was observed in patients receiving 0.5 cc versus 1.25 cc mDHAM.  Zelen et al concluded that, in patients with refractory plantar fasciitis, mDHAM is a viable treatment option. 

In a retrospective case-series study, Forbes and Fetterolf (2012) demonstrated the use of dehydrated human amniotic membrane (dHAM) allografts in the treatment of wounds of various etiologies.  Amniotic membrane was applied to a series of chronic wounds referred to a formal wound clinic for aggressive management, after prior, traditional treatment methods were found ineffective, over a period of 1 month.  In each case, failure of traditional therapy was followed by placement of a dehydrated amniotic membrane allograft and the healing time course was documented with charted measurements.  Wounds treated with the amniotic membrane allograft demonstrated improved healing, with a change in the healing trajectory from that previously noted.  The authors concluded that dehydrated human amniotic membrane represented a potentially effective addition to existing wound care therapies, with further formal clinical studies indicated.

Sheikh et al (2014) stated that non-healing wounds present a significant social and economic burden.  Chronic non-healing wounds are estimated to affect as many as 1 to 2 % of individuals during their lifetime, and account for billions of dollars of expense annually on both a national and global basis.  These researchers described the use of a novel dehydrated amniotic membrane allograft (EpiFix®; MiMedx Group, Inc., Kennesaw, GA) for the treatment of chronic non-healing wounds.  They described the results of EpiFix treatment in 4 patients who had not achieved wound closure with both conservative and advanced measures, and had been referred for a definitive plastic surgery procedure.  Healing was observed in a variety of wounds with 1 to 3 applications of the dehydrated amniotic membrane material.  The material was well-tolerated by patients.  Healed wounds did not recur in long-term follow-up.  The authors conclude that further investigation of the use of dehydrated amniotic membrane in broader application to various types of dermal wounds should be considered.

Zelen et al (2014) noted that diabetic foot ulcers (DFU) are notoriously slow to heal and even in cases where primary healing is achieved ulcers frequently recur.  An optimal treatment for DFU would be one that supports both rapid and long-term healing.  These investigators evaluated recurrence rates of DFU healed with use of dehydrated human amnion/chorion membrane (dHACM).  A total of 22 patients with chronic DFU that healed with the use of dHACM were eligible for inclusion.  All eligible patients had completed a single-center randomized clinical trial comparing rates of primary healing over a 12-week period with dHACM versus a standard regimen of care.  Follow-up examinations were scheduled for 9 to 12 months after primary healing with dHACM.  Subsequent evaluation of clinical records was made with IRB approval and patient consent.  Eighteen of 22 eligible patients (81.8 %) returned for follow-up examination.  Mean wound size prior to treatment with dHACM was 3.1 ± 3.8 cm2, median 1.7 cm2 (0.7, 13.5).  Mean time to wound closure after dHACM initiation was 3.1 ± 2.8 weeks (median of 2.0 weeks, range of 1.0 to 9.0 weeks).  At the 9 to 12 month follow-up visit 17 of 18 (94.4 %) wounds treated with dHACM remained fully healed.  The authors concluded that these findings supported the effectiveness of dHACM for treatment of DFU.  The main drawbacks of this study included its retrospective study design and small sample size.  Furthermore, 4 patients were lost to follow-up and the researchers were unaware of the status of their wound.  They stated that larger studies are needed to confirm their findings.

Zelen and colleagues (2015) stated that advanced therapies such as bioengineered skin substitutes (BSS) and dHACM have been shown to promote healing of chronic diabetic ulcers. An interim analysis of data from 60 patients enrolled in a prospective, randomized, controlled, parallel group, multi-center clinical trial showed that dHACM (EpiFix, MiMedx Group Inc., Marietta, GA) is superior to standard wound care (SWC) and BSS (Apligraf, Organogenesis, Inc., Canton, MA) in achieving complete wound closure within 4 to 6 weeks.  Rates and time to closure at a longer time interval and factors influencing outcomes remained unassessed; therefore, the study was continued in order to achieve at least 100 patients.  With the larger cohort, these researchers compared clinical outcomes at 12 weeks in 100 patients with chronic lower extremity diabetic ulcers treated with weekly applications of Apligraf (n = 33), EpiFix (n = 32) or SWC (n = 35) with collagen-alginate dressing as controls.  A Cox regression was performed to analyze the time to heal within 12 weeks, adjusting for all significant covariates.  A Kaplan-Meier analysis was conducted to compare time-to-heal within 12 weeks for the 3 treatment groups.  Clinical characteristics were well-matched across study groups.  The proportion of wounds achieving complete closure within the 12-week study period were 73 % (24/33), 97 % (31/32), and 51 % (18/35) for Apligraf, EpiFix and SWC, respectively (adjusted p = 0.00019).  Subjects treated with EpiFix had a very significant higher probability of their wounds healing [hazard ratio (HR: 5.66; adjusted p: 1.3 x 10−7] compared to SWC alone.  No difference in probability of healing was observed for the Apligraf and SWC groups.  Patients treated with Apligraf were less likely to heal than those treated with EpiFix [HR: 0.30; 95 % confidence interval (CI): 0.17 to 0.54; unadjusted p: 5.8 x 10−5].  Increased wound size and presence of hypertension were significant factors that influenced healing.  Mean time-to-heal within 12 weeks was 47.9 days (95 % CI: 38.2 to 57.7) with Apligraf, 23.6 days (95 % CI: 17.0 to 30.2) with EpiFix group and 57.4 days (95 %CI: 48.2 to 66.6) with the SWC alone group (adjusted p = 3.2 x 10−7).  Median number of grafts used per healed wound were 6 (range of 1 to 13) and 2.5 (range of 1 to 12) for the Apligraf and EpiFix groups, respectively.  Median graft cost was $8918 (range of  $1,486 to 19,323) per healed wound for the Apligraf group and $1,517 (range of $434 to 25,710) per healed wound in the EpiFix group (p < 0.0001).  The authors concluded that these findings provided further evidence of the clinical and resource utilization superiority of EpiFix compared to Apligraf for the treatment of lower extremity diabetic wounds.

As noted by the authors, limitations of this study included:
  1. patients were followed for only 1 week following complete healing,
  2. wound recidivism was not recorded, and
  3. the cost data were obtained from a CMS reimbursement schedule, and these do not reflect the actual cost of material across all clinical settings. 

They did not examine ancillary costs related to differences in product handling, storage and application procedures, which may have further impacted costs.  Moreover, they stated that additional studies are needed to evaluate the recurrence rate over time.

Zelen, et al. (2016) continued the aformentioned in order to achieve at least 100 patients. With the larger cohort, the investigators compared clinical outcomes at 12 weeks in 100 patients with chronic lower extremity diabetic ulcers treated with weekly applications of Apligraf (n = 33), EpiFix (n = 32) or SWC (n = 35) with collagen-alginate dressing as controls. A Cox regression was performed to analyse the time to heal within 12 weeks, adjusting for all significant covariates. A Kaplan-Meier analysis was conducted to compare time-to-heal within 12 weeks for the three treatment groups. The investigators stated that clinical characteristics were well matched across study groups. The proportion of wounds achieving complete closure within the 12-week study period were 73% (24/33), 97% (31/32), and 51% (18/35) for Apligraf, EpiFix and SWC, respectively (adjusted P = 0·00019). Subjects treated with EpiFix had a significant higher probability of their wounds healing [hazard ratio (HR: 5·66; adjusted P: 1·3 x 10(-7) ] compared to SWC alone. No difference in probability of healing was observed for the Apligraf and SWC groups. Patients treated with Apligraf were less likely to heal than those treated with EpiFix [HR: 0·30; 95% confidence interval (CI): 0·17-0·54; unadjusted P: 5·8 x 10(-5) ]. Increased wound size and presence of hypertension were significant factors that influenced healing. Mean time-to-heal within 12 weeks was 47·9 days (95% CI: 38·2-57·7) with Apligraf, 23·6 days (95% CI: 17·0-30·2) with EpiFix group and 57·4 days (95%CI: 48·2-66·6) with the SWC alone group (adjusted P = 3·2 x 10(-7) ). Median number of grafts used per healed wound were six (range 1-13) and 2·5 (range 1-12) for the Apligraf and EpiFix groups, respectively. 

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Zelen, et al. (2016) to be at low risk of bias.

In an in-vitro study, Massee et al (2016) evaluated PURION processed dehydrated human amnion/chorion membrane allografts (dHACM, EpiFix, MiMedx Group, Marietta, GA) for their ability to alter stem cell activity. Human bone marrow mesenchymal stem cells (BM-MSCs), adipose derived stem cells (ADSCs), and hematopoietic stem cells (HSCs) were treated with soluble extracts of dHACM tissue, and were evaluated for cellular proliferation, migration, and cytokine secretion.  Stem cells were analyzed for cell number by DNA assay after 24 hours, closure of an acellular zone using microscopy over 3 days, and soluble cytokine production in the medium of treated stem cells was analyzed after 3 days using a multiplex ELISA array.  Treatment with soluble extracts of dHACM tissue stimulated BM-MSCs, ADSCs, and HSCs to proliferate with a significant increase in cell number after 24 hours.  dHACM treatment accelerated closure of an acellular zone by ADSCs and BM-MSCs after 3 days, compared to basal medium.  BM-MSCs, ADSCs, and HSCs also modulated endogenous production of a number of various soluble signals, including regulators of inflammation, mitogenesis, and wound healing.  dHACM treatment promoted increased proliferation and migration of ADSCs, BM-MSCs, and HSCs, along with modulation of secreted proteins from those cells.  The authors concluded that dHACM may impact wound healing by amplifying host stem cell populations and modulating their responses in treated wound tissues.  Moreover, they stated that "Additional studies will be required to further characterize stem cell responses to dHACM and how these results translate in vivo".

Torabi et al (2016) developed a novel limb salvage technique using dHACM to generate granulation tissue over critical structures and then definitively closing the wound with split thickness skin grafts (STSG).  Between November 5, 2014, and March 30, 2015, 7 patients underwent dHACM + STSG limb salvage.  Demographics included 8 to 64 years of age, and 2 female and 5 male patients.  Wounds included 2 with exposed tendons, 3 with exposed bone, and 2 with exposed bone and tendon; dHACM and STSG was successful in 6 of the 7 patients.  None developed infection during dHACM treatment, STSG, and in the post-operative phase, even in the cases where initial antibiotic treatment was inadequate due to bacterial resistance.  All wounds remain stably closed.  The authors concluded that although a larger sample size is needed to fully evaluate this novel treatment modality, this early experience suggested dHACM þ STSG is a viable, low-cost alternative to free flap reconstruction.  These investigators stated that future studies will include a randomized controlled trial (RCT), and will be aimed at optimizing patient selection, timing of treatment, and analyzing the cost utility of dHACM and STSG in comparison to free flap reconstruction in addition to understanding the biological response within the wounds.

Serena, et al. (2014) reported on a multicenter, randomized, controlled study to evaluate the safety and efficacy of one or two applications of Epifix dehydrated human amnion/chorion membrane allograft and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. The primary study outcome was the proportion of patients achieving 40% wound closure at 4 weeks. Of the 84 participants enrolled, 53 were randomized to receive allograft and 31 were randomized to the control group of multilayer compression therapy alone. At 4 weeks, 62% in the allograft group and 32% in the control group showed a greater than 40% wound closure (p = 0.005), thus showing a significant difference between the allograft-treated groups and the multilayer compression therapy alone group at the 4-week surrogate endpoint. After 4 weeks, wounds treated with allograft had reduced in size a mean of 48.1% compared with 19.0% for controls. The investigators concluded that venous leg ulcers treated with allograft had a significant improvement in healing at 4 weeks compared with multilayer compression therapy alone.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Serena, et al. (2014) to be at low risk of bias.

In a multi-center RCT, Bianchi and colleagues (2018) evaluated the efficacy of EpiFix allograft as an adjunct to multi-layer compression therapy for the treatment of non-healing full-thickness venous leg ulcers.  These ersearchers randomly assigned 109 subjects to receive EpiFix and multi-layer compression (n = 52) or dressings and multi-layer compression therapy alone (n = 57).  Patients were recruited from 15 centers around the USA and were followed-up for 16 weeks.  The primary end-point of the study was defined as time to complete ulcer healing. Participants receiving weekly application of EpiFix and compression were significantly more likely to experience complete wound healing than those receiving standard wound care and compression (60 % versus 35 % at 12 weeks, p = 0.0128, and 71 % versus 44 % at 16 weeks, p = 0.0065).  A Kaplan-Meier analysis was performed to compare the time-to-healing performance with or without EpiFix, showing a significantly improved time to healing using the allograft (log-rank p = 0.0110).  Cox regression analysis showed that subjects treated with EpiFix had a significantly higher probability of complete healing within 12 weeks (HR: 2.26, 95 % CI: 1.25 to 4.10, p = 0.01) versus without EpiFix.  The authors concluded that these findings confirmed the advantage of EpiFix allograft as an adjunct to multi-layer compression therapy for the treatment of non-healing, full-thickness venous leg ulcers.

The authors stated that these results may not be generalized to other amniotic membrane products seeing that scientific papers have been published describing differences among the products.  They noted that it must also be recognized that all patients received a high level of care in a wound care center.  For ethical reasons, per study protocol, patients receiving standard care were allowed to exit the study and receive advanced wound care treatments if their wound did not reduce by a minimum of 40 % within 8 weeks of study enrolment.  Although these subjects were classified as non-healers in the final analysis due to their status at 8 weeks, they continued to be followed-up, with only 1 patient having complete healing at weeks 12 and 16.  It should be noted that the study results remained unchanged and statistically significant even when these censored data were included.  Moreover, this was an industry-sponsored study (it was funded by MiMedx Group),

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Bianchi, et al. (2018) to be at low risk of bias.

Tettelbach et al (2019a) carried out a multi-center RCT at 14 wound care centers in the U.S. to confirm the efficacy of dHACM for the treatment of chronic lower extremity ulcers in persons with diabetes.  Patients with a lower extremity ulcer of at least 4 weeks duration were entered into a 2-week study run-in phase and treated with alginate wound dressings and appropriate off-loading.  Those with less than or equal to 25 % wound closure after run-in were randomly assigned to receive weekly dHACM application in addition to off-loading or standard of care (SOC) with alginate wound dressings, for 12 weeks.  A total of 110 patients were included in the intent-to-treat (ITT) analysis, with n = 54 in the dHACM group and n = 56 in the no-dHACM group.  Of the participants, 98 completed the study per protocol, with 47 receiving dHACM and 51 not receiving dHACM.  The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per-protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT-70 % versus 50 %, p = 0.0338, per-protocol-81 % versus 55 %, p = 0.0093).  A Kaplan-Meier analysis was performed to compare the time-to-healing performance with/without dHACM, showing a significantly improved time to healing with the use of allograft, log-rank p < 0.0187.  Cox regression analysis showed that dHACM-treated subjects were more than twice as likely to heal completely within 12 weeks than no-dHACM subjects (hazard ratio [HR]: 2.15, 95 % confidence interval [CI]: 1.30 to 3.57, p = 0.003).  At the final follow-up at 16 weeks, 95 % of dHACM-healed ulcers and 86 % of healed ulcers in the no-dHACM group remained closed.  The authors concluded that these findings confirmed that dHACM is an effective treatment for lower extremity ulcers in a heterogeneous patient population.

The authors stated that an unfortunate weakness in any study of advanced wound care products compared with a "SOC group" is that the level of treatment provided as "SOC" was specified by study protocol and was generally of higher quality and more consistent than what may be provided outside a clinical trial setting, which may reduce the true effect size between treatment and control study arms.  In a meta-analysis from 1999, standard "good" wound care consisted of wet-to-dry dressings and resulted in a healing rate of approximately 24 % after 12 weeks.  In contemporary practice, a wider variety of more advanced dressings is used, and current "SOC" for treatment of lower extremity diabetic ulcers frequently consists of alginate dressings.  In the present study, alginate dressings, absorbent non-adhesive hydro-polymer secondary dressings, and gauze were used in lieu of basic moist-to-dry dressings, which the authors believed increased the rates of healing in the SOC group and reduced the treatment effect size.  A 12-week healing rate of 50 % with alginate dressings, double the rate expected with simple wet-to-dry dressings, spoke to the overall influence of advanced dressings on rates of wound healing.  Achieving 70 % healing within 12 weeks provided further evidence of the efficacy of dHACM compared with other advanced treatments.  In a perfect world, all wounds could be adequately off-loaded at all times, and patients would be 100 % compliant with the use of the prescribed off-loading device.  As in most other wound treatment studies, the inability to truly monitor off-loading compliance was a study weakness.  In the present study, clinicians were allowed to use their judgement regarding the appropriate off-loading device to prescribe, including the use of full-contact casting and when off-loading was no longer needed once healing occurred.  Given the variety of off-loading devices used, these researchers were unable to determine if the type of off-loading device influenced these findings.  As no patients' wounds were off-loaded with full-contact casting, these investigators did not know if this would have improved treatment results in either study group.  Variations in clinical recommendations for continued off-loading of healed wounds was not specified per study protocol, and it was unknown how this influenced the observed rates of wound recurrence.  This was an industry-sponsored study; further studies with independent funding sources are needed to determine the clinical effectiveness of this therapy.

Brantley et al (2019) stated that pressure injuries (PIs; pressure ulcers) affect about 3 million adults in the U.S. and cost an estimated $11 billion dollars annually to treat.  Prevention is most desirable, however, once a patient develops a pressure injury, the focus shifts to effective treatment and rapid closure to improve health outcomes.  These researchers examined outcomes in 10 patients with Stage II and III PIs treated with dHACM allografts.  All patients were treated with weekly application of dHACM plus standard wound care and followed for 8 weeks; 2 PIs were Stage II and 8 were Stage III.  The average pressure injury size at dHACM initiation was 3.42 ± 1.76 cm2.  After the 1st application of dHACM 7/10 (70 %) of PIs responded to treatment with a reduction in wound size.  Within 2 weeks of dHACM initiation into the plan of care, 4/10 (40 %) of PIs had reduced in size by greater than 50 %.  By week 4, 60 % of PIs (6/10) had reduced in size by greater than 50 %.  Overall, during the 8 week evaluation period, 3 PIs healed completely and 9 of 10 PIs reduced in size.  The authors concluded that dHACM allografts appeared to be a viable treatment option for Stage II and III PIs.

The authors stated that the drawbacks of this study were those inherent to any single-center product evaluation and any study on the treatment of pressure ulcers.  Immobility, neurogenic bowel and bladder, poor nutrition, multiple co-morbidities, and care-giver preferences are common issues in patients developing pressure ulcers.  These confounding factors made protocol design and data interpretation difficult when examining new treatments for PIs.  In the present evaluation, treatment was frequently interrupted due to removal of dressings and allograft.  These findings may have improved if allograft material had been replaced immediately if removed.  These researchers stated that although in the present study they only evaluated the use of dHACM in patients with Stage II and III PIs, given their observations, it is plausible that similar benefits to wound healing may also occur in patients with Stage IV PI.  They stated that more studies on the use of advanced technologies in these types of wounds is needed.  This study was sponsored and funded by MiMedx Group.

On February 13, 2019, the Agency for Healthcare Research and Quality's (AHRQ, 2019) Technology Assessment Program just posted a draft systematic review on "Skin Substitutes for Treating Chronic Wounds" for review.  The draft noted that "We identified 74 commercially available skin substitutes and categorized them based on the Davison-Kolter classification system.  Sixty-eight (92 %) were categorized as acellular dermal substitutes, mostly replacements from human amniotic membranes and animal tissue sources.  Three systematic reviews and 17 RCTs examined use of 13 distinct skin substitutes, including acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes in diabetic foot ulcers and venous leg ulcers.  Twenty-seven experimental ongoing clinical trials examined an additional 12 skin substitutes with similar classifications.  Studies rarely reported clinical outcomes such as amputation, wound recurrence at least 2 weeks after treatment ended, and patient-related outcomes such as return to function, pain, exudate, and odor.  The lack of studies examining the efficacy of most skin substitute products and the need for better-designed and -reported studies providing more clinically relevant data in this field is this Technical Brief’s clearest implication".  This AHRQ review cited 4 studies for EpiFix (and all 4 are cited in CPB 0244); and none for EpiCord.

EPIFLO Transdermal Continuous Oxygen Therapy [TCOT] for Wound Healing

According to Ogenix, Inc., (Beachwood, OH), EPIFLO transdermal continuous oxygen therapy (TCOT) is an FDA-cleared, 3-ounce, 24/7 oxygen therapy that effectively treats many chronic wounds (e.g., burns, diabetic foot ulcers, pressure sores, surgical wounds, and venous stasis ulcers).  EPIFLO is designed to deliver oxygen directly to a wound.  Unlike negative pressure wound therapy and hyperbaric chambers, chronic wound patients who receive EPIFLO do not have to endure dozens of treatment visits, each lasting upwards of 90 minutes, nor tolerate being tethered to a vacuum pump.  EPIFLO is small enough to fit inside one’s pocket; thus it is portable. In this regard, EPIFLO is not hyperbaric oxygen therapy.

Banks and Ho (2008) examined the effectiveness of the EpiFLO device as an adjunct treatment modality in chronic wound management.  This study included 3 men with spinal cord injury (SCI), who each presented with a stage IV pressure ulcer in the pelvic region.  They were treated with the EpiFLO device as an adjunct therapy.  In Case 1, the patient was monitored for 9 weeks, whereas in Cases 2 and 3, the patients were monitored for 5 weeks.  Healing was determined on a weekly basis by wound dimensions and volume, which were compared before and after the intervention.  Comparison of pre- and post-treatment outcome measurements showed significant improvement with EpiFLO in each case.  The authors concluded that EpiFLO seems to have had a positive effect on the healing rate of chronic pressure ulcers in individuals with SCI.  The findings of this small case-series study need to be validated by well-designed studies.

Bakri and colleagues (2008) tested the hypothesis that local transdermal delivery of oxygen improves oxygenation in sternotomy wounds after cardiac surgery; the secondary hypothesis was that supplemental inspired oxygen improves sternal wound PsqO(2).  After undergoing cardiopulmonary bypass, a total of 30 patients randomly received:
  1. 2 EpiFlo oxygen generators that provided oxygen at 6 ml/hr into an occlusive wound dressing, or
  2. identical-appearing inactive generators. 

PsqO(2) and temperature were measured in the wound approximately 5-mm below the skin surface.  PsqO(2) and arterial oxygen (Pao(2)) were measured 1 hr after intensive care unit admission (Fio(2) = 60 %) and on the 1st and 2nd post-operative mornings at Fio(2) of both 30 % and 50 % in random order.  Data from 4 patients were excluded for technical reasons.  Patient characteristics were similar in each group, as were type of surgery and peri-operative management.  Increasing Fio(2) from 30 % to 50 % improved Pao(2) from 99 [84 to 116] to 149 [128 to 174] mm Hg (p < 0.001, mean [95 % CI]) and sternal wound PsqO(2) from 23 [16 to 33] to 27 [19 to 38] mm Hg (p < 0.001).   In contrast, local oxygen delivery did not improve tissue oxygenation: 24 [14 to 41] versus 25 [16 to 41] mm Hg (p = 0.88).  The authors concluded that additional inspired oxygen improved Pao(2) and sternal wound PsqO(2) after cardiopulmonary bypass surgery, and may, consequently, reduce infection risk.  However, oxygen insufflated locally into an occlusive dressing did not improve wound PsqO(2) and, therefore, does not appear to be useful clinically in cardiac surgery patients to reduce sternal wound infections.

Schreml et al (2010) noted that oxygen is a pre-requisite for successful wound healing due to the increased demand for reparative processes such as cell proliferation, bacterial defense, angiogenesis and collagen synthesis.  The author stated that even though the role of oxygen in wound healing is not yet completely understood, many experimental and clinical observations have shown wound healing to be impaired under hypoxia.  However, this review did not provide any clinical data to support the use of TCOT for wound healing.

In a prospective, controlled study, Blackman et al (2010)
  1. examined the clinical efficacy of a pressurized topical oxygen therapy (TWO(2)) device in outpatients (n = 28) with severe diabetic foot ulcers (DFU) referred for care to a community wound care clinic; and
  2. evaluated ulcer reoccurrence rates after 24 months. 

A total of 17 patients received TWO(2) 5 times per week (60-min treatment, pressure cycles between 5 and 50 mb) and 11 selected a silver-containing dressing changed at least twice per week (control).  Patient demographics did not differ between treatment groups, but wounds in the treatment group were more severe, perhaps as a result of selection bias.  Ulcer duration was longer in the treatment (mean of 6.1 months, SD 5.8) than in the control group (mean of 3.2 months, SD 0.4) and mean baseline wound area was 4.1 cm2 (SD 4.3) in the treatment and 1.4 cm2 (SD 0.6) in the control group (p = 0.02).  Fourteen of 17 ulcers (82.4 %) in the treatment group and 5 of 11 ulcers (45.5 %) in the control group healed after a median of 56 and 93 days, respectively (p = 0.04).  No adverse events were observed and there was no re-occurrence at the ulcer site after 24 months' follow-up in either group.  The authors noted that although the absence of randomization and blinding may have under- or over-estimated the treatment effect of either group, the significant differences in treatment outcomes confirmed the potential benefits of TWO(2) in the management of difficult-to-heal DFUs.  Moreover, they stated that clinical efficacy and cost-effectiveness studies as well as studies to elucidate the mechanisms of action of TWO(2) are needed.

In a pilot study, Woo et al (2012) evaluated the effectiveness of TCOT on chronic wound healing in 9 patients.  After 4 weeks of treatment, mean wound surface area and wound infection check-list scores were significantly reduced.  Signs of bacterial damage were also reduced.  The authors concluded that findings from this study suggested TCOT may be beneficial in promoting chronic wound healing.  These preliminary findings from a small pilot study need to be validated by well-designed studies.

Driver, et al. (2017) reported on a prospective, randomized, blinded, multicenter, parallel study conducted from October 2009 to November 2012 to evaluate healing time and the proportion of diabetic foot ulcers (DFUs) healed after 12 weeks of moist wound therapy (MWT) with or without transcutaneous oxygen therapy (TCOT). Study participants (persons with type 1 or type 2 diabetes and a nonhealing [>1-month but <1-year duration], 1 cm2 to 10 cm2 in area, infection-free DFU) were randomized to TCOT or a sham device (control) in addition to receiving MWT. TCOT treatment consisted of continuous administration of 98+% oxygen to the wound site using a 15-day epiFlo device with dressings changed every 3 to 7 days per care plan or more often when clinically required. Potential participants completed demographic and clinical screening and wound and laboratory evaluations at baseline, and wound evaluations, evaluation of adverse events, debridement, and treatment once weekly until the wound healed or up to 12 weeks. The primary endpoint was defined as complete wound closure by week 12. Wound measurements were made utilizing acetate tracings. Original tracings were collected at approximately 6-week intervals and analyzed upon study closure. Data were collected via paper case report forms and entered into an electronic database after the patient’s final visit. Statistical analysis was performed on datasets exported from the electronic database. Wound measurement data were analyzed using chi-squared. Time to complete closure was analyzed using Kaplan-Meier analysis in conjunction with the log-rank test. Of the 130 potential participants, 8 with protocol violations were excluded from analysis. In the intent-to-treat (ITT) population (N = 122, average age 59 years [range 28–85 years]), the majority were male (74%), Caucasian (81%), and had a plantar ulcer (76%). Mean baseline wound area was 2.3 ± 1.7 cm2 (range 0.4–8.9 cm2) and 2.0 ± 1.7 cm2 (range 0.6–8.7 cm2) in the control and TCOT groups, respectively. HbA1c (%) was 7.9 ± 1.7 in the control and 8.0 ± 1.7 in the treatment group. In the TCOT group, 35 of 65 (54%) wounds healed compared to 31 of 63 (49%) in the control arm, a difference that was not statistically significant (p = .4167). In the per-protocol population (PP) (i.e., patients without protocol violations), 34 of 61 wounds (56%) in the TCOT group and 31 of 61 (49%) in the control group healed. In the ≥65 years PP subgroup, 14 of 17 (82%) in the TCOT and 8 of 16 (50%) in the control arm healed (p = .049). Median time to complete closure in the PP group was 63 days for the TCOT and 77 days for the control group, a difference that was not statistically significant (P >.05). No device-related serious adverse events occurred in either group. The investigators reported that wound outcomes of patients in both groups were good, but the TCOT device did not appear to offer added benefit over moist wound healing treatment and offloading to facilitate the healing of small, nonsevere diabetic foot ulcers of relatively healthy patients. The investigators stated that the data suggest the device may offer a greater benefit to older patients. The investigators stated that studies including a more diverse and larger sample patient population are warranted.

Also, an UpToDate review on "Basic principles of wound management" (Armstrong and Meyr, 2013) does not mention the use of transdermal continuous oxygen therapy as a therapeutic option.

Esano A

Esano A is a single-layer, decellularized, dehydrated human amniotic membrane allograft that is designed to act as a cover or barrier for acute and chronic wounds and function as a protective coverage from the surrounding environment for acute and chronic wounds. Esano A dosage is per square centimeter, depending on the size of the wound. Subsequent to standard wound preparation, Esano A is applied directly to the wound and adheres without requiring fixation to the wound bed. This product is supplied in a single use package in a variety of sizes (CMS, 2023a).

Esano AAA

Esano AAA is a tri-layer, decellularized, dehydrated human amniotic membrane allograft that is designed to act as a cover or barrier for acute or chronic wounds and function as a protective coverage from the surrounding environment for acute and chronic wounds. Esano AAA dosage is per square centimeter, depending on the size of the wound. Subsequent to standard wound preparation, Esano AAA is applied directly to the wound and adheres without requiring fixation to the wound bed. This product is supplied in a single use package in a variety of sizes (CMS, 2023a).

Esano AC

Esano AC is a dual-layer, decellularized, dehydrated human amniotic membrane allograft that is designed to act as a cover or barrier for acute and chronic wounds and function as a protective coverage from the surrounding environment for acute and chronic wounds. Esano AC dosage is per square centimeter, depending on the size of the wound. Subsequent to standard wound preparation, Esano AC is applied directly to the wound and adheres without requiring fixation to the wound bed. This product is supplied in a single use package in a variety of sizes (CMS, 2023a).

Esano ACA

Esano ACA is a tri-layered, decellularized, dehydrated human amniotic membrane allograft that is designed to act as a cover or barrier for acute and chronic wounds and function as a protective coverage from the surrounding environment for acute and chronic wounds. Esano ACA dosage is per square centimeter, depending on the size of the wound. Subsequent to standard wound preparation, Esano ACA is applied directly to the wound and adheres without requiring fixation to the wound bed. This product is supplied in a single use package in a variety of sizes (CMS, 2023a).

Excellagen

According to the manufacturer, Excellagen (pharmaceutically formulated bovine full length fibrillin collagen gel 2.6%) is indicated for the management of wounds including: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/graft, post-Moh’s surgery, post laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second degree burns and skin tears) and draining wounds (CMS, 2013). It is applied immediately following wound debridement. It is an acellular biological modulator designed for platelet activation (when applied to debrided wounds and in the presence of a small influx of blood), resulting in the localized release of platelet-derived growth factors that are essential to wound healing. Excellagen also provides a substrate and scaffold for chemotaxis, cellular adhesion, migration, and proliferation to promote granulation tissue growth. Excellagen is supplied as a sterile gel in a package of 4 ready-to-use 1 mL glass syringes with fill volume of 0.5cc.

E-Z Derm

E-Z Derm Biosynthetic Wound Dressing (Brennen Medical, Inc., St. Paul, MN) is a porcine-derived xenograft that has been chemically cross-linked with an aldehyde to provide durability and storage.  The dermal elements from the original pig dermis are likely all deactivated in the chemical process, unlike the frozen pig dermis which is still available.  It appears that the product is a collagen scaffold. E-Z Derm has been used as an alternative to allografts in the treatment of burn wounds, especially for partial thickness skin losses, temporary coverage prior to autograft and to protect meshed autografts 

E-Z Derm is a biosynthetic wound dressing made from porcine tissue chemically treated to cross-link collagen with an aldehyde to add strength and allow storage at room temperature (Snyder, et al., 2012). Because E-Z Derm is composed of porcine tissue, it is considered a porcine xenograft. The shelf life is 18 months. The company Web site promotes E-Z Derm for the temporary coverage of wounds prior to autograft, partial thickness skin loss, to protect meshed autografts, for outpatient skin loss, donor sites, skin ulcerations, and abrasions.

EZ-Derm is a porcine dermis xenograft that is used as temporary coverage for skin loss injuries. It reduces pain, fluid loss, and protein. It provides a barrier to external contamination and it provides a moist wound healing and thus protects underlying tissue in the treatment of burns, abrasions, donor sites, decubitus and chronic vascular ulcers. It can be used on any person except those who have a known sensitivity to porcine products, on patients with histories of multiple serum allergies, or on wounds with large amounts of eschar. As the wound heals, EZ-Derm will naturally slough off; as this occurs the dry edges may be trimmed off to avoid mechanical dislodgment (shearing). EZ Derm, all dermis porcine xenograft is supplied in rolls (3" wide by 12", 24" or 48" long). EZ Derm is also supplied in sheets, 7"x18" and patches, 3"x4" and 2"x2". Shelf life of EZ Derm is 18 months from date of manufacture, at room temperature storage.

E-Z Derm Biosynthetic Wound Dressing was cleared for marketing under the 510(k) process in July 1994. There is very little evidence that the use of E-Z Derm is beneficial in wound healing. In a prospective, randomized trial (n = 32), Healy and Boorman (1989) compared E-Z Derm with Jelonet as a burn dressing in patients with partial skin thickness burns.  The bacterial colonization rate, need for surgical treatment, time for spontaneous healing, analgesic requirements and frequency of dressing changes were assessed in each group.  No statistically significant differences were found between the 2 groups, for any of these factors.

In a controlled, prospective study (Vanstraelen, 1992), calcium sodium alginate and E-Z Derm were compared in the treatment of split-thickness skin graft donor sites on 20 patients.  Half of each donor site was dressed with each material.  Time to complete healing, quality of regenerated skin and patient comfort were evaluated.  Time to healing was 8.1 days with alginate and 11.3 days with E-Z Derm (p < 0.001).  Quality of healed skin was consistently good with the alginate, and better than under E-Z Derm in 95 % of patients (p < 0.001).  Hypertrophic scarring was not observed under alginate dressings but occurred in 25 % of E-Z Derm-dressed sites (p <  0.01).  Furthermore, evidence was found that allergic reactions to E-Z Derm could occur.  Alginate was preferred by 75 % of patients and none preferred E-Z Derm (p < 0.01); the remainder had no preference.  The author concluded that E-Z Derm is inferior to calcium sodium alginate as a dressing for split-thickness skin donor sites.

Fibrin Sealant for Breast Reconstruction

The use of fibrin sealant has been proposed as a means of preventing seroma formation following breast cancer surgery.  Carless and Henry (2006) performed a systematic review of RCTs to examine the effectiveness of fibrin sealants in reducing post-operative drainage and seroma formation after breast cancer surgery.  Studies were identified by computer searches of Medline, Embase, the Cochrane Central Register of Controlled Trials and manufacturer websites (to June 2005), and bibliographic searches of published articles.  Trials were eligible for inclusion if they reported data on post-operative drainage and the number of patients who developed a seroma.  A total of 11 trials met the criteria for inclusion.  In general, the trials were small and of poor methodological quality.  Fibrin sealant did not reduce the rate of post-operative seroma (relative risk 1.14, 95 % CI: 0.88 to 1.46), the volume of drainage (weighted mean difference - 117.7, 95 % CI: - 259.2 to 23.8 ml), or the length of hospital stay (weighted mean difference - 0.38, 95 % CI: - 1.58 to 0.83 days).  The authors concluded that the current evidence does not support the use of fibrin sealant in breast cancer surgery to reduce post-operative drainage or seroma formation.

Cipolla et al (2010) evaluated the effectiveness of fibrin glue in the prevention of seroma formation after axillary lymphadenectomy.  A total of 159 breast cancer patients about to undergo quadrantectomy or mastectomy plus axillary lymphadenectomy were enrolled in the study and randomized into 2 groups:
  1. fibrin glue spray applied to the axillary fossa plus placement of closed suction drainage were used in 80 patients (group A), and
  2. placement of closed suction drainage was only used in 79 patients (group B). 

Patients in group A showed a slight advantage with regard to the mean duration of axillary drainage placement (4.5 +/- 1.3 days in group A versus 5.1 +/- 1.6 days in group B) and number of seroma aspirations (6.3 +/- 1.1 in group A versus 6.7 +/- 1.2 in group B).  No statistically significant differences were observed between the 2 groups of patients regarding the mean volume of total axillary drainage and of total seroma volume.  The authors concluded that the use of fibrin glue does not prevent seroma formation and does not reduce seroma magnitude and duration.

Llewellyn-Bennett et al (2012) noted that latissimus dorsi (LD) flap procedures comprise 50 % of breast reconstructions in the United Kingdom.  They are frequently complicated by seroma formation.  In a randomized study, these researchers investigated the effect of fibrin sealant (Tisseel) on total seroma volumes from the breast, axilla and back (donor site) after LD breast reconstruction.  Secondary outcomes were specific back seroma volumes together with incidence and severity of wound complications.  Consecutive women undergoing implant-assisted or extended autologous LD flap reconstruction were randomized to either standard care or application of fibrin sealant to the donor-site chest wall.  All participants were blinded for the study duration but assessors were only partially blinded.  Non-parametric methods were used for analysis.  A total of 107 women were included (sealant = 54, control = 53).  Overall, back seroma volumes were high, with no significant differences between control and sealant groups over 3 months.  Fibrin sealant failed to reduce in-situ back drainage volumes in the 10 days after surgery, and did not affect the rate or volume of seromas following drain removal.  The authors concluded that the findings of this randomized study, which was powered for size effect, failed to show any benefit from fibrin sealant in minimizing back seromas after LD procedures.

Fish Skin Graft (Omega3 Wound ECM / Omega3 Wound Matrix)

Lullove et al (2021) stated that omega-3–rich fish skin grafts have been shown to accelerate wound healing in full-thickness wounds.  In a blinded, multi-center, randomized controlled clinical trial, these researchers compared the fish skin graft with standard of care (SOC) using collagen alginate dressing in the management of treatment-resistant diabetic foot ulcers (DFUs), defined as superficial ulcers not involving tendon capsule or bone.  Patients with DFUs who were first treated with SOC (off-loading, appropriate debridement, and moist wound care) for a 2-week screening period were then randomized to either receiving SOC alone or SOC plus fish skin graft applied weekly for up to 12 weeks.  The primary endpoint was the percentage of wounds closed at 12 weeks.  A total of 49 patients were included in the final analysis.  At 12 weeks, 16 of 24 patients' DFUs (67 %) in the fish skin arm were completely closed, compared with 8 of 25 patients' DFUs (32 %) in the SOC arm (p = 0.0152 [n = 49]; significant at p < 0.047).  At 6 weeks, the percentage area reduction was 41.2 % in the SOC arm and 72. 8% in the fish skin arm.  The authors concluded that the application of fish skin graft to previously non-responsive DFUs resulted in significantly more fully healed wounds at 12 weeks than SOC alone.  The study findings support the use of fish skin graft for chronic DFUs that do not heal with comprehensive SOC treatment.

The authors stated that this study had several drawbacks.  They were aware that clinical trials attract adherent patients who fit a narrow spectrum of care.  In DFU trials, such patients often had well-controlled hemoglobin A1c and were adherent with off-loading.  This prospective, randomized trial was no different in that regard, but the model used is the best option for evaluating a product such as the one studied herein.  It was not possible to blind either the person applying the product or the patient to the material being applied.  Thus, this trial included a third investigator who was blinded to evaluation of closure.  Intrinsic bias remains a concern owing to the patient and caregiver knowing the therapy being applied.  Both study arms received a once-weekly visit that included debridement, re-application, and dressing change in the clinic; patients in the SOC arm were additionally allowed dressing changes at home, whether by themselves or a caregiver.  Such dressing changes were performed in accordance with the frequency and care level presented by the manufacturer in the instructions for use for the specific product.  Additional dressing changes at home could expose a wound to unknown factors, potentially resulting in stalled healing.  To minimize the risk of delayed healing, patients and/or their caregivers were assessed for adherence, and both verbal and written instructions were given.  In most cases the caregiver was a licensed home care nurse.

FlexHD

FlewxHD is an acellular dermal matrix derived from human allograft skin, used for hernia repair and breast reconstruction.

FlexHD is a human allograft skin minimally processed to remove epidermal and dermal cells while providing the acellular matrix of the dermis (Snyder et al, 2012).  It is processed using proprietary procedures developed by Musculoskeletal Transplant Foundation (MTF, Edison, NJ) to preserve and maintain the natural biomechanical, biochemical and matrix properties of the dermal graft.  FlexHD is used to support cellular repopulation and vascularizaton in applications at the surgical site.  It is indicated for use to replace damaged or inadequate integumental tissue.  Ethicon promotes Flex HD for hernia repair and breast reconstruction.  There is limited available published evidence on FlexHD prehydrated acellular dermal matrix.  Primary studies included a retrospective medical record review of the use of FlexHD in tissue expander breast reconstruction (Rawlani et al, 2011) and an uncontrolled case series of the use of FlexHD in single-stage breast reconstruction (Rosenberg et al, 2011).  Other studies reported on the use of both FlexHD and Alloderm human acellular dermal tissue matrix in breast reconstruction, but do not report detailed analysis of the comparative efficacy of these products (Topol et al, 2008; Cahan et al, 2011).

FloGraft

FloGraft is a cryopreserved liquid, injectable amniotic fluid-derived allogfaft used in soft tissue repair.

FlowerDerm / FlowerFlo (FlowerAmnioFlo) / FlowerPatch (FlowerAMINOPatch)

FlowerDerm is a hydrated acellular (human) dermal allograft matrix used for the treatment of non-healing wounds and burn injuries.  FlowerDerm contains extracellular matrix (ECM) that provides a scaffold for cellular ingrowth vascularization, tissue regeneration and formation of granulation tissue.  The typical patient population includes individuals with chronic, non-infected, full thickness diabetic lower extremity ulcers, patients with chronic, non-infected, partial or full-thickness diabetic lower extremity skin ulcers due to venous insufficiency that have not adequately responded following conventional ulcer therapy and patients with 2nd and 3rd degree burns.  FlowerDerm allografts are hydrated in saline and transported and stored at ambient temperature.  FlowerDerm is supplied as a thin (0.5 mm) allograft, meshed and un-meshed, in a variety of sizes; as a medium (1 mm) allograft, meshed or unmeshed, in a variety of sizes; and as a thick (2 mm) unmeshed allograft in several sizes.  FlowerDerm may be cut and shaped to the appropriate size.  It is applied over the wound site following wound bed preparation.  Absorbable/non-absorbable suture material and/or tissue adhesives may be used to apply the graft to the site, if necessary.  There is a lack of evidence regarding the effectiveness of FlowerDerm.

FlowerFlo is a 100 % acellular liquid amniotic fluid allograft intended for the treatment of non-healing wounds and burn injuries.  FlowerFlo delivers cytokines, proteins and growth factors to help generate soft tissue.  The typical patient population includes individuals with chronic, non-infected, full thickness diabetic lower extremity ulcers, patients with chronic, non-infected, partial or full-thickness diabetic lower extremity skin ulcers due to venous insufficiency that have not adequately responded following conventional ulcer therapy and patients with 2nd and 3rd degree burns.  FlowerFlo delivers cytokines, proteins and growth factors to help regenerate soft tissue.  FlowerFlo is prescribed by a qualified health care profession for injection on or in the wound site, in a physician office, out-patient, or in-patient setting.  The dosage is per cubic centimeter (cc), depending on the size of the wound, intended for external application.  There is a lack of evidence regarding the effectiveness of FlowerFlo.

FlowerPatch is a dehydrated (human) amniotic membrane allograft used for the treatment of non-healing wounds and burn injuries.  FlowerPatch delivers cytokines, proteins and growth factors help generate soft tissue.  The product is directed to patients with chronic, non-infected, full thickness diabetic lower extremity ulcers due to venous insufficiency that have not adequately responded following conventional ulcer therapy and patients with 2nd and 3rd degree burns.  FlowerPatch is transported and stored at ambient temperature.  It is supplied in single-use packages in the following sizes: 2 cm X 2 cm, 2 cm X 4 cm, 4 cm X 6 cm, 4 cm X 8 cm.  FlowerPatch is prescribed by a qualified health care professional for administration in a physician office, out-patient, or in-patient setting.  FlowerPatch may be cut and shaped to the appropriate size.  It is applied over the wound site following wound preparation.  Absorbable/non-absorbable suture material and/or tissue adhesives may be used to apply the graft to the site, if necessary.  There is a lack of evidence regarding the effectiveness of FlowerPatch.

Willett et al (2014) assessed the effectiveness of micronized dehydrated human amnion/chorion membrane (μ-dHACM) as a disease-modifying intervention in a rat model of osteoarthritis (OA). It was hypothesized that intra-articular injection of μ-dHACM would attenuate OA progression.  Lewis rats underwent medial meniscal transection (MMT) surgery to induce OA; 24 hours post-surgery, μ-dHACM or saline was injected intra-articularly into the rat joint.  Naïve rats also received μ-dHACM injections.  Microstructural changes in the tibial articular cartilage were assessed using equilibrium partitioning of an ionic contrast agent (EPIC-μCT) at 21 days post-surgery.  The joint was also evaluated histologically and synovial fluid was analyzed for inflammatory markers at 3 and 21 days post-surgery.  There was no measured baseline effect of μ-dHACM on cartilage in naïve animals.  Histological staining of treated joints showed presence of μ-dHACM in the synovium along with local hyper-cellularity at 3 and 21 days post-surgery.  In MMT animals, development of cartilage lesions at 21 days was prevented and number of partial erosions was significantly reduced by treatment with μ-dHACM. EPIC-μCT analysis quantitatively showed that μ-dHACM reduced proteoglycan loss in MMT animals.  The authors concluded that μ-dHACM was rapidly sequestered in the synovial membrane following intra-articular injection and attenuated cartilage degradation in a rat OA model.  They stated that these data suggested that intra-articular delivery of μ-dHACM may have a therapeutic effect on OA development.

Fluid Flow and Fluid GF

Fluid Flow and Fluid GF (BioLab Sciences, Inc.) are human amniotic flowable allografts intended for homologous use and support the repair of soft tissue injury by providing natural growth factors and other extracellular components to the injured area to promote healing, reduce inflammation, and reduce healing time (CMS, 2019). "The patient population indicated for use of Fluid Flow and Fluid GF include acute and chronic wounds and soft tissue injury, muscle and meniscus tears, ligament and tendon sprains, degenerative tissue disorders and Inflammatory conditions (tendonitis and fasciitis)." The products are available in 0.5cc, 1cc and 2cc sizes.

FortaDerm and FortaDerm Antimicrobial

FortaDerm is a single-layer fenestrated sheet of porcine collagen.  FortaDerm is a skin substitute intended for the management of wounds including: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, post-Moh's surgery, post-laser surgery, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, and skin tears) and draining wounds.  It is supplied dry in sheet form in sizes ranging from 5x5 cm to 12x36 cm.  FortaDerm is packaged in sterile, sealed single pouches and is administered by surgically applying and fixing it to a wound using sutures or other fixation method.  FortaDerm is used similarly to other collagen wound dressings. 

FortaDerm Antimicrobial PHMB is a sterile single-use sheet dressing made of collagen matrix and is coated with polyhexamethylene biguanide hydrochloride (PHMB) (CMS, 2014).  It is intended for the management of wounds and as an effective barrier to resist microbial colonization within the dressings and reduce microbes penetrating through the dressing.  It is supplied dry in sheet form in sizes ranging from 4x4 cm to 12x36 cm.  FortaDerm Antimicrobial PHMB is packaged in sterile, sealed single pouches.  FortaDerm Antimicrobial PHMB Wound Dressing is a skin substitute designed for use on acute and chronic, partial and full-thickness wounds.  It is surgically applied and fixed to a wound using sutures or other fixation method based on the size of the wound being treated.

Fortiva Porcine Dermis

Fortiva Porcine Dermis is a non-crosslinked porcine dermis, designed to act as a scalffold that allows for neovascularization and reincorporation with the individual's own tissue. It is sused in soft tissue repair procedures such as hernia repair.

Gammagraft Skin Substitute

GammaGraft (Promethean LifeSciences, Inc., Pittsburgh, PA) is an irradiated human skin allograft acquired from cadaveric donors.  According to the manufacturer, its main applications are as a temporary graft for treating burns, partial and full thickness wounds, anc chronic wounds including venous stasis ulcers, diabetic foot ulcers, and full-thickness wounds (Promethean LifeSciences, 2008).  The manufacturer states that GammaGraft has both the epidermal and the dermal layers of human skin which makes it more durable and effective as a vapor barrier than most wound covers, especially some artificial skins, which lack the keratinocyte layer that is found in the epidermis.  The manufacturer states that the irradiation process that GammaGraft undergoes produces 2 key advantages: the irradiation acts as a preservation and sterilization agent significantly reducing any risk of viral transmission of disease and allowing Gammagraft to be stored at room temperature for up to 2 years. The graft is stored in an aluminum foid package and preserved in a penicillin/gentamycin solution. The manufacturer explains that the ability to store GammaGraft at room temperature for up to 2 years makes GammaGraft readily available for use upon opening a foil pack, without the need for thawing, cleansing, and rehydration.  The manufacturer also states that GammaGraft can be applied in a clinical setting without incurring operating room time for application. To use GammaGraft, the wound area is debrided, the graft is placed and a nonadherent dressing is applied, followed by a gauze dressing (Snyder, et al., 2012).

According to the manufacturer, for years, cadaver derived allograft skin has been the gold standard in the treatment of wounds and burns. For this reason, all bioengineered grafts have attempted to replicate the performance of allograft skin, and in this sense are "skin substitutes," whereas GammaGraft is human skin allograft. However, some allografts (i.e. GammaGraft) are mislabeled as "skin substitutes." Allografts differ in structure, tissue origin, and in some cases, differ from bioengineered "skin substitutes" in terms of how they are approved by the FDA. Both GammaGraft and Alloskin, are human cadaver skin that has simply been preserved. They are regulated by the FDA as human tissue for transplantation and not devices. Other products regulated under the same regulations do not retain the original structure of the donor skin and in fact, still other products are of bovine or porcine origin and may or may not be combined with synthetic materials.

There is a lack of evidence in the peer-reviewed published medical literature on the safety and effectiveness of Gammagraft Skin Substitute.

Genesis Amniotic Membrane

Genesis Amniotic Membrane (Genesis Biologics, Inc., Anaheim, CA) is a dehydrated, collagenous human tissue allograft used for the treatment of acute and chronic wounds, soft tissue injuries, and infection prevention. The placental product contains collagen, cytokines, and growth factors that aid in wound healing and reduced scarring. According to the manufacturer, the Genesis Amniotic Membrane is indicated for use for diabetic patients experiencing issues with wound healing. It is also indicated for patients who have undergone surgical reconstructions and other complex operative procedures. The product is applied in a manner that prevents displacement over the open wound. There is no need for any suturing or adhesions upon application.

Gore Bio-A Fistula Plug

An anal fistula is a small channel or tunnel between the anal canal and the surrounding skin that most commonly develops after an anal abscess bursts, creating an opening. Gore BIO-A Fistula Plusg is a synthetic bioabsorbable scaffold used in sphincter-preserving anal fistula repair.

In a retrospective review of a database of patient records, Heydari et al (2013) evaluated the safety and effectiveness of the use of a new synthetic fistula plug made of bioabsorbable polymers in the treatment of crypto-glandular anal fistulas.  A total of 48 patients (39 men and 9 women; mean age of 49.9 years) with 49 fistulas were treated with the synthetic plug between November 2009 and March 2012.  Types of fistula were as follows: 24 superficial trans-sphincteric, 18 medium trans-sphincteric, 5 deep trans-sphincteric, and 1 medium inter-sphincteric.  The fistula tract was cleaned by using curettage, and a synthetic plug was sized to fit the tract and inserted.  A draining seton was used pre-operatively in 1 patient.  Main outcome measures were complete closure of the fistula, with no discharge/residual fistula (verified by endo-anal ultrasonography), perineal pain level (assessed with a visual analog scale), and fecal continence.  Follow-up was conducted at 1 week and 1, 3, 6, and 12 months post-operatively.  The overall healing rate was 69.3 % (34/49 fistulas, 33/48 patients); 8 patients (24.2 %) had healing by 3 months after surgery, 21 patients (63.6 %) had healed by 6 months, and 4 patients (12.1 %) had healed by 12 months.  By 3 months, no patient had perineal pain or fecal incontinence.  No plug became dislodged, and no patient had the onset of anal stenosis, bleeding, local infection, or any other complication.  The authors concluded that in patients with crypto-glandular anal fistulas, the use of a bioabsorbable synthetic plug provided a high rate of healing without causing fecal incontinence or other major adverse effects.  Moreover, they stated that larger and randomized studies of this treatment are needed.  Major drawbacks of this study included small number of patients and the retrospective non-randomized nature of the study.

Grafix

Grafix Core and Grafix Prime are extracellular matrix containing growth factors for acute and chronic wounds, including diabetic foot ulcers and burns.

Grafix Core is an allograft containing endogenous mesenchymal stem cells indicated for the treatment of deep chronic wounds, limb salvage procedures, tendon repair and burns.  Grafix Prime is an allograft containing endogenous mesenchymal stem cells indicated for upper epithelial layer chronic wounds and burns. 

Grafix CORE is an allograft derived from human chorionic placental tissue "intended" for patients with acute and chronic wounds including, but not limited to, diabetic foot ulcers, venous stasis ulcers and pressure ulcers that have not responded to standard of care therapy. Grafix CORE has one layer (a thick stromal layer), a collagen rich membrane, mesenchymal stem cells (MSCs), and anti-inflammatory cytokines and regenerative growth factors. The thick stromal layer of Grafix CORE has been used in wounds with exposed bone and tendon to help promote granulation of deep tissue. The collagen matrix provides a physiological microenvironment for cells and proteins to promote cellular adhesion and migration in addition to supporting growth factor function. Cytokines and growth factors, epidermal growth factor and transforming growth factor-beta3 in Grafix CORE mediate integral events such as angiogenesis, cell recruitment and proliferation. Once thawed and rinsed, Grafix CORE is applied to the wound and covered with a standard, non-adherent dressing. Additional applications are used as needed with frequency ranging from every 7-14 days until the wound is closed. Grafix CORE is supplied as a cryopreserved membrane mounted on nitrocellulose paper and is available in 2 sizes; 2cm x 2cm and 5cm x 5cm. According to the manufacturer, the presence of MSCs in Grafix distinguishes it from all other skin substitutes.

Grafix PRIME is an allograft derived from the amniotic membrane of human placental tissue used for the management of acute and chronic wounds including, but not limited to, diabetic foot ulcers, venous stasis ulcers and pressure ulcers that have not responded to standard of care therapy. Additional uses include burns, adhesion barriers, and Mohs procedures. Grafix PRIME has two layers (epithelial layer and stromal layer) and is comprised of a collagen rich membrane, mesenchymal stem cells, and anti-inflammatory cytokines and regenerative growth factors. The collagen matrix provides a physiological microenvironment for cells and proteins to promote cellular adhesion and migration in addition to supporting growth factor function. Cytokines and growth factors, epidermal growth factor and transforming growth factor-beta3 in Grafix PRIME mediate integral events such as angiogenesis, cell recruitment and proliferation. Once thawed and rinsed, Grafix PRIME is applied to the wound and covered with a standard, non-adherent dressing. Additional applications are used as needed with frequency ranging from every 7-14 days for up to 12 weeks or until the wound is closed. Grafix PRIME is supplied as a cryopreserved membrane mounted on nitrocellulose paper and is available in 3 sizes; 2cm x 2cm and 5cm x 5cm, and 7.5cm x 15cm. According to the manufacturer, the presence of mesenchymal stem cells in Grafix  distinguishes it from all other skin substitutes. Mesenchymal stem cells coordinate the tissue repair process through down regulation of inflammation, by stimulating blood vessel formation (angiogenesis), and by supporting fibroblast and epithelial cells resulting in rapid wound closure.

As part of an agreement with the FDA, Grafix is indicated as a "wound cover" for the treatment of acute and chronic wounds. The manufacturer has announced its intent to submit a Biologics License Application to support clinical indications for Grafix.

The functionality, clinical use, and patient population of GrafixPL CORE is the same as Grafix CORE (CMS, 2017). GrafixPL CORE is a lyopreserved chorion-derived placental membrane retaining the extracellular matrix, growth factors, and endogenous viable cells of the native tissue. The product functions as a protective barrier supporting the repair of acute and chronic wounds. GraflixPL Core is available in 3 sizes: 16 mm disc, 2 cm x 3 cm, and 5 cm x 5 cm. GrafixPL CORE is applied directly to the wound on a weekly basis for up to 12 weeks or until the wound is closed, the same as Grafix CORE.

GrafixPL Prime is a placental tissue allograft categorized as a skin substitute and intended for homologous use as a wound cover (CMS, 2017). It is a three-dimensional matrix, designed for application directly to acute and chronic wounds, including but not limited to diabetic foot ulcers, (DFUs), venous leg ulcers (VLUs), pressure ulcers, surgical wounds, burns, dehisced wounds, and wounds with exposed tendon, bone, and/or muscle by acting as a wound cover or barrier. It is applied directly to the wound weekly for up to 12 weeks or until the wound is closed. Grafix PL Prime is supplied as a lyopreserved amnion-derived placental membrane between two pieces of plastic mesh backing, packaged in a sealed foil pouch. It is available in 3 sizes: 16mm disc, 2cm X 3cm, and 5 cm X 5 cm.

In a randomized, controlled study, Lavery et al (2014) compared the efficacy of Grafix Prime, a human viable wound matrix (hVWM) (n = 50), to standard wound care (n = 47) to heal diabetic foot ulcers (DFUs).  Subjects included adults with type 1 or type 2 diabetes who have foot ulcers that were present for at least 1 month (4 weeks) and no longer than 1 year (52 weeks).  Excluded were subjects with large ulcers (greater than 15 cm2), infection, inadequate circulation to the foot, and exposed muscle, tendon, bone or joint capsule.  Wounds in both groups received standard wound care that included surgical debridement, off-loading and non-adherent dressings.  The wound dressing was petroleum impregnated gauze (Adaptic) and either saline moistened gauze or an adhesive hydrocellular foam (Allevyn) for moderately draining wounds. The primary endpoint was the proportion of patients with complete wound closure by 12 weeks.  Wound closure was independently confirmed via a central wound core laboratory with 2 blinded wound care experts who reviewed all wounds via digitized acetate tracing and photography.  Secondary end-points included the time to wound closure, adverse events and wound closure in the crossover phase.  The proportion of patients who achieved complete wound closure was significantly higher in patients who received Grafix (62 %) compared with controls (21 %, p = 0·0001).  The median time to healing was 42 days in Grafix patients compared with 69·5 days in controls (p = 0·019).  There were fewer Grafix patients with adverse events (44 % versus 66 %, p = 0·031) and fewer Grafix patients with wound-related infections (18 % versus 36·2 %, p = 0·044).  Among the study subjects that healed, ulcers remained closed in 82·1 % of patients (23 of 28 patients) in the Grafix group versus 70 % (7 of 10 patients) in the control group (p = 0·419). 

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Lavery, et al. (2014) to be at low risk of bias.

Fryberg et al (2017) reported the results of a prospective, multicenter, open-label, single-arm clinical trial to establish clinical outcomes when Grafix Prime viable cryopreserved human placental membrane (vCHPM) is applied weekly to complex diabetic foot ulcers (DFUs) with exposed deep structures. Patients with type 1 or type 2 diabetes and a complex DFU extending through the dermis with evidence of exposed muscle, tendon, fascia, bone and/or joint capsule were eligible for inclusion. Of the 31 patients enrolled, 27 completed the study. The mean wound area was 14·6 cm2 , and mean duration was 7·5 months. For patients completing the protocol, the primary endpoint, 100% wound granulation by week 16, was met by 96·3% of patients in a mean of 6·8 weeks. Complete wound closure occurred in 59·3% (mean 9·1 weeks). The 4-week percent area reduction was 54·3%. There were no product-related adverse events. Four patients (13%) withdrew, two (6·5%) for non-compliance and two (6·5%) for surgical intervention. 

Limitations of the study include a lack of a well-defined guideline-supported standard of care that includes nutritional support and blood glucose control.  Certain baseline measurements necessary for evaluation (wound culture, nutrition, lymphocyte count) relevant to comparison of treatment and control groups were not reported, as were certain important outcomes (rate of secondary amputation at 4 to 6 months).  Additional studies are needed to compare Grafix to advanced wound care dressings.

Johnson et al (2017) noted that advances in tissue preservation have led to the commercialization of human placental membranes for the purposes of wound management with each product being characterized by different compositions and properties.  The a priori specification of the research question in this investigator-initiated study focused on the clinical outcomes in 2 non-randomized, however statistically equal and homogenous patient cohorts receiving either a viable intact cryopreserved human placental membrane (vCPM; (Grafix) or a dehydrated human amnion/chorion membrane (dHACM; EpiFix), for the management of wounds at a single center.  A total of 79 patients with 101 wounds were analyzed: 40 patients with 46 wounds received vCPM and 39 patients with 55 wounds received dHACM.  The proportion of wounds achieving complete wound closure was 63.0 % (29/46) for vCPM and 18.2 % (10/55) for dHACM (p < 0.0001) for all treated wounds combined.  The authors stated that this was the first comparative effectiveness study to report on the clinical outcomes associated with the use of different placental wound care products once broadly implemented in the clinical setting.  Moreover, these researchers stated that although treatment cohorts in the study were well balanced as demonstrated by the lack of statistically significant differences for key patient and wound characteristics between the 2 treatment groups, they recognized that the retrospective and non‐randomized nature of this single‐center study presented significant drawbacks.  High quality evidence for non‐DFU wound types does not currently exist in the literature for vCPM and dHACM; however, the objective of this present study was to review and report the aggregated outcomes for both placental products without patient or wound exclusions.  These investigators stated that while additional data points such as patient vascular status and glycemic control would have contributed to an improved understanding of the study outcomes, the authors found these results to be compelling and worthy of review within the medical community while representing a contribution to the growing body of comparative effectiveness research in wound care.

Ananian et al (2018) analyzed clinical outcomes and product cost between GrafixPrime viable cryopreserved placental membrane (vCPM) and Dermagraft human fibroblast-derived dermal substitute (hFDS) for the treatment of chronic diabetic foot ulcers in a prospective, multicenter, single-blind study. The outcomes of 62 patients were analyzed: 31 patients in the vCPM treatment group and 31 patients in the hFDS treatment group. Utilizing a non-inferiority trial design and the established treatment regimen of 8 applications for hFDS, the investigators demonstrated that vCPM was not inferior to hFDS for the proportion of patients achieving complete wound closure (9.68, 90% CI: [10.67, 28.94]). However, preliminary findings show that vCPM may have better outcomes for wounds ≤ 5 cm2 : 81.3% (13/16) of wounds in the vCPM group vs. 37.5% (6/16) of wounds in the hFDS group reached complete closure at the end of treatment (p = 0.0118).

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Ananian, et al. (2018) to be at moderate risk of bias.

Grafix Cryo-Preserved Placental Membrane

Lavery et al (2018) reported the results of the single-arm, open-label extension phase of the Grafix (cryo-preserved placental membrane; CPM; Osiris Therapeutics, Inc., Columbia, MD) multi-center, blinded, randomized, controlled clinical trial for chronic diabetic foot ulcers (DFUs).  A total of 26 patients in the standard wound care (SWC) arm whose DFUs did not close in the blinded phase chose to receive weekly applications of the CPM in an open-label extension phase.  In the extension phase, 17 (65.4 %) patients closed their wounds in a median of 34 days and 3 visits.  There were fewer total adverse events (AEs) (24 CPM versus 52 SWC) and index wound-related infections (5 CPM versus 12 SWC) during the CPM application compared with the number of AEs for the same patients during the SWC treatment in the blinded phase of the trial.  The authors concluded that these findings corroborated the benefits of this CPM combined with SWC over SWC alone for chronic DFUs previously reported for the blinded randomized phase of the trial, which directly related to lower health care costs.

The authors stated that although the use of a 3rd party for blinded assessment of wound closure reduced bias of the open-label phase of the trial, bias inherently could not be eliminated from these types of studies.  This bias was due to knowledge of the treatment assignment that may influence the behavior of patients.  The small sample size (n = 26) was an additional limitation of this study.  Selection bias was always an issue in RCTs.  There were strict inclusion and exclusion criteria that did not necessarily reflect the general population of patients with DFUs.

In a prospective, multi-center, single-blind study, Ananian et al (2018) analyzed clinical outcomes and product cost between a viable cryo-preserved placental membrane (vCPM) and a human fibroblast-derived dermal substitute (hFDS) for the treatment of chronic DFUs.  The outcomes of 62 patients were analyzed: 31 patients in the vCPM treatment group and 31 patients in the hFDS treatment group.  Utilizing a non-inferiority trial design and the established treatment regimen of 8 applications for hFDS, these researchers demonstrated that vCPM was not inferior to hFDS for the proportion of patients achieving complete wound closure (9.68, 90 % CI: 10.67 to 28.94]). However, preliminary findings showed that vCPM may have better outcomes for wounds of less than or equal to 5 cm2 : 81.3 % (13/16) of wounds in the vCPM group versus 37.5 % (6/16) of wounds in the hFDS group reached complete closure at the end of treatment (p = 0.0118).  A preliminary product cost analysis for wounds less than or equal to 5 cm2 may showed significant savings for patients treated with vCPM.  Average per-patient costs during the course of treatment were $3,846 and $7,968 (p < 0.0001) for vCPM and hFDS patients, respectively.  The authors concluded that these findings may be used as guidance to wound care providers and payers. 

The authors stated that the main drawbacks of this study included wound closure assessment after 8 weekly applications, which was not common in clinical studies for DFUs, and the lack of a follow-up period after the treatment phase of the trial.  In addition, the imbalance of the number of plantar wounds and chronicity of DFUs between the 2 groups could have negatively impacted clinical outcomes recorded for the vCPM treatment group.  Although the sample size was sufficient to meet the primary end-point, it was not large enough to make definitive conclusions about analyses performed for wounds less than or equal to 5 cm2.  These researchers stated that these are interesting data findings and future studies are needed to confirm these preliminary results.  Furthermore, the single-blind design of the study, the lack of stratification by wound location and size for analyses, as well as the lack of specificity regarding wound location, were also recognized as limitations.  These investigators stated that as placental membrane products become more widespread in the wound care space, future comparative analyses using other placental products will provide valuable data for health care providers and payers.

Raspovic et al (2018) evaluated the effectiveness of vCPM for DFU management using Net Health's WoundExpert electronic health records (EHR).  The primary end-point was the proportion of DFUs that achieved complete closure.  Other end-points included time and number of grafts to closure, probability of wound closure by week 12, and the number of wound-related infections and amputations.  De-identified EHR data for 360 patients with 441 wounds treated with vCPM were extracted from the database.  Average patient age was 63.7 years with a mean wound size of 5.1 cm2 and an average wound duration of 102 days prior to vCPM treatment.  For evaluation of clinical outcomes, 350 DFUs larger than 0.25 cm2 at baseline were analyzed.  Closure at the end of treatment was achieved in 59.4 % of wounds with a median treatment duration of 42.0 days and 4 applications of vCPM.  The probability of wound closure at week 12 was 71 %, and the number of amputations and wound-related infections was 13 (3.0 %) and 9 (2.0 %), respectively.  Data also showed a correlation between wound size and closure rate as well as a correlation between greater 50 % wound area reduction by week 4 and wound closure by week 12.  The authors concluded that the results of this study mirrored previous RCT efficacy data, supporting the benefits of vCPM for DFU management.

The authors stated that the most obvious drawback was the retrospective nature and absence of a control cohort in this trial, which relied on a large database.  Also, the lack of a standardized treatment algorithm and treatment selection bias were known drawbacks of observational studies.  The data obtained were only as good as the data recorded, thus potentially introducing measurement error.  Measurement error occurred when any measurement about a subject was not accurate. The methods and tools used to measure wounds, define infection, or define "healing" may be systematically different among the centers that participated in the study.  Selection bias was also a possibility since patients in this cohort were more likely to have insurance or the resources that could pay for this therapy or adjunctive therapies that made advanced wound care product more effective.  Furthermore, these researchers stated that this study also outlined the importance of future studies to validate 50 % wound area reduction as a predictive surrogate marker of closure for vCPM and other advanced wound care modalities.

In a prospective, single-center, open-label, single-arm study, Farivar et al (2018) compared the efficacy of a human viable wound matrix (hVWM) of cryo-preserved placental tissue for the treatment of refractory chronic venous leg ulcers (VLUs) with standard therapy.  This trial enrolled patients with Clinical, Etiology, Anatomy, and Pathophysiology clinical class C6 VLUs.  The ulcers of all enrolled patients had failed to heal after a trial of standard therapy of at least 12 weeks, which included weekly multi-layer compression therapy along with local wound care.  The same patients subsequently received application of hVWM (Grafix) every 1 to 2 weeks in addition to standard therapy.  Healing with hVWM therapy was then compared with standard therapy, with each patient serving as his own control.  There were 30 VLUs in 21 consecutive eligible patients who were enrolled in the study.  All patients were men with an average age of 67 years (standard deviation [SD], ± 10.8 years), and the average area of venous ulcers before hVWM initiation was 12.2 cm2 (SD, ± 14.6 cm2; range of 3.3 to 12.3 cm2).  Duplex ultrasound (US) confirmed superficial or deep system venous reflux in all patients.  Complete ulcer healing was achieved in 53 % (16/30) of VLUs refractory to standard therapy after application of hVWM.  There was a mean reduction in wound surface area by 79 % (SD, ± 27.3 %; p < 0.001 compared with standard therapy) after a mean treatment time of 10.9 weeks; 80 % of VLUs were reduced in size by half compared with 25 % with standard therapy (p < 0.001).  The mean rate of reduction in ulcer area after hVWM applications was 1.69 % per day versus 0.73 % per day with standard therapy (p = 0.01).  The authors concluded that cryo-preserved placental tissue (hVWM) improved healing processes to achieve complete wound closure in a significant proportion of chronic VLUs refractory to standard therapy; adjunctive therapy with hVWM provided superior healing rates in refractory VLUs.

This was a small (n = 21), single-center, open-label, single-arm study with relatively short follow-up (mean of 10.9 weeks).  Moreover, the authors noted that relative wound surface area reduction per day was statistically significant, whereas absolute surface area reduction per day was not.  This perhaps was indicative of the fact that hVWM therapy may be more beneficial in closure of smaller wounds compared with larger ones even though baseline wound size at initiation of each therapy did not differ significantly.  However, it was difficult to examine this for certain because of the sample size studied; larger randomized trials are needed for further analysis.  These researchers did not perform a comparative cost-benefit analysis in this small study; in the future, this information will facilitate decision-making on the overall benefit of this treatment modality.  The study could not rule out that some ulcers may have healed with standard therapy.  Importantly, though, the wound healing rate during standard therapy was significantly slower than during hVWM therapy, and wounds with greater than or equal to 50 % wound area reduction were significantly higher with hVWM treatment too.  These 3 end-points together showed the same directionality and indicated an overall better and more rapid wound healing response to hVWM.  These investigators stated that larger studies are needed to confirm these preliminary findings.

Graftjacket Regenerative Tissue Matrix for Rotator Cuff Repair

In a prospective, multi-center, randomized study, Barber et al (2012) evaluated the safety and effectiveness of arthroscopic acellular human dermal matrix augmentation of large rotator cuff tear repairs. Patients undergoing arthroscopic repair of 2-tendon rotator cuff tears measuring greater than 3 cm were randomized by sealed envelopes opened at the time of surgery to arthroscopic single-row rotator cuff repair with Graftjacket acellular human dermal matrix augmentation (group 1) or without augmentation (group 2).  Pre-operative and post-operative functional outcome assessments were obtained by use of the American Shoulder and Elbow Surgeons (ASES), Constant, and University of California, Los Angeles scales.  Gadolinium-enhanced magnetic resonance imaging (MRI) evaluation of these repairs was obtained at a mean of 14.5 months (range of 12 to 24 months).  Adverse events were recorded.  There were 22 patients in group 1 and 20 in group 2 with a mean age of 56 years.  The mean follow-up was 24 months (range of 12 to 38 months).  The ASES score improved from 48.5 to 98.9 in group 1 and from 46.0 to 94.8 in group 2.  The scores in group 1 were statistically better than those in group 2 (p = 0.035).  The Constant score improved from 41.0 to 91.9 in group 1 and from 45.8 to 85.3 in group 2.  The scores in group 1 were statistically better than those in group 2 (p = 0.008).  The University of California, Los Angeles score improved from 13.3 to 28.2 in group 1 and from 15.9 to 28.3 in group 2 (p = 0.43).  Gadolinium-enhanced MRI scans showed intact cuffs in 85 % of repairs in group 1 and 40 % in group 2 (p < 0.01).  No adverse events were attributed to the presence of the matrix grafts.  The authors concluded that acellular human dermal matrix augmentation of large (greater than 3 cm) rotator cuff tears involving 2 tendons showed better ASES and Constant scores and more frequent intact cuffs as determined by gadolinium-enhanced MRI.  Intact repairs were found in 85 % of the augmented group and 40 % of the non-augmented group (p < 0.01).  No adverse events related to the acellular human dermal matrix were observed.  (Level II, lesser-quality randomized controlled trial).  This was a small study (n = 22) with short-term follow-up (mean follow-up was 24 months).  These findings need to be validated by well-designed studies.

The American Academy of Orthopaedic Surgeons (AAOS) guideline on "Optimizing the Management of Rotator Cuff Problems" (2010) had no recommendations for the use of acellular human dermal matrix grafts/Graftjacket.

The University of New South Wales (Australia)’s clinical practice guidelines on "The Management of Rotator Cuff Syndrome in the Workplace" (2013) had no recommendations for the use of acellular human dermal matrix grafts/Graftjacket.

Graftjacket Tissue Matrix

Graftjacket tissue matrix is a wound care product derived from cadaveric skin, which undergoes a process that removes the epidermis and dermal cells. The human dermal tissue is preserved, which purportedly reduces the rejection response and allows the body to accept the matrix. Over time, the body’s natural repair process supposedly converts the matrix into living tissue. Graftjacket tissue matrix is indicated for full-thickness diabetic foot ulcers greater than three week duration that extend through the dermis, but without tendon, muscle, joint capsule or bone exposure. 

Graftjacket tissue matrix (Wright Medical Technology, Inc, Arlington, TN) is an acellular regenerative tissue matrix that is designed to provide a scaffold for wound repair. Donated human tissue is treated to remove the epidermis and cellular components, but it retains collagen, elastin, and proteoglycans, and the internal matrix of the dermis remains intact (Snyder, et al., 2012). The tissue is then cryogenically preserved. The company states that removal of the cellular component reduces rejection, retention of dermal proteins allows for revascularization and cellular repopulation, and the preserved tissue matrix reduces inflammation.

In a pilot, prospective, randomized study (n = 40), Brigido et al (2004) ascertained the effectiveness of this tissue product in wound repairing of diabetic foot ulcers compared with conventional treatment.  Only a single administration of the tissue matrix was required.  After 1 month of treatment, preliminary results showed that this novel tissue matrix promoted faster healing at a statistically significant rate over conventional treatment.  Results of this study are promising, but they need to be verified by further investigation with larger sample sizes and longer follow-ups.

Graftjacket Xpress Flowable Soft-Tissue Scaffold is a micronized (finely ground) decellularized soft tissue scaffold indicated for the repair or replacement of damaged or inadequate integumental tissue, specifically deep, dermal wounds that exhibit tunneling, and extension from the wound base that may extend deep into the tendon and bone (CMS, 2006).  Graftjacket Xpress is a soft tissue graft (reconstituted as a "gel"), which is comprised solely of human dermal tissue, including its native protein and collagen structure and essential biochemical composition.  The re-hydrated skin substitute scaffold is placed into the tunnels or tracts, and is intended to produce the same or superior clinical outcomes with a minimally invasive procedure.  There is a lack of peer-reviewed published medical literature on the effectiveness and safety of the Graftjacket Xpress.

Lanier et al (2010) retrospectively identified tissue expander/implant breast reconstructions by 5 surgeons at a single institution from 2005 to 2008 and divided into 2 cohorts:
  1. use of acellular dermal matrix (ADM) (n = 75) versus
  2. standard submuscular placement (n = 52). 

The ADM group had a statistically significant higher rate of infection (28.9 % versus 12.0 %, p = 0.022), re-operation (25.0 % versus 8.0 %, p = 0.011), expander explantation (19.2 % versus 5.3 %, p = 0.020), and overall complications (46.2 % versus 22.7 %, p = 0.007).  When stratifying by breast size, a higher complication rate was not observed with the use of ADM in breasts less than 600 g, whereas ADM use in breasts larger than 600 g was associated with a statistically significant higher rate of infection when controlling for the occurrence of skin necrosis.  The ADM cohort had a significantly higher mean initial tissue expander fill volume (256 ml versus 74 ml, p < 0.001) and a significantly higher mean initial tissue expander fill ratio (49 % versus 17 %, p < 0.001).  The authors concluded that further work is needed to define the ideal patient population for ADM use in tissue expander/implant breast reconstruction.

Spear et al (2011) examined the use of ADM for correction or prevention of implant-associated breast deformities.  Patients who underwent primary aesthetic breast surgery or secondary aesthetic or reconstructive breast surgery using ADM and implants between November of 2003 and October of 2009 were reviewed retrospectively.  Patient demographics, indications for ADM, and ADM type and inset pattern were identified.  Pre-operative and post-operative photographs, success or failure of the procedure, complications, and need for related or unrelated revision surgery were recorded.  A total of 52 patients had ADM placed alongside 77 breast prostheses, with a mean follow-up of 8.6 months (range of 0.4 to 30.4 months).  Indications included prevention of implant bottoming-out (n = 6), treatment of malposition (n = 32), rippling (n = 20), capsular contracture (n = 16), and skin flap deficiency (n = 16).  Seventy-four breasts (96.1 %) were managed successfully with ADM.  Three failures consisted of 1 breast with bottoming-out following treatment of capsular contracture, 1 breast with major infection requiring device explantation, and 1 breast with recurrent rippling.  There was a 9.1 % total complication rate, consisting of 3 mild infections, 1 major infection necessitating explantation, 1 hematoma, and 1 seroma.  The authors concluded that based on this experience in 77 breasts, ADM has shown promise in treating and preventing capsular contracture, rippling, implant malposition, and soft-tissue thinning.

Williams and Holewinski (2015) reported on a small study of a limb preservation strategy that includes application of Graftjacket Regenerative Tissue Matrix. Medical history, physical examination and full wound assessment were completed for all patients. Systemic antibiotics and appropriate offloading were prescribed as needed. Wounds were debrided to create a bleeding bone and/or wound base for HADWM (Graftjacket regenerative tissue matrix, Wright Medical Technology, Inc., licensed by KCI, an Acelity company, San Antonio, TX). Healing progress was monitored over four weeks with weekly postoperative visits. 'Healed' was defined as full epithelialisation without drainage. The investigators reported that lower extremity ulcers, 16 in 13 patients, were treated with HADWM between May 2004 and July 2013. The median patient age was 76 years (range: 38-90). The average number of comorbidities was three per patient, while 6 (46%) patients had ≥4 comorbidities. Diabetes mellitus (92%) and peripheral vascular disease (77%) were the two most common. All 16 (100%) wounds healed without complications. There were no recurrences in the 11 wounds of the nine patients available for follow-up. Of these patients two had previously advised to receive major leg amputations retained functional limbs.

Reyzelman and Bazarov (2015) reported on a review of the clinical literature to estimate the comparative effectiveness Graftjacket regenerative tissue matrix (HADWM) versus standard care in healing diabetic foot ulcers (DFUs). Outcomes from three prospective, controlled clinical trials, which included 154 patients with DFUs, were pooled. A comparative analysis revealed a statistically significant reduction in mean wound healing time, 1.7 weeks, as well as a nearly four-fold improvement in the chance of healing ulcers treated with HADWM versus moist wound-care. The authors concluded that these pooled results suggest that HADWM may improve healing outcomes for these difficult-to-heal lower extremity wounds.

Barber and colleagues (2008) examined the failure mode of supraspinatus tendon repairs with and without human dermal allograft augmentation.  A total of 10 matched pairs of human cadaveric supraspinatus muscles and tendons were detached from their greater tuberosity insertions and then reattached with 4 simple sutures in 2 suture anchors as a control group.  One shoulder from each matched pair was augmented with human dermal allograft secured to the humerus and the supraspinatus tendon using the same sutures and suture anchors.  Additional interrupted mattress sutures secured the edges of the dermal allograft to the supraspinatus tendon.  Each construct was preloaded at 10 N and then cyclically loaded between 10 N and 100 N for 10 cycles at 20 N/s followed by destructive testing at 33 mm/s.  Force and displacement were recorded.  The mean failure strengths for the control and augmented constructs were 273 +/- 116 N and 325 +/- 74 N, respectively (p = 0.047).  No significant displacement occurred during the cyclic phase, and no anchors failed.  These constructs failed by 2 different mechanisms: tendon-suture interface failure (8/10 non-augmented repairs and 6/10 augmented repairs) and suture breakage (2/10 non-augmented repairs and 4/10 augmented repairs).  The authors concluded that this examination of the failure characteristics and ultimate failure load of supraspinatus tendon tears augmented with GraftJacket supported the study hypothesis that a human dermal allograft significantly increased the strength of a repaired tendon.

The main drawback of this study was it was a time-zero study of an artificially produced supraspinous tendon tear.  All tendons studied in this series were intact, and there was no obvious degeneration or delamination commonly observed in the clinical setting.  Thus, this model simplified a complex multi-factorial pathologic process and evaluated it at only 1 time interval (time zero).  The data generated at time zero could not be assumed to persist throughout the heling period.  Furthermore ,this study provided no information on the healing potential of such a construct.

El-Kassaby et al (2014) stated that oro-nasal fistula (ONF) following cleft palate (CP) repair are a challenging problem associated with high recurrent rates.  Acellular dermal matrix allograft is an available tissue substitute.  In a prospective study, these researchers evaluated the effectiveness of acellular dermal matrix in the repair of ONF associated with CP that is recurrent or larger than 15 mm in any dimension.  This trial included 12 patients with repaired CP suffering from ONF of the hard palate of greater than 15 mm in diameter; age ranged from 12 to 25 years.  Acellular dermal matrix was firmly secured between repaired oral and nasal mucosal layers.  Patients were clinically followed-up for 6 months post-operatively to assess total time for complete healing, dehiscence and/or re-fistulization.  Acellular dermal matrix was integrated with successful fistula closure in all except 1 patient where failure of graft integration was noticed early post-operatively.  In 6 patients, the oral mucosal layer showed dehiscence, through which the graft was exposed.  Graft integration extended from 4 to 12 weeks post-operatively during which patients were instructed to follow a soft diet and meticulous oral hygiene measures.  The authors concluded that acellular dermal matrix allografts were safe and effective adjuncts for use in closure of ONF in the hard palate that was recurrent or larger than 15 mm in any dimension.

In a retrospective, cohort study, Susarla et al (2015) examined the rate of canine eruption in alveolar clefts repaired with cancellous autograft versus cancellous autograft mixed with allograft.  This trial included patients in mixed dentition who underwent primary repair of unilateral or bilateral alveolar cleft defects.  Patients were divided into 2 groups based on the method of bony reconstruction (group 1, iliac crest autograft; group 2, iliac crest autograft harvested through a minimal access approach and mixed 1:2 with demineralized bone allograft).  Secondary predictor variables were demographic and anatomic factors potentially related to canine eruption.  The outcome variable was the velocity of canine eruption, measured as the change in vertical distance from the incisal edge to the maxillary occlusal plane (mm/month).  Descriptive, bi-variate, and linear regression statistics were computed.  The study sample included 57 alveolar cleft defects; 19 were repaired with autograft alone and 38 were repaired with autograft plus allograft.  The sample's mean age was 9.9 ± 2.3 years at the time of repair; 31 clefts (54.4 %) were part of a bilateral deformity.  Canine root formation was 50 % complete at the time of surgery in most patients (59.6 %).  Mean duration of follow-up was 23.7 ± 13.2 months.  Mean canine eruption velocity was 0.20 ± 0.18 mm/month and was not associated with the method of bony repair (p = 0.58).  The authors concluded that the use of allograft bone to augment bone graft volume resulted in similar rates of canine eruption compared with autograft bone alone.

Otto et al (2017) stated that bone grafts from the iliac crest are most commonly used for osteoplasties of the cleft alveolus.  To preclude undue donor site morbidity custom-milled allogeneic bone grafts might be an appropriate choice.  This technical note showcased the repair of an alveolar cleft using an individualized allogeneic bone graft in a 36-year old woman.  She was asking for an alternative to the iliac crest bone grafting.  Her alveolus was successfully build up by a custom-milled cancellous bone block allograft (maxgraft® 80 bone builder).  Custom-milled cancellous bone block allografts could greatly facilitate alveolar cleft repair and may present an effective therapeutic option under the premise that resorption resistance corresponded to autografts.  The authors concluded that further clinical studies are needed to examine the potential of bone block allografts for alveolar cleft osteoplasty.

Shirzadeh et al (2018) noted that the chin is a common donor site for alveolar cleft bone grafting.  The amount of bone available at this site can be limited, because conservative harvesting with mixed dentition must consider the incisive nerve, the unerupted mandibular canine, and the integrity of the inferior mandibular border.  Patients with non-syndromic unilateral alveolar cleft in the mixed dentition stage were selected for this study.  The volume of bone obtained from the mandibular symphysis (symphysis menti), degree of alteration in lower lip sensation, anterior tooth vitality, remaining bone in the alveolar cleft, and bone defects at the donor site 1 year after surgery were evaluated.  A total of 18 patients were enrolled in this study.  The mean volume of bone harvested from the symphysis was 2.1 mL (range of 1.6 to 2.3 ml).  For all cases, the bone volume harvested from the symphysis was insufficient to fill the alveolar cleft defect, and allograft had to be added to completely fill the cleft.  Allograft was admixed in the range of 0.5 to 1 ml with autogenous bone harvested from the mandible.  Lower lip sensation and vitality of the anterior teeth of the mandible were within the normal range 1 year after surgery in all cases; 14 of 18 patients (77.8 %) had normal bone height or bone height at least 3/4 of the expected height in the grafted alveolar cleft after 1 year; only 10 % of the defect remained in the mandible.  The authors concluded that the amount of bone yielded by conservative mono-cortical bone harvest from the mandibular symphysis during the mixed dentition stage for unilateral alveolar cleft bone grafting was insufficient in volume and should be mixed with allograft.  However, donor site morbidity was low with this approach.

Blume et al (2019) stated that cleft lip and palate is the most common congenital deformity with severe effects on the quality of life (QOL) of affected patients.  The deformity often includes an alveolar cleft (AC).  In most cases, osteoplasty will be performed using autogenous bone transplants harvested from the iliac crest.  Thus, this treatment represents a highly invasive procedure.  With freeze-dried bone allografts (FDBAs) becoming an increasingly accepted alternative to autogenous bone grafting for several indications, their application might also be suitable for AC reconstruction.  These researchers presented the use of a customized allogenic bone block in a guided bone regeneration procedure for reconstruction of a unilateral AC and the successful insertion of dental implants after a healing period of 6 months.  The use of FDBA appeared to represent a successful therapeutic option for AC reconstruction.  The allogenic bone block demonstrated high volume stability with ideal integration and re-vascularization, resulting in functional bone tissue suitable for implantation and esthetic rehabilitation.  The authors concluded that further investigations, especially concerning the long-term stability of the augmented bone and dental implants, are needed to draw definite conclusion regarding the performance of allogenic bone blocks in orofacial cleft osteoplasty.

Cockcroft and Markelov (2018) noted that trapeziectomy with interpositional arthroplasty using Repriza acellular dermal matrix is a novel technique to treat primary and secondary carpometacarpal (CMC) joint arthritis.  Early studies with non-autograft interposition indicated promising post-trapeziectomy space maintenance with results similar to ligament reconstruction with tendon interposition, without the potential risks and increased operating time of harvesting a tendon autograft.  A total of 11 patients in a retrospective cohort were followed for a minimum of 6 weeks (mean of 12).  Subjective and objective data were collected to assess pain, subjective improvement of symptoms, radiographic measurements of 1st metacarpal subsidence, key pinch strength, grip strength, and range of motion (ROM).  Early outcomes in this cohort compared favorably to other treatment series.  On average, patients received a significant pain reduction of 63 %, with 36 % of patients admitting to complete pain resolution; 100 % of patients admitted to overall subjective improvement in symptoms; 91 % of patients achieved post-operative opposition of the thumb and 5th digit.  Comparison with pre-operative x-rays showed mean thumb metacarpal subsidence of 27 %.  Zigzag deformity and extra-articular acellular dermal matrix migration, due to lack of patient compliance with splint, were observed complications.  Only 8.3 % subsidence was observed with an impressive 45 % pain reduction, in a salvage patient after revision surgery for a NuGrip implant.  The authors concluded that this was a safe and effective primary or salvage technique for Eaton grades III and IV thumb CMC arthritis with a mean subsidence within the range observed with ligament reconstruction with or without tendon interposition.  These researchers stated that long-term study with a larger sample size is needed to investigate this technique further.  The main drawbacks of this study were its retrospective design, small sample size (n = 11) and short follow-up period (mean of 12 weeks).

Helicoll 

Hilicoll (EnColl Corporation) is a bovine collagen acellular dermal matrix. Helicoll is a semi-occlusive, self-adhering and sterilized Type- 1 collagen sheet for wound treatments, second degree burns, and chronic ulcers. It is indicated for use as a topical collagen wound dressing, and topical wound management including partial and full-thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (abrasions, lacerations, second-degree burns, skin tears, and for surgical wounds, donor sites/grafts, post-Mohs’ surgery, post-laser surgery, podiatric, wound dehiscence).

Biodegradable collagen dressings are derived from animal tissues; they maintain a moist environment that promotes healing and the formation of granulation tissue. Helicoll is individually packaged and intended as a single application for an individual patient. Product should be trimmed to size prior to contact with the patient. It is supplied in a multiple sizes ranging from 2x2 to 6x26 square inches.

hMatrix

hMatrix acellular dermis is a dermal scaffold processed from donated human skin.  The skin is processed to remove the epidermal layer from the dermis as well as the epidermal and dermal cells from the collagen and elastin that constitutes the dermal matrix.  The dermal matrix is then packaged and sterilized using low-dose gamma irradiation; the product is stored and supplied frozen.  hMatrix is indicated for use to replace damaged or inadequate integumental tissue.  It is designed for homologous use only.  Specific uses of hMatrix include use as a wound covering, abdominal wall repair, breast reconstruction, and for use in supplemental support, reinforcement, or covering of tendons or periosteum.  There are few published studies addressing the use of hMatrix for wound treatment.

hMatrix is a dermal substitute derived from the dermal layer of human skin by removing the epidermal layer and cellular components from the dermis. It is indicated for use to replace damaged or inadequate integumental tissue, indicated for homologous use only. Specific uses of hMatrix include use as a wound covering, abdominal wall repair, breast reconstruction, soft tissue grafting in craniomaxillofacial applications, and for use in supplement support, reinforcement, or covering of tendons or periosteum. hMatrix contains elastin, collagen, proteoglycans, and vascular channels which provide an ideal environment for revascularization and cellular repopulation when surgically implanted or grafted. When used as a wound covering, hMatrix is placed over the derided wound site and the graft is fixed via the use of sutures or staples. hMatrix is packaged frozen and is designed for single-use. It is provided in three thicknesses in specific sizes ranging from 1cm x 2cm to 5cm x 10cm to allow for patient specific needs, as determined by surgeons.

In an evidence-based review, Clemens and Kronowitz (2012) evaluated the clinical impact of acellular dermal matrix for breast reconstruction in the setting of radiation therapy.  The MEDLINE and EMBASE databases were reviewed for articles published between January of 2005 and February of 2012.  The authors also reviewed their institutional experience of consecutive patients who met these criteria between January of 2008 and October of 2011.  A total of 13 articles were identified for review: 3 animal studies on acellular dermal matrix and 10 with level III evidence of its use in humans.  The 10 clinical studies included 246 irradiated patients.  The M. D. Anderson experience included 30 irradiated acellular dermal matrix patients for a total of 276 irradiated patients evaluated in this review.  Use of acellular dermal matrix in implant-based breast reconstruction in the setting of radiation therapy did not predispose to higher infection or overall complication rates or prevent bioprosthetic mesh incorporation.  However, the rate of mesh incorporation may be slowed.  Its use allowed for increased intra-operative saline fill volumes, which improved aesthetic outcomes and allowed patients to awake from surgery with a formed breast.  The authors concluded that use of acellular dermal matrix for implant-based breast reconstruction does not appear to increase or decrease the risk of complications, but it might provide psychological and aesthetic benefits.  They stated that multi-center or single-center RCTs that provide high-quality, level I evidence are warranted.

Shridharani and Tufaro (2012) conducted a systematic review of acellular dermal matrices in head and neck reconstruction.  After searching the PubMed database and following further refinement (based on the authors' inclusion and exclusion criteria), the authors identified 30 studies that provided information about patients who had undergone head and neck reconstruction with the use of acellular dermal matrix.  Studies had to report quantifiable objective results in patients who were older than 1 year and younger than 90 years.  The authors excluded single case reports, studies with fewer than 10 patients, and studies not published in English.  The optimal material used as an implant for reconstruction possesses the following properties: facilitation of vascular ingrowth, decreased propensity to incite inflammation, biologic inertness, resistance to infection, and ease of handling.  Acellular dermal matrix possesses many of these properties and is utilized in reconstructing nasal soft tissue and skeletal support, tympanic membrane, peri-orbital soft tissue, extra-oral and intraoral defects, oropharyngeal defects, dura mater, and soft-tissue deficits from parotidectomy.  Furthermore, it is used to assist in preventing Frey syndrome following parotidectomy and surgical treatment of facial paralysis.  The authors concluded that use of acellular dermal matrix for head and neck reconstruction has expanded exponentially and is validated in many studies.  Moreover, they noted that further prospective RCTs are needed to further examine the effectiveness of acellular dermal matrix in head and neck reconstruction.

In a systematic review, Janis et al (2012) examined the benefits of acellular dermal matrices in abdominal wall reconstruction.  The MEDLINE database was reviewed, including all publications as of December 31, 2011, using the search terms "dermal matrix" or "human dermis" or "porcine dermis" or "bovine dermis," applying the limits "human" and "English language".  Prospective and retrospective clinical articles were identified.  A total of 40 eligible articles were identified and included in this review; 35 of the studies were level IV; the remaining studies were level III.  Acellular dermal matrix was used to reconstruct the abdominal wall in a wide range of clinical settings, including trauma, tumor resection, sepsis, and hernia repairs.  The operative methods varied widely among clinical studies.  While the heterogeneity of the patient populations and techniques limited interpretation of the data, concerns were identified regarding high rates of hernia recurrence with acellular dermal matrix use.  The authors concluded that high-quality data derived from level I, II, and III studies are needed to determine the indications for acellular dermal matrix use and the optimal surgical techniques to maximize outcomes in abdominal wall reconstruction.

Ellis and Kulber (2012) reviewed the current literature on the use of acellular dermal matrix in forearm, wrist, and hand reconstruction.  A comprehensive literature search was performed using the Cochrane Database of Systematic Reviews, MEDLINE, PubMed, and Web of Knowledge.  Articles were categorized as acellular dermal matrix used in soft-tissue repair and in ligament reconstruction.  Search terms included "acellular dermal matrix," "biologic dressing," "skin replacement," "dermal allograft," "AlloDerm," "FlexHD," "Permacol," and "Strattice".  These were all cross-referenced with "forearm," "wrist," and "hand".  Data extraction focused on indications, surgical techniques, clinical outcomes, and complications.  Exclusion criteria included regeneration templates, neonatal foreskin, and review articles.  More than 100 articles published between 1994 and 2011 were identified.  Upon final review, 5 prospective case-control studies, 3 retrospective case-control studies, 4 case reports, 1 cross-sectional cohort, 1 prospective consecutive series, and 1 study type unknown were evaluated.  Matrix was most commonly used in burn reconstruction.  It has also been used in ligament and joint reconstruction for first carpometacarpal arthritis.  One article illustrated the use of porcine matrix in basal joint arthritis, a practice that was abruptly terminated because of a concern over increased infections.  The authors concluded that the clinical indications for acellular dermal matrix have increased throughout the last 15 years.  Hand surgeons have been cautious but diligent in developing alternative treatment options in hand reconstruction, with a focused effort to reduce donor-site morbidity.  They stated that although acellular dermal matrices continue to find innovative uses to solve upper extremity surgical problems, more comparative prospective trials are needed.

Human Health Factor 10 Amniotic Patch (HHF10-P)

Human Health Factor 10 Amniotic Patch (HHF10-P) (Wolver and Poole Distribution, LLC) is a single-layer amniotic allograft derived from donated and screened, full-term human birth tissue, specifically the immunoprivileged amnion layer. It is a semi-transparent, minimally manipulated, terminally sterilized membrane allograft. HHF10-PTM is intended for homologous use to act as a covering or barrier to offer protection from the surrounding environment in clinical applications. HHF10-P is supplied as either a 2 cm x 2 cm or 4 cm x 4 cm size in dual-layer, sterile 4 mm packaging.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of HHF10-P.

Hyalomatrix

Hyalomatrix (Anika Therapeutics, Inc., Bedford, MA, formerly Fidia Advanced Biopolymers, Abano Terme, Italy) is a bilayered wound dressing composed of a nonwoven pad made of a benzyl ester of hyaluronic acid (HYAFF 11), a long-acting derivative of hyaluronic acid, and a semipermeable silicone membrane providing a microenvironment (Snyder, et al., 2012). The nonwoven pad contacts the wound and, according to the manufacturer, "provides a three dimensional matrix for cellular invasion and capillary growth." The silicone membrane "controls water vapor loss, provides a flexible covering for the wound surface, and adds increased tear strength to the device." The HYAFF 11 matrix is biodegradable. The company believes that "when the integration of the HYAFF based material in the newly formed dermal matrix has progressed, a well-vascularized granulation tissue forms. This provides for wound closure via spontaneous re-epithelialization or acts as a suitable dermal layer for skin grafting." 

Hyalomatrix KC Wound Dressing was cleared for marketing under the 510(k) process in July 2001 for "the management of wounds in the granulation phase such as pressure ulcers, venous and arterial leg ulcers, diabetic ulcers, surgical incisions, second degree burns, skin abrasions, lacerations, partial-thickness grafts and skin tears, wounds and burns treated with meshed grafts. It is intended for use as a temporary coverage for wounds and burns to aid in the natural healing process." it also provides a wound preparation to support the implantation of autologous skin grafts. In the FDA 510(k) database, the 510(k) refers to Laserskin Dressing as the device; however, in the 510(k) summary, the proprietary name is Hyalomatrix KC Wound Dressing and the name Laserskin is not mentioned (Snyder, et al., 2012).

Hyalomatrix PA is a bilayered, sterile, flexible, and conformable non-woven pad entirely composed of HYAFF 11, a benzyl ester of hyaluronic acid. The hyaluronic acid is derived from bacterial fermentation. The HYAFF 11 serves as a scaffold to allow cell colonization and capillary growth. On the back layer of the HYAFF 11 is a semipermeable silicone membrane that does not contact the patient and controls water vapor loss. Hyalomatrix PA is applied directly to a wound. After two to three weeks the silicone layer is removed, but the HYAFF II layer is mostly or completely absorbed into the underlying tissue, and the underlying tissue typically has healed or has become ready for grafting. Hyalomatrix PA is packaged in several different sizes: 5 cm x 5 cm sold separately and in boxes of 5 and 10 (in individual pouches); 10 cm x 10 cm sold separately; and 10 cm x 20 cm sold separately.

Hyalomatrix PA Wound Dressing was cleared for marketing under the 510(k) process in December 2007. The company refers to Hyalomatrix PA by its trade name Hyalomatrix. In the 510(k) documents Hyalomatrix is described as a bilayered dressing composed of a nonwoven pad made of HYAFF 11 and a semipermeable silicone membrane. Hyalomatrix "is indicated for the management of wounds including: partial and full-thickness wounds; second-degree burns; pressure ulcers; venous ulcers; diabetic ulcers; chronic vascular ulcers; tunneled/undetermined wounds; surgical wounds (donor sites/grafts, post-Mohs surgery , post-laser surgery, podiatric, wound dehiscence); trauma wounds (abrasions, lacerations, skin tears); and draining wounds. The device is intended for one-time use." The predicate device was "Hyalomatrix KC (Laserskin) Wound Dressing."

Jaloskin (Anika Therapeutics, Inc., Bedford, MA) was cleared for marketing under the 510(k) process in January 2010 for "the management of superficial moderately exuding wounds including pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, skin tears) and first and second degree burns." Jaloskin is a semipermeable, transparent film dressing, composed of HYAFF 11 only. The hyaluronic acid is derived from bacterial fermentation. Anika Therapeutics, Inc. (Bedford, MA), acquired Fidia Advanced Biopolymers S.r.l. (currently Anika Therapeutics S.r.l.) in December 2009. The Anika Therapeutics Web site advertises Hyalomatrix and Jaloskin.

The manufacturer cites preclinical studies to suport the theoretical basis for use of Hyalomatrix, showing that fetal skin contains high levels of sustained hyaluronic acid (Longaker, et al., 1989; Longaker, et al., 1991; Wilgus, 2007; Dillon, et al., 1994; Longas, et al., 1987; Moseley, et al., 2003). Fetal skin can regenerate without scarring. With age, the skin’s ability to produce hyaluronic acid decreases, tissue elasticity decreases, and wound healing is fibrotic.

Caravaggi et al (2003) reported on a total of 79 patients with diabetic dorsal (n = 37) or plantar (n = 42) ulcers were randomized to either the control group with nonadherent paraffin gauze (n = 36) or the treatment group with HYAFF-based autologous dermal and epidermal tissue-engineered grafts (n = 43).  Weekly assessment, aggressive debridement, wound infection control, and adequate pressure relief (fiberglass off-loading cast for plantar ulcers) were provided in both groups.  Complete wound healing was assessed within 11 weeks.  Safety was monitored by adverse events.  The investigators reported that complete ulcer healing was achieved in 65.3 % of the treatment group and 49.6 % of the control group, a difference that was not statistically significant (p = 0.191).  Plantar foot ulcer healing was not statistically significantly different (55 % and 50 %) in the treatment and control groups, but dorsal foot ulcer healing was significantly different, with 67 % in the treatment igroup and 31 % in the control group (p = 0.049). 

Uccioli et al (2011) evaluated the efficacy of a HYAFF autograft in the treatment of diabetic foot ulcers compared with standard care in 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month). Subjects were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. There was no significant difference between treatment and control groups in the primary efficacy outcome: at 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). 

Caravaggi et al (2011) reported on the FAST study, which evaluated the performance and safety of Hyalomatrix PA dermal substitute in the treatment of chronic wounds of different etiology. This was a multicenter, prospective, observational study involving 70 Italian centers and 262 elderly patients. Patients were observed from the start of treatment with a dermal substitute (Hyalomatrix PA [HPA]) until healthy dermal tissue suitable for a thin autograft was visible or until the growth of new epithelium from the wound edge was reported. Tracking the wound edge advancement was used to assess the dermal substitute's performance. The main endpoint was the reduction in threshold area (≥ 10%) of the ulcer. Treated ulcers were characterized as follows: 46% vascular, 25% diabetic foot, 12% traumatic wounds, 2% pressure ulcers and 15% other. The investigators reported that reepithelization (≥ 10%) was achieved in 83% of ulcers in a median time of 16 days. Twenty-six percent (26%) of wounds achieved 75% reepithelization within the 60-day follow-up period using only HPA treatment. A follow-up showed that 84% of ulcers achieved complete reepithelialization by secondary intention. The primary limitation of this open-label observational study was a lack of best standard-of-care comparison group.

Motolese et al (2013) presented a series of 16 patients affected by venous ulcers who underwent Hyalomatrix PA grafting for reconstructive surgery. The authors reported that the average area grafted per procedure was 153 cm(2). The length of followup ranged from 0.5 to 1 year. The final results were considered to be good in 12 cases, fair in 3 cases, and poor in one case. Limitations of this study include its retrospective design (case series) and lack of comparison group.

Alvarez and colleagues (2017) provided an analysis of a prospective, parallel, randomized, single-center study involving 16 subjects in an outpatient wound care center setting.  The aim of the study was to evaluate the safety and effectiveness of a hyaluronic acid extracellular matrix (HA; Hyalomatrix Wound Matrix, Fidia Farmaceutici S.p.a., Abano Terme, Italy) for the treatment of chronic VLUs.  Each subject with a VLU was randomized (1:1) to receive either HA plus compression with a multilayer compression bandage (MLC) or standard care consisting of a non-adherent primary dressing plus a MLC (control).  All wounds were VLUs (confirmed by duplex imaging) and all had adequate arterial circulation (ABI greater than 0.75).  All VLUs had a history of not healing for more than 6 months, and all were in the lower leg (between the mid-calf and below malleoli).  Traditional MLC with a short stretch and elastic cohesive bandage was used in all patients.  The primary end-point was incidence of wound healing at 12 and 16 weeks, and secondary end-points were time to healing and ulcer recurrence.  Wound evaluations were performed weekly and wound surface area was measured by photo-digital planimetry.  The incidence of wound healing at 12 weeks was 66.6 % for the HA group and 14.2 % for the control (p = 0.066).  At week 16, 87.5 % were healed in the HA group compared with 42.8 % in the control (p = 0.059).  The mean time to healing in the HA-treated group was 41 days compared with 104 days in the control (p = 0.029).  The authors concluded that the findings of this interim analysis indicated that continuation of the present study is needed.  They stated that a more reliable power calculation from these findings forecasts that the inclusion of 50 to 60 participant would be needed to achieve the statistical goal (p < 0.05) related to the primary end-point.  The main drawbacks of this study were its small size (n = 16), open-label design, and a single-center setting.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Alvarez, et al. (2017) to be at moderate risk of bias.

InnovaBurn and InnovaMatrix XL

InnovaBurn and InnovaMatrix XL are sterile single-use medical devices consisting of extracellular matrix derived from porcine placental material used for safe and effective wound treatment. They are made of collagen, elastin, laminin, fibronectin, hyaluronic acid, and sulfated glycosaminoglycan and available in a variety of sheet sizes. This biodegradable wound matrix of InnovaBurn and InnovaMatrix XL acts as a protective cover to the wound. The products are intended for use in the management of wounds, including: partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor site/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds, (abrasions, lacerations, and skin tears), partial-thickness second degree burns, and draining wounds. InnovaBurn or InnovaMatrix XL is applied on a wound following wound bed preparation with standard debridement methods. The products are fully resorbable without requiring removal. InnovaBurn and InnovaMatrix XL are supplied terminally sterile, in a single use package, and in a variety of sizes up to 400 square centimeters (CMS, 2023e).

InnovaMatrix AC

InnovaMatrix AC received Food and Drug Administration (FDA) clearance as a medical device consisting of an extracellular matrix derived from porcine placental material for wound treatment. InnovaMatrix AC is comprised of collagen, elastin, laminin, fibronectin, hyaluronic acid and sulfated glycosaminoglycans and is a biodegradable wound matrix that functions as a protective cover to the wound. Indications for the management of wounds include the following: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears), and draining wounds. This medical device is applied to wound bed following standard debridement methods. Additionally, the product will fully resorb and will not necessitate removal. InnovaMatrix is available as terminally sterile, in a single use package, and in a variety of sizes.

InnovaMatrix FS

InnovaMatrix FS (Triad Life Sciences, Inc.) is a sterile, single use, medical device consisting of decellularized extracellular matrix (ECM) derived from porcine placental material used for safe and effective wound treatment. InnovaMatrix FS is composed of collagen, elastin, laminin, fibronectin, hyaluronic acid and sulfated glycosaminoglycans and is produced in fenestrated sheets in a variety of sizes. This biodegradable wound matrix provides a protective cover to the wound. The wound dressing is provided in fenestrated sheets that are approximately 40-100 microns thick in sizes ranging from 2 x 2cm to 5 x 5cm. InnovaMatrix FS received FDA 510(k) premarket notification (K210580) in April 2021. InnovaMatrix FS has the identical indications for use as the predicate device InnovaMatrix (K193552). The technological characteristics are similar to the technological characteristics of the predicate wound dressing. The only modification for the subject device is the addition of fenestrations to the predicate device.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of InnovaMatrix FS.

InnovaMatrix PD

InnovaMatrix PD is a sterile single use medial device consisting of extracellular matrix derived from porcine placental material used for safe and effective wound treatment. This product is made of collagen, elastin, laminin, fibronectin, hyaluronic acid and sulfated glycosaminoglycans and is available in particulate form in a variety of sizes. This biodegradable wound matrix acts as a protective cover to the wound. This product is intended for use in the management of wounds, including: partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor site/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds, (abrasions, lacerations, and skin tears), draining wounds, and partial-thickness second-degree burns. InnovaMatrix PD is applied on a wound following wound bed preparation with standard debridement methods. The product is fully resorbable without requiring removal. InnovaMatrix PD is supplied terminally sterile, in single use packaging, and in a variety of sizes up to 500 mg (CMS, 2023e).

Integra (Collagen-Glycosaminoglycan Copolymer)

Integra is a bilayered matrix wound dressing composed of a porous layer of cross-linked bovine tendon collagen and glycosaminoglycan and a semipermeable polysiloxane (silicone) layer. Integra Dermal Regeneration Template, Integra Bilayer Matrix Wound Dressing, and Integra Meshed Bilayer Wound Matrix (Integra LifeSciences Corporation, Plainsboro, NJ) are identical products composed of an acellular, biodegradable collagen-glycosaminoglycan (C-GAG) copolymer matrix coated with a thin silicone elastomer.  Bovine type I collagen and chondroitin-6-sulfate, one of the major glycosaminoglycans, are co-precipitated, freeze-dried and cross-linked.  The collagen structure is manufactured.  The pore size has been determined to maximize in-growth of cells, and the degree of cross-linking as well as GAG composition, is designed to control the rate of matrix degradation.  This extra-cellular matrix analog incorporates in approximately 2 to 3 weeks forming a neodermis with new vasculature.  The Integra acellular cryo-preserved allodermis is clinically used in conjunction with ultra thin (0.003 to 0.006 inch) meshed split-thickness autografts in large burn wounds. According to the manufacturer, the silicone layer allows for controlled water vapor loss and provides a flexible covering for the wound surface. The collagen-glycosaminoglycan matrix is biodegradable and provides a scaffold for cell entry and capillary growth. The silicone membrane is temporary and the collagen-glycosaminoglycan matrix is remodeled as the wound area is repaired. Integra can be stored at room temperature.

In April 2001, FDA approved Integra dermal regeneration template has received premarket approval from the FDA "for the post excisional treatment of life-threatening full-thickness or deep partial-thickness thermal injury where sufficient autograft is not available at the time of excision or not desirable due to the physiological condition of the patient." Bilayer Matrix Wound Dressing was cleared for marketing under the 510(k) process in August 2002 and is indicated "for the management of wounds including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic and vascular ulcers, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, and skin tears) and draining wounds. This device is intended for one-time use."

In January 2016, the FDA approved the Integra Dermal Regeneration Template (Omnigraft Dermal Regeneration Template) for certain diabetic foot ulcers that last for longer than 6 weeks and do not involve exposure of the joint capsule, tendon or bone, when used in conjunction with standard diabetic ulcer care.  The approval was based upon the clinical results of a multi‐center, randomized, controlled clinical trial (the Foot Ulcer New Dermal Replacement Study (FOUNDER) Study) (Driver et al, 2015). Omnigraft Dermal Regeneration Matrix (Omnigraft) is an advanced wound care device, comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan with a polysiloxane (silicone) layer. The collagen-glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth. Integra Dermal Regeneration Template (IDRT) is indicated for the treatment of burns and scar contractures. Through a supplemental PMA to IDRT, Omnigraft is indicated for use in the treatment of partial and full-thickness neuropathic diabetic foot ulcers that are greater than six weeks in duration, with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care. This new indication expands the use of the product to hospital outpatient departments and physician offices.

Integra Meshed Bilayer Wound Matrix is an advanced wound care device comprised of a porous matrix of cross-linked bovine tendon collagen and glyscosaminoglycan with a polysiloxane (silicone) layer. It allows draining of wound exudates and provides a flexible adherent covering for the wound surface. The collagen-glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth. It is indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds (donor sites/grafts, post-Moh‟s surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, and skin tears) and draining wounds. It also may be used with negative pressure wound therapy. The manufacturer states that wound closure is typically complete within 30 days. The dosage is based on size of the wound for this single use product. Integra Meshed Bilayer Wound Matrix is packaged in sterile, single-use, double peel packages containing phosphate buffer. It is available in four sizes: 500 square centimeters (8" x 10" sheets), 250 square centimeters (4"x10" sheets), and 125 centimeters (4"x5" sheets), and 25 square centimeters (2"x2" sheets). 

Stern et al (1990) stated that Integra artificial skin is an effective means of treatment for full-thickness burns.  In this histological study, serial biopsy specimens were obtained from 131 patients during a period of 7 days to 2 years after application; 6 sequential phases of repair were discerned.  Additionally, there were occasional unusual histological features, eosinophilic infiltration, and/or macrophage-derived giant cell formation in the wound area; however, such findings did not clinically correlate with a negative response to Integra.  These investigators found that the use of Integra resulted in good repair, with rare exceptions.  An intact dermis was achieved as well as definitive closure of a complete epidermal layer with a minimum of scarring.

Dantzer and Braye (2001) presented a series of 31 patients who underwent Integra grafting for reconstructive surgery at a total of 39 operational sites.  The average area grafted per procedure was 267 cm2.  Complications (e.g., silicone detachment, failure of the graft, and hematoma) were observed in 9 cases.  The length of follow-up ranged from 0.5 to 4.0 years.  Two patients (2 sites) were lost to follow-up; the final results in the remaining patients were considered to be good in 28 cases, average in 6 cases and poor in 3 cases.  The disadvantages of using Integra in reconstructive surgery are the necessity of 2 operations, the risks of infection under the silicone layer, of the silicone becoming detached and of recurrence of contraction.  On the other hand, Integra has many advantages including its immediate availability, the availability of large quantities, the simplicity and reliability of the technique, and the pliability and the cosmetic appearance of the resulting cover.

Ryan et al (2002) examined retrospectively the mortality and length of stay (LOS) of 270 adults with acute burns greater than or equal to 20 % of body surface area (BSA), and determined the effect of Integra on outcome.  No difference in mortality was found between patients who received Integra (30 %; n = 43) and patients who did not (30 %; n = 227).  Surviving Integra patients (n = 30) stayed longer, but they were more extensively injured than survivors who did not receive Integra (n = 158), and therefore longer hospitalizations were expected.  In a sub-group analysis, mean LOS of Integra patients with 2 or more mortality risk factors (age over 60 years, burn size greater than 40 % BSA, or inhalation injury; n = 15) was 63 days compared with 107 days in patients with 2 or more risk factors (n = 29) who did not receive Integra (p = 0.014).  The authors concluded that the use of Integra in severely injured burned adults was associated with a marked decrease in LOS.

In a post-approval study, Heimbach and associates (2003) assessed the safety and effectiveness of Integra involving 216 burn injury patients who were treated at 13 burn care facilities in the United States.  The mean total body surface area burned was 36.5 % (range of 1 to 95 %).  Integra was applied to fresh, clean, surgically excised burn wounds.  Within 2 to 3 weeks, the dermal layer regenerated, and a thin epidermal autograft was placed.  The incidence of invasive infection at Integra-treated sites was 3.1 % (95 % confidence intervals [CI]: 2.0 to 4.5%) and that of superficial infection 13.2 % (95 % CI: 11.0 to 15.7 %).  Mean take rate of Integra was 76.2 %; the median take rate was 95 %.  The mean take rate of epidermal autograft was 87.7 %; the median take rate was 98 %.  The authors concluded that these findings further supported the conclusion that Integra is a safe and effective treatment modality in the hands of properly trained clinicians under conditions of routine clinical use at burn centers.

Heitland and colleagues (2004) stated that the clinical use of Integra has been celebrated enthusiastically as an improvement in burn therapy over a period of more than 10 years.  Many case-reports have shown the positive effects of the treatment with Integra as a skin substitute.  In this study, these investigators examined the alterations of Integra-usage in Germany.  Fifteen German burn centers have been interviewed respectively over a time period of 6 years with interviews in the years 1999, 2001, and 2003.  The goal of this study was to focus on the problems associated with the use of artificial skin and to create a manual for Integra-therapy including indication, pre-, intra-, and post-operative treatment.  Since the first Integra Users seminar in Germany in 1999, repeated interviews have been conducted with 15 German burn centers.  The collected results of the last 6 years were evaluated.  These results demonstrated a change in the indication for the therapy with artificial skin towards extensive full thickness burned patients and as extended indication especially for post-traumatic reconstruction.  This study provided guidelines for the usage and handling of Integra and showed that Integra is an important reconstructive dermal substitute for the severely burned or post-traumatic patients if it is handled by a skilled surgeon in a correct way.

In a review on the use of Integra for full-thickness burn surgery, Fette (2005) stated that there are a lot more benefits than harms for patients.  Some of the potential benefits include no histological or immunological harms, better scar appearance, less hypertrophic scarring, less itching, better movements, thinner epidermal grafts and smaller meshes possible, immediate availability, and prolonged shelf time.  Potential harms include inability to replace both dermal and epidermal components, as well as the need for sequential operative procedures.

Driver et al (2015) noted that individuals with diabetes mellitus are at an increased risk of developing a diabetic foot ulcer (DFU).  These researchers evaluated the safety and effectiveness of Integra Dermal Regeneration Template (IDRT) for the treatment of non-healing DFUs.  The Foot Ulcer New Dermal Replacement Study was a multi-center, randomized, controlled, parallel group clinical trial conducted under an Investigational Device Exemption (IED).  A total of 32 sites enrolled and randomized 307 subjects with at least 1 DFU.  Consented patients were entered into the 14-day run-in phase where they were treated with the standard of care (0.9 % sodium chloride gel) plus a secondary dressing and an off-loading/protective device.  Patients with less than 30 % re-epithelialization of the study ulcer after the run-in phase were randomized into the treatment phase.  The subjects were randomized to the control treatment group (0.9 % sodium chloride gel; n = 153) or the active treatment group (IDRT, n = 154).  The treatment phase was 16 weeks or until confirmation of complete wound closure (100 % re-epithelialization of the wound surface), whichever occurred first.  Following the treatment phase, all subjects were followed for 12 weeks.  Complete DFU closure during the treatment phase was significantly greater with IDRT treatment (51 %) than control treatment (32 %; p = 0.001) at 16 weeks.  The median time to complete DFU closure was 43 days for IDRT subjects and 78 days for control subjects in wounds that healed.  The rate of wound size reduction was 7.2 % per week for IDRT subjects versus 4.8 % per week for control subjects (p = 0.012).  The authors concluded that for the treatment of chronic DFUs, IDRT treatment decreased the time to complete wound closure, increased the rate of wound closure, improved components of quality of life and had less adverse events compared with the standard of care treatment.  They stated that IDRT could greatly enhance the treatment of non-healing DFUs.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Driver, et al. (2015) to be at low risk of bias.

Integra Flowable Wound Matrix (LifeSciences Corp., Plainsboro, NJ) was cleared through the FDA 510(k) process in 2007.  It is comprised of granulated cross-linked bovine tendon collagen and glycosaminoglycan.  The granulated collagen-glycosaminoglycan is hydrated with saline and applied in difficult to access wound sites and tunneled wounds via injection with a syringe.  It is indicated for the management of wounds including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (e.g., abrasions, lacerations, second degree burns, skin tears) and draining wounds; however, there is insufficient scientific evidence regarding its effectiveness for these or any other indications.

Integra Matrix Wound Dressing is comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan.  The collagen-glycosaminoglycan biodegradable matrix is intended to provide a scaffold for cellular invasion and capillary growth.  The Integra Matrix Wound Dressing was cleared by the FDA for use in the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining wounds.  However, there is insufficient scientific evidence regarding its effectiveness for these or any other indications.

Integra Wound Matrix for Osteoradionecrosis of the Jaw

Beech and Farrier (2016) examined the use of the Integra skin regeneration system intra-orally to promote healing of an intra-oral defect in osteoradionecrosis (ORN); thus, avoiding the necessity for mucosal flaps, free flaps, or skin grafts.  These researchers reported on the case of a 54-year-old man who presented with a pathological mandibular fracture at the angle, related to previous radiotherapy for tonsillar carcinoma, after the development of ORN.  The fracture site was debrided and fixed with a reconstruction plate and the intra-oral defect was dressed using the Integra bi-layer system and an overlying pack.  Three weeks later, the pack and silicone layer of the regeneration system were removed, showing early granulation over the previously exposed bone.  At 8 weeks post-operative, the defect had healed completely with no need for further reconstruction.  Using the method described, excellent healing was observed with the Integra skin regeneration system.  A new use for the Integra skin regeneration system has been identified in the authors' unit.  The authors concluded that this method was minimally invasive and resulted in good healing in the case presented.  The need for further reconstruction with associated increased patient morbidity was avoided in this case.

The authors did accept that there are limitations to this technique.  The skin regeneration system requires a blood supply for the development of a neo-dermis from either bone or neighboring mucosa in the defect.  In cases where no healthy vascularized bone can be found, or where there is a poor-quality local blood supply in the mucosa, the technique will not work.  Furthermore, larger defects would be very difficult to manage in this way and are more likely to require free tissue transfer.

Srivastava et al (2020) noted that the use of biologic skin substitutes for the management of soft tissue defects as an alternative to autologous skin grafts has expanded over the last 20 years.  In a case-series study, these researchers reported their experience with Integra bi-layer wound matrix for reconstruction of intra-oral oncologic defects.  Case records of 6 patients with intra-oral oncologic defects reconstructed with Integra bi-layer wound matrix were retrospectively reviewed.  The surgical defect location, size, and time to removal of surgical splint varied.  Clinically, normal oral epithelialization was noted for all patients; 1 patient demonstrated a small area of dehiscence and bone exposure after adjuvant radiation therapy, which resolved with minimal intervention.  The authors concluded that Integra bi-layer wound matrix was a viable and versatile option for reconstruction of intra-oral oncologic surgical defects.  These researchers advocated further exploration of wound healing with Integra matrix, surgical techniques, and cost-effectiveness is advocated.

Furthermore, an UpToDate review on “Management of late complications of head and neck cancer and its treatment” (Galloway and Amdur, 2022) does not mention Integra wound matrix as a management / therapeutic option.

Integuply

Integuply is an acellular human dermis derived from aseptically processed human allograft skin tissue. It is indicated for the repair or replacement of damaged or inadequate integumental tissue or for other homologous uses of human integument. Integuply is typically used in conjunction with a chronic wound care management regimen for the treatment of diabetic ulcers, charcot foot ulcers, venous ulcers, trauma wounds, pressure ulcers, pressure ulcers, partial and full thickness wounds, and surgical wounds. When applied to wounds, Integuply becomes vascularized and incorporated into the wound bed to provide an effective means of wound closure. The matrix and preserved vascular channels in Integuply acts as a scaffold to facilitate angiogenesis and migration of growth factors that stimulate cell migration. Integuply is applied topically to the wound site and secured by suturing or stapling to the skin surrounding the wound. Typically only one application is needed. It can be meshed or non-meshed. Integuply is supplied in 38 different sizing and thickness configurations and is packaged freeze dried.

Interfyl

According to the manufacturer Alliqua Biomedical, Inc., Interfyl is a decellularized and dehydrated placental disc (chorionic plate) derived extracellular matrix (ECM). Its connective-tissue matrix (CTM) serves as a scaffold for recipient cells in the wound to regenerate soft tissue. Because it is not cross-linked and does not contain cells, Interfyl reduces the likelihood of immunogenic and inflammatory responses as compared to other HCT/Ps, thereby minimizing inflammation and scarring. Interfyl is intended for use as the replacement or supplementation of damaged or inadequate integumental tissue by providing support for the body’s normal healing processes. Indications for Interfyl include treatment of deep dermal wounds, irregularly-shaped and tunneling wounds, augmentation of deficient/inadequate soft tissue, and the repair of small surgical defects. Interfyl is supplied as single-dose flowable product syringes containing 250 mg in 1.5 mL, and as particulate product in vials containing 50 mg and 100 mg.

Irradiated Cadaveric Grafts for the Treatment of Burn

Khodadadi et al (2016) stated that looking for an appropriate skin substitute for temporary and permanent coverage of wounds remains one of the main obstacles of researchers.  These investigators examined the rate of inflammation, symbiosis, and survival of grafted allograft skin from brain-dead donors (BDDs) in rabbits.  After receiving negative serologic tests of BDDs, these researchers prepared partial thickness skin grafts.  They were then used in treating wounds of 5 rabbits in comparison with split-thickness skins taken from cardiac dead donors.  On histopathological examinations, these investigators found no difference between the skins.  All samples were separated from the baseline in 15 to 20 days.  The authors concluded that gamma-irradiated freeze-dried human split-thickness skin taken from BDDs was safe and can be used for the treatment of deep skin burns.  They stated that the findings of this study including other tissue banks, showed the promising results for future usage in patients.  Having skin from BDDs enabled clinicians not only to increase the skin but also to decrease the number of discarded samples due to microbial contamination because of fully sophisticated laboratory checked organ donors and retrieval in sterile operating theater setting.

Furthermore, UpToDate reviews on “Overview of surgical procedures used in the management of burn injuries” (Leon-Villapalos and Dziewulski, 2020), “Overview of the management of the severely burned patient” (Gauglitz and Williams, 2020) do not mention irradiated cadaver grafts as a management / therapeutic option. An UpToDate review “Treatment of deep burns” (Phelan and Bernal , 2020) states that allografts (human cadaveric origin) can be used as temporary bridges for coverage, although there is no specific reference to the need for irradiation of the allografts. "Allografts may be more effective than xenografts. Allografts have also been used over micrografts to help secure autografts in place and to cover donor sites between harvests. Allografts are available in various sizes and can be meshed similarly like autografts. The use of allografts may help decrease wound size, which in turn can decrease the area of skin that is ultimately harvested for burn wound closure. Although considered temporary, some incorporation of allografts can be expected. When the wound bed is ready for autografting, the allografts are removed. While not considered permanent, some adherence and incorporation into the wound bed could be expected, which can be associated with a moderate-to-significant blood loss. Less-incorporated grafts can essentially be peeled from the wound bed."

Jacob's Ladder External Closure Device for Wound Closure

OrthoGuidelines’ webpage on “Wound Management” states that “Limited evidence supports use of negative pressure wound therapy for management of fasciotomy wounds with regard to reducing time to wound closure and reducing need for skin grafting”.  It also notes that “Future research is needed to further clarify the relative benefits associated with use of negative pressure wound therapy, with particular consideration for austere environments.  This work has important implications for forward surgical teams utilized by the military.  However, there may be barriers to performing this work in civilian settings due to the substantial benefits of negative pressure wound therapy in terms of patient care (fewer dressing changes, easier nursing care) as well as theoretical benefits (including reduction in nosocomial contamination due to sterile placement in the operating room, improved granulation tissue formation to improve skin graft bed).  Adequately powered high quality studies are needed to explore the relationship between management of fasciotomy wounds and complication such as infection as well as rate of and time to delayed wound closure and/or skin graft.  Independent variables important to study include type of wound care method (i.e., negative pressure wound therapy versus wet to dry gauze), use of dermatotaxis techniques (i.e., “Jacob’s ladder” or “shoestring” technique versus traditional), time to closure or skin graft, timing for definitive fixation/definitive hardware.  Both hard outcomes as well as functional outcomes and health-related quality of life outcomes are needed to adequately guide decision-making”.  

There is a lack of evidence on the effectiveness of Jacob's Ladder External Closure Device for wound closure.

Keramatrix 

Keramatrix (Keraplast Technologies, LLC) is an open-cell wound dressing comprised of freeze-dried acellular, animal-derived keratin protein. Keramatrix provides a biocompatible cell-growth substrate or scaffold for growth of new tissue in three dimensions and is resorbed into the developing tissue. When a wound occurs, the epithelium is lost and thus the keratin based skin structure is also lost; keramatrix substitutes the outer layer of the skin by introducing a replacement keratin-based structure. When placed in the wound bed it provides a cell-growth-friendly structure for tissue regeneration and maintains moist wound healing environment. Through interaction with enzymes in the healing wound, Keramatrix is degraded to a gel which is resorbed. Keramatrix is indicated for the patient population with the following types of chronic wounds: pressure ulcers, venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers and donor sites and grafts. It is supplied in various sizes.

According to the manufacturer, Keramatrix is significantly different than "standard care" wound products because of Keramatrix’ combination of moist wound healing, growth-friendly structure and resorption into the wound, causing minimal disturbance to developing tissue. 

Kerasorb

According to the manufacturer, Keraplst Research Limited, "Kerasorb Wound Matrix is clinically indicated for the patient population with the following types of chronic wounds: pressure ulcers (stages I-IV), venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers, and donor sites and grafts." Kerasorb is supplied in single use pouches containing one 10 cm x 10 cm foam wound matrix. It is applied to the wound area using aseptic technique similar to Keramatrix and other cellular and /or tissue based products for the skin wounds.

Keroxx Flowable Wound Matrix

Keroxx Flowable Wound Matrix (Molecular Biologicals, Inc., San Antonio, TX) is an injectable version of the single-use matrix sheet Keramatrix. Keroxx Flowable Wound Matrix is a wound matrix comprised of keratin enriched proteins containing the active ingredient Replicine Functional Keratins which are biologically active proteins extracted using proprietary processes where the inherent alpha-helical structure of the keratin molecule remains intact. These keratin proteins are extracted from sheep wool and are placed in an open celled injectable gel format. When Keroxx is injected, the Replicine Functional Keratins are absorbed into the developing tissues in the wound and provide a biocompatible matrix or scaffold for cellular proliferation, migration and capillary growth to aid in the growth of new tissue. The Replicine Functional Keratins have been shown to activate keratinocyte cells present in the wound and stimulate them to quickly enter a hyperproliferative phase essential for wound healing. Keroxx flowable is used to treat patients with chronic wounds such as pressure ulcers, diabetic ulcers, donor sites and grafts.

LiquidGen

Skye LiquidGen is an allograft tissue matrix for use as an in vivo wound covering to fill tissue defects or localized areas of inflammation.  According to the manufacturer, LiquidGen can be applied directly to the surgical site, mixed with patients own blood or used with other carriers to cover or fill soft tissue defects.  LiquidGen is cryopreserved, and can be stored for up to 2 years.  There are a lack of published clinical studies of the effectiveness of LiquidGen.

Matriderm

Matriderm (Dr. Suwelack Skin and Health Care AG) is a collagen-elastin matrix designed to support dermal regeneration after severe skin injuries.  The matrix provides a structure for the invasion of native cells to regenerate the dermis.  After placement, Matriderm is covered with a very thin, split-thickness, skin graft.  The company Web site promotes Matriderm for treating severe burn injuries (Snyder et al, 2012).  This product does not seem to be available in the United States and is not listed on the FDA Web site.  A company called Suwelack Matrix Systems, Inc., Stony Brook, NY, USA, was established in 2005 but does not have any products listed on the FDA Web site.  

Matrion

Matrion (LifeNet Health, Virginia Beach, VA) is a regenerative human placental allograft procured and processed from donated human tissue. Matrion is a matrix scaffold derived from an intact decellularized placental membrane comprising both amniotic and chorionic layers. The resulting decellularized placental membrane is available in membrane, injectable, and sponge configurations for use in wound, tendon, and nerve applications. Decellularized placental membrane modulates inflammation in the surgical site, enhances healing, and acts as a barrier. Matrion is supplied as a decellularized placental allograft and is freeze-dried and stored at ambient room temperature.

Matrix HD

Matrix HD (RTI Biologics, Alachua, FL) is a human dermal allograft restricted to homologous use for wound care; protection, reinforcement or covering of soft tissue in horizontal and vertical augmentation procedures.  Matrix HD is sterile dehydrated acellular dermis from donated human tissue.  The allograft provides a natural collagen scaffold skin substitute to support the body's regenerative processes.  Matrix HD is typically used in conjunction with a chronic wound care management regime for the treatment of diabetic ulcers, charcot foot ulcers, venous ulcers, trauma wounds, pressure sore/ulcers, partial and full thickness wounds, and surgical wounds.  Once the wound bed is prepared, the graft is placed and secured with sutures.  Two allografts may be applied, one on top of the other, for optimal healing results. Matrix HD is supplied in patient specific sizes, ranging from 2 x 3 cm to 10 x 10 cm, so that the surgeon can utilize the amount of tissue needed.  The size is selected by the surgeon depending on the size of the wound.

Mediskin

Mediskkin is frozen irradiatied porcine xenograft with a dermal and epidermal layer. It has been used for partial-thickness skin ulcerations and abrasions. Other applications may include temporary covering for full-thickness skin loss, toxic epidremal necrolysis (TEN) and meshed autograft protection.

Mediskin is a frozen irradiated porcine-derived de-cellularized fetal skin product with a dermal and epidermal layer.  Mediskin a frozen irradiated porcine xenograft that has a shelf life of 24 months. It may reduce pain, protein, and fluid loss, provide a barrier to external contamination and a moist wound healing site, and protect underlying tissue in the treatment of burns, abrasions, donor sites, decubitus and chronic vascular ulcers. It also provides an optimal environment for wound healing. Mediskin may also be used as temporary wound cover. It can be used on any person except those who have a known sensitivity to porcine products, on patients with histories of multiple serum allergies, or on wounds with large amounts of eschar. As the wound heals, Mediskin will naturally slough off. It is supplied in rolls (3" wide by 12, 24 or 48" long) and is also supplied in 7" x 18" sheets and patches of 3" x 4" and 2" x 2". According to the manufacturer, the product differs from others as it is a porcine xenograft, temporary skin substitute. There are few published studies addressing the use of Mediskin for wound treatment. The use of porcine-derived decellularized fetal skin products (e.g., Mediskin®) has not been established since there are currently no published studies addressing the use of Mediskin®.

Membrane Graft and Membrane Wrap

Membrane Graft and Membrane Wrap (BioLab Sciences, Inc.) are human amniotic allograft membranes used to repair tissue deficits and to reduce healing time for chronic wounds and post-surgical wounds. "The patient population for use of the products includes children and adults suffering from non-healing acute and chronic wounds (diabetic, venous, mixed, venous-arterial, pressure ulcers), complex and /or open surgicalwounds and burns." The product is available in six sizes: 1 x 1cm, 1 x 2cm, 2 x 3cm, 4 x 4cm, 4 x 6cm, and 4 x 8cm.

Memoderm

MemoDerm (Memometal, Inc., Memphis, TN) is a sterile acellular dermal allograft derived from aseptically processed cadaveric human skin tissue that is terminally sterilized (Snyder et al, 2012).  It is intended for the repair or replacement of damaged or inadequate integumental tissue or for other homologous uses of human integument. It has been used for repairs (e.g., rotator cuff) and wounds (e.g., chronic diabetic ulcer). The allograft acts as a scaffold of collagen and elastin fibers that are preserved during the process that renders the allograft acellular.  During the granulation phase of the wound repair/regeneration cycle, the matrix of intact collagen network and preserved vascular channels in MemoDerm acts as a scaffold to facilitate angiogenesis and migration of growth factors that stimulate cell migration.  When applied to wounds, MemoDerm has been shown to become vascularized and incorporated into the wound bed and provide an effective means for wound closure.  MemoDerm is supplied freeze-dried and must be rehydrated prior to use.  Once rehydrated, the allograft can be applied topically to the wound and secured by suturing and stapling to the skin surrounding the wound.

Microlyte Matrix

Microlyte Matrix is made up of an ultrathin polyelectrolyte multilayer matrix coated with a resorbable polymer. Its functionality as a wound matrix product involves enhancement of wound granulation and maintenance of a moist wound healing environment which facilitates cell growth, neovascularization, and wound closure. Microlyte Matrix is indicated for the management of the following: wounds; partial and full thickness wounds including pressure ulcers, venous stasis ulcers, diabetic ulcers, first and second-degree burns, abrasions and lacerations, donor sites and surgical wounds. Additionally, this wound matrix product may be used over debrided and grafted partial thickness wounds. Microlyte Matrix is applied to wounds as a dry, flexible polymer film and its size is dependent on wound size.

MicroVas

MicroVas (MicroVas Technologies, Inc., Tulsa OK) is a radiofrequency stimulation device used to increase circulation to an extremity or body part in order to speed wound healing.  According to the manufacturer, MicroVas is indicated for the treatment of stage III and IV pressure ulcers.  The manufacturer states that the MicroVas is also indicated for the treatment of chronic and non-healing diabetic and venous ulcers, treatment of ischemic rest pain, muscle disuse atrophy, diabetic neuropathy, and paresthesia relating to neuropathy.  However, there is a lack of scientific evidence to support its effectiveness for these indications.

A meta-analysis concluded that there is no reliable evidence of benefit of electromagnetic therapy generally in healing of pressure sores (Olyaee Manesh et al, 2006) or venous leg ulcers (Ravaghi et al, 2006).  Additionally, a systemic review of the literature on treatment of pressure sores concluded that the effectiveness of electrotherapy on pressure sores is unknown (Cullum and Petherick, 2007). 

Miroderm

MIRODERM (Miromatrix Medical) is a non-crosslinked acellular wound matrix that is derived from porcine liver and is processed and stored in a phosphate buffered aqueous solution. The manufacturer states that it is clinically indicated for the management of wounds. MIRODERM is used on a chronic wound where it provides a scaffold to maintain and support a healing environment through constructive remodeling. It is used to cover the entire surface of the wound bed and extend slightly beyond all wound margins. MIRODERM is available in fenestrated and non-fenestrated form, in seven sizes ranging from 9 cm² to 120 cm².

Miro3D Wound Matrix

Miro3D wound matrix is a single use, sterile, porcine-derived non-crosslinked acellular collagen matrix. Its porous scaffold acts as a protective environment for wound management. Miro3D is produced by drying perfusion decellularized porcine liver in ambient air, cutting the resulting sponge-like scaffold into four defined sizes. Package is dry in a polyethylene terephthalate glycol plastic tray with a snap-on lid and sealed Tyvek lid. The distinct three-dimensional shape of Miro3D is beneficial to its application to deep, tunneling, and irregular wound beds, which may otherwise require multiple layers of other products/treatments or surgical treatment with full-thickness skin grafts. Miro3D is available in the following sizes: 2 cm x 2 cm x 2 cm, 3 cm x 3 cm x 2 cm, 5 cm x 5 cm x 2 cm, and 5 cm x 10 cm x 2 cm (CMS, 2023e).

Mirragen Advanced Wound Matrix

Mirragen Advanced Wound Matrix consists of biocompatible and resorbable borate-based bioactive glass fibers and particulates. It is a synthetic resorbable matrix that covers the wound, absorbs exudate, and serves as a scaffold to enable cellular migrations, revascularization, and soft tissue regeneration within the wound bed. By mimicking the microstructure of the extracellular matrix, the fiber structure of Mirragen Advanced Wound Matrix acts as a skin substitute in the wound healing process.

MLG Complete

MLG Complete (Samaritan Biologics, LLC) is a resorbalbe, full thickness amnion-chorion derived allograft for management of wounds and burn injuries. MLG Complete is a sterile, single use, dehydrated allograft derived from donated human amnion-chorion membrane that is applied directly to the wound. MLG Complete acts as a cover and a barrier that offers protection from the surrounding environment. MLG Complete dosage is per sq. cm, depending on the size of the wound. MLG Complete is intended for external application. MLG Complete is supplied in a variety of sizes.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of MLG Complete.

MVASC

Gould, et al. assessed the impact of a processed microvascular tissue (PMVT) (mvasc) allograft on wound closure and healing in a prospective, single-blinded, multicenter, randomizsed controlled clinical trial of 100 subjects with Wagner Grade 1 and 2 chronic neuropathic diabetic foot ulcerations. In addition to standard wound care, including standardized offloading, the treatment arm received PMVT while the control arm received a collagen alginate dressing. The primary endpoint was complete wound closure at 12 weeks. Secondary endpoints assessed on all subjects were percent wound area reduction, time to healing, and local neuropathy. Novel exploratory sub-studies were conducted for wound area perfusion and changes in regional neuropathy. Weekly application of PMVT resulted in increased complete wound closure at 12 weeks (74% vs 38%; P = .0003), greater percent wound area reduction from weeks four through 12 (76% vs 24%; P = .009), decreased time to healing (54 days vs 64 days; P = .009), and improved local neuropathy (118% vs 11%; P = .028) compared with the control arm. Enhanced perfusion and improved regional neuropathy were demonstrated in the substudies. The authors concluded that this study demonstrated increased complete healing with PMVT and supports its use in treating non-healing DFUs. They also stated that observed benefit of PMVT on the exploratory regional neuropathy and perfusion endpoints warrants further study..Limitations of this study include its small sample size single-blind design, 

MyOwnSkin

MyOwn Skin, from BioLab Sciences, Inc., is a fully autologous, homologous skin product that is manufactured from a harvested sample of the patients' partial-thickness skin, and is composed of viable skin cells and an organized extracellular matrix (CMS, 2019). MyOwn Skin is composed of a patient’s own viable skin cells and contains extracellular matrix components to support cellular attachment and proliferation for tissue and skin repair. It is used to repair tissue deficits and to reduce healing time for chronic wounds and post-surgical wounds, with minimal to no rejection. The product is available in a variety of sizes, ranging from 1 cm x 1 cm to 10 cm x 10 cm.

Myriad Morcells

Myriad Morcells is a morcellized (powder) format of Myriad Matrix that easily conforms to optimize contact with irregular wound beds.

NeoMatrix Wound Matrix

NeoMatriX Wound Matrix is a single-use, medical device made up of acellular axolotol dermal extracellular matrix intended to facilitate wound healing for chronic and hard-to-heal wounds. This FDA-cleared device is developed from farm raised hybrid amphibian variants sourced from a closed herd in a dedicated facility. NeoMatriX Wound Matrix is indicated for use in the management of wounds, including partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor site/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds, (abrasions, lacerations, second-degree burns and skin tears), and draining wounds. This product is applied on a wound after standard wound preparation and wound debridement. NeoMatriX Wound Matrix does not require removal as it is fully resorbable. It is supplied terminally sterile, in an individual use package, and in a variety of sizes (CMS, 2022b).

NeoPatch Chorioamniotic Membrane Allograft

NeoPatch is a wound covering derived from terminally sterilized, dehydrated human placental membrane tissue comprised of both amnion and chorion.  NeoPatch is an allograft intended for use as a wound covering, and applied externally to the wound.  The constituent epithelium, basement membranes and collagen-rich extracellular matrix provide a protective covering to the wound.  Individuals presenting with wounds including lower extremity ulceration caused by diabetes, chronic venous disease, and other chronic conditions, or who present with acute wounds may be appropriate for treatment with NeoPatch.  NeoPatch is supplied in the following sizes: 14 mm round, 18 mm round, 24 mm round, 2 cm x 3 cm, 3 cm x 5 cm, 4 cm x 4 cm, 5 cm x 6 cm.  There is a lack of evidence regarding the effectiveness of NeoPatch chorioamniotic membrane allograft.

NeoStim DL

NeoStim DL is a double layer dehydrated amnion membrane allograft sourced from donated human amniotic membrane. It acts as a barrier or protective covering from the encompassing environment for acute and chronic wounds, including partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds and trauma wounds. NeoStim DL is applied after standard wound preparation. It is applied directly without requiring fixation to the wound bed and is fully resorbable. NeoStim DL is sterile and supplied in an individual use package (CMS,2023c).

NeoStim Membrane

NeoStim Membrane is a single layer dehydrated amnion membrane allograft sourced from donated human amnion membrane. It acts as a barrier or protective covering from the encompassing environment for acute and chronic wounds, including partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds and trauma wounds. NeoStim Membrane is applied after standard would preparation. It is applied directly without requiring fixation to the wound bed and is fully resorbable. NeoStim Membrane is sterile and supplied in an individual use package (CMS,2023c).

NeoStim TL Membrane

NeoStim TL is a triple layer dehydrated amnion membrane allograft sourced from donated human amniotic membrane. It acts as a barrier or protective covering from the encompassing environment for acute and chronic wounds, including partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds and trauma wounds. NeoStim TL is applied after standard would preparation. It is applied directly without requiring fixation to the wound bed and is fully resorbable. NeoStim TL is sterile and supplied in an individual use package (CMS,2023c).

Neox 100 and CLARIX 100

NEOX 100 (Amniox Medical, Inc.) is a cryopreserved skin graft substitute comprised of human amniotic membrane and umbilical cord used as a wound covering in chronic non-healing dermal wounds, such as diabetic foot and venous leg ulcers, to modulate inflammation and encourage healing (CMS, 2014).  NEOX 100 is supplied in 3 different sizes: 2x2 cm, 4.0x4.0 cm, and 7.0x7.0 cm.  NEOX 100 is a quick-peel matrix administered by placing the appropriately sized product to completely cover the wound bed after debridement, and is secured to the wound edges using sutures or surgical staples, at the discretion of the physician. 

CLARIX 100 is cryopreserved human amniotic membrane, umbilical cord and additinal proteins used as a surgical wrap or barrier, quick-peel matrix. CLARIX 100 is comprised of human amniotic tissue that contains biology which modulates inflammation and permits rapid regenerative healing of surgical wounds (CMS, 2017). CLARIX 100 differs from NEOX in that rather than being used as a wound covering for dermal ulcers and defects, and CLARIX 100 is a surgical covering, wrap, or barrier to modulate inflammation and promote healing. It is supplied as a single use graft in differing sizes, and stored at 80 degrees C to 4 degrees C. The dosage per administration depends on the size of the surgical site; the graft is placed to completely cover the site, and is secured using sutures or surgical staples, at the discretion of the physician. The grafts are supplied cryopreserved in a sealed foil pouch.

NEOX Cord and Clarix Cord

NEOX 1k (Amniox Medical, Inc.) is a non-implantable cryopreserved biological skin graft substitute comprised of human amniotic membrane retrieved from electively donated umbilical cords (CMS, 2013).  NEOX 1k is used as a wound covering in chronic non-healing dermal wounds, ulcers and defects, such as diabetic ulcers, to modulate inflammation and encourage healing.  It is supplied as a single-use graft in 4 different sizes: 1.5x1.5 cm; 2.5x2.5 cm; 4.0x3.0 cm; 6.0x3.0 cm.  NEOX 1k is administered by placing the appropriately sized product to completely cover the wound bed after debridement, and is secured to the wound edges using sutures or surgical staples, at the discretion of the physician.

Clarix Cord IK is cryopreserved human amniotic membrane, umbilical cord and additional proteins, used as a surgical wrap or barrier, 1 mm thick form.

NEOX CORD RT and CLARIX CORD 1K are also non-implantable biological products used for wound healing and surgical coverings (CMS, 2017). NEOX CORD 1K is the updated brand name for NEOX 1K, the same product. NEOX CORD RT is similar to NEOX CORD 1K, but it is terminally sterilized in addition to the NEOX CORD 1K aseptic process. CLARIX CORD 1K is identical to NEOX CORD 1K, but it used as a surgical covering, wrap, or barrier. NEOX CORD RT and CLARIX CORD 1K are supplied as single-use grafts in sizes ranging from 2.0 cm² to 24.0 cm². The graft is placed to completely cover the site, and is secured using sutures or surgical staples.

Marston et al (2019) stated that clinical trials of potential new therapies for diabetic foot ulcers (DFUs) rarely enroll patients whose wounds extend to muscle, fascia, or bone with clinical and radiographic evidence of underlying osteomyelitis.  These researchers carried out an open-label, multi-center trial of cryo-preserved human umbilical cord (TTAX01) in 32 subjects presenting with such complex wounds with a mean duration of 6.1 ± 9.0 (range of 0.2 to 47.1) months and wound area at screening of 3.8 ± 2.9 (range of 1.0 to 9.6) cm2.  Aggressive surgical debridement at baseline resulted in 17 minor amputations and an increase in mean wound area to 7.4 ± 5.8 (range of 1.1 to 28.6) cm2.  All subjects were placed on systemic antibiotics for at least 6 weeks in conjunction with baseline application of TTAX01.  Repeat applications were made at no less than 4-week intervals over the 16-week trial.  Initial closure occurred in 18 of 32 (56 %) wounds, with 16 (50 %) of these having confirmed closure in 16 weeks with a median of 1-product application.  Cases with biopsy confirmed osteomyelitis (n = 20) showed initial closure in 12 (60 %) wounds and confirmed closure in 10 (50 %) wounds; 4 of the 5 ulcers presenting as recurrences experienced confirmed closure.  Mean overall time to healing was 12.8 ± 4.3 weeks.  Mean wound area reduction from baseline was 91 % for all wounds.  Of the 16 wounds without confirmed closure during the 16-week treatment period, 5 (31.3 %) achieved 99 to 100 % wound area reduction by their final visit.  The product was well-tolerated; 2 minor amputations occurred during the study period due to recurrent or persistent osteomyelitis; however, there were no major amputations.  The authors stated that The reported study was one of several to be conducted in the clinical development of this investigational new biologic; the encouraging findings in this study require confirmation in larger studies involving randomized comparison to other treatment strategies for patients with complex non-healing DFUs.

Marston et al (2020) noted that an open-label, multi-center, 16-week trial of cryo-preserved human umbilical cord (TTAX01) was previously undertaken in 32 subjects presenting with a Wagner grade 3 or 4 diabetic foot ulcer, with 16 (50 %) of these having confirmed closure following a median of 1-product application (previous study).  All but 2 subjects (30/32; 94 %) consented to participate in this follow-up study to 1-year post-exposure.  No restrictions were placed on treatments for open wounds.  At 8-week intervals, subjects were evaluated for adverse events (AEs) and wound status (open or closed).  Average time from initial exposure to end of follow-up was 378 days (range of 343 to 433), with 29 of 30 (97 %) subjects completing a full year; AEs were all typical for the population under study, and none was attributed to prior exposure to TTAX01.  One previously healed wound re-opened, 1 previously unconfirmed closed wound remained healed, and 9 new wound closures occurred, giving 25 of 29 (86.2 %) healed in the ITT population.  Three of the new closures followed the use of various tissue-based products; 3 subjects whose wounds were healed required subsequent minor amputations due to osteomyelitis, 1 of which progressed to a major amputation (1/29; 3.4 %); 1 additional subject underwent 2 minor amputations prior to healing.  The authors concluded that the study found TTAX01 to be safe in long-term follow-up and associated with both a low rate of major amputation and a higher than expected rates of healing.  These researchers believe that the healing outcomes and favorable safety data generated in this initial study support proceeding to a prospective, multi-center, randomized study of TTAX01 in treating Wagner grade 3 to 4 wounds.

NeoxFlo

NeoxFlo cryopreserved human amniotic membrane and umbilical cord product in particulate form obtained from donated human placental tissue (CMS, 2014).  It is intended to be used as a wound covering for dermal ulcers and defects such as diabetic ulcers, to replace or supplement damaged or inadequate integumental tissue.  NeoxFlo can be prepared by the physician as a suspension with normal saline for topical application or applied in dry form topically.  It is especially intended for use in difficult to reach wounds that are either irregularly shaped or tunneled.  Neox Flo it is supplied in a single-use vial in 3 different doses: 25 mg, 50 mg and 100 mg.  The typical chronic wound patient will receive an average of 1 to 2 applications of NeoxFlo to facilitate healing.  The dosage depends on the wound size.

NeuroMatrix™ Collagen Nerve Cuff and NeuroMend™ Collagen Nerve Wrap

Peripheral nerves possess the capacity of self-regeneration after traumatic injury.  Transected peripheral nerves can be bridged by direct surgical coaptation of the 2 nerve stumps or by interposing autografts or biological (veins) or synthetic nerve conduits.  Nerve conduits are tubular structures that guide the regenerating axons to the distal nerve stump.  Early synthetic nerve conduits were primarily made of silicone because of the relative flexibility and biocompatibility.  Nerve conduits are now made of biodegradable materials such as collagen, aliphatic polyesters, or polyurethanes (Pfister et al, 2007).  Studies are in progress to assess the long-term biocompatibility of these implants and their effectiveness in nerve reconstruction.

According to the Collagen Matrix, Inc. (Franklin Lakes, NJ) website, NeuroMatrix is a resorbable, semi-permeable collagen-based tubular matrix that provides a protective environment for peripheral nerve repair after injury and creates a conduit for axonal growth across a nerve gap.  The device slowly resorbs in vivo.  The device is engineered from highly purified type I collagen fibers and are composed of dense fibers for mechanical strength.  Collagen Nerve Cuff was cleared by the FDA via the 510(k) process in September 2001.  It is intended for use in repair of peripheral nerve discontinuities where gap closure can be achieved by flexion of the extremity; however, there is insufficient scientific evidence regarding its effectiveness for peripheral nerve repair or for any other indication.

NeuroMend Nerve Wrap is a resorbable, semi-permeable, type 1 collagen nerve wrap used in peripheral nerve repair.

NeuroMend (Collagen Matrix, Inc., Franklin Lakes, NJ) is a resorbable, collagen-based rolled membrane matrix intended for use in the management of peripheral nerve injuries in which there has been no substantial loss of nerve tissue.  It has the same technological characteristics as NeuroMatrix.  Collagen Nerve Wrap was cleared by the FDA via the 510(k) process on July 14, 2006; however, there is insufficient scientific evidence regarding its effectiveness for peripheral nerve repair or for any other indication.

Novachor

Novachor (Organogenesis, Inc., Canton, MA) is comprised of the chorion layer of the placental membranes. This membrane is known to contain 1) collagen types I, III, V, VI laminin, fibronectin and proteoglycans; 2) trophic proteins; 3) growth factors; 4) Tissue Inhibitors of Matrix Metallo-proteinases (TIMPs); and 5) pluri-potential cells. It is intended to be applied as a graft for acute and chronic wounds, including but not limited to, neuropathic ulcers, venous stasis ulcers, pressure ulcers, burns, post-traumatic wounds and post-surgical wounds. It is administered by applying the product to a wound using sutures or other fixation method. The product provides a physical covering which protects the wound and supports endogenous healing.

Novafix and Novafix DL

Novafix (DCI Donor Services, Inc.) is indicated for use in the management of wounds, including: partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor sites, post-laser surgery, post-Mohs surgery, podiatric wounds and wound dehiscence), trauma wounds (abrasions, lacerations, partial thickness burns, skin tears), and draining wounds. Apply Novafix into the wound bed, and position as needed to completely contact the entire surface of the wound bed and extend slightly beyond wound margins. As medically necessary, Novafix can be secured to the wound site with the physicain's preferred fixation method based on the type of wound, location of wound, patient's mobility and patient compliance. Novafix is supplied in sizes: 15mm disc, 2cm x 2cm, 4cm x 4cm, and 5cm x 5cm.

Novafix DL (Triad Life Sciences, Inc) is a sterile, single use, dehydrated human amnion chorion membrane allograft used for safe and effective wound treatment. Novafix DL will fully resorb into the wound and provide a scaffold for cellular infiltration and vascularization. Working as a skin substitute, Novafix DL permits the ingress of cells and soft tissue formation in the defect space or wound bed. Novafix DL is intended for use in the management of wounds, including: partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor site/grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, wound dehiscence), trauma wounds, (e.g., abrasions, lacerations, partial thickness burns, skin tears), and draining wounds. It is applied on a wound after the wound bed is prepared with standard debridement methods. The product will fully resorb and does not have to be removed from the wound bed. Novafix DL is supplied terminally sterile, in a single use package in a variety of sizes. Novafix DL may be fenestrated, and/or reapplied as necessary.

NovoSorb SynPath

NovoSorb SynPath consists of a sterile, acellular, synthetic dermal matrix and contains a porous network of non-toxic, biodegradable synthetic polymers to support the proliferation of important cells involved in cellular repair. A sealing membrane covers the matrix which reduces water vapor loss and helps keep the wound environment moist. The clinician will determine the appropriate time to remove the membrane based on wound progression, the need for surgical closure or grafting, or application of another dermal template. NovoSorb SynPath is indicated for the management of partial and full thickness wounds, chronic ulcers (pressure, venous, diabetic), surgical wounds, and traumatic wounds. Following wound site preparation, the clinician applies the textured side of NovoSorb SynPath directly into the wound surface flush against the wound bed. This product is available in a sterile, inner transparent pouch encased by an outer aluminized pouch and ranges in sizes from 2 cm x 2 cm square to 20 cm x 40 cm square.

NuCel Liquid Wound Covering

NuCel liquid wound covering (Nutech Medical, Birmingham, AL) is derived from healthy living donors.  It is an unique in-vivo liquid wound covering, providing a defensive barrier at the surgical site in situations where a patch covering is either inadequate or inconvenient.  Mixed with patients' own blood, NuCel is applied directly to the surgical site, offering surgeons the ability to spread the amniotic membrane over an irregular or larger area, including over large bone void fill constructs for spine fusion or large trauma repair.  However, there is a lack of evidence regarding the effectiveness of the NuCel liquid wound covering.

NuDYN DL

NuDYN DL is dual layer, dehydrated amniotic and chorionic membrane allograft derived from donated human placenta aimed to function as a barrier or wound covering for acute and chronic wounds. The product serves as a physical barrier by providing a protective covering for acute and chronic wounds/ulcers such as pressure ulcers, venous ulcers, diabetic ulcers, partial and full-thickness wounds, chronic vascular ulcers, tunneled/undermined wounds, traumatic wounds, (abrasions, lacerations, partial thickness burns, skin tears), wound dehiscence, draining wounds, tunneled / undermined wounds, and surgical wounds such as podiatric, post-laser surgery, post-Moh's surgery, and donor sites/grafts. NuDYN DL is applied by a physician or other qualified healthcare professional to the wound/ulcer following appropriate wound/ulcer preparation with debridement. Product fixation is required to prevent displacement. NuDYN DL is fully resorbable without requiring removal from wound/ulcer beds. The product is terminally sterilized, for single-use, and available in a variety of sizes in square centimeters to cover and protect different sizes of wounds/ulcers (CMS, 2023d).

NuDYN DL MESH

NuDYN DL MESH is a dual layer, meshed style dehydrated amniotic and chorionic membrane allograft derived from donated human placenta aimed to function as a barrier or wound covering for acute and chronic wounds. The product serves as a physical barrier by providing a protective covering for acute and chronic wounds/ulcers such as pressure ulcers, venous ulcers, diabetic ulcers, partial and full-thickness wounds, chronic vascular ulcers, tunneled/undermined wounds, traumatic wounds, (abrasions, lacerations, partial thickness burns, skin tears), wound dehiscence, draining wounds, tunneled/undermined wounds, and surgical wounds such as podiatric, post-laser surgery ,post-Moh's surgery, and donor sites/grafts. NuDYN DL MESH is applied by a physician or other qualified healthcare professional to the wound/ulcer following appropriate wound/ulcer preparation with debridement. Product fixation is required to prevent displacement. NuDYN DL MESH is fully resorbable without requiring removal from wound/ulcer beds. The product is terminally sterilized, for single-use, and available in a variety of sizes in square centimeters to cover and protect different sizes of wounds/ulcers (CMS, 2023d).

NuDYN SL

NuDYN SL is a dehydrated human amnion membrane allograft derived from donated human placenta aimed to be used as a barrier or wound covering for acute and chronic wounds/ulcers. The product serves as a physical barrier by providing a protective covering for acute and chronic wounds/ulcers such as pressure ulcers, venous ulcers, diabetic ulcers, partial and full-thickness wounds, chronic vascular ulcers, tunneled/undermined wounds, traumatic wounds,(abrasions, lacerations, partial thickness burns, skin tears), wound dehiscence, draining wounds, tunneled / undermined wounds, and surgical wounds such as podiatric, post-laser surgery, post-Moh's surgery, and donor sites/grafts. NuDYN SL is applied by a physician or other qualified healthcare professional to the wound/ulcer following appropriate wound/ulcer preparation with debridement. Product fixation is required to prevent displacement. NuDYN SL is fully resorbable without requiring removal from wound/ulcer beds. The product is terminally sterilized, for single-use, and available in a variety of sizes in square centimeters to cover and protect different sizes of wounds/ulcers (CMS, 2023d).

NuDYN SLW

NuDYN SLW is a hydrated human amnion membrane allograft derived from donated human placenta aimed to be used as a barrier or wound covering for acute and chronic wounds/ulcers. The product serves as a physical barrier by providing a protective covering for acute and chronic wounds/ulcers such as pressure ulcers, venous ulcers, diabetic ulcers, partial and full thickness wounds, chronic vascular ulcers, tunneled/undermined wounds, traumatic wounds, (abrasions, lacerations, partial thickness burns, skin tears), wound dehiscence, draining wounds, tunneled / undermined wounds, and surgical wounds such as podiatric, post-laser surgery, post-Moh's surgery, and donor sites/grafts. NuDYN SLW is applied by a physician or other qualified healthcare professional to the wound/ulcer following appropriate wound/ulcer preparation with debridement. Product fixation is required to prevent displacement. NuDYN SLW is fully resorbable without requiring removal from wound/ulcer beds. The product is terminally sterilized, for single-use, and available in a variety of sizes in square centimeters to cover and protect different sizes of wounds/ulcers (CMS, 2023d).

Nushield

Nushield is an allograft produced from human placental membrane and includes the amniotic epithelial layer, the amniotic basement membrane, the amniotic stroma, the chorionic basement membrane, and the chorionic stroma. This membrane contains (1) collagen types III, IV, laminin and proteglycans; (2) cross-linked hyaluronic acid; (3) trophic proteins; (4) growth factors; (5) Tissue Inhibitors of Matrix metallo-proteinases (TIMPs); and (6) multipotential cells. Nushield is intended to be applied as an on-lay graft for acute and chronic wounds, including, but not limited to, neuropathic ulcers, venous stasis ulcers, pressure ulcers, burns, post-traumatic wounds and post-surgical wounds. it is also used as a wound covering and as a barrier for the protection of tendons, nerves and dura. The product will be sterilely packaged for single-use and available in the following sizes: 2x3 cm, 4x4 cm, and 6x6 cm. Nushield will also be expandable (meshed) form.

Oasis Burn Matrix

Oasis Burn Matrix (Cook Biotech Inc., West Lafayette, IN) is a extracellular matrix created from the submucosal layer of porcine small intestine.  The submucosa is extracted in a manner that removes all cells but leaves the submucosa matrix intact.  This matrix is intended to provide an acellular scaffold that accommodates remodeling of host tissue.  The Oasis Burn Matrix has increased thickness allowing application for an extended period of time.  There is a lack of evidence in the peer-reviewed published medical literature on the effectiveness of the Oasis Burn Matrix.

Oasis Tri-Layer Matrix

Oasis tri-layer matrix (Healthpoint Biotherapeutics, Fort Worth, TX) is an extra-cellular matrix derived from porcine small intestinal submucosa (SIS).  It is indicated for the management of wounds, including partial and full-thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (abrasions, lacerations, 2nd degree burns, and skin tears), drainage wounds, and surgical wounds.  After the wound bed is free of exudate and devitalized tissue, the wound matrix is applied over the wound.  Once applied, tissues adjacent to the SIS matrix deliver cells and nutrients to the wounded tissues using the SIS material as a conduit.  The cells rapidly invade the SIS material and capillary growth follows, allowing nutrients to enter the matrix.  SIS is strong at the time of placement, and is gradually re-modeled while the host system reinforces and rebuilds the damaged site with host tissue.  As healing occurs, sections of Oasis Ultra Tri-Layer Wound Matrix may gradually peel.  All dressings should be changed every 7 days, or as necessary.  Oasis Ultra Tri-Layer Wound Matrix is supplied in sterile peel-open packages intended for one-time use.  It is supplied in 2 sizes: 7 x 10 cm and 7 x 20 cm. According to the manufacturer, OASIS Ultra Tri-Layer Wound Matrix differs from other products because it is a wound matrix with 3 layers. However, there is a lack of evidence regarding the effectiveness of the Oasis tri-layer matrix.

Oasis Wound Dressing

Oasis wound dressing (Cook Biotech Inc., West Lafayette, IN), a tissue-engineered collagen matrix derived from the porcine small intestinal submucosa (SIS).  Oasis Wound Matrix was cleared for marketing under the 510(k) process and is indicated "for the management of wounds including: partial and full-thickness wounds; pressure ulcers; venous ulcers; diabetic ulcers; chronic vascular ulcers; tunneled, undermined wounds; surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence); trauma wounds (abrasions, lacerations, second-degree burns, and skin tears); draining wounds. The device is intended for one-time use."

Oasis Wound Matrix is a naturally derived, extracellular matrix (ECM) created from the submucosal layer of porcine small intestine. Oasis Wound Matrix is indicated for treatment of difficult-to-heal chronic venous or diabetic partial and full-thickness ulcers of the lower extremity that have failed standard wound therapy of at least four weeks duration. 

Oasis Wound Matrix is an extracellular matrix derived from porcine small intestinal submucosa (Snyder, et al., 2012). According to the manufacturer, the intestinal material is absorbed into the wound during the healing process. Oasis is applied to wounds after débridement. The edges of the Oasis sheet extend beyond the wound edges and are secured with tissue sealant, bolsters, dissolvable clips, sutures, or staples. The sheet is rehydrated with sterile saline and covered with a nonadherent, primary wound dressing followed by a secondary dressing to contain exudate. Oasis is reapplied every 7 days or as needed.

In a prospective, randomized, controlled multi-center study (n = 120), Mostow and colleagues (2005) examined the effectiveness of Oasis in the treatment of chronic leg ulcers.  Patients were randomly assigned to receive either weekly topical treatment of SIS combined with compression therapy (n = 62) or compression therapy alone (n = 58).  Ulcer size was determined at enrollment and weekly throughout the treatment.  Healing was assessed weekly for up to 12 weeks.  Recurrence after 6 months was recorded.  The primary outcome measure was the proportion of ulcers healed in each group at 12 weeks.  After 12 weeks of treatment, 55 % of the wounds in the Oasis group were healed, as compared with 34 % in the standard-care group (p = 0.0196).  None of the healed Oasis-treated subjects who were seen at the 6-month follow-up experienced ulcer recurrence.  These investigators concluded that Oasis, as an adjunct therapy, significantly improved healing of chronic leg ulcers over compression therapy alone.  Moreover, the authors noted that a definitive link between the composition of Oasis and its positive effects on chronic wounds has not been established.  Also, the limited number of wounds examined at the 6-month follow-up suggested that more research especially longer follow-up is needed to ascertain recurrence after treatment with Oasis.

In another randomized, prospective, controlled multi-center study (n = 73), Niezgoda et al (2005) compared healing rates at 12 weeks for patients with full-thickness diabetic foot ulcers treated with Oasis versus Regranex gel.  Patients with at least 1 diabetic foot ulcer were entered into the trial and completed the protocol.  They were randomized to receive either Oasis (n = 37) or Regranex gel (n = 36) and a secondary dressing.  Wounds were cleansed and debrided, if needed, at a weekly clinic visit.  Dressings were changed as needed.  The maximum treatment period for each patient was 12 weeks.  After 12 weeks of treatment, 18 (49 %) Oasis-treated subjects had complete wound closure compared with 10 (28 %) Regranex-treated patients.  These researchers concluded that although the sample size was not large enough to demonstrate that the incidence of healing in the Oasis group was statistically superior (p = 0.055), the study results showed that treatment with Oasis is as effective as Regranex in healing full-thickness diabetic foot ulcers by 12 weeks.  One of the drawbacks of this study was that the findings did not reach statistical significance, namely, the overall healing rates between groups were similar.  In addition, there were more cases of infection in the Oasis-treated group than the Regranex-treated group.  Furthermore, the 6-month follow-up evaluation did not allow for adequate evaluation of long-term effectiveness.

Romanelli et al (2007) compared the effectiveness of Oasis wound matrix versus Hyaloskin in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology.  The purpose of the study was to examine whether a single extracellular matrix component, such as hyaluronan (Hyaloskin), can stimulate healing of mixed arterial/venous ulcers or whether a more integrated extracellular replacement that contains multiple active extracellular matrix components is needed.   Fifty-four patients were prospectively selected for enrollment into a randomized trial.  The enrolled patients met the following criteria: age greater than 18 years with mixed arterial/venous leg ulcer by clinical and instrumental assessment, venous reflux by Doppler flow studies, ankle brachial pressure index greater than 0.6 and less than 0.8, ulcer duration greater than 6 weeks and size 2.5 to 10 cm(2), and 50 % or more granulation tissue on the wound bed.  Patients were excluded if they were diabetics, were smokers, had clinical signs of wound infection, an ankle brachial pressure index less than 0.06, had necrotic tissue on the wound bed, had known allergy to the treatment products or were unable to deal with the protocol.  Patients who met the inclusion/exclusion criteria were randomized to treatment with OASIS (n = 27) or Hyaloskin (n = 27).  The sequence of randomization was generated through every other patient selection by the clinician.  Patients were advised not to use any compression system during the study.  After 16 weeks of treatment, patients in each group were evaluated on 4 criteria:
  1. complete wound healing,
  2. time to dressing change,
  3. pain, and
  4. comfort. 

Complete wound closure was achieved in 82.6 % of Oasis-treated ulcers compared with 46.2 % of Hyaloskin-treated ulcers (p < 0.001).  Statistically significant differences favoring the Oasis treatment group were also reported for time to dressing change (p < 0.05), pain (p < 0.05) and patient comfort (p < 0.01).  The authors stated that these results suggest that Oasis is an effective treatment for difficult-to-heal mixed arterial/venous ulcers and that replacement of the major components of the dermal extracellular matrix is more effective than replacing it with hyaluronan alone.

In a randomized comparison of Oasis wound matrix versus moist wound dressing, Romanelli et al (2010) evaluated complete wound healing, time to dressing change, and formation of granulation tissue in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology.  Fifty adults with lower leg ulcers of mixed arterial/venous (n = 23) and venous (n = 27) etiology were prospectively selected for enrollment.  Patients had the following characteristics: venous or mixed arterial/venous leg ulcer by clinical and instrumental assessment and ankle brachial index ranging between 0.6 and 0.8, ulcer duration of greater than 6 months, ulcer size of greater than 2.5 cm(2), and 50 % granulation tissue on wound bed.  Patients were excluded for clinical signs of infection, ankle brachial index less than 0.6, necrotic tissue on wound bed, known allergy to treatment products, or if they were unable to deal with the protocol.  Patients who met the inclusion/exclusion criteria were randomized to treatment with Oasis (n = 25) or with standard moist wound dressing (petrolatum-impregnated gauze; n = 25).  The investigators reported that extracellular matrix-treated ulcers achieved complete healing on average in 5.4 weeks as compared with 8.3 weeks for the control group treated with moist wound dressing (p = 0.02) and at the primary time point evaluated (8 weeks), complete wound closure was achieved in 80 % of extracellular matrix-treated ulcers compared with 65 % of ulcers in the control group (p < 0.05).  Statistically significant differences favoring the extracellular-matrix treatment group were also reported for time to dressing change (p < 0.05), and for percentage of granulation tissue formed (p < 0.05).  The authors concluded that overall, the biological extracellular matrix was more beneficial than moist wound dressings for the treatment of patients with mixed arterial/venous or venous ulcers.  Although current methods of standard care can be effective in the treatment of lower extremity ulcers, in this study, Oasis significantly reduced time to healing as compared with moist wound dressing in chronic, difficult-to-heal mixed arterial/venous leg ulcers.

O'Donnell and Lau (2006) examined if more "modern" complex wound dressings further improve the healing of venous ulcers over that with simple wound dressings.  These investigators conducted a systematic review of RCTs of wound dressing trials that were published from October 1, 1997, through September 1, 2005.  They searched MEDLINE, CINAHL, and the Cochrane Controlled Trials Registry Database to identify RCTs.  Criteria for ultimate selection included treatment with compression and an objective outcome describing the proportion of wounds healed.  A total of 20 RCTs were identified that satisfied these criteria and were classified into 3 wound dressing classes:
  1. semi-occlusive/occlusive group (n = 8),
  2. growth factor group (n = 7), and
  3. human skin equivalent group (n = 5). 

Assessment of study design quality for the 20 RCTs showed a low percentage (less than 49 %) of RCTs that incorporated at least 3 of 7 indicators of trial quality, but it seemed better in the 5 RCTs that showed significance for ulcer healing; 4 of the studies used at least 6 of the 7 characteristics of adequate study design.  Five (25 %) of the 20 RCTs had a statistically significantly improved proportion of ulcers healed in the experimental dressing group over control values: zinc oxide paste bandage (79 % versus 56 %) and Tegasorb (59 % versus 15 %) in the semi-occlusive/occlusive group and peri-lesional injection of granulocyte-macrophage colony-stimulating factor (57 % versus 19 %) and porcine collagen derived from small-intestine submucosa (Oasis; 55 % versus 34 %) in the growth factor group.  In the sole significant RCT from the human skin equivalent group, Apligraf (63 %) was superior to Tegapore (48 %).  Four of these 5 studies also showed an improved time to complete healing by Kaplan-Meier estimate.  The authors concluded that certain wound dressings can improve both the proportion of ulcers healed and the time to healing over that achieved with adequate compression and a simple wound dressing.  The selection of a specific dressing, however, will depend on the dressing characteristics for ease of application, patient comfort, wound drainage absorption, and expense.

Omega3 MariGen, Omega3 MariGen Shield, Omega3 Wound ECM, Omega3 Wound Matrix (Kerecis fish skin graft)

Marigen is an omega 3, acellular, dermal extracellular matrix xenograft made from fish (piscine) dermis (CMS, 2014). Marigen contains natural insoluble proteins such as collagen as well as proteoglycans, glycosaminoglycans, and fibronectin. These provide a scaffold for revascularization and repopulation by the patient's cells for wound healing. Marigen is used as a wound covering and wound matrix for full-thickness wounds and burns, or as a covering for damaged membranes. It is supplied in the following sizes: 3x3.5cm, 3x7cm, and 7x10cm. Kerecis Omega3 products, such as the Omega3 MariGen, are not available in all countries and may be known by different names.

KerecisOmega3 is an extracellular matrix (ECM) xenograft made from fish (piscine) dermis designed for transplant into damaged tissue such as chronic wounds (CMS, 2017). Keresis Omega3 contains natural insoluble proteins such as collagen and proteoglycans, glycosaminoglycans, and fibronectin.KerecisOmega3 Wound ECM also contains growth factors such as IGF-1 and TGFf32. According to the manufacturer,KerecisOmega3 acellular fish skins refocus the healing process of the tissue damage. The skin acts as a scaffold for revascularization and repopulation of the patient's cells, which are under attack from matrix metalloproteinases (MMPs) in the inflamed wound. It is used as a wound covering and wound matrix for full thickness wounds and burns as a covering for damaged membranes. Omega 3 is supplied in a sealed, sterilized package in the following sizes: 3 x 3.5cm (10 per package); 3 x 7 cm (10 per package); and 7 x 10cm (10 per package). The product is shipped freeze dried and must be rehydrated before it is applied.

Dorweiler and colleagues (2018) stated that theKerecisOmega3 wound matrix is a decellularized skin matrix derived from fish skin and represents an innovative concept to achieve wound healing.  These investigators reported the cumulative experience of 3 centers for vascular surgery regarding use of the Omega3 wound matrix in selected patients with complicated wounds.  In this study, a total of 23 patients with 25 vascular and/or diabetes mellitus-associated complicated wounds and partially exposed bony segments were treated with the Omega3 wound matrix.  In several patients, conventional wound treatment with vacuum therapy had previously been performed sometimes over several weeks without durable success.  Following initial debridement in the operating room, the matrix was applied and covered with a silicone mesh.  In the further course, wound treatment was conducted at an out-patient setting if possible.  A total of 25 wounds were treated with localization at the level of the thigh (n = 2), the distal calf (n = 7), the forefoot (n = 14) and the hand (n = 2).  The time to heal varied between 9 and 41 weeks and between 3 and 26 wound matrices were applied per wound.  Interestingly, a reduction of analgesics intake was noted when the treatment with the Omega3 wound matrix was initiated.  The authors concluded that the novel Omega3 wound matrix in this study represented an effective therapeutic option in 25 complicated wounds.  These researchers stated that further studies are needed to examine the impact of the Omega3 wound matrix on stimulation of granulation tissue and re-epithelialization as well as the potential anti-nociceptive and analgesic effects.

The authors stated that the limitations of this study included the small sample size (n = 23 patients) despite a multi-center approach and the differing selection criteria and treatment end-points; however, the primary objective of this investigation was to evaluate the efficacy and usefulness of this preparation in the context of a pilot series.  For this reason, no control group was included.  Having said that, the initiation of a follow-up study with a control group is currently at the planning stage.

Ciprandi et al (2022) stated that more specific strategies are needed to support children requiring skin grafting.  These investigators identified procedures that reduce operating times, post-operative complications, pain, and hospital LOS.  Patient safety, optimal wound bed support and quick micro-debridement with locoregional anesthesia were prioritized.  Ultimately, a novel acellular FSG derived from north Atlantic cod was selected for use.  These researchers admitted consecutive pediatric patients with various lesions requiring skin grafting for definitive wound closure.  All FSGs were applied and bolstered in the operating room following debridement.  In a cohort of 15 patients, the average age was 8 years and 9 months (range of 4 years 1 month to 13 years 5 months); NPWT was administered to 12 patients.  Rapid wound healing was observed in all patients, with a wound area coverage of 100 % and complete healing in 95 % of wounds.  Time until engraftment in patients receiving NPWT was reduced by approximately 50 % (to an average 12 days) from the standard experience of 21 days.  A total of 10 patients received locoregional anesthesia and were discharged after day surgery.  The operating time was less than 60 mins, and no complications or allergic reactions were reported.  Excellent pliability of the healed wound was achieved in all patients, without signs of itching and scratching in the post-operative period.  This case series was the 1st and largest using FSG to treat pediatric patients with different wound etiologies.  These investigators attributed the rapid transition to acute wound status and the good pliability of the new epidermal-dermal complex to the preserved molecular components of the FSG, including omega-3.  The authors concluded that FSG represented an innovative and sustainable solution for pediatric wound care that resulted in shorter surgery time and reduced hospital LOS, with accelerated wound healing times.  Moreover, these researchers stated that further controlled clinical investigations using intact FSG for wound management in the pediatric population should be considered to make conclusive decisions regarding its place in wound management in this specific population.  The authors noted that the main drawbacks of this trial were the small patient number (n = 15) and the lack of a control arm to compare against standard of care practices.

Reda et al (2023) stated that the 2020 Nagorno-Karabakh war was an armed conflict between Azerbaijan and Armenia over an ethnically and historically significant region.  These investigators reported on the forward deployment of acellular FSG fromKerecisthat contains intact epidermis and dermis layers.  The usual intention of treatment under adverse circumstances is to temporize wounds until better treatment can be attained, although ideally, rapid coverage and treatment are necessary to prevent long-term complications and loss of life and limb.  An austere environment, such as the one experienced during the conflict described here, presented considerable logistical barriers for the treatment of wounded soldiers.  Dr. H. Kjartansson from Iceland and Dr. S. Jeffery from the U.K. traveled to Yerevan to deliver and train on using FSG in wound management.  The primary objective was to use FSG in patients where stabilization and improvement in the wound bed were needed before skin grafting.  Other objectives were to improve healing time, achieve earlier skin grafting, and have better cosmetic outcomes upon healing.  Over the course of 2 trips, several patients were managed with FSG.  Injuries included large-area full-thickness burn and blast injuries.  Management with FSG induced wound granulation several days sooner in all cases, and even weeks in some instances, allowing a stepdown in the reconstruction ladder with earlier skin grafting procedures and a reduction in requirement of flap surgery.  The authors concluded that this study described a successful 1st instance of forward deployment of FSGs to an austere environment.  FSG, in this military context, has shown great portability, with easy transfer of knowledge.  More importantly, management with FSG has shown faster granulation rates in burn wounds for skin grafting, resulting in improved patient outcomes with no documented infections.  Moreover, these researchers stated that the concept of employing FSG in military medical facilities, such as field hospitals, should be further examined in a controlled environment, where a more detailed analysis can be performed; and secondary outcomes can be evaluated.

Lantis et al (2023) stated that DFUs remain a cause of significant morbidity.  In a prospective, randomized-controlled, multi-center study, these researchers examined the use of omega-3-rich acellular fish skin graft (FSG) compared with collagen alginate therapy (CAT) in the management of DFUs.  A total of 102 patients with a DFU (n = 51 FSG, n = 51 CAT) participated in this trial as ITT candidates, with 77 of those patients included in the PP analysis (n = 43 FSG, n = 34 CAT).  Six months after treatment, patients with healed ulcers were followed-up for ulcer recurrence.  A cost analysis model was employed in both treatment groups.  The proportion of closed wounds at 12 weeks was compared, as were the secondary outcomes of healing rate and mean PAR.  Diabetic foot wounds treated with FSG were significantly more likely to achieve closure than those managed with CAT (ITT: 56.9 % versus 31.4 %; p = 0.0163).  The mean PAR at 12 weeks was 86.3 % for FSG versus 64.0 % for CAT (p = 0.0282).  The authors concluded that treatment of DFUs with FSG resulted in significantly more wounds healed and an annualized cost savings of $2,818 compared with CAT. Moreover, these researchers stated that future studies should compare materials such as FSG with other advanced cellular and/or tissue-based products.

The authors stated that this study had several drawbacks.  Although the findings of this study were positive, a larger cohort of patients, encompassing more study sites, would greatly strengthen the statistical analysis.  Moreover, inclusion of more diverse patients with a greater variety of DFUs and co-morbidities, along with a larger, longer, and more detailed follow-up would afford more robust and inclusive real-world findings.  Another difficulty in a trial with a tissue-based therapy is that it is quite difficult to mask the assessor and participant.  Furthermore, non-tissue-based best clinical practice requires multiple dressing changes a week, whereas tissue-based clinical practice requires a single weekly dressing.  The necessity of the different dressing regimens, while a real-world problem, introduced a differential in how the wounds were treated between the 2 groups.  This study population represented the sites selected and their geographic locations.  Black and Hispanic populations were quite under-represented in this study.  Future studies need a greater emphasis on urban centers, which tend to have a higher proportion of individuals of color.  Given recent FDA guidelines, it is likely that in the future all such studies will require a more robust diversity plan; however, the female-to-male ratio in this trial was in line with the overall incidence of DFUs.  The recorded dropout rate was 24.5 % of the total enrollment, with several reasons for dropping out.  This rate fell within the range reported in similar studies in which DFUs were treated using advanced tissue therapies such as porcine small intestine submucosa tri-layer matrix, dehydrated human amnion/chorion membrane, and bilayer dermal regeneration template.  Factors that contributed to the withdrawal rate in this trial included protocol violations, loss to follow-up, and the number of serious AEs, especially the incidents of infections in the control group, which accounted for removal of these patients from the trial.  Although this was a single-masked study, patients in each arm could easily recognize which product they received owing to the differences in appearance of FSG and CAT, and the 2 incidents of patient self-termination were associated with the patient wishing to receive a cellular and/or tissue product as perceived as better than CAT.  The withdrawal rate in this study was largely affected by the global COVID-19 pandemic, which hindered many in-person visits and subsequently resulted in many participants being lost to follow-up.  According to the protocol, participants were terminated if their index ulcers were not reduced by 50 % after 6 weeks of consecutive treatment.  This allowed participants with unsatisfactory results to exit the study and seek better alternatives.  A total of 7 participants exited the study following this guidance.  Patients with non-healing wounds are at risk of infection, osteomyelitis, sepsis, and cellulitis if left untreated; therefore, it was appropriate to remove these 7 patients from the trial.

MariGen Shield is a bilayer composed of resorbable acellular fish dermal matrix skin substitute attached to a thin, transparent, porous, soft silicone layer. The fish dermal matrix layer is made from wild-caught Atlantic Cod and is approximately 1 mm in thickness and porosity. The silicone layer is a transparent polyurethane film single-coated with soft, medical grade silicone that is affixed to a scaly side of the fish dermal matrix. The silicone layer is conformable to the wound surface and can be peeled off as the fish dermal matrix is resorbed. MariGen Shield is indicated for the management of partial and full-thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (abrasions, lacerations, partial-thickness burns, skin tears), surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric wound dehiscence), draining wounds. MariGen Shield is individually packaged in a variety of sizes and dosed equally to the wound size in centimeters (CMS 2022b).

Omeza Collagen Matrix

Omeza Collagen Matrix is an anhydrous acellular matrix made up of hydrolized fish collagen infused with cod liver oil and other plant-derived oils and waxes. Omeza Collagen Matrix is intended for homologous use and indicated treat chronic non-healing wounds such as venous, diabetic and pressure injury/ulcers, as well as surgical sites and trauma wounds to help in the healing process. Omeza Collagen Matrix supports critical phases of wound healing by delivering diverse collagen types in an anhydrous transporter that creates a conforming physical collagen microstructure at the wound site for cellular migration and wound revascularization. Eventually, the patient’s cells replace the acellular matrix with a native extracellular matrix, and the hydrolyzed fish collagen microstructure biodegrades. The cod liver oil and other oils and waxes within this product facilitate its final conformability to the irregularities of the wound site. Omeza Collagen Matrix is available in a sterile, single use 1.6 g vial from which it is dispensed and applied directly or via suitable applicator to the wound bed by a physician, podiatrist, nurse practitioner, or surgeon.

Orcel

Orcel is a bilayered skin substitute that uses human epidermal keratinocytes and dermal fibroblasts that are cultured into two separate layers on a bovine collagen sponge. As healing occurs at the site of the wound, the OrCel dissolves and the patient’s own skin cells then replace the OrCel cells to create a new skin surface.  Orcel is indicated for dystrophic epidermolysis bullosa in children; andr for full thickness (3rd degree) and partial thickness (2nd degree) burns. 

Orcel is an absorbable bilayered cellular matrix, made of bovine collagen, in which human dermal cells have been cultured. OrCel (Forticell Bioscience, Inc., formerly Ortec International, Inc., New York, NY) is composed of normal, human, allogeneic, epidermal keratinocytes and dermal fibroblasts (Snyder, et al., 2012). The cells are cultured in two separate layers into a type I bovine collagen sponge. Neonatal human fibroblasts and keratinocytes are obtained from the same donor. According to the manufacturer, the matrix is designed to provide a structure for host cell invasion along with a mix of cytokines and growth factors. The matrix is absorbed as the wound heals. Because of the extensive culturing process, the cells do not express the antigens responsible for rejection. The cells produce growth factors. When this dressing is applied to the open wound created where the patient's healthy skin was removed, the patient's own skin cells migrate into the dressing and take hold, along with the cultured cells, as healing commences.  The dressing is gradually absorbed during the healing process.

Orcel was approved by the FDA under its humanitarian device exemption (HDE) in February 2001 for healing donor site wounds in burn victims, and for use in patients with recessive dystrophic epidermolysis bullosa (RDEB) undergoing hand reconstruction surgery to close and heal wounds created by the surgery, including those at donor sites (Snyder, et al., 2012). Composite Cultured Skin (Ortec International, Inc., New York, NY) is "indicated for use in patients with mitten hand deformities due to Recessive Dystrophic Epidermolysis Bullosa (RDEB) as an adjunct to standard autograft procedures (i.e., skin grafts and flaps) for covering wounds and donor sites created after the surgical release of hand contractures (i.e., "mitten" hand deformities)." OrCel has also received PMA approval for treating fresh, clean, split-thickness, donor site wounds in burn patients and may, therefore, be used by physicians off-label on chronic wounds. A PMA application with FDA has been filed for treating venous leg ulcers. Studies will test OrCel in treating diabetic foot ulcers. The manufacturer indicates that it will promote OrCel for treating chronic and acute wounds. Forticell Bioscience, Inc., is the former Ortec International, Inc.

Santema et al (2016) conducted a Cochrane systematic evidence review to determine the benefits and harms of skin grafting and tissue replacement, including Orcel, for treating foot ulcers in people with diabetes. In April 2015 the authors searched: The Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched clinical trial registries to identify ongoing studies. We did not apply restrictions to language, date of publication or study setting. The investigators searched for randomized clinical trials (RCTs) of skin grafts or tissue replacements for treating foot ulcers in people with diabetes. Two review authors independently extracted data and assessed the quality of the included studies. The authors included seventeen studies with a total of 1655 randomized participants in this review. The authors reported that risk of bias was variable among studies. Blinding of participants, personnel and outcome assessment was not performed in most trials, and this lack of a blinded outcome assessor may have caused detection bias when ulcer healing was assessed. The authors found that nearly all studies (15/17) reported industry involvement; at least one of the authors was connected to a commercial organization or the study was funded by a commercial organization. In addition, the funnel plot for assessing risk of bias appeared to be asymmetrical; suggesting that small studies with 'negative' results are less likely to be published. Thirteen of the studies included in this review compared a skin graft or tissue replacement with standard care. Four studies compared two grafts or tissue replacements with each other. When the authors pooled the results of all the individual studies, the skin grafts and tissue replacement products that were used in the trials increased the healing rate of foot ulcers in patients with diabetes compared to standard care (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence). However, the strength of effect was variable depending on the specific product that was used (e.g. OrCel RR 1.75, 95% CI 0.61 to 5.05, and EpiFix RR 11.08, 95% CI 1.69 to 72.82). The authors found that, based on the four included studies that directly compared two products, no specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement. Sixteen of the included studies reported on adverse events in various ways. No study reported a statistically significant difference in the occurrence of adverse events between the intervention and the control group. Only two of the included studies reported on total incidence of lower limb amputations. The authors found fewer amputations in the experimental group compared with the standard care group when they pooled the results of these two studies, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). The authors concluded that, based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone. However, the available data was insufficient for the authors to draw conclusions on the effectiveness of different types of skin grafts or tissue replacement therapies. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.

Orion Amniotic Membrane

Orion amniotic membrane is a sterile dehydrated dual layered human amniotic membrane allograft that is designed to act as a barrier or cover for acute and chronic wounds and function as a barrier to protect wounds from the surrounding environment. Subsequent to standard wound preparation, Orion amniotic membrane is applied directly to the wound for use in a patient on a single occasion. This product is packaged in a primary foil pouch and a secondary Tyvek pouch and sterilized by e-beam for sterility assurance level of 10-6 and is available in multiple sizes (CMS, 2023a).

OrthADAPT

OrthADAPT Bioimplant is a highly organized Type 1 collagen scaffold derived from Equine Pericardium used as a scaffold for soft tissue repair and reinforcement. OrthADAPT Bioimplant is intended to be used for implantation to reinforce the repair or reconstruction of soft tissues, including the reinforcement of soft tissues repaired by sutures or suture anchors during surgical repair. The inherent properties of this xenograft provide support to challenging tendon repairs in both sports medicine and lower extremity surgical repairs, such as reinforcement of rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons. The use of equine-derived decellularized collagen products (e.g., OrthADAPT™ and Unite™) has not been established as shown by the lack of evidence on the subject.

OrthoFlo

OrthoFlo is an amniotic fluid derived allograft used to "supplement the ability of existing synovial fluid to lubricate and protect" (MiMedx Group, Inc.) (CMS, 2017). OrthoFlo protects, reduces inflammation, lubricates and addresses pain of the joints. OrthoFlo is clinically intended for patients with joint pain due to disease or trauma, resulting in the reduction in lubricating properties of the synovial fluid. OrthoFlo is an amniotic fluid product that is optimally filtered to retain the natural macromolecular and physiologically active components of amniotic fluid, while removing low molecular weight by-products produced in utero. OrthoFlo is administered by a physician. It is injected in the joint with or without ultrasound guidance, as needed, to protect, lubricate, and reduce inflammation. Dosage is determined by the physician. OrthoFlo is supplied in single-use 0.5 mL, 1 mL, 2 mL, and 4 mL vials. MiMedx describes OrthoFlo as a Human Tissue Product for which FDA premarket approval is not required. While MiMedx’s packaging information describes OrthoFlo as an amniotic fluid derived product indicated for "homologous use", the stated indication is supplementation of synovial fluid in the knee joint in order to cushion, lubricate and reduce inflammation.

OviTex

Sawyer (2018) stated that biologic and resorbable synthetic materials are used commonly for crural repair reinforcement during laparoscopic hiatal herniorrhaphy.  Recently, an ovine polymer-reinforced bio-scaffold (OPRBS) has been developed for reinforcement of abdominal wall and hiatal herniorrhaphies.  In a retrospective chart review, these investigators reported the 1st series on the use of OPRBS in hiatal hernia repairs.  This study was carried out on a consecutive series of patients (n = 25) undergoing laparoscopic or open hiatal herniorrhaphy between August 2016 and May 2017.  Data collected included demographics, co-morbidities and symptoms, details of operation, complications, and post-operative follow-up.  Laparoscopic repair was completed in 23 of 24 patients.  Reinforcement with OPRBS was accomplished in all cases.  Fundoplication was constructed in 24 of 25 patients (96 %).  Mean follow-up was 14.2 months.  Good-to-excellent symptom control or resolution has been achieved for heartburn (95 %), dysphagia (94.7 %), regurgitation (100 %), nausea and vomiting (100 %), dyspnea (100 %), and chest pain or discomfort (85.7 %).  Post-operative esophagogastroduodenoscopy with dilation resulted in resolution of persistent post-operative dysphagia in 2 patients (8 %).  To-date there have been no clinical recurrences of hiatal hernia.  The authors concluded that OPRBS in hiatal hernia repair have been associated with excellent early patient outcomes in this study.  These investigators noted that OPRBS represent a new paradigm in hernia repair, as it was the 1st clinically available biological repair material reinforced with embroidered resorbable or permanent synthetic polymer.  Relative weaknesses of this trial included the small sample size (n = 25), and short-term (mean of 14.2 months) follow-up.  These researchers stated that long-term follow-up and additional studies are needed to confirm these findings.

In a retrospective, single-center study, Parker et al (2021)examined  the outcomes of a novel biosynthetic scaffold mesh for ventral hernia repair (VHR) in higher risk patients over a 12-month post-operative period.  Two cohorts of 50 consecutive patients who underwent VHR with TELA Bio OviTex biosynthetic or synthetic mesh were compared.  Endpoints included surgical site occurrence (SSO), re-admission rate, and hernia recurrence following VHR at 12 months post-operatively.  OviTex mesh placement was associated with higher risk Ventral Hernia Working Group (VHWG) distribution and more contaminated CDC wound class distribution compared to synthetic mesh placement (VHWG grade 3: 68 % versus 6 %, p < 0.001; CDC class greater than I: 70 % versus 6 %, p < 0.001).  Furthermore, concomitant procedures were carried out more often with OviTex mesh placement than synthetic mesh placement (70 % versus 10 %, p < 0.001).  The OviTex mesh performed comparably to synthetic mesh in terms of incidences of SSO (36 % versus 22 %, p = 0.19), re-admission rates (24 % versus 14 %, p = 0.31), and hernia recurrence (6 % versus 12 %, p = 0.74).  On further evaluation, patients who developed SSO with OviTex mesh (n = 18) had a 17 % hernia recurrence whereas those with synthetic mesh (n = 11) had an associated 55 % hernia recurrence (p = 0.048).  The authors concluded that the OviTex biosynthetic mesh was used in higher risk patients and performed similarly to synthetic mesh regarding rate of SSO, re-admissions, and hernia recurrence.  In addition, patients who developed SSO with Ovitex mesh were significantly less likely to have hernia recurrence than those with synthetic mesh.  Overall, the data suggested that biosynthetic mesh is a more desirable option for definitive hernia repair in higher risk patients.  Moreover, these researchers stated that further prospective, multi-center studies using TELA Bio OviTex mesh for open VHR are ongoing and needed to support the validity of these findings. 

The authors stated that drawbacks of this trial included its retrospective design at a single institution over a 1-year time period, which did not account for a selection bias in terms of mesh used by surgeons in a consecutive series of hernia repairs.  An effort to limit the influence of this bias was made by collecting data from multiple surgeons across multiple specialties and hospitals, including 1 trauma surgeon, 1 plastic surgeon, and 3 GI surgeons.  An attempt was also made to match the VHWG grade and CDC wound classification of contemporary cases several years before the use of OviTex; the primary drawback was that other forms of biologic mesh were used instead for these same patients with VHWG grade-3 and CDC wound classification II to IV.  Data collection was carried out via retrospective chart review and did not exclude the possibility of a confirmation bias; follow-up at 12-months was felt to be reasonable in both groups based on clinic visits and available cross-sectional imaging.  Although consecutive patients were used in data collection, considerable variance existed including multiple surgeons with varying surgical approaches as well as location of the mesh placement.  The study had 100 total patients (n = 50 for both synthetic and biosynthetic mesh use); thus, it was limited by a relatively small sample size.  Overall, the optimal approach and mesh selection for complicated VHR remains unclear in the literature and requires continued investigation.

Sivaraj et al (2022a) carried out a retrospective analysis on 109 patients, who underwent VHR with reinforced biosynthetic ovine rumen (RBOR) (n = 50) or synthetic polypropylene mesh (n = 59).  Demographic characteristics, co-morbidities, post-operative complications, and recurrence rates were analyzed and compared between the groups.  Multi-variate logistic regression models were fit to examine associations of mesh type with overall complications and SSO.  Patients who underwent VHR with RBOR were older (mean age of 63.7 versus 58.8 years, p = 0.02) and had a higher rate of renal disease (28.0 % versus 10.2 %, p = 0.01) compared with patients with synthetic mesh.  Despite an unfavorable risk profile, patients with RBOR had lower rates of SSO (16.0 % versus 30.5 %, p = 0.12) and similar hernia recurrence rates (4.0 % versus 6.78 %, p = 0.68) compared with patients with synthetic mesh.  The use of synthetic mesh was significantly associated with higher odds for overall complications (3.78, p < 0.05) and SSO (3.87, p < 0.05).  The authors concluded that compared with synthetic polypropylene mesh, the use of RBOR for VHR mitigated SSO while maintaining low hernia recurrence rates at 30-month follow-up.

The authors stated that drawbacks of this trial were related to its retrospective nature and limited sample size; therefore, the significant difference in post-operative fistula formation between the groups may be related to a low sample size and warrants further investigation.  Furthermore, there was a 5-month mean follow-up difference between the 2 cohorts, which may have contributed to the difference in hernia recurrence observed, although the difference was not significant.  However, this trial was the 1st to compare outcomes following VHR with RBOR or synthetic mesh in low-to-intermediate risk patient cohorts with comparable defect sizes.  These data provided important insights for pre-operative surgical planning and counseling of patients undergoing VHR.  These investigators showed that the use of biosynthetic mesh reduced SSO with low hernia recurrence rates compared with patients treated with synthetic mesh.  Moreover, these investigators stated that future studies should aim to prospectively compare the effectiveness of hybrid biosynthetic mesh to synthetic mesh in a prospective, randomized fashion.

Sivaraj et al (2022b) carried out a retrospective analysis of 141 patients who had undergone VHR with biologic mesh, including non-cross-linked porcine ADM (NC-PADM) (n = 51), cross-linked porcine ADM (C-PADM) (n = 17), RBOR (n = 36), and bovine ADM (BADM) (n = 37) at the Stanford University Medical Center between 2002 and 2020.  Post-operative donor site complications and rates of hernia recurrence were compared between patients with different biologic mesh types.  Abdominal complications occurred in 47.1 % of patients with NC-PADM, 52.9 % of patients with C-PADM, 16.7 % of patients with RBOR, and 43.2 % of patients with BADM (p = 0.015).  Relative risk (RR) for overall complications was higher in patients who had received NC-PADM (RR = 2.64, p = 0.0182), C-PADM (RR = 3.19, p = 0.0127), and BADM (RR = 2.11, p = 0.0773) compared with those who had received RBOR.  Furthermore, RR for hernia recurrence was also higher in all other mesh types compared with RBOR.  The authors concluded that these data indicated that RBOR decreased abdominal complications and recurrence rates after VHR compared with NC-PADM, C-PADM, and BADM.  These researchers stated that using reinforced biologic meshes for VHR may lead to improved outcomes relative to current biologic mesh types.  These researchers noted that this was the 1st exploratory study to statistically compare post-operative complications and rates of hernia recurrence among 4 biologic mesh types in a sizeable patient cohort.  This study provided valuable information for pre-operative surgical planning and counseling of patients undergoing abdominal wall repair with biologic mesh implantation.  These investigators stated that future studies should aim to prospectively compare the impact of biologic mesh type on post-operative complications in a randomized fashion.

The authors stated that drawbacks of this trial included its retrospective nature and a relatively small sample size in each subgroup.  As biologic mesh has proven to be especially beneficial in the setting of complicated VHR, each subgroup included patients who had received prior hernia repairs.  However, to analyze post-operative outcomes and recurrence rates with statistical robustness, these investigators adjusted for differences in baseline characteristics using Poisson regression.  Furthermore, the presence of incarcerated hernia in a subset of the patients may have introduced a degree of outcome bias; however, the overall incidence of incarceration was low.

DeNoto (2022) noted that of all hernia types, large ventral hernias have the most impact on patient QOL; however, they are also the most difficult type of hernia to repair and are associated with high rates of complications.  In a case-series study, these researchers described repair of large ventral hernias with an ovine reinforced biologic in a complex patient cohort with co-morbidities and concomitant procedures.  They carried out bridged repair with an ovine reinforced biologic (OviTex 1S-P or 2S-P) in 19 consecutive high-risk patients over a 5-year period. In all cases the reinforced biologic was used as an underlay.  Of the 19 patients, 6 (32 %) experienced a SSO including infection, seroma, abscess, fistula, bioloma, or bowel obstruction; and 3 patients (16 %) had recurrences with 2 out of 3 of the recurrences occurring within 6 months of surgery.  The authors concluded that rates of SSO's and recurrences using ovine reinforced tissue matrix (RTM) were in line with or better than other published studies of bridged repair using biologic or synthetic mesh reinforcement.  These researchers stated that ovine RTM's should be considered in complex large ventral hernia repairs.  Moreover, these investigators stated that future studies are needed to make more definitive comparisons than to those results in the literature.  A RCT in which high-risk patients receive a synthetic, traditional biologic, or reinforced biologic matrix would help to make more definitive comparisons among the 3 different matrix types.  Pre- and post-operative standardization in such a trial would also help to remove any compounding factors.

The authors stated that this study was limited by a lack of control group(s).  Furthermore, the sample size was relatively small (n = 19) and follow-up was not regimented to specific time-points.  The surgical technique was also not completely standardized.

In a prospective, non-randomized,  single-arm, multi-center clinical trial, DeNoto et al (2022) examined the performance of OviTex 1S (TELA Bio Inc., Malvern, PA) over 24 months when used for ventral hernia repair.  A total of 92 patients with ventral hernias were enrolled in this study.  The surgical approach (open, laparoscopic, or robotic) and plane of placement (retro-rectus, intra-peritoneal, or pre-peritoneal) were at the discretion of the surgeon.  Patients were characterized as high risk for a SSO based on the following co-morbidities: BMI between 30 and 40, active smoker, chronic obstructive pulmonary disease (COPD), diabetes mellitus, coronary artery disease, advanced age (75 years or older).  Subjects underwent physical examinations to examine safety events and completed QOL surveys at 1 months, 3 months, 12 months, and 24 months post-surgery.  A total of 65 of the 92 enrolled patients (70.7 %) completed 24-month follow-up.  The Kaplan Meier estimate for risk of recurrence at day 730 (24 months) was 2.6 %; among subjects who completed their 24-month visit or had a previous recurrence, the unadjusted rate of recurrence was 4.5 % (3/66). SSOs were observed in 38.0 % of patients (35/92).  The most prevalent SSO was surgical site infection occurring in 20.7 % (19/92) of patients, followed by seroma formation, which occurred in 13.0 % of patients; however, only 3.3 % required intervention.  HerQLes and EQ-5D assessments showed improvement from baseline as soon as 3 months post-surgery.  Continued improvement was observed through 24 months.  The authors concluded that the BRAVO study showed that use of the ovine reinforced tissue matrix OviTex 1S was a viable option for use in ventral hernia repair.  Moreover, these researchers stated that additional studies with longer term follow-up data are needed to draw definitive conclusions on the use of OviTex 1S.

The authors stated that this study had several drawbacks.  First, this was a non-randomized, observational study with no comparisons to a direct control. Addition of a control arm could aid in definitively determining any direct effects of ventral hernia repair with a reinforced biologic.   Second, this study did not require a single surgical technique or plane of placement that may contribute to varying results.  Third, evaluation of recurrence was based primarily on clinical examination, potentially missing asymptomatic recurrences.  Fourth, due to the heterogeneity of ventral hernia repair patients and the unique study design for each clinical trial, comparisons with results published in the literature should be made with caution.   Long term follow-up visits occurred during the period of March 2020 through August 2021 when COVID 19 was having significant impacts on healthcare facilities and staff. To account for higher than expected lost to follow-up, Kaplan Meier analysis was used and these results were displayed alongside unadjusted observed results.

Goetz et al (2022) stated that in case of potential contamination, implantation of synthetic meshes in hernia and abdominal wall surgery is problematic due to a higher risk of mesh infection.  As an alternative, a variety of different biologic meshes have been used.  However, relevant data comparing outcome after implantation of these meshes are lacking.  Between January 2012 and October 2021, biologic meshes were used for reconstruction of the abdominal wall in 71 patients with pre-operative or intra-operative abdominal contamination.  In a retrospective study, semi-resorbable biologic hybrid meshes (BHM) and completely resorbable meshes (CRM) were compared and analyzed using a Castor EDC database.  In 28 patients, semi-resorbable biologic hybrid meshes were used; in 43 patients, completely resorbable meshes were used.  Both groups showed no difference in age, gender, BMI, operation duration, hernia size and Charlson co-morbidity index.  The risk degree of SSO was graded according to the Ventral Hernia Working Group (VHWG) classification, and the median value was 3 (range of 2 to 4) in the BHM group and 3 (range of 2 to 4) in the CRM group.  Hernia recurrence within 24 months after hernia repair was significantly lower in the BHM group (3.6 % versus 28.9 %; p = 0.03), while post-operative complication rate, with respect to seromas in need of therapy (61.4 % versus 55.5 %, p = 0.43) and operative revision (28.6 % versus 16.3 %, p = 0.22) was not different in either group.  The authors suggested that semi-resorbable biologic hybrid meshes are safe to use in complex patients with possible wound contamination and could potentially reduce the risk of hernia recurrence compared to CRM in a mid-term follow-up period.  These researchers stated that despite the heterogeneity of the presented retrospective study, these findings showed actual clinical courses of complex patients.  Moreover, these investigators stated that for definitive clinical and economic conclusions, further prospective, randomized trials and long-term follow-up data are needed.

The authors stated that this study had several drawbacks mainly because of the retrospective study design without randomization.  Generally, a possible bias in patient selection could not be completely excluded, although the presence of stomata was the only significant difference in patient characteristics between both groups.  In addition, an increasing experience of the surgeons due to non-contemporaneous mesh usage was possible and the patient number (28 versus 43) as well as the follow-up period (16 months versus 31.5 months) differed in both groups.

In a retrospective, multi-center study, Timmer et al (2022) examined mesh behavior and clinical outcomes of open complex abdominal wall reconstruction (CAWR) with the use of a polypropylene reinforced tissue matrix.  This trial included adult patients who underwent open CAWR with the use of a permanent polypropylene reinforced tissue matrix (OviTex) between June 2019 and January 2021.  A total of 55 consecutive patients from 4 hospitals in the Netherlands were analyzed, 46 patients with a ventral hernia and 9 patients with an open abdomen.  Most patients with a ventral hernia had 1 or more complicating co-morbidities (91.3 %) and 1 or more complicating hernia characteristics (95.7 %).  Most procedures were carried out in a (clean) contaminated surgical field (69.6 % CDC 2 to 4; 41.3 % CDC 3 to 4).  All 9 patients with an open abdomen underwent semi-emergent surgery; and 12 out of 46 patients with a ventral hernia (26.1 %) and 4 of 9 patients with an open abdomen (44.4 %) developed a post-operative surgical site infection that made direct contact with the mesh as confirmed on computed tomography (CT), suspicious of mesh infection.  No patient needed mesh explantation for persistent infection of the mesh.  During a median follow-up of 13 months, 4 of 46 ventral hernia patients (8.7 %) developed a CT-confirmed hernia recurrence.  The authors concluded that polypropylene reinforced tissue matrix could withstand infectious complications and provided acceptable mid-term recurrence rates in this retrospective study on open complex abdominal wall reconstructions.  Moreover, these researchers stated that longer follow-up data from prospective studies are needed to determine further risk of hernia recurrence.

The authors stated that a main drawback of this trial was its retrospective design.  Standardized inclusion criteria regarding patient characteristics (e.g., level of contamination), pre-operative patient optimizing (e.g., the use of botulinum toxin), as well as the performed surgical techniques (e.g., the use of component separation technique (CST), mesh position and use of negative pressure wound therapy (NPWT)) were absent.  Second, although the multi-center design provided the opportunity to report on a real-life clinical practice cohort of 55 patients, which was relatively large for studies specifically examining one type of mesh, clinical heterogeneity was high.  Third, the follow-up by telephone questionnaire was only mid-term follow-up and may be less accurate to evaluate the actual recurrence rate; longer follow-up data after 1 year from prospective studies are needed.  Another drawback was the absence of patient reported outcome measures (PROMs).  A key question that is put forward more and more is how abdominal wall reconstruction affects the patients’ quality of life, and which parameter reflects this outcome best.  The absence of a recurrence is often used to express a successful repair.  Although, without PROMs, it was unclear if a patient who repeatedly visits the emergency department for an ongoing wound complication is better off than a patient with a (asymptomatic) hernia recurrence.

Morales-Conde et al (2022) noted that the use of mesh is a common practice in VHR.  Lack of consensus on which prosthetic material works better in different settings remains.  In a meta-analysis, these investigators examined the available evidence on hernia recurrence and complications following repair with synthetic, biologic, or biosynthetic/bioabsorbable meshes in hernias grade 2 to 3 of the Ventral Hernia Working Group modified classification.  They carried out a literature search in January 2021 using Web of Science (WoS), Scopus, and Medline (via PubMed) databases; RCTs and observational studies with adult patients undergoing VHR with either synthetic, biologic, or biosynthetic/bioabsorbable mesh were included.  Outcomes were hernia recurrence, SSO, surgical site infection (SSI), 30 days re-intervention, and infected mesh removal.  Random-effects meta-analyses of pooled proportions were performed.  Quality of the studies was assessed, and heterogeneity was explored through sensitivity analyses.  A total of 25 studies were eligible for inclusion.  Mean age ranged from 47 to 64 years and participants' follow-up ranged from 1 to 36 months.  Biosynthetic/bioabsorbable mesh reported a 9 % (95 % CI: 2 % to 19 %) rate of hernia recurrence, lower than synthetic and biologic meshes.  Biosynthetic/bioabsorbable mesh repair also showed a lower incidence of SSI, with a 14 % (95 % CI: 6 % to 24 %) rate, and there was no evidence of infected mesh removal.  Rates of seroma were similar for the different materials.  The authors concluded that this meta-analysis did not show meaningful differences among materials; although, there appeared to be a trend towards lower recurrence and complication rates after grade 2 to 3 VHR using biosynthetic/slowly absorbable mesh reinforcement.  Thus, biosynthetic/slowly absorbable mesh could be an interesting option as an alternative to synthetic meshes and biologic implants in 2 to 3 grades.  However, these researchers stated that these findings should be interpreted with caution because of the lack of direct head-to-head comparative studies between biosynthetic/slowly absorbable versus synthetic meshes and/or biological implants.  Differences in patient characteristics and the selection bias in single-arm observational studies made it difficult to have conclusive results.

These researchers stated that future research should focus on RCTs with defined control groups to allow for head-to-head comparisons among the different mesh materials like the COMpACT-BIO Trial (RCT NCT04597840, clinicaltrials.gov) whose purpose is to examine the clinical and economic benefit of the use of biosynthetic mesh in contaminated incisional hernia repair in comparison to the standard of repair.  This is a prospective, randomized, longitudinal, multi-center study, which also offers a standardized technique of repair, that still is open and in a recruitment phase.

Zhou et al (2022) carried out a network meta-analysis to examine potential differences in patient outcomes when different meshes, especially biological meshes, were used for VHR.  PubMed, Embase, Cochrane Library, and Clinical Trials.gov databases were searched for studies comparing biological meshes with biological or synthetic meshes for VHR.  The outcomes were hernia recurrence rate, SSI, and seroma.  These researchers carried out a 2-step network meta-analysis to examine the outcomes of several biological meshes: non-cross-linked human acellular dermal matrix (NCHADM), non-cross-linked porcine ADM (NCPADM), non-cross-linked bovine ADM (NCBADM), cross-linked porcine ADM (CPADM), and porcine small intestinal submucosa (PSIS).  From 6,304 publications, 23 studies involving 2,603 patients were included.  These investigators found no differences between meshes in recurrence at 1-year follow-up and in SSI rate.  NCBADM was associated with the lowest recurrence rate and the lowest SSI rate.  NCHADM implantation was associated with the lowest rate of seroma.  PSIS was associated with a higher risk of seroma than NCHADM (pooled RR 3.89, 95 % CI: 1.13 to 13.39) and NCPADM (RR 3.42, 95 % CI: 1.29 to 9.06).  The authors concluded that this network meta-analysis found no differences in recurrence rate or SSI among different biological meshes.  The incidence of post-operative seroma was higher with PSIS than with acellular dermal matrices.  These researchers observed large heterogeneity in the studies of VHR using biological meshes; thus, well-designed RCTs are needed.

de Figueiredo et al (2023) stated that VHR is one of the most common operations performed worldwide, and using mesh is standard of care (SOC) to decrease recurrence.  Biologic meshes are increasingly used to minimize complications associated with synthetic mesh, but with significantly higher cost and unclear effectiveness.  Until recently, most of the evidence supporting the use of biologic meshes was from retrospective cohorts with high heterogeneity and risk of bias.  In a systematic review and meta-analysis of RCTs, these investigators compared the outcomes of synthetic and biologic mesh in elective open VHR.  They carried out a literature search of PubMed, Embase, and Cochrane Library databases to identify RCTs comparing biologic and synthetic mesh in elective open VHR.  The post-operative outcomes were assessed by means of pooled analysis and meta-analysis.  Statistical analysis was performed using RevMan 5.4.  Heterogeneity was assessed with I2 statistics.  A total of 1,090 studies were screened, and 22 were fully reviewed; 4 RCTs and 632 patients were included in the meta-analysis; 58 % of patients had contaminated wounds (Wound Classification II to IV).  Hernia recurrence (odds ratio [OR] 2.75; 95 % CI: 1.76 to 4.31; p < 0.00001; I2 = 0 %) and SSI (OR 1.53; 95 % CI: 1.02 to 2.29; p = 0.04; I2 = 0 %) were significantly more common in patients with biologic mesh.  The rates of seroma, hematoma, and mesh removal were similar in both groups.  The authors concluded that as compared to synthetic mesh, biologic meshes resulted in increased hernia recurrences and SSIs.  Current evidence supports macro-porous, uncoated synthetic mesh as the implant of choice for elective open VHR, and its use should be considered even in contaminated cases.

PalinGen

According to the manufacturer Amino Technology LLC, PalinGen Membrane and PalinGen Hydromembrane are human allografts comprised of amniotic membrane, providing a wound covering and support for native tissues. These human allografts provide a biological and physical barrier to support and protect naturally occurring and surgical wounds in vivo. The manufacturer states that PalinGen Membrane and PalinGen Hydromembrane are commonly used in the treatment of chronic wounds, and they are also indicated for the repair and reconstruction of a recipient’s cells or tissues, including venous leg ulcers, diabetic ulcers, pressure ulcers and in orthopedic, cardiac and ophthalmologic conditions. PalinGen Membrane and PalinGen Hydromembrane are supplied in ten different sizes, ranging from 1 sq.cm to 64 sq.cm. 

PalinGen XPlus Membrane and PalinGen XPlus Hydromembrane are human allografts comprised of amniotic membrane. They provide a wound covering and support for native tissues. The manufacturer states that they are used to repair or replace soft tissue defects, soft trauma defects, tendinitis, tendinosis, chronic wound repair and localized inflammation. The patient population for the item are older Type I patients with diabetes for the treatment of chronic wounds. These products have also been used in the repair and reconstruction of a recipient’s cells or tissues including venous leg ulcers, diabetic ulcers, pressure ulcers, and in orthopedic, cardiac and ophthalmologic conditions. PalinGen XPlus Membrane and PalinGen XPlus Hydromembrane are supplied in ten different sizes, ranging from 1 sq.cm to 64 sq.cm.

PalinGen Flow and PalinGen SportFlow are human allografts comprised of amnion and amniotic fluid components, providing a liquid allograft to "aid in the healing" and repair of chronic wounds. PalinGen Flow and PalinGen SportFlow contain key growth factors, cytokines, amino acids, carbohydrates, hyaluronic acid, extracellular matrix proteins, and cellular components recognized as intrinsic to the complex wound healing process. According to the manufacturer, PalinGen Flow and PalinGen SportFlow are commonly used in the treatment of chronic wounds that are most prevalent in older populations, particularly in patients with Type I diabetes. PalinGen Flow and PalinGen SportFlow are amniotic membrane and fluid that are suspended in liquid. The product is applied directly on or in the wound with a 20-23 gauge needle. The prescribed dosage varies by the size of the wound. Typical doses range from 0.25 cc to 4.0 cc, depending on the size, depth and type of wound. PalinGen Flow and PalinGen SportFlow are similar, but separate, products. They are supplied in liquid form in vials containing 0.25 cc, 0.5 cc, 1 cc, 2 cc, and 4 cc. These products are cryopreserved and should be stored frozen at a temperature of -80°C +/- 15°.

ParaDerm Dermal Matrix

The ParaDerm dermal matrix is a biocompatible collagen matrix that promotes cellular infiltration and proliferation.

Parietex Composite (PCO) Mesh

Parietex™ Composite (PCO) mesh has a resorbable collagen barrier on one side to limit visceral attachments and a 3-D polyester knit structure on the other to promote tissue ingrowth and ease of use.  There is a lack of evidence regarding the clinical value of the Parietex Composite Mesh in the treatment of genito-urinary (e.g., uterine or vaginal vault) prolapse.

On July 13, 2011, the FDA issued a statement that serious complications are not rare with the use of surgical mesh in trans-vaginal repair of pelvic organ prolapse.  The FDA reviewed the literature from 1996 to 2011 to evaluate safety and effectiveness and found surgical mesh in the trans-vaginal repair of pelvic organ prolapse does not improve symptoms or quality of life more than non-mesh repair.  The review found that the most common complication was erosion of the mesh through the vagina, which can take multiple surgeries to repair and can be debilitating in some women.  Mesh contraction was also reported, which causes vaginal shortening, tightening, and pain.   In addition, the FDA’s update stated that "Both mesh erosion and mesh contraction may lead to severe pelvic pain, painful sexual intercourse or an inability to engage in sexual intercourse.  Also, men may experience irritation and pain to the penis during sexual intercourse when the mesh is exposed in mesh erosion".

Permacol Biologic Implant

Permacol Biologic Implant, also known as Permacol Surgical Implant (Covidien, Mansfield, MA), received FDA 510(k) marketing clearance in March 2005.  It is an implant composed of acellular cross-linked porcine dermal collagen and is intended as a dermal scaffold for soft tissue surgical repairs, including hernia repair, muscle flap reinforcement, rectal prolapse (including intussusception), rectocele repair, abdominal wall defects, plastic and reconstructive surgery, and complex abdominal wall repair.  According to the manufacturer, Permacol is bio-compatible and eventually becomes vascularized enabling incorporation into host tissue with associated cell and microvascular ingrowth.

Armellino et al (2006) described 6 cases of complicated incisional hernia repairs using Permacol.  In 1 woman the incisional hernia was associated with an enterovaginal fistula.  Three cases presented severe wound infections, 2 of which related to a previous polypropylene mesh repair, while another had an irreducible recurrent incisional hernia and 1 woman presented complete evisceration.  None of the patients had post-operative or porcine-graft-related complications.  Over a follow-up period of 3 to 24 months no recurrence or wound infection were reported. 

Parker et al (2006) reported the results of Permacol in the repair of complicated abdominal wall defects in a retrospective review of medical records (n = 9).  Indications for surgery included re-operative incisional hernia repair after removal of an infected mesh (n = 3), reconstruction of a fascial defect after resection of an abdominal wall tumor (n = 2), incisional hernia repair in a patient with a previous abdominal wall infection after a primary incisional hernia repair (n = 1), incisional hernia repair in a patient with an ostomy and an open midline wound (n = 1), emergent repair of incisional hernia with strangulated bowel and multiple intra-abdominal abscesses (n = 1), and excision of infected mesh and drainage of intra-abdominal abscess with synchronous repair of the abdominal wall defect (n = 1).  At a median follow-up of 18.2 months, 1 recurrent hernia existed after intentional removal of the Permacol.  This patient developed an abdominal wall abscess 7 months after hernia repair secondary to erosion from a suture.  Overall, 1 patient developed exposure of the Permacol after a skin dehiscence.  The wound was treated with local wound care, and the Permacol was salvaged.  Despite the presence of contamination (wound classification II, III, or IV) in 5 of 9 patients (56 %), no infectious complications occurred.

In a retrospective review, Mitchell et al (2008) compared outcomes of congenital diaphragmatic hernia (CDH) repair with synthetic Gore-Tex (W. L. Gore and Associates, Neward, DE) to bioprosthetic Permacol (Tissue Science Laboratories Inc, Andover, MA).  Primary repair was performed in 63 patients and patch repair in 37 patients, divided between Gore-Tex (n = 29) and Permacol (n = 8).  Overall recurrences were 1 (2 %), 8 (28 %), and 0 in the primary, Gore-Tex, and Permacol groups, respectively.  Median follow-up was 57 months for Gore-Tex and 20 months for Permacol.  Median time to recurrence in the Gore-Tex group was 12 months, with no Permacol recurrences.  Both the Gore-Tex and Permacol groups had similar co-morbidities, including prematurity, congenital heart disease (76 % and 63 %, respectively), and the need for extracorporeal membrane oxygenation support (38 % and 25 %).  The authors concluded that Permacol may have lower recurrence rates compared to Gore-Tex and is a promising alternative biologic graft for CDH repair.

Hsu et al (2008) reported the results of a retrospective review of all patients in a single institution who underwent consecutive abdominal wall reconstruction with Permacol during 2006 (n = 28).  Factors evaluated were body mass index, relevant co-morbidities, etiology of hernia, hernia defect size based on CT scan and intra-operative measurement, size of Permacol implant, length of hospital stay, and post-operative complications.  Surgical technique was standardized among 6 surgeons and involved a single layer of acellular porcine dermis as a subfascial "underlay" graft under moderate tension upon maximal hernia reduction.  Tissue expanders were not required for skin closure.  Mean intra-operative hernia size was 150cm2 (range of 10cm2 to 600cm2).  Mean age was 55 years with an average body mass index (BMI) of 34 (largest BMI of 61.4).  Defects were attributed to either a previous laparotomy incision or open abdomen.  Mean hospital stay was 9.67 days.  At a mean follow-up of 16 months, there were 3 recurrent hernias (10.7 %) based on physical examination and post-operative CT scan evaluation.  One patient developed a superficial wound dehiscence, which was successfully treated with local wound care, and 1 patient developed a cellulitis, which was successfully treated with antibiotic therapy.  Four patients (14.3 %) developed a chronic, non-infected fluid collection lasting greater than 1 month that later resolved.  No patient required removal of the implant due to infection.  The authors concluded that Permacol can be used in the reconstruction of both small and large ventral hernias and that the biodegradable matrix serves as a safe and useful alternative to both synthetic mesh and AlloDerm.

Saray (2003) reported the feasibility of Permacol for facial contour augmentation (n = 8).  It was used as a filler implant in reconstruction of post-traumatic soft-tissue defects, correcting post-parotidectomy hallowing and secondary nasal surgery to cover osseocartilaginous irregularities.  However, the author reported a potential risk of inflammation and skin contractures in thin-skinned patients when implants were placed superficially.

Giordano et al (2016) reported on the results from the initial 30 patients enrolled in the MASERATI 100 prospective, observational clinical trial of Permacol paste in the treatment of anorectal fistula. Patients (N = 30) with anal fistula presenting to 10 European academic surgical units were treated with a sphincter-preserving technique using Permacol paste. Fistula healing was assessed at 1, 3, 6 and 12 months after treatment, with the primary end-point of fistula healing at 6 months post-surgery. Fecal continence and patient satisfaction were recorded at each follow-up visit and adverse events were monitored throughout the follow-up. Of the 28 patients with data at 6 months post-surgery, 15 (54%) were healed, and the healing rate was maintained at 12 months. Healing after treatment with Permacol paste was similar for intersphincteric to transsphincteric fistulae and primary or recurrent fistulae. Only one patient exhibited an adverse event (perianal abscess) that was possibly related to the treatment. At the last outpatient visit, over 60% of patients were satisfied or very satisfied with the operation.

Giordano et al (2015) conducted a retrospective study to evaluate clinical outcomes following the use of Permacol porcine collagen surgical implant in complex abdominal wall repair. A subset analysis of seven European sites from a multicenter retrospective study included patients undergoing open or laparoscopic surgery and treated with Permacol surgical implant. Inguinal, parastomal, diaphragmatic, perineal, and hiatal repairs were excluded. Only patients with at least 12 months of follow-up after surgery were included. A total of 109 patients (56 males and 53 females) were included. Patients had a median of two comorbidities (range 0-6). Thirty-three per cent of patients were treated for recurrent hernia. All but one case used an open approach. Sixty-six per cent were Center for Disease Control wound class II-IV at the time of surgery. Fascial closure was achieved in 69%. Median follow-up length was 720 days (range 368-2857). Recurrence rates at 1 and 2 years were 9.2 and 18.3 %, respectively, and were higher in cases without fascial closure. One-year recurrence was higher following use of an onlay technique (P = 0.025). In a multivariate analysis, among 16 comorbidities examined only fascial closure significantly impacted 1-year recurrence (P = 0.049).

Data from case reports suggest that Permacol is a promising dermal scaffold for soft tissue surgical repairs however, there is insufficient evidence of its effectiveness as an alternative to synthetic meshes and information on the potential complications associated with its use is lacking.

PermeaDerm B

PermeaDerm B is an FDA 510(k) cleared biosynthetic wound covering consisting of an adherent and transparent monofilament nylon knitted fabric that bonded to a thin, slitted, silicone membrane. It is indicated for partial thickness burn wounds, donor sites and coverage of meshed autograft. PermeaDerm B functions as a wound covering by providing a moist wound healing environment on cleanly prepared wounds after hemostasis has been determined. Physical slits within the product are configured to form pores when stretched. The nylon side is covered with a mixture of USP Pharmaceutical Grade hypoallergenic porcine gelatin and a pure fraction of aloe vera. PermeaDerm B has 2,280 parallel slits per square foot and is supplied in 5 x 10, 10 x 15,  or 15 x 30-inch sheets. It is applied to a prepared wound and covered with any clinical selected secondary absorbent outer dressing.

PermeaDerm C

PermeaDerm C is an FDA 510(k) cleared biosynthetic wound covering consisting of an adherent and transparent monofilament nylon knitted fabric that is bonded to a thin, slitted, silicone membrane. It is indicated for partial thickness wounds, pressure sores, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds (donor sites/grafts, post-Mohs, post-laser surgery, podiatric, wound dehiscence, trauma wounds (abrasions, lacerations, second-degree burns, and skin tears) and draining wounds. PermeaDerm C functions as a wound covering by providing a moist wound healing environment on cleanly prepared wounds after hemostasis is determined. Physical slits within the product are configured to form pores when stretched. The nylon side is covered with a mixture of USP Pharmaceutical Grade hypoallergenic porcine gelatin and a pure fraction of aloe vera. PermeaDerm C has 4,464 slits per square foot, which are parallel and perpendicular in orientation. It supplied in 5 x 5-inch sheets and is applied to a prepared wound and covered with any clinician selected secondary absorbent outer dressing.

PermeaDerm Glove

PermeaDerm Glove is an FDA 510 (k) cleared biosynthetic wound covering consisting of an adherent and transparent monofilament nylon knitted fabric that is bonded to a thin, slitted silicone membrane. It is indicated for debrided partial thickness hand burns. PermeaDerm Glove functions as a wound covering by providing a moist wound healing environment on cleanly prepared wounds after hemostasis has been determined. Physical slits within the product are configured to form pores when stretched. The nylon side is covered with a mixture of USP Pharmaceutical Grade hypoallergenic porcine gelatin and a pure fraction of aloe vera. PermeaDerm Glove comes in sizes extra-small to extra-large. It is applied to a prepared wound and covered with any clinician selected secondary absorbent outer dressing.

Phoenix Wound Matrix

Phoenix Wound Matrix is a sterile, 3D electrospun synthetic polymer matrix consisting of two non-woven bioresorbable synthetic polymers, polyglycolic acid (PGA) and polylactide-co-caprolactone (PLCL). The Phoenix Wound Matrix is indicated for the management of partial to full thickness acute and chronic wounds, and burns including: pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts/post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining wounds. It is constructed to provide scaffold support for cellular migration, adherence, and proliferation for tissue regeneration and repair of acute and chronic wounds and burns. Following thorough debridement, Phoenix Wound Matrix functions as a synthetic graft/skin substitute, placed within the area of the wound environment to support wound healing. Phoenix Wound Matrix serves as a protective barrier and persisting within the wound environment until complete degradation via hydrolysis, within 7-14 days. Phoenix Wound Matrix requires reapplication every 7-14 days or as clinically needed following the appropriate steps in best-practice standard of care for wound management. Phoenix Wound Matrix ranges in size from a 16 mm disc to a 20 x 10 cm sheet and is packaged as a sterile, single-use product, within an inner protective pouch as one matrix per pouch/box.

Placental Tissue Matrix Allograft

Lullove (2015) stated that damaged connective tissue commonly leads to lower extremity injuries. These injuries can result in inflammation, reduced mobility, and chronic pain.  Conservative treatment may include orthotics, offloading the injury, physical therapy, and/or NSAIDs.  If conservative treatment fails, surgical intervention may be required.  Even after successful surgery, these procedures often result in reduced joint mobility and tendon or ligament strength.  A novel flowable tissue matrix allograft, derived from human placental connective tissue, has recently been made available for minimally invasive treatment of damaged or inadequate tissue  (PX50®, Human Regenerative Technologies LLC, Redondo Beach, CA).  Based on the universal role of connective tissue in the body, and its reported anti-microbial, anti-adhesive, and anti-inflammatory properties, these researchers assessed the effects of using this placental tissue matrix in the treatment of a series of lower extremity injuries.  In this pilot study, 9 of 10 patients reported pain levels of 2 or less by week 4 using the VAS pain scale.  They stated that this short-term pilot study showed that injectable, flowable amniotic allografts can be used for orthopedic sports injuries of the lower extremities.  The findings of this small (n = 10), pilot study need to be validated by well-designed studies.

Schneider et al (2016) noted that biomaterials based on decellularized tissues are increasingly attracting attention as functional alternatives to other natural or synthetic materials. However, a source of non-cadaver human allograft material would be favorable.  These researchers established a decellularization method of vascular tissue from cryo-preserved human placenta chorionic plate starting with an initial freeze-thaw step followed by a series of chemical treatments applied with a custom-made perfusion system.  This novel pulsatile perfusion set-up enabled us to successfully decellularize the vascular tissue with lower concentrations of chemicals and shorter exposure times compared to a non-perfusion process.  The decellularization procedure described here led to the preservation of the native extracellular matrix architecture and the removal of cells.  Quantitative analysis revealed no significant changes in collagen content and a retained glycosaminoglycan content of approximately 29 %.  In strain-to-failure tests, the decellularized grafts showed similar mechanical behavior compared to native controls.  In addition, the mechanical values for ultimate tensile strength and stiffness were in an acceptable range for in-vivo applications.  Furthermore, biocompatibility of the decellularized tissue and its re-cellularizationability to serve as an adequate substratum for upcoming re-cellularization strategies using primary human umbilical vein endothelial cells (HUVECs) was demonstrated.  HUVECs cultured on the decellularized placenta vessel matrix performed endothelialization and maintained phenotypical characteristics and cell specific expression patterns.  Overall, the decellularized human placenta vessels can be a versatile tool for experimental studies on vascularization and as potent graft material for future in-vivo applications.  These investigators stated that in the US alone more than 1 million vascular grafts are needed in clinical practice every year.  Despite severe disadvantages, such as donor site morbidity, autologous grafting from the patient's own arteries or veins is regarded as the gold standard for vascular tissue repair.  Besides, strategies based on synthetic or natural materials have shown limited success.  Tissue engineering approaches based on decellularized tissues are regarded as a promising alternative to clinically used treatments to overcome the observed limitations.  However, a source for supply of non-cadaver human allograft material would be favorable.  The authors  established a decellularization method of vascular tissue from the human placenta chorionic plate, a suitable human tissue source of consistent quality.  The decellularized human placenta vessels can be a potent graft material for future in-vivo applications and furthermore might be a versatile tool for experimental studies on vascularization.

PolyCyte

PolyCyte (Predictive Biotech) is a minimally manipulated human tissue allograft derived from the Wharton's jelly of the umbilical cord. It is processed to preserve the cytokines, growth factors and proteins of Wharton's jelly for homologous use. PolyCyte is intended for use in repair, reconstruction, replacement or supplementation of a recipient's cells or tissue by performing the same basic functions of Wharton's jelly in the recipient as it would in the donor. The amount and administration (injected or topical) of the allograft is determined by the clinician based on the intended use in each patient. The product is distributed as a liquid allograft contained in a vial that is shipped frozen for preservation (-80C on dry ice) and is intended to be stored in that frozen state (-60C to -80C or colder) until used or expiration date is reached. It can be ordered in 3 vial sizes: 0.5 mL, 1 mL or 2 mL. The product is simply drawn up after proper thawing using a 21G-23G needle to syringe and then prepared and applied.

There is a lack of evidence regarding the effectiveness of the Polycyte allograft.

PriMatrix Acellular Dermal Tissue Matrix

PriMatrix Acellular Dermal Tissue Matrix is an acellular collagen dermal tissue matrix derived from fetal bovine skin. Primatrix creates a scaffold capable of being integrated, remodeled and eventually replaced by functional host tissue.

PriMatrix acellular dermal tissue matrix, formerly known as DressSkin (TEI Biosciences Inc., Boston, MA) was cleared by the FDA via the 510(k) process. PriMatrix is used for the management of wounds including second degree burns, draining, surgical, and trauma wounds, as well as pressure, diabetic, and venous ulcers. 

Primatrix is an animal-derived, extracellular matrix dermal substitute intended to act as a scaffold to allow cell and vascular penetration (Snyder et al, 2012). According to the manufacturer, TEI biological matrix products are derived from fetal bovine dermis collagen.  In producing this product, the epidermis, hair, muscle, and fascia are removed.  The dermis is then treated to remove cells and infectious agents while preserving biological properties and structures.  The product is converted to sheets, freeze dried, and sterilized. When applied to a wound, the product product may assist in the wound healing process.

Primatrix Dermal Repair Scaffold was cleared for marketing under the 510(k) process and "is intended for the management of wounds that include: partial and full thickness wounds; pressure, diabetic, and venous ulcers; second degree burns; surgical wounds-donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence; trauma wounds-abrasions, lacerations, and skin tears; tunneled/undermined wounds; draining wounds."  However, there is insufficient scientific evidence regarding the effectiveness of PriMatrix acellular dermal tissue matrix for wound healing.  Available evidence is comprised primarily of small, retrospective studies.  A systematic evidence review of would healing products prepared for the Agency for Healthcare Research and Quality found no studies of Primatrix of sufficient quality to meet criteria for inclusion in the systematic evidence review (Snyder et al, 2012).

Neill et al (2012) reported the findings of 7 patients who underwent 2-stage skin grafting with bovine fetal collagen (BFC) as an initial wound cover.  Split-thickness skin grafts (STSGs) were successfully placed on the wounds after completion of interval management; BFC proved to be a resilient acellular dermal matrix that could proceed to assimilation and skin grafting under a variety of wound conditions.  The authors concluded that BFC may prove to be a valuable material, as the role of acellular dermal matrices in skin grafting becomes better defined.  They stated that "Such initial results encourage further use of BFX in cases of interval STSG reconstruction.  Subgroups of such patients could lend themselves to prospective studies that could further define this strategy and the contribution of BFC".  This was a small (n = 7) case-series report.

Hayn (2013) reported that PriMatrix was used to treat complex surgical or traumatic wounds where the clinical need was to avoid skin flaps and to build new tissue in the wound that could be re-epithelialized from the wound margins or closed with a subsequent application of a STSG.  A total of 43 consecutive cases were reviewed having an average size of 79.3 cm(2), 50 % of which had exposed tendon and/or bone.  In a subset of wounds (44.7 %), the implantation of PriMatrix was also augmented with negative pressure wound therapy (NPWT).  Complete wound healing was documented in over 80 % of the wounds treated, whether the wound was treated with the PriMatrix alone (95.2 %) or when supplemented with NPWT (82.4 %).  The scaffold successfully incorporated into wounds with exposed tendon and/or bone to build vascularized, dermal-like tissue.  The new tissue in the wound supported STSGs however, in the majority of the cases (88.3 %); wound closure was achieved through re-epithelialization of the incorporated dermal scaffold by endogenous wound keratinocytes.  The authors concluded that PriMatrix was found to offer an effective alternative treatment strategy for definitive closure of challenging traumatic or surgical wounds on patients who were not suitable candidates for tissue flaps.  Moreover, the authors noted that "A comparison of this study to other clinical reports was limited by its retrospective nature where patients and wounds did not meet any specific inclusion/exclusion criteria.  To definitively identify any clinical benefits the PriMatrix wound healing technology offers over other alternatives, formal prospective, randomized clinical studies with long-term follow-up wound assessments are required". 

In a prospective multi-center study, Kavros et al (2014) evaluated the healing outcomes of chronic diabetic foot ulcers treated with PriMatrix, a fetal bovine acellular dermal matrix.  Inclusion criteria required the subjects to have a chronic diabetic foot ulcer (DFU) that ranged in area from 1 to 20 cm2 and failed to heal more than 30 % during a 2-week screening period when treated with moist wound therapy.  For qualifying subjects, PriMatrix was secured into a clean, sharply debrided wound, dressings were applied to maintain a moist wound environment, and the diabetic ulcer was pressure off-loaded.  Wound area measurements were taken weekly for up to 12 weeks and PriMatrix was re-applied at the discretion of the treating physician.  A total of 55 subjects were enrolled at 9 U.S. centers with 46 subjects progressing to study completion.  Ulcers had been in existence for an average of 286 days and initial mean ulcer area was 4.34 cm2.  Of the subjects completing the study, 76 % healed by 12 weeks with a mean time to healing of 53.1 ± 21.9 days.  The mean number of applications for these healed wounds was 2.0 ± 1.4, with 59.1 % healing with a single application of PriMatrix and 22.9 % healing with 2 applications.  For subjects not healed by 12 weeks, the average wound area reduction was 71.4 %.  The authors concluded that the findings of this of this multi-center prospective study suggested that PriMatrix used in conjunction with a center’s standard of care wound therapy offers a cost-effective strategy to heal diabetic foot ulcers over that of other advanced wound therapy products based on 12-week healing outcomes as well as number of applications needed to achieve successful closure.  The main drawback of this study was the lack of a direct comparison within the study to standard of care as well as to other advanced therapies.  The authors stated that the findings from this study should be expanded to include these clinical efficacy comparisons as well as cost-effectiveness comparisons in order to maximize health benefits per dollar spent for the treatment of diabetic foot ulcers.

PRISMA Matrix Wound Dressing for Pressure Ulcer

In an in-vitro study, Bourdillon et al (2017) examined if there are differences in the ability of wound dressings to modulate certain factors known to affect wound healing.  A selection of anti-microbial dressings (AQUACEL Ag Extra , AQUACEL Ag+ Extra , IODOFLEX , ACTICOAT 7 and PROMOGRAN PRISMA matrix) were tested for their effect on both bacterial bio-burden and human dermal fibroblasts.  Some dressings underwent further evaluation for activity against Pseudomonas aeruginosa biofilms using a colony-drip flow reactor model.  The ability of in-vitro biofilms to produce proteases, and the effect of PROMOGRAN PRISMA matrix on such proteases, was also investigated.  All anti-microbial dressings tested reduced vegetative bacterial load; however, only PROMOGRAN PRISMA matrix was able to significantly reduce biofilm populations (p = 0.01).  Additionally, PROMOGRAN PRISMA matrix was the only dressing that did not inhibit dermal fibroblast growth.  All other dressings were detrimental to cell viability.  In-vitro biofilms of Pseudomonas aeruginosa were demonstrated as being capable of releasing bacterial proteases into their surroundings, and incubation with PROMOGRAN PRISMA matrix led to a 77 % reduction in activity of such proteases (p = 0·002).  The authors concluded that the unique ability of PROMOGRAN PRISMA matrix to reduce in-vitro vegetative bacteria, biofilm bacteria and bacterial proteases while still allowing dermal fibroblast proliferation may help re-balance the wound environment and reduce the occurrence of infection.

Pro3-C Amniotic Membrane

The Pro3 Placenta and Cord is a line of regenerative tissue matrices that help to support healing without adhesion or scar formation.  Thicknesses differ between Pro3-Placenta and Pro3-Cord for unique application use.  Pro3-Placenta is single-layer amnion that is ideal for dermatological application such as topical wounds and burns.  Pro3- Cord preserves maximum natural thickness (8x thicker than Pro3-Placenta); and helps support tendon and deep soft tissue healing.  The proprietary process of recovering Pro3-Cord and Pro3-Placenta preserves the natural healing properties to facilitate regenerative healing as opposed to scar-mediated healing.  Pro3 Amniotic Membranes can be stored at room temperature for up to 5 years and does not require any special preparation in the operating room. 

There is a lack of evidence on the effectiveness of Pro3-C amniotic membrane for wound care.

Procenta

Procenta (Lucina BioSciences, LLC) is an acellular, sterile, human placental-derived allograft. It is indicated to treat chronic non-healing wounds, such as venous stasis and diabetic foot ulcers for the purpose of providing an extracellular matrix (ECM) scaffold and soluble proteins to assist in the wound healing process. It is intended for homologous use only. When Procenta is placed in the wound bed, it acts as a hydrophilic extracellular matrix scaffold and provides a rich source of collagens, glycosaminoglycans (GAG), including hyaluronic acid and soluble growth factors directly to the site of the wound. The ECM is acellular and provides 3-dimensional structural support for healing. The bioactive nature of the scaffold and soluble factors stimulate the recipient's native dermal progenitor cells, resulting in resolution of the wound. Procenta is supplied in a single use vial containing one 200 mg placental allograft, providing coverage for up to a 6 cm2 wound surface area. Once removed from the vial, it is applied into the wound bed by a physician. It is packaged as a 200 mg, acellular human placental-derived allograft in a vial which is contained in a peel pouch placed in an outer box. It is packaged sterile, pre-hydrated, ready to use and is shelf stable at room temperature for 2 years.

There is a lack of evidence regarding the effectiveness of the Procenta allograft.

ProgenaMatrix

According to the manufacturer, Cell Constructs I, LLC., ProgenaMatrix is a graft matrix composed of human keratin proteins selectively extracted from human hair. ProgenaMatrix is indicated for dry and exuding partial and full thickness wounds such as pressure (stage I-IV) and venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers, donor sites and grafts, first and second-degree burns, superficial injuries, cuts,, abrasions and surgical wounds."  ProgenaMatrix is applied directly to the wound bed after debridement of the wound site to remove necrotic debris, biofilm, and non-viable tissue. Each matrix provides the same amount of human keratin proteins per square centimeter of product. It is supplied in sizes: 2cm x 2cm, 4cm x 4cm, 6cm x 6cm 10cm x 10cm; and 12cm x 12cm.

ProLayer Human Allograft Acellular Dermal Matrix

Stilwell and Delaney (2022a) noted that dermal acellular matrices may be used to replace or repair integumental soft tissues compromised by disease, injury or surgical procedures.  A primary consideration when using this biomaterial in-vivo is its biocompatibility and immunogenicity, both of which influence its incorporation into the surrounding tissue.  In an animal model, ProLayer Acellular Dermal Matrix (ADM) was implanted into 12 rats.  There was no effect on metabolic function, and subsequent necropsy analyses indicated tissue incorporation and blood vessel infiltration with no untoward tissue reaction, including encapsulation in each case.  The authors concluded that this animal study demonstrated the biocompatibility of ProLayer ADM.  No unexpected tissue reaction or encapsulation was found.  There was strong evidence of tissue incorporation and blood vessel infiltration.  No infections were noted nor was there a discernible impact on metabolism; animal growth and development subsequent to implantation were normal.  Moreover, these researchers stated that these findings were demonstrated in an animal model and may not directly correlate in humans.

Stilwell and Delaney (2022b) stated that dermal acellular matrices may be used to replace or repair integumental soft tissue compromised by disease, injury or surgical procedures.  These biomaterials are used surgically for a wide range of regenerative medicine applications, including sports medicine applications such as tendon augmentation and rotator cuff repair, which call for especially robust and resilient dermal matrix materials that will resist suture pullout.  Using standard testing protocols, ProLayer ADM exhibited a suture retention strength as strong as the force a 2-0 suture (typically used for these procedures) is expected to withstand.  The authors concluded that ProLayer ADM was designed to offer optimal suture retention and tensile strength while retaining essential flexibility and pliability characteristics allowing for secure placement and suturing.  These attributes, along with its validated terminal sterility, room temperature storage and a pre-hydrated format, are designed to make ProLayer ADM an ideal extracellular dermal matrix tissue for a wide range of clinical applications.

ProMatrX ACF

ProMatrX ACF is a human allograft comprised of amnion and amniotic fluid, providing a liquid allograft to "aid in the healing" and repair of chronic wounds. ProMatrX ACF contains key growth factors, cytokines, amino acids, carbohydrates, hyaluronic acid, extracellular matrix proteins, and cellular components recognized as intrinsic to the complex wound healing process. According to the manufacturer Amino Technology, ProMatrX ACF is commonly used in the treatment of chronic wounds that are most prevalent in older populations, particularly in patients with Type I diabetes. ProMatrX ACF is amniotic membrane and fluid suspended in liquid. The product is applied directly on or in the wound with a 20-23 gauge needle. The prescribed dosage varies by the size of the wound. Typical doses range from 0.25 cc to 4.0 cc, depending on the size, depth and type of wound. ProMatrX ACF is supplied in liquid form in vials containing 0.25 cc, 0.5 cc, 1 cc, 2 cc, and 4 cc. These products are cryopreserved and should be stored frozen at a temperature at -80°C +/- 15°.

Promogran

Promogran Matrix Wound Dressing (Ethicon) is a sterile primary dressing comprised of freeze-dried composite of 55 perccent collagen and 45 percent oxidized regenerated cellulose. It is intended to bind and protect teh functionality of growth factors, such as platelet-derived growth factors (PDGR) in hostile proteolytic environments. Promogran Matrix wound ressing is indicated for the management of exuding wounds including: diabetic ulcers, venous ulcers, ulcers caused by mixed vascular etiologies, full thickness and partial thickness wounds, donor sites and other bleeding surface wounds, abrasions, traumatic wound healing by secondary intention, and dehisced surgical wounds.

PuraPly

According to the manufacturer Organogenesis, Inc., PuraPly Antimicrobial Wound Matrix (PuraPly AM) and Puraply Wound Matrix (PuraPly) is a single-layer fenestrated sheet of porcine collagen. PuraPly Am is a double-layer fenestrated and cross-linked sheet of porcine collagen, coated with polyhexamethylene biguanide hydrochloride (PHMB) to resist microbial colonization and reduce microbial penetration within the matrix. The two products are prescribed by a physician or other qualified health care professional and indicated for the management of wounds. They are typically administered in an outpatient setting but may be administered inpatient or in the office setting. PuraPly and PuraPly AM are administered by applying the product to a wound using sutures or other fixation methods. PuraPly AM and PuraPly are supplied in a single-layer or double-layer fenestrated sheet of porcine intestinal collagen, approximately 0.05 to 0.07 rnm in thickness. The products are available in a range of sizes from 2 cm x 4 cm to 6 cm x 9 cm.

Puros

Puros Dermis Allograft Tissue Matrix (Zimmer Dental) is a natural biological matrix designed for soft tissue augmentation, periodontal/peri-implant soft tissue management, and guided tissue regeneration procedures (Snyder et al, 2012). T he tissue is treated using the Tutoplast sterilization procedure to kill bacteria, destroy cells, remove prions, and reduce potential tissue rejection.  The manufacturer’s Web site does not specifically state if Puros Dermis is derived from human tissue, although this may be implied.  Puros Dermis does not have 510(k) clearance or premarket approval, suggesting that this is a human-derived tissue product.

RECELL Autologous Cell Harvesting Device (RECELL)

The RECELL Autologous Cell Harvesting Device (RECELL) is a stand-alone, battery powered cell separation device that requires operation by a licensed healthcare professional the patient’s point of care. Specifically, the device processes a small, thin split-thickness skin sample 0.006-0.008 inch (0.15-0.20 mm) in depth to prepare an autologous Regenerative Epidermal Suspension (RES) for immediate delivery onto the wound surface. This process provides a type of epidermal autograft that is indicated for the treatment of acute thermal burn wounds in patients 18 years of age and older. This device is intended to achieve epidermal regeneration and definitive wound with reduction in skin donor use.

Gravante et al (2007) compared results obtained with the ReCell system and the classic skin grafting for epidermal replacement in deep partial thickness burns.  These investigators recruited all patients with deep partial thickness burns admitted at the Burn Centre of S. Eugenio Hospital in Rome over 2 years.  Enrollment was carried out with a controlled strategy--sampling chart--that allowed homogeneous groups (ReCell and skin grafting) for age, gender, type of burns and TBSA.  They evaluated as primary endpoints of the study the time for complete epithelization (both treated area and biopsy site) as well as aesthetic and functional quality of the epithelization (color, joint contractures).  Secondary endpoints were the assessment of infections, inflammations or any adverse effects of the ReCell procedure, particular medications assumed, and post-operative pain.  A total of 82 patients were analyzed in 2 homogeneous groups.  All of them received adequate epidermal replacement; however, skin grafting was faster than the ReCell system (p < 0.05).  In contrast, the ReCell system biopsied areas and post-operative pain were smaller than classic grafting (p < 0.05).  The aesthetic and functional outcomes were similar between procedures.  The authors concluded that the ReCell system was a feasible, simple and safe technique.  It gave similar results to skin grafting but, harvesting minor areas, could open possible future applications in the management of large-burns patients.

The authors stated that the ReCell procedure took longer than skin grafts, mainly due to the time required by trypsin to digest intercellular bonds (20 mins).  These researchers tried to optimize operating times beginning with the biopsy and, during digestion, preparing the receiving areas.  However, times were still longer than skin grafting; and this probably produced greater surgical stresses for the patient and additional costs for the operating room, consisting in those for the ReCell kit and those for the longer operation time, without real benefits concerning outcomes (function and aesthetic) over classic treatments.  In this context, patients with greater burns would probably benefit more with this procedure.  In fact, in large burns (e.g., 60 % TBSA, 30 % deep dermal, 30 % full thickness burns) the factor ‘‘additional costs’’ will or might be reduced due to a shorter hospitalization time.  Using cells would reduce the donor sites necessary to cover deep dermal injured areas and the rest of the donor sites could be used to cover full thickness injured areas.  These investigators noted that the ReCell procedure was generally well-tolerated, even in the immediate post-operative period.  All patients received the same post-operative analgesics and with the same doses; however, those that underwent skin grafts complained of an additional painful site (the area of harvesting).  The ReCell biopsy site, on the contrary, were only 1 to 4 cm2 and produced little if no pain at all.  However, both issues (the patient’s surgical stress and the increased economic aspects) need to be verified in specific studies and in patients with larger burns.

Holmes et al (2018) noted that early excision and autografting are standard of care (SOC) for deeper burns; however, donor sites are a source of significant morbidity.  To address this, the ReCell Autologous Cell Harvesting Device (ReCell) was designed for use at the point-of-care (POC) to prepare a non-cultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin.  In a prospective study, these researchers examined the clinical performance of ReCell versus meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns.  Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. A recruitment target was established aiming to yield 90 evaluable subjects such that the noninferiority analysis is sufficiently powered. However, the analysis population for incidence of definitive closure consisted of 83 subjects in a modified per protocol population that was defined post hoc to exclude 14 subjects who dit not complete the 52-week followup, plus four ASCS subjects who were treated with topical silver sulfadine (which was thought to impair wound healing). At 4 weeks, 97.6 % of the ASCS-treated sites were healed compared with 100 % of the Controls.  Pain and assessments of scarring at the treatment sites were reported to be similar between groups.  Significant differences were observed between ReCell and Control donor sites.  The mean ReCell donor area was approximately 40 times smaller than that of the Control (p < 0.0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (p = 0.04). Subject-reported pain at the treatment site during the first 16 weeks was not significantly different between the ASCS and control sites. Similarly, long-term results at 16, 24, and 52 weeks showed no difference in subject satisfaction with appearance  or in scarring at the ASCS-treated sites compared with the control sites. At the treatment sites, a greater number of total adverse events occurred with the ReCell treatment than the Control treatment (35.6% vs 21.8%, respectively, P = .0013). The authors concluded that this study provided evidence that the treatment of deep partial-thickness burns with ASCS resulted in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG.  Moreover, these researchers stated that these findings have potential implications for a paradigm shift in the approach used to achieve rapid and permanent closure of burn injuries.  In addition, achieving definitive closure using less skin compared with standard autografting has the potential to decrease the number of surgical procedures needed to achieve wound closure as well as reducing hospital LOS; therefor, decreasing the overall costs related to the treatment of burn injuries. However, this was a relatively small open-label study, and might not be generalizable to all burns patients (NICE, 2020).

Holmes et al (2019) stated that STSG are the SOC for burns undergoing autografting but are associated with donor skin site morbidity and limited by the availability of uninjured skin.  The ReCell was developed for POC preparation and application of a suspension of non-cultured, disaggregated, autologous skin cells, using 1 cm2 of the patient's skin to treat up to 80 cm2 of excised burn.  In a prospective, within-subject controlled, randomized, multi-center trial, these researchers examined ReCell in combination with a more widely meshed STSG than a pre-defined SOC meshed STSG (ReCell treatment) for the treatment of mixed-depth burns, including full-thickness (n = 30 subjects).  Treatment areas were randomized to receive standard meshed STSG (Control treatment) or ReCell treatment, such that each subject had 1 Control and 1 ReCell treatment area.  Effectiveness measures were evaluated and included complete wound closure, donor skin use, subject satisfaction, and scarring outcomes up to 1 year following treatment.  Twenty-six of the 30 subjects were included in the per protocol analysis. At 8 weeks, 85 % of the Control-treated wounds were healed compared with 92 % of the ReCell-treated wounds, establishing the non-inferiority of ReCell treatment for wound healing.  Control-treated and ReCell-treated wounds were similar in mean size; however, mean donor skin use was significantly reduced by 32 % with the use of ReCell (p < 0.001); however, it is uncertain if this 32 % reduction was clinically meaningful.  Secondary safety and effectiveness outcomes were similar between the treatments. This noninferiority study was limited by small sample slze. The authors concluded that ReCell, combined with widely meshed STSG, was a safe and effective POC treatment for mixed-depth burns without confluent dermis, achieving short- and long-term healing comparable to standard STSG, while significantly decreasing donor skin use. It is unclear if the advantages of ReCell used as an adjunctive in this way justify the increased expense (NICE, 2020).

In a National Institute for Health and Care Excellence (NICE) medical technology guidance, Peirce and Carolan-Rees (2019) stated that the gold standard treatment for deep burns is an autologous skin graft; in larger burns this may be meshed to increase the area covered.  However, long-term aesthetic and functional outcomes of graft scars may be poor.  ReCell is a medical device that processes skin samples in the operating room into a cell suspension to be sprayed on or dripped onto a wound.  It has been claimed to improve healing and scar appearance.  This device was evaluated by the NICE Medical Technologies Evaluation Program.  Two groups were defined: ReCell compared to conventional dressings in shallower burns, and meshed grafts plus ReCell compared to meshed grafts alone in larger deeper burns.  The manufacturer's clinical evidence submission included 3 papers and 8 conference abstracts.  The External Assessment Centre (EAC) excluded 2 of these papers and added 7 abstracts.  In general, the evidence did not fit the defined groups, but suggested that ReCell was clinically comparable to skin grafts for partial thickness burns; however, ReCell is not used in this way in the U.K.  The manufacturer submitted an economic model in which the ReCell treatment of partial thickness burns reduced the requirement for later skin grafts.  This indicated that ReCell alone was cost-saving in comparison to conventional dressings.  The EAC indicated that this model was clinically inappropriate; however, data were unavailable to populate a new model.  The NICE Medical Technologies Guidance recommended that additional research was needed to address the uncertainties regarding the potential benefits of the ReCell procedure/system.  

Following publication of NICE's original guidance on RECELL in 2014, NICE commissioned NHS's Centre for Healthcare Evaluation, Device Assessment and Research (CEDAR) to design and run a trial to see whether ReCell cell spray could improve outcomes in patients with severe burns. However, in September 2018 the manufacturer withdrew the product from sale in Europe and also withdrew funding from the study. This was just prior to the start of recruitment and so no data was collected.

Willits and Cole (2020) summarized new evidence and information that had become available since prior NICE medical technology guidance on RECELLL was published in 2014, and that had been identified as relevant for the purposes of this report. The assessment stated: "Overall, the reporting of results in the included studies was poor . . .  All results should therefore be considered bearing in mind the limitations of the informing studies." The report concluded: "The evidence base to support the uptake of ReCell since the publication of the original Assessment Report is poor in terms of quality, quantity, and generalisability." The assessment identified three economic studies of RECELL, one of which was published in a journal (citing Kowal, et al., 2019). The assessment stated that the main limitation of the model appears to be related to the poor quality evidence informing the inputs.

Hayes et al (2020) stated that venous leg ulcers (VLUs) have a significant impact on approximately 3 % of the adult population worldwide, with a mean NHS wound care cost of £7,600 per VLU over 12 months.  The SOC for VLUs is compression therapy, with a significant number of ulcers failing to heal with this treatment, especially with wound size being a risk factor for non-healing.  In a prospective, randomized multi-center, pilot study, these researchers examined the safety and effectiveness of ASCS combined with compression therapy compared with standard compression alone (Control) for the treatment of VLUs.  Incidence of complete wound closure at 14 weeks, donor site closure, pain, Health-Related Quality of Life (HRQoL), satisfaction, and safety were assessed in 52 patients.  At Week 14, VLUs treated with ASCS + compression had a statistically greater decrease in ulcer area compared with the Control (8.94 cm2 versus 1.23 cm2, p = 0.0143).  This finding was largely driven by ulcers greater than 10 to 80 cm2 in size, as these ulcers had a higher mean percentage of re-epithelialization at 14 weeks (ASCS + compression: 69.97 % and Control: 11.07 %, p = 0.0480).  Furthermore, subjects treated with ASCS + compression experienced a decrease in pain and an increase in HRQoL compared with the Control.  The authors concluded that the findings of this study showed that the use of ASCS + compression accelerated healing in large VLUs.  Moreover, these researchers stated that further investigation is needed to examine the effect of ASCS + compression on wounds evaluating the healing outcomes and the impact that the decrease in wound size has on pain and cost-effectiveness of the treatment.

Manning et al (2022) noted that there is an urgent need for interventions that improve healing time, prevent amputations and recurrent ulceration in patients with diabetes-related foot wounds.  In an open-label study, subjects were randomized to receive an application of non-cultured autologous skin cells ("spray-on" skin; ReCell) or SOC interventions for large (greater than 6 cm2), adequately vascularized wounds.  The primary outcome was complete healing at 6 months, determined by assessors blinded to the intervention.  A total of 49 eligible foot wounds in 45 subjects were randomized.  An evaluable primary outcome was available for all wounds.  The median (inter-quartile range [IQR]) wound area at baseline was 11.4 (8.8 to 17.6) cm2 .  A total of 32 (65.3 %) index wounds were completely healed at 6 months, including 16 of 24 (66.7 %) in the spray-on skin group and 16 of 25 (64.0 %) in the SOC group (unadjusted OR [95 % CI]: 1.13 (0.35 to 3.65), p = 0.845).  Lower body mass index (BMI; p = 0.002) and non-plantar wounds (p = 0.009) were the only patient- or wound-related factors associated with complete healing at 6 months.  Spray-on skin resulted in high rates of complete healing at 6 months in patients with large diabetes-related foot wounds, but was not significantly better than SOC.  These researchers concluded that interventions that improve healing time, reduce recurrent ulceration and the incidence of major limb amputations in patients with diabetes‐related foot wounds remain a priority.  However, these researchers stated that currently there is no evidence to support the routine use of spray‐on skin to achieve these goals for this subset of patients.  They stated that further investigation is needed in the clinical characterization of the wounds, their healing trajectory as well as the role of wound healing interventions.  These investigators stated that future studies in this research area will need to recruit from many centers, and have a robust easily assessable primary outcome, preferably measured by the patient without the need for regular travel to the trial center.

Biaragi, et al. (2022) conducted a systematic review evaluating the efficacy of autologous skin cell suspensions (ASCS) on the re-epithelialization of partial thickness burn injuries and skin graft donor site wounds. Four databases (EMBASE, Google Scholar, MEDLINE, Web of Science), grey literature and select journal hand-searching identified studies from 1975 - 2020. Randomized trials evaluating partial thickness burn management with non-cultured ASCS compared to any other intervention were included. Time to re-epithelialization (TTRE) was the primary outcome. Three independent researchers completed screening, data extraction and certainty of evidence assessment using Cochrane Risk of Bias Tool and Grading of Recommendations Assessment, Development and Evaluation. Five trials (n = 347) reported on adults (2 trials) and children (1 trial) with burn wounds, and adults with donor site wounds (2 trials). The effect of ASCS compared to control on TTRE in adult burn wounds was not estimable. TTRE was shorter in pediatric burn wounds (SMD -1.75 [95% CI: -3.45 to -0.05]) and adult donor site wounds (SMD-5.71 [95% CI: -10.61 to-0.81]) treated with ASCS. The investigators stated that the certainty of evidence was very low. The very low certainty of evidence was due to serious to very serious ratings for risk of bias, indirectness, imprecision, inconsistency, and strongly suspected publication bias. The authors concluded that, compared to standard care, ACSC may reduce pediatric partial thickness burn wound and adult split-thickness skin graft donor site TTRE. A limitation of this study is that it focused on TTRE, and did not analyze potential benefits of ASCS related to donor site morbidity. The authors stated that, if they decided to narratively synthesize the burn wound
re-epithelialization results more definitively without considering the different study designs, the results favor the skin grafted groups in both studies with better re-epithelialization outcomes than the ASCS groups (Bariagi, et al., 2022). The investigators explained that the choice of TTRE as the main or primary outcome of the systematic evidence review aligned with advice provided in the Cochrane Handbook for Systematic Reviews of Interventions which states that main outcomes should be selected based on them being considered essential outcomes for decision-making (Biaragi, et al., 2022). A comment also argued that the studies by Holmes, et al. cited above received significant funding from the military and was included in the FDA submission, limiting risk of bias (Holmes, et al., 2022). The authors replied that that steps were undetaken to minimize bias, but that they cannot assume the included studies are unbiased based on GRADE criteria (Baraigi, et al., 2022).

Biaragi, et al. (2023) stated that the Biobrane RECELL Autologous skin Cell suspension and Silver dressings (BRACS) Trial evaluated three dressings for the re-epithelialization of partial-thickness burns in children. Eligible children (age ≤ 16 years; ≥5% total body surface area burned (TBSA); ≤48 h of injury) were randomized to silver dressings, RES/Biobrane or Biobrane. Regenerative Epidermal Suspension (RES) was prepared with the RECELL autologous cell harvesting device. Burn wound re-epithelialization in days was assessed as the primary outcome. Secondary outcomes evaluated at the primary endpoint of >95% TTRE included pain, itch, ease of dressing application, intervention fidelity, treatment satisfaction, scar severity, health related quality of life, health resource utilisation and adverse effects. The median time to re-epithelialization in days (primary outcome) was no different for RES/Biobrane at 12 (IQR: 5.6–18.4; n = 7) and slower by two days for Biobrane at 14 (IQR: 6.3–21.7; n = 7) when compared to silver dressings 12 (IQR: 3.7–20.3; n = 8). Reduced pain, fewer infections, no sepsis, no skin graft, and the lowest impact on health-related quality of life were reported in the RES/Biobrane group compared to other groups. Due to the COVID-19 pandemic, recruitment suspension resulted in a smaller cohort than expected and an underpowered study. The investigators stated that the findings indicated that burn wounds achieved ≥95% re-epithelialisation in a median of two days slower in wounds treated with Biobrane only when compared to a median TTRE for burn wounds treated with RES/ Biobrane and silver dressings, which demonstrated the same TTRE. The protocol pre-specified that four days would be considered a clinically meaningful difference . Thus, based othe findings from 22 participants, a clinically meaningful difference in the burn wound TTRE was not demonstrated. The investigators noted that the pilot trial findings should be interpreted cautiously; however, they indicate that a fully powered randomized controlled trial is warranted to substantiate the role of RES for medium to large pediatric partial-thickness burn management. Limitations of this study include the small sample size and focus on pediatric patients with superficial partial thickness to mid-dermal depth burns.

Carson, et al. (2023) analyzed data from electronic medical records collected from January 2019 through August 2020 from 500 healthcare facilities in the United States to assess duration of hospital stay and costs associated with autologous skin cell suspension. Adult patients receiving inpatient treatment with autologous skin cell suspension (ASCS) ± split-thickness skin grafts (STSG) for small burns (total body surface area [TBSA]<20 %), were identified and matched to patients receiving STSG using baseline characteristics. Length of stay (LOS) was assumed to cost $7554/day and to account for 70% of overall costs. Mean LOS and costs were calculated for the ASCS± STSG and STSG cohorts. A total of 151 ASCS± STSG and 2243 STSG cases were identified; 63.0 % of patients were male and the average age was 44.2 years. Sixty-three matches were made between cohorts. LOS was 18.5 days with ASCS± STSG and 20.6 days with STSG (difference: 2.1 days [10.2 %]). This difference led to bed cost savings of $15,587.62 per ASCS± STSG patient. The investors found overall cost savings with ASCS± STSG were $22,268.03 per patient. Limitations of this study include the use of retrospective observational data and industry sponsorship.

In an industry sponsored analysis, Foster, et al. (2021) modeled the economic impact of autologous skin cell suspension (ASCS) by conducting a primary research survey using real world from burn centers on the current state of treatment care in order to identify trends since 2011 that impact evaluation of new interventions. Ten percent of U.S. burn centers were surveyed in 2019 by a panel of health economists on current burn center practice patterns and outcomes. Survey data functioned as real world data with National Burn Repository (NBR) 8.0 data in a previously developed health economic model (BEACON). A health economic evaluation (HEE) was conducted with ASCS compared to standard of care (SOC) in a cost-effectiveness model for inpatients with deep-partial thickness (DPT) and full-thickness (FT) burn injury involving >10% total body surface area (TBSA). The costs-effectiveness model incorporated costs of patient care from RWD and data from the NBR predictive equations method. The investigators reported that ASCS was cost-saving in both FT and DPT burns across all TBSA ranges. Cost savings increased with burn size due to the reduced number of autograft procedures, LOS and costs compared to SOC. Savings ranged from 1% to 43% in 10% and 40 % TBSA, respectively in FT, and 25% to 41% in 10% and 40% TBSA, respectively among DPT burns. For a hypothetical BC with an average of 341 patients, the use of ASCS is expected to reduce overall costs by an estimated $15.8M for the center and $79.5K (17.4% reduction) per patient, on average. 

Kowal, et al. (2019) used health economic modeling to estimate cost-effectiveness and burn center budget-impact for the use of the RECELL Autologous Cell Harvesting Device to prepare autologous skin cell suspension (ASCS) compared to standard of care (SOC) split-thickness skin graft (STSG) for the treatment of severe burn injuries requiring surgical intervention for definitive closure. A hospital-perspective model using sequential decision trees depicts the acute burn care pathway (wound assessment, debridement/excision, temporary coverage, definitive closure) and predicts the relative differences between use of ASCS compared to SOC. Clinical inputs and ASCS impact on length of stay (LOS) were derived from clinical trials and real-world use data, American Burn Association National Burn Repository database analyses, and burn surgeon interviews. Hospital resource use and unit costs were derived from three US burn centers. A budget impact calculation used Monte Carlo simulation to estimate the overall impact to a burn center. The investigators found ASCS treatment is cost-saving or cost-neutral (\2% difference) and results in lower length of stay (LOS) compared to SOC across expected patient profiles and scenarios. The investigators reported that, in aggregate, ASCS treatment saves a burn center 14–17.3% annually. The investigators stated that results are sensitive to, but remain robust across, changing assumptions for relative impact of ASCS use on LOS, procedure time, and number of procedures.

REGUaRD

REGUaRD (New Life Medical, LLC) is a donated allograft placental membrane tissue. REGUaRD is a hydrated acellular (human) dermal allograft matrix used for the treatment of non-healing wounds and bum injuries. REGUaRD contains extracellular matrix (ECM) that provides a scaffold for cellular ingrowth vascularization, tissue regeneration and formation of granulation tissue. REGUaRD is supplied as a thin (0.5mm) allograft, in a variety of sizes. REGUaRD may be cut and shaped to the appropriate size. REGUaRD is administered by a health care professional in a physician's office, outpatient surgery center, or acute care facility. The size is determined by the injury or wound. REGUaRD is packaged in the following sizes: 2cm X 2cm, 2cm X 4cm, 4cm X 4cm, 4cm X 6 and 4cm X 8cm and stored at ambient temperatures.

Relese

Relese (StimLabs, LLC) is a sheet skin substitute product comprised of dehydrated human amniotic membrane that contains non-viable cells and is intended for use as a selective barrier and to protect wounds from the surrounding environment for chronic and acute wounds including dermal ulcers and other defects. The processed membrane is fenestrated and cut into various sizes, and presented in a sterilized, dehydrated sheet graft form.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of Relese.

ReNu (Amniotic Membrane and Fluid Allograft)

Bullard and Souza (2008) conducted a retrospective radiographic review of all patients treated by a single surgeon with a 3-level anterior cervical discectomy and fusion with plate fixation. These researchers compared fusion success rates and pseudarthrosis results with published data for 3-level anterior cervical constructs including; anterior cervical discectomy and fusion with plating (ACDFP) and anterior cervical corpectomy with and without plating (ACCP, ACC).  In this study, these investigators reviewed a series of 1,416 patients carried out by a single surgeon between May 2001 and February 2008.  Of these, 127 patients met standard criteria including a minimum of 6 months follow-up, no previous cervical surgeries, and flexion/extension lateral radiographs.  Pseudarthrosis was defined as abnormal movement between the spinous processes, lucency at the graft vertebral body interface or absence of trabecular bone spanning the complete fused space.  Fusion was identified by the absence of abnormal motion of the fused segments on flexion / extension lateral radiographs and the presence of continuous trabecular bone formation at the graft / endplate junction.  Of the 127 patients, 124 had successful fusions and 3 had pseudarthrosis; 376 out of 381 (98.7 %) levels fused while only 5 (1.3 %) levels developed pseudarthrosis.  The authors concluded that the findings of this study presented the largest reported series of patients undergoing a 3-level ACDFP by a single surgeon with close follow-up, and suggested that 3-level ACDFP utilizing a standardized modified Smith-Robinson technique had an acceptably high level of fusion in comparison to other modalities.  This study provided no data on the use of allogeneic amniotic tissue and fluid after plantar fasciitis debridement.

Werber and Martin (2013) reviewed the background information and previous clinical studies that considered the use of allogeneic amniotic tissue and fluid (granulized amniotic membrane and amniotic fluid) in the treatment of chronic diabetic foot wounds.  This innovation represents a relatively new approach to wound management by delivering a unique allograft of live human cells in a non-immunogenic structural tissue matrix.  Developed to fill soft tissue defects and bone voids and to convey anti-microbial and anti-inflammatory capabilities, granulized amniotic membrane and amniotic fluid does not require fetal death, because its procurement is performed with maternal consent during birth.  In the present investigation, 20 chronic wounds (20 patients) that had been treated with standard wound therapy for a mean of 36.6 ± 31.58 weeks and with a mean baseline area of 10.15 ± 19.54 cm(2) were followed-up during a 12-week observation period or until they healed.  A total of 18 of the wounds (90 %) healed during the 12-week observation period, and none of the wounds progressed to amputation.  The authors concluded that from their experience with the patients in the present case series, they believed that granulized amniotic membrane and amniotic fluid represents a useful option for the treatment of chronic diabetic foot wounds.  Level of Clinical Evidence = IV.  This was a small (n= 20) uncontrolled study that addressed the use of allogeneic amniotic tissue and fluid for the management of chronic diabetic foot wounds (not following plantar fasciitis debridement).

Renuva

According to the Musculoskeletal Transplant Foundation, Renuva is an allograft adipose matrix derived from processed donated human adipose tissue (CMS, 2019). Renuva is intended for the replacement of damaged or inadequate integumental adipose tissue matrix such as facial deformities, craniofacial deformities, breast reconstructions, or for other homologous uses into areas of the body where native fat would exist. Renuva® Allograft Adipose Matrix may also be used for the reinforcement or supplemental support in underlying adipose tissue matrix as the result of damage or naturally occurring defects e.g., cleft lip, Parry-Romberg syndrome, and facial LDS." The matrix is dehydrated and must be rehydrated prior to use. When ready to use, the allograft is injected into the site subcutaneously. The matrix is available in three sizes: 1.5cc, 3cc and 5cc tissue package.

Repliform

Repliform is an acellular human dermis for pelvic floor repair.

LifeCell also produces Repliform, which seems to be the same product as AlloDerm (Snyder, et al., 2012). Repliform Tissue Regeneration Matrix is a human acellular dermis. The donor human skin is processed and then freeze-dried to remove cells while maintaining the collagen, elastin, and proteoglycans. Repliform is processed by LifeCell Corp. and distributed by Boston Scientific Corp. The Boston Scientific Web site promotes Repliform for pelvic floor repair and says it "is intended for the repair or replacement of damaged or inadequate integumental tissue such to repair enteroceles, rectoceles and/or cystoceles and for pelvic floor reinforcement."

Repriza

Repriza is a prehydrated, ready-to-use, acellular dermal matrix derived from human allograft tissue.  It is intended for implantation during plastic and reconstructive surgeries wherever an acellular dermal matrix may be used. For example, it may be used to support implants in a defined pocket such as in breast reconstruction, and abdominal wall reconstruction procedures.  Repriza can also be used in a range of applications to augment soft tissue irregularities and for implantation in irregularities such as a depression over the nasal bridge.  Repriza is a "surgical implant" and "would have no other use outside the surgical setting".  The scaffold is gradually integrated with, and ultimately replaced by the body's own tissue.  The quantity of product used varies based upon surgical application, individual patient circumstances, and the dimensions of the surgical site.  Repriza is supplied sterile and ready to use in two sizes: 4 x 12 cm and 6 x 16 cm.  Custom sizes and thicknesses are available upon request.  According to the manufacturer, Repriza is used in the same indications and same manner as Alloderm and Graft Jacket; however, there is a significant difference in the cost of the materials.

Resolve Matrix

Resolve Matrix is a thin, flexible, yet durable acellular biologic dermal substitute which facilitates the body’s regenerative tissue repair during the wound healing process. This product is distinctively derived from porcine peritoneum membrane and processed using the optrix tissue cleansing methodology. Resolve Matrix is indicated for the management of topical wounds, including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds, trauma wounds, draining wounds, and tunneled or undermined wounds. Resolve Matrix has a nominal thickness of ±0.3 mm and is supplied in multiple sizes (CMS, 2023e).

Restorigin Amnion Patch

Restorigin Amnion Patch (Parametrics Medical) is derived from the amnion layer of fetal membranes in the umbilical cord. It is intended to provide a protective barrier while providing a regenerative tissue matrix with anti-inflammatory, anti-scarring and anti-microbial properties to facilitate healing of chronic, non-healing wounds and burns. There are no peer-reviewed published studies evaluating the safety and efficacy of Restorigin.

Restorigin Amniotic Fluid Therapy (AFT)

Restorigin Amniotic Fluid Therapy (AFT) (Parametrics Medical) is an amniotic fluid product that is derived from donated human birth tissue and fluid. It is intended for the protection and treatment of non-healing wounds and burn injuries. Restorigin amniotic fluid contains collagen substrates, growth factors, and cytokines (not an all-inclusive list). There are no peer-reviewed published studies evaluating the safety and efficacy of Restorigin.

Restrata

Restrata is a wound matrix that is classified as a skin substitute. It consists of nano-scale materials to provide a resorbable scaffolding to facilitate cell migration, revascularization, and soft tissue formation and reinforcement in the prepared wound bed. Restrata is indicated for wound management and includes partial and full thickness wounds, pressure sores, venous, diabetic and chronic vascular ulcers, wounds with tunneling or undermining, surgical (e.g. donor site/grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, wound dehiscence) trauma and draining wounds. This product is highly porous and allows for cellular infiltration and vascularization before completely degrading via hydrolysis into the wound bed. Restrata dosage includes size selection appropriate to the prepared wound bed and is reapplied every 7 days or as required. The physician will size Restrata to desired configuration of the wound bed and hydrate before appropriate fixation method depending on wound type/location. Restrata is available in a single use double peel package in a variety of sizes.

Revita

Revita (StimLabs, LLC.) is a human cellular and tissue based product – donated allograft placental tissue (CMS, 2017).  It is comprised of dehydrated, sterile human amniotic membrane and chorionic membrane obtained from donated human placental tissue.  Revita is comprised of all 3 layers of placental membrane (amnion, intermediate, and chorion layers).  Revita allograft is intended to be used as a wound covering, or barrier membrane, over chronic and acute wounds, including dermal ulcers or defects.  It is supplied in 2 x 2 cm, 2 x 3 cm, 4 x 4 cm, 4 x 6 cm, and 6 x 8 cm sheets.  There is a lack of evidence regarding the effectiveness of Revita.

Revitalon

Revitalon is a human tissue allograft made of donated amniotic membrane derived from the inner lining of donated placenta.  Revitalon can be used as a covering for full-thickness wounds, damaged membranes, and as a dressing for burns. It is comprised of native human amnion and chorion consisting of collagen types I, III, IV, V, VI, laminin, fibronectin, nidogen, and proteoglycans. The amnion is comprised of five layers of collagen and fibronectin and is tough, transparent, nerve-free, and nonvascular. Revitalon allografts are supplied in a single-sized package and provided in the following sizes: 1 cm round dot, 2x2 cm, 4x4 cm, and 4x6 cm.

Signature APatch

The Signature APatch is a cryopreserved, minimally engineered amniotic membrane allograft for homologous precision cut matrix for direct application as a would cover or physical barrier to acute or chronic wounds, including but not limited to venous leg ulcers, pressure ulcers, diabetic foot ulcers, surgical wounds, burns, and wounds with exposed tendon, muscle, and/or bone. The product is applied directly to the wound for up to 12 weeks or until the wound is closed as a part of a semi-wet dressing standard of care. Signature APatch is available as a cryopreserved tissue, prepared and packages aseptically in a 15 mL cryovial. It comes in a single size configuration as a hexagon patch with 2.5 cm sides, 5.0 cm in diameter, and total surface area of 16 cm squared. The product is thawed in a sterile gloved hand for 5 minutes and cut and shaped to size prior to application following wound preparation. Signature APatch can be used in combination with tissue adhesives or semi-wet dressings for allograft application if necessary (CMS, 2022c).

There is a lack of evidence regarding the effectiveness of Signature APatch product.

Silver-Coated Wound Dressings (e.g., Acticoat, Actisorb, Mepitel Ag)

Silver-coated wound dressings produce sustained release of ionic silver to decrease the incidence of infection.  As the dressing material accumulates fluid, silver ions are released from the dressing into the wound environment.  Silver-coating technology was developed to prevent wound adhesion, limit nosocomial infection, control bacterial growth, and facilitate burn wound care through a silver-coated dressing material.  Silver- coated wound dressings such as Acticoat and Actisorb offer new forms of dressing for burn wounds, but require further investigation.  Well-controlled clinical trials are needed comparing clinical outcomes of silver-coated wound dressings with standard wound dressings in patients in various phases of burn wound care.  An evidence review prepared for the Cochrane Collaboration (Bergin et a., 2006) concluded: "Despite the widespread use of dressings and topical agents containing silver for the treatment of diabetic foot ulcers, no randomised trials or controlled clinical trials exist that evaluate their clinical effectiveness.  Trials are needed to determine clinical and cost-effectiveness and long-term outcomes including adverse events."

Choi et al (2019) stated that antibiotic or silver-based dressings are widely used in burn wound care.  The authors’ standard method of dressing pediatric extremity burn wounds consists of an antibiotic ointment or nystatin ointment-impregnated non-adherent gauze (primary layer), followed by rolled gauze, soft cast pad, plaster and soft casting tape (3M™ Scotchcast™, St. Paul, MN).  These researchers compared their standard ointment-based primary layer versus Mepitel Ag (Molnlycke Health Care, Gothenburg, Sweden) in the management of pediatric upper and lower extremity burn wounds.  Children with a new burn injury to the upper or lower extremities, who presented to the burn clinic were eligible.  Eligible children were enrolled and randomized, stratified by burn thickness, to be dressed in an ointment-based dressing or Mepitel Ag.  Study personnel and subjects were not blinded to the dressing assignment after randomization.  Dressings were changed approximately once- or twice-weekly, until the burn wound was healed or skin-grafted.  The primary outcome was time to wound healing and p-value of < 0.05 was considered significant.  A total 0f 96 children with 113 upper or lower extremity burns were included in the analysis.  Mepitel Ag (hazard ratio [HR] 0.57 (95 % confidence interval [CI]: 0.40 to 0.82); p = 0.002) significantly reduced the rate of wound healing, adjusting for burn thickness and fungal wound infection.  The incidence of fungal wound infections and skin grafting was similar between the 2 groups.  Children randomized to standard ointment dressings were significantly less likely to require 4 or more burn clinic visits than those in the Mepitel Ag (4 % versus 27 %; p = 0.004).  The authors concluded that the findings of this study showed that their standard ointment-based dressing significantly increased the rate of wound healing compared to Mepitel Ag for pediatric extremity burn injuries.

Skin Substitute for Moh's Surgery

Lu and Khachemoune (2023) stated that the data on skin substitute usage for managing Mohs micrographic surgery (MMS) wounds remain limited.  In a systematic review, these investigators provided an overview of skin substitutes employed for MMS reconstruction, summarized clinical characteristics of patients undergoing skin substitute-based repair following MMS, and identified advantages and limitations of skin substitute implementation.  A systematic review of Ovid Medline, Embase, Cochrane Library, and Web of Science databases, from inception to April 7, 2021, identified all cases of MMS defects repaired using skin substitutes.  A total of 687 patients were included.  The mean patient age was 70 years (range of 6 to 98 years).  Commonly used skin substitutes were porcine collagen (n = 397), bovine collagen (n = 78), Integra (n = 53), Hyalofill (n = 43), amnion/chorion-derived grafts (n = 40), and allogeneic epidermal-dermal composite grafts (n = 35).  Common factors influencing skin substitute selection were cost, healing efficacy, cosmetic outcome, patient comfort, and ease of use.  Some articles did not specify patient and wound characteristics.  The authors concluded that skin substitute usage in MMS reconstruction is not well-guided.  These researchers stated that blinded randomized control trials (RCTs) comparing the effectiveness of skin substitutes and traditional repair methods are imperative for establishing evidence-based guidelines on skin substitute usage following MMS.

SkinTE

SkinTE (PolarityTE, Inc., Salt Lake City, UT) is a fully autologous, homologous product for the repair, reconstruction, replacement, supplementation and regeneration of defects or functional losses of the skin of human patients. SkinTE is manufactured from a harvested sample of the patient’s full-thickness skin, composed of viable skin cells and an organized extracellular matrix, with no additional cell or tissue source from another human (allogeneic) or (xenogeneic). Following application to a wound bed, the product functions to regenerate full-thickness functional skin across the entire surface, including all layers (epidermis, dermis, hypodermis), and regenerate functional appendages native to skin. The product is intended to be used by physicians for homologous uses of the skin and integumentary system. The product is appropriate from treatment of acute burns requiring excision, grafting, and chronic wounds. Patients with functional loss of skin due to scarring may also be appropriate for treatment with SkinTE. The manufacturer states that SkinTE is patient and case specific, intended for autologous use, and single application only. The dosage of SkinTE corresponds to the surface area of the wound being treated in square centimeters.

StrataGraft

StrataGraft is a bioengineered, allogeneic, cellularized scaffold product. It consists of fully-stratified epithelial layer comprised of differentiated, multilayered, epidermal keratinocytes from a single human donor. StrataGraft has metabolically active cells that produce and secrete a myriad of growth factors and cytokines. StrataGraft is indicated for topical application by a healthcare provider for the treatment of adults with thermal burns containing intact dermal elements for which surgical intervention is clinically indicated (deep partial-thickness burns). The product does not stay permanently engrafted, but undergoes replacement by the patient’s own cells over time. This eliminates or reduces the need for autografting achieve definitive closure of the majority of treated wounds.

Strattice

Strattice Reconstructive Tissue Matrix is a reconstructive tissue matrix (surgical mesh) that supports tissue regeneration. It is derived from porcine dermis and undergoes non-damaging proprietary processing that removes cells and significantly reduces the key component believed to play a major role in the xenogeneic rejection response. Strattice is used by surgeons as a surgically implanted soft tissue patch to reinforce a patient's soft tissue where weakness exists, and for the surgical repair of damaged or ruptured soft tissue, such as in hernia repair, open abdominal repairs and in breast reconstruction, post mastectomy. Once implanted, Strattice promotes rapid revascularization [cell repopulation and white cell migration] and provides for management and strong repair of partial and full thickness wounds; pressure ulcers; venous ulcers; diabetic ulcer; chronic vascular ulcers; tunneled/undermined wounds; surgical wounds; trauma wounds; draining wounds; or other bleeding surface wounds. Strattice is available to physicians in 2 versions: pliable and firm, in various sizes: Pliable: 5 cm x 16 cm and 8 cm x 16 cm, and Firm: 6 cm x 16 cm, 10 cm x 16 cm, 16 cm x 20 cm, 20 cm x 20 cm, and 20 cm x 25 cm. The physician will determine the most appropriate size and version to be used based on each individual patient case.

The use of Strattice porcine-derived decellularized collagen products has been proposed for use in various surgical procedures and in the treatment of dermal wounds.  Currently, there is insufficient evidence to allow for proper evaluation regarding the effectiveness of this technology.

Stravix and StravixPL

Stravix (Osiris Therapeutics Inc.) is a cryo-preserved human placental tissue, composed of the Wharton’s jelly and umbilical amniotic membrane.  Stravix is processed from human umbilical cord and contains a collagen/hyaluronic acid (HA)-rich extracellular matrix; endogenous bio-factors with anti-inflammatory, angiogenic, anti-scarring, and anti-microbial properties; as well as viable endogenous cells, including mesenchymal stem cells (MSCs).  The manufacturer states that Stravix is currently indicated for inpatient surgical applications only, including as a wound cover in deep, acute wounds; surgical wound repair; and the majority of applications are surgical -- below the knee, leg and foot tendon repairs, and neurovascular repair.  Stravix is supplied as a cryo-preserved placental tissue packaged in a wide-mouth jar.  It is available in 2 sizes (3 x 6 cm and 2 x 4 cm).  When stored frozen at -80° C, Stravix has a 2-year shelf-life.  Specifically, Stravix/StraviPL are used for deeper wounds in higher risk patients and the wounds located in areas subject to high shear force.  The quantity and size of the product used vary based upon wound size and physician recommendation.  Stravix/StravixPL are approximately 10 times thicker than Grafix Prime and GrafixPL Prime; and dosing recommendation is weekly for up to 12 weeks or until the wound is closed.

Supra SDRM

Supra SDRM (PolyMedics Innovations Inc.) is a novel, resorbable synthetic skin substitute, guided wound closure matrix, built as a bimodal foam membrane structure for the management of epidermal and dermal wounds, including those caused by burns, pressure ulcers, and venous ulcers, among other wounds. Supra SDRM is composed of a tripolymer of polylactide, trimethylene carbonate, E-caprolactone and polyvinyl alcohol. It is highly permeable to oxygen and water vapor, providing a favorable environment for wound healing. Supra SDRM is fully malleable at room temperature and becomes more pliable at body temperature and can be conformed three dimensionally to multiple anatomical orientations. It is available in multiple sizes.

There is a lack of evidence in the peer-reviewed published medical literature to support the effectiveness of Supra SDRM. 

Suprathel

Suprathel (Polymedics Innovations GmbH, Denkendorf, Germany) is a synthetic, biocompatible, and absorbable skin substitute made from polymers of lactic acid (Snyder et al, 2012). Suprathel is a composed entirely of synthetic materials, including a tripolymer of polyactide, trimethylene carbonate and ε–caprolactone. It is an alloplastic, absorbable "skin substitute" with properties similar to the skin. It is highly permeable to oxygen and water vapor, providing a particularly favorable environment for wound healing. Suprathel is used for epidermal and dermal wounds, such as split skin graft donor sites and partial thickness burns. Suprathel may also be used for partial and full thickness wounds.The Suprathel membrane is applied once to a clean débrided wound surface and then breaks down during the healing process.  According to the manufacturer, the products of Suprathel degradation stimulate the healing process by increasing angiogenesis and rebuilding the dermis.  The acidification of the wound bed by breakdown products is also supposed to have a bactericidal effect. Suprathel is fully malleable at room temperature, and becomes more pliable at body temperature.  Suprathel Wound and Burn Dressing was cleared for marketing under the 510(k) process in May 2009 for "temporary coverage of noninfected skin defects, such as superficial wounds, under sterile conditions.  The dressing is intended to maintain a moist wound healing environment.  A moist wound healing environment allows autolytic débridement.  The Suprathel Wound and Burn Dressing is used in the management of: partial and full thickness wounds; pressure (stage I and IV) and venous ulcers; ulcers caused by mixed vascular etiologies; venous stasis and diabetic ulcers; 1st and 2nd degree burns; partial thickness burns; cuts and abrasions; acute wounds; trauma wounds; surgical wounds; superficial wounds; grafted wounds and donor sites."

Depending on the wound size, the appropriate square centimeters of the Suprathel membrane(s) shall be applied. A protective gauze should be applied over Suprathel on areas subject to mechanical stress, such as the extremities and the dorsal side of the torso. This protective dressing should comprise a fatty gauze and absorbent gauze. Suprathel, together with the gauze, shall remain unchanged until wound healing is completed. If Suprathel remains longer on the skin, it will be absorbed completely in approximately 60 days, without irritation to the upper epithelial layers. Suprathel is available in four sizes: 5 x 5 cm; 9 x 10 cm; 18 x 10 cm; and 18 x 23 cm square sheet membranes. Suprathel is also available in hand-shaped pads that can be used on the flexor and/or exterior side of the hand.

Schwarze et al (2008) conducted a prospective, randomized, nonblinded, clinical study to evaluate the impact on wound healing of Suprathel in partial-thickness burn injuries. Thirty patients with second-degree burn injuries were included in the study. Burn injuries were randomly selected, partly treated with Omiderm  (a polyurethane membrane) and partly treated with Suprathel. The first gauze change was applied the fifth day postoperatively, followed by regular wound inspection until complete reepithelization. The study focused on patient pain score, healing time, analysis of wound bed, ease of care, and treatment costs. The authors found that there was no significant difference between the 2 materials tested regarding healing time and reepithelization. There was a significant lower pain score for patients treated with Suprathel (p = 0.0072). Suprathel becomes transparent when applied, thus allowing close monitoring of wound healing. In contrast to Omiderm, Suprathel shows better attachment and adherence to wounds. When interviewed, patients reported Suprathel as their treatment preference. As dressing material, Omiderm is more cost-effective than Suprathel. The authors concluded that Suprathel represents a reliable epidermal skin substitute, with a good impact on wound healing and pain reduction in partial-thickness burn injuries. Although it is less cost-effective than Omiderm, the significant increase of patient comfort makes this material represent a reliable and solid treatment alternative when dealing with partial-thickness burn injuries. Further studies with this synthetic dressing on other types of wounds are warranted.

Hundeshagen et al (2018) conducted a prospective, randomized, controlled trial comparing Mepilex Ag (M), a silver-impregnated foam dressing, and Suprathel (S), a DL-lactid acid polymer, in the outpatient treatment of partial-thickness burns in pediatric and adult patients. Sixty-two patients were randomized to Mepilex Ag (n=30) or Suprathel (n=32). The investigators monitored time to reepithelialization, wound pain, discomfort during dressing changes, and treatment cost. Objective scar characteristics (elasticity, transepidermal water loss, hydration, and pigmentation) and subjective assessments (Patient and Observer Scar Assessment Scale) were measured at 1 month post burn. The investigators found that time to re-epithelialization was not different between the groups (12 days; p = 0.75). Pain ratings were significantly reduced during the first 5 days after burn in the Suprathel group in all patients (p = 0.03) and a pediatric subgroup (p < 0.001). Viscolelasticity of burned skin was elevated compared with unburned skin in the Mepilex Ag group at 1 month post burn. Patients treated with Suprathel reported better overall scar quality (p < 0.001). The cost of treatment per square centimeter for Mepilex Ag was considerably lower than that of Suprathel. The investigators concluded that both dressings are feasible and efficacious for the outpatient treatment of minor and selected moderate partial-thickness burns. Reduced pain, especially in a pediatric patient population, may be advantageous, despite increased treatment cost. The investigators note that burn depth was assessed clinically only by experienced burn physicians. While their observed healing times in general support the overall accuracy of their clinical judgment, future studies should involve objective assessment tools, such as laser Doppler, to further improve diagnostic precision and group comparability. 

Blome-Eberwein et al (2021) conducted a retrospective chart review encompassing a 4-year study period to assess complications and outcomes using absorbable synthetic membrane (Suprathel) to treat second degree burns. The review included 229 burn patients, 138 pediatric, with superficial and deep second-degree wounds, treated with Suprathel (Polymedics, Denkendorf, Germany). Patients were treated under anesthesia or moderate sedation. The wound bed was prepared by using either rough debridement or dermabrasion excision. After hemostasis, the membrane was applied to the wound with an outer layer dressing of fatty gauze, bridal veil, absorptive gauze and an ACE® wrap. The outer dressing was removed every one to four days, depending on exudate, in order to closely follow the wound through the translucent membrane and fatty gauze layers. After complete epithelialization, the dressing separated and could be removed. The study focused on the need for subsequent grafting, healing time, patient pain level, hypertrophic scarring and rate of infection. The authors found that all wounds in this study that were treated with Suprathel healed without grafting. The average TBSA (Total Body Surface Area) was 8.9% (1%-60%). Average time to healing was 13.7 days for ≥ 90% epithelialization with 11.9 days for pediatric patients versus 14.7 days for adults. Throughout the treatment period, the average pain level was 1.9 on a 10-point scale. 27 patients developed hypertrophic scarring in some areas (11.7%). Average Length of stay (LOS) was 6.9 days. The rate of infection was 3.8% (8/229). Failure or progression to full thickness in part of the wounds was 5.2% (12/229). The authors concluded that in treating second-degree burn wounds, Suprathel provides a simple, effective solution alternative with good outcomes and less pain than conventional and previously studied treatment options in the same institution. Fewer dressing changes and easier overall management of the wounds contribute to its favorable profile. Limitations of the study include that it was retrospective and lacked a control group. A prospective long-term outcome study with control group is in preparation.

SureDerm Acellular Dermal Matrix

According to HansBiomed Corp., SureDerm is a human acellular dermal matrix indicated for use in "skin reconstruction to repair skin loss from burn injuries, car accidents, congenital diseases, periodontal diseases, urinary incontinence, and ulcers or malformations" (CMS, 2019). SureDerm is supplied as 0.25-0.59mm, 0.6-0.99mm, 1.0-1.39mm, 1.4-1.79mm and 1.8mm and over.

SurFactor and NuDyn

Surgenex, LLC, offers SurFactor and NuDyn, which are the same products, marketed under different names. Any reference to SurFactor equally applies to NuDyn. These products are acellular, flowable allograft tissue matrix derived from donated human amniotic membrane. They function in support of wound healing and soft tissue repair and are indicated for use in patients with acute, chronic or non-healing wounds, burns, or surgical wounds and in patients with soft tissue injuries or inflammatory conditions such as plantar fasciitis, bursitis, tendonitis, ligament and tendon sprains, nerve entrapment and ankle capsulitis. They are available in 0.5 cc, 1 cc and 2 cc dose sizes. The vial is packaged in a foil pouch and then terminally sterilized using e-beam irradiation. The prescribed dosage depends on the size of the wound, injury and/or scope of the treatment. SurFactor and NuDyn are intended for topical application to the wound surface, to irrigate a wound bed and/or injected directly into the site of the lesion, wound margins or in surrounding tissue near the inflammation.

There is a lack of evidence regarding the effectiveness of the SurFactor or NuDyn allografts.

surgiGRAFT

surgiGraft (Synergy Biologics) is a minimally manipulated human amnion-only regenerative extracellular tissue matrix derived from human placental tissue (amniotic tissue) which has been processed into an allograft. The allograft is intended for reconstruction, repair, or replacement of donor recipient tissue in the following conditions: neuropathic ulcers, venous stasis ulcers, post-traumatic wounds, pre- and post- surgical wounds and pressure ulcers, diabetic wounds, burn wounds, scar tissue, scarring, and adhesion barrier up to and including nerve bundle and peripheral wrap as a wound covering. surgiGraft serves to act as a tissue barrier/covering or to provide lubrication. It is offered in both dry and hydrated forms.  surgiGraft is administered by placing the stromal side onto the external wound area followed by the clinician’s standard closing procedures. There are no peer-reviewed published studies evaluating the safety and efficacy of surgiGraft. 

SurgiGRAFT-DUAL

According to Synergy Biologics, LLC., SurgiGRAFT-DUAL is a bilayer human amniotic tissue allograft intended for use to repair or replace dermal tissue, including in the treatment of chronic, non-healing wounds including neuropathic ulcers, post-traumatic and pressure ulcers (CMS, 2019). The minimally-processed bilayer allograft contains collagen types IV, V, and VII that will promote cellular differentiation and wound healing. SurgiGRAFT-DUAL is applied topically to chronic, non-healing wounds. It is available in sizes 2 x 2 cm, 2 x 3 cm, 2 x 4 cm, 2 x 8 CM, 4 x 4 cm; and 12 mm, 15 mm and 18 mm diameter rounds.

SurgiMend®

SurgiMend Collagen Matrix (TEI Biosciences, Boston, MA) was cleared through the FDA 510(k) process in 2007.  It is an acellular dermal tissue matrix derived from fetal or neonatal bovine dermis and is intended for implantation to reinforce soft tissue where weakness exists and for the surgical repair of damaged or ruptured soft tissue membranes.  According to the 510(k) letter to the manufacturer, it is specifically indicated for plastic and reconstructive surgery, muscle flap reinforcement, hernia repair (e.g., abdominal, inguinal, femoral, diaphragmatic, scrotal, umbilical, and incisional hernias), reinforcement of soft tissues repaired by sutures or suture anchors, during tendon repair surgery, including re-inforcement of the rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons.  It is not intended to replace normal body structure or provide the full mechanical strength to support tendon repair of the rotator cuff, patellar, Achilles, biceps, quadriceps or other tendons.  Sutures used to repair the tear and sutures or bone anchors used to attach the tissue to the bone provide biomechanical strength for the tendon repair. 

There is insufficient scientific evidence regarding the effectiveness of SurgiMend for use as an implant for the surgical repair of soft tissue deficiencies or for any other indications. There are few published reports of SurgiMend (Cheng & St. Cyr, 2012). Endress, et al. (2012) reported on a retrospective comparison of 49 breast reconstructions in 28 patients with SurgiMend with 123 reconstructions in 91 patients without the use of a graft. The study found no significant differences in overall complication rates in the group managed with SurgiMend (20.8%) versus the group managed without use of a graft (13.0%). The authors reported that the duration of drainage was significantly shorter in the group managed with SurgiMend (8.5 days) versus the comparison group (11 days). Gaster, et al. (2013) reported on a prospective study of 17 breast reconstructions in 12 patients with Surgimend. The authors reported that SurgiMend demonstrated a very infrequent inflammatory response. The authors stated that further studies are needed to characterize the molecular mechanisms uncerlying tissue incorporation of this product.

SurGraft

According to the manufacturer, Surgenex, LLC., SurGraft is a dehydrated human amniotic membrane allograft "intended for the treatment of non-healing wounds and burn injuries" (CMS, 2019). "SurGraft is directed for use in patients with acute or chronic wounds, including but not limited to, chronic, non-infected, diabetic foot ulcers, chronic, non-infected, partial or full-thickness diabetic foot skin ulcers (due to venous insufficiency), pressure ulcer, surgical wounds and burns which have not adequately responded to conventional therapy." The manufacturer also stated that "SurGraft is minimally manipulated Human Cell Tissue Product (HCT/P) intended for homologous use." Surgraft is supplied in five sizes: 2 x 2 cm, 2 x 3, 2 x 4 cm and 4 x 8 cm.

SurGraft FT

SurGraft FT is a full thickness dehydrated amniotic and chorionic tissue allograft sourced from donated human amniotic and chorionic membrane. This product is intended to act as a barrier and protective covering from the encompassing environment for acute and chronic wounds, including partial- and full-thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. SurGraft FT is applied after standard wound preparation. It is applied directly without requiring fixation to the wound bed and is fully resorbable. SurGraft FT is sterile and supplied in an individual use package in a variety of sizes (CMS,2023c).

SurGraft TL

SurGraft TL is a triple-layer amniotic tissue allograft produced from donated human amniotic membrane. This product is designed to function as a barrier and provide protective coverage from the surrounding environment for acute and chronic wounds such as partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor site/grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, wound dehiscence), trauma wounds (e.g., abrasions, lacerations, partial thickness burns, skin tears), and draining wounds. SurGraft TL dosage is per square centimeter and wound size dependent. After standard wound preparation, SurGraft TL is placed directly to the wound and adheres to the wound bed without fixation. This product is fully resorbable and does not require removal from the wound bed. SurGraft TL is available in a single use package in various sizes (CMS, 2023b).

SurGraft XT

SurGraft XT is a dual layer dehydrated amniotic allograft sourced from donated human amniotic membrane. This product is intended to act as a barrier and protective covering from the encompassing environment for acute and chronic wounds, including partial- and full-thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds. SurGraft XT is applied after standard wound preparation. It is applied directly without requiring fixation to the wound bed and is fully resorbable. SurGraft XT is sterile and supplied in an individual use package in a variety of sizes (CMS,2023c).

Symphony

Symphony is a bioengineered skin substitute made up of an extracellular matrix (ECM) and hyaluronic acid (HA). Specifically, the product’s three layers of ovine-derived ECM contain more than 150 essential ECM proteins which include structural proteins, adhesion proteins, and signaling proteins. These components in combination with a single layer of HA provide a conducive environment that is critical to the wound healing process. Furthermore, Symphony’s design scaffolds the patient’s own cells to rebuild dermal tissues in acute and chronic wounds.

TAG

TAG is a sterile, dehydrated, triple layer amniotic allograft primarily consisting of amniotic membrane from donated human placental tissue. This product is intended to function as a barrier ad provide protective coverage from the surrounding environment for acute and chronic wounds. TAG is applied directly to the wound after standard wound preparation and may be held in place using a secondary dressing. The graft can be rehydrated in-situ with sterile water or 0.9% saline if desired. The product is supplied as 2.56 cm x 2.56 cm and 10 cm x 13 cm sizes and packaged in a primary foil pouch and secondary Tyvek pouch and sterilized by e-beam (CMS, 2022c).

There is a lack of evidence regarding the effectiveness of TAG.

Talymed

Talymed (Marine Polymer Technlogies, Inc., Danvers, MA) is a sterile advanced wound matrix comprised of shortened fibers of poly-N-acetylglucosamine, isolated from microalgae (Snyder, et al., 2012). Talymed is indicated for the management of wounds including: diabetic ulcers, venous ulcers, pressure wounds, ulcers caused by mixed vascular etiologies, full thickness and partial thickness wounds, second degree burns, surgical wounds, traumatic wounds healing by secondary intention, chronic vascular ulcers and dehisced surgical wounds and bleeding surface wounds, abrasions and lacerations. Talymed is placed on the open wound and covered with a transparent dressing. New wound matrix can be reapplied as necessary. Talymed™ is provided as a 5 x 5 cm and 10 x 10 cm patch that should be cut to fit wound size. According to the manufacturer, Talymed is similar to Oasis Wound Matrix, Integra Flowable Wound Matrix, and PriMatrix Dermal Repair Scaffold, but is created from a different source and has a different mechanism of action.

Talymed was cleared for marketing under the 510(k) process (K102002) in July 2010 for "the management of wounds including: diabetic ulcers; venous ulcers; pressure wounds; ulcers caused by mixed vascular etiologies; full thickness and partial thickness wounds; second degree burns; surgical wounds-donor sites/grafts, post-Mohs surgery, post laser surgery, and other bleeding surface wounds; abrasions, lacerations; traumatic wounds healing by secondary intention; chronic vascular ulcers; dehisced surgical wounds."

Hankins et al (2012) evaluated in terms of number needed to treat (NNT), the comparative clinical and cost efficacy of targeted advanced wound care matrices (AWCMs) as adjuncts to compression therapy for the treatment of chronic venous leg ulcers (VLUs) from the U.S. health care system (payer) perspective.  A review of published articles (from the earliest available Medline publication date to June 1, 2011) identified randomized controlled trials (RCTs) evaluating complete wound closure rates for up to 24 weeks in patients with VLUs treated with targeted AWCMs (Apligraf, Oasis, or Talymed) plus compression therapy compared with compression therapy alone.  The most favorable estimates of product efficacy (i.e., those that were statistically significant compared with compression therapy) were used.  These included statistically adjusted results for Apligraf as reported in the product insert and the biweekly application for Talymed.  Based on the reported efficacy of targeted AWCMs, these researchers calculated the NNT to achieve 1 additional treatment success (i.e., complete wound closure) over that which was achieved with standard therapy alone; 95 % CIs were estimated using the Wilson score method proposed by Newcombe.  Cost efficacy, defined as the incremental cost per additional successfully treated patient, was then calculated by multiplying the NNT associated with each treatment by the product acquisition cost per treated VLU episode.  One study for each of 3 targeted AWCMs (Apligraf [n = 130 treatment, n = 110 control]; Oasis Wound Matrix [n = 62 treatment, n = 58 control]; and Talymed [n = 22 treatment, n = 20 control]) met inclusion criteria.  Study designs and wound characteristics varied.  Average VLU sizes were 1 cm2, 10 to 12 cm2, and 10 to 13 cm2 in the studies of Apligraf, Oasis, and Talymed, respectively.  Ulcer duration exceeded 12 months for 50 % of patients in the Apligraf study and was at least 7 months for 47 % of patients in the Oasis study; patients with ulcers exceeding 6 months were excluded from the study of Talymed.  Length of follow-up was 24 weeks for Apligraf, 12 weeks for Oasis, and 20 weeks for Talymed.  NNT point estimates of clinical efficacy were 2 for Talymed, 5 for Oasis, and 6 for Apligraf; 95 % CIs ranged from 2 to 8 for Talymed, 3 to 24 for Apligraf, and 3 to 39 for Oasis.  Incremental costs (95 % CIs) per additional successfully treated patient were $1,600 ($1,600 to $6,400) for Talymed, $3,150 ($1,890 to $24,570) for Oasis, and $29,952 ($14,976 to $119,808) for Apligraf.  The authors concluded that the most expensive AWCM for the treatment of VLUs did not appear to provide the greatest comparative clinical or cost efficacy.  Conclusions must be tempered by the small number of available studies (n = 3), variability in trial duration (from 12 to 24 weeks) and baseline wound characteristics, and limitations in study quality.  Given the high prevalence, economic burden, and substantial disability of VLUs, and the wide variation in costs for AWCMs, payers need more high-quality head-to-head comparisons to guide coverage and reimbursement determinations for these products.

TenoGlideTM Tendon Protector Sheet

TenoGlide tendon protector sheet (Tendon Wrap tendon protector, Integra LifeSciences Corp., Plainsboro, NJ) was cleared through the FDA 510(k) process in 2006.  It is an absorbable implant that provides a non-constricting, protective encasement for injured tendons and is comprised of a porous matrix of cross-linked bovine Type I collagen and glycosaminoglycan.  According to the manufacturer's website, TenoGlide provides a protective biocompatible interface, which provides a protective environment and gliding surface while the tendon is healing (e.g., tendons damaged by compression from trauma or after primary repair).  However, there is insufficient scientific evidence regarding its effectiveness for tendon repair or for any other indications.

TenSIX

TenSIX is an acellular dermal matrix with natural histomorphology preserved. TenSIX is derived from aseptically processed cadaveric human skin tissue that is terminally sterilized.  It is made from human donor skin, which undergoes a process that removes the epidermis and dermal cells, thereby creating an acellular dermis.  "Human cadaveric dermal tissue" is referred to as acellular dermal allograft.  TenSIX acts as a scaffold to facilitate angiogenesis and migration of growth factors that stimulate cell migration.  Once rehydrated, the allograft can be applied topically to the wound and secured in the preferred manner of choice by the physician.  Typically this is accomplished by the suturing or stapling the allograft to the skin surrounding the wound. TenSIX allograft tissue is to be used for the repair or replacement of damaged or inadequate integumental tissue or for the other homologous of human integument. It is used in women and tendon coverage. Most notably, it will be used for wounds resulting from chronic diabetic foot ulcers.  

The Provant Wound Closure System

The Provant Wound Closure System (Regenesis Biomedical Inc., Scottsdale, AZ) uses a low-level radiofrequency signal that proponents state accelerates healing of chronic wounds by stimulating the production of endogenous growth factors and the proliferation of fibroblasts and epithelial cells, in a process the manufacturer has labeled "Cell Proliferation Induction" or CPI.  The Provant Wound Closure System (Regenesis was cleared by the FDA as a wound healing device based on a 510(k) premarket notification.  Treatment with the Provant System is usually administered for 30 mins right through dressing twice-daily.  However, there is insufficient clinical evidence to support its effectiveness.  Available evidence on CPI has focused mainly on the effects of low-level radiofrequency signals on growth factors and cell proliferation in vitro.  Peer-reviewed literature is limited to a small short-term randomized controlled pilot study which found that the Provant system accelerated closure of pressure wounds (Ritz et al, 2002).  This finding needs to be verified by larger multicenter studies.  Furthermore, studies would need to assess if CPI adds to the effectiveness of standard methods of chronic wound management.

TheraGenesis

TheraGenesis is a bilayer wound matrix, meshed and non-meshed which consists of a porcine tendon-derived atelo-collagen layer and a silicone film layer. Additionally, the biodegradable collagen matrix functions as a scaffold for cellular and capillary in-growth. TheraGenesis is intended for the treatment of patients with chronic and traumatic wounds including but not limited to diabetic foot ulcers, venous leg ulcers, burns, and other chronic and traumatic wounds and tissue deficits. TheraGenesis is available as a single-use, bi-layered wound matrix. The physician administers it as a wound covering to assist in the repair or replacement of lost or damaged tissue.

TheraSkin

TheraSkin (Soluble Systems, Newport News, VA) is a biologically active, cryopreserved human skin allograft with both epidermis and dermis layers.  It is similar to living skin equivalent (LSE) and provides a supply of living cells, fibroblasts and keratinocytes and a fully developed extracellular matrix (Snyder, et al., 2012).  However, TheraSkin is a minimally manipulated allograft and contains a larger quantity of collagens compared to living skin equivalent. TheraSkin does not contain any synthetic or animal materials. According to the manufacturer, TheraSkin is designed to promote wound healing by providing cellular and extracellular components with growth factors, cytokines and collagen and to be a natural barrier to infection. TheraSkin has been used for repair of human skin, including  dehisced surgical wounds, diabetic foot ulcers, necrotizing fasciitis, pressure ulcers, radiation burns and venous stasis ulcers. It has also been used for repaif of skin over any wound including those with exposed bone and joint capsule, muscle or tendon. TheraSkin is regulated by the FDA as a human cellular and tissue based product.  The FDA generally permits products regulated solely as human tissue to be commercially distributed without premarket clearance or approval.  TheraSkin is marketed by Soluble Systems and tissue is provided by the Skin and Wound Allograft Institute (SWAI, Virginia Beach, VA), a wholly owned subsidiary of LifeNet Health, Inc.

TheraSkin is cryopreserved human skin procured from consented and screened tissue donors that is used to provide a physiological and mechanical barrier that reduces environmental contamination and assists in the promotion of granulation tissue and epithelialization. The finished allograft is between 0.2 to 0.5 mm in thickness and contains both human epidermis and dermis tissues. The product is provided in a meshed form at a 1:1.5 ratio. TheraSkin contains: 1) both collagen and elastin which provide structural support and resilience, 2) a compliment of growth factors to assist healing, 3) multiple cytokines that assist in epithelialization and modulate the proliferation and differentiation of epithelium, and 4) structures that allow phagocytosis of bacteria without requirement of antibody production. TheraSkin is most commonly used in the treatment of partial and full-thickness wounds including chronic wounds, pressure ulcers, diabetic foot ulcers, venous stasis ulcers and burns. TheraSkin is generally applied like an autograft, insuring that the dressing is in close contact with the wound surface and that shear is minimized. According to the manufacturer, clinical experience supports up to five weekly to bi-weekly applications of cryopreserved human skin allograft to close the wound to the point of treatment with non-biologic wound dressings or to prepare the wound bed for autograft.

Landsman et al (2010) evaluated the safety and efficacy of TheraSkin in a retrospective study of 188 patients with either a diabetic foot ulcer (n = 54) or a venous leg ulcer (n = 134).  Multi-variate logistic regression was used to evaluate the relationship between baseline wound size and the proportion of healed wounds after 12 and 20 weeks from initial allograft application.  The authors found that by the 12th week, diabetic foot ulcers closed 60.38 % of the time and venous leg ulcers closed 60.77 % of the time.  After 20 weeks, the number of closed diabetic foot ulcers increased to 74.1 % and the number of venous leg ulcers increased to 74.6 %.  The mean wound size in the diabetic foot ulcer group was 6.2cm2 (± 11.8) and 11.8cm2 (± 22.5) in the venous leg ulcer group.  The mean number of TheraSkin allografts required ranged from 1 to 8, with an average of 2.03 (± 1.47) at the 12-week point and an average of 3.23 (± 2.77) at the 20-week point.  Multi-variate logistic regression was used to calculate the odds of wound healing by week 12 and week 20 in each group.  No adverse events related to TheraSkin were reported.

Sanders et al (2014) reported on a prospective, multicenter, randomized, controlled clinical trial to compare Dermagraft, an in vitro-engineered, human fibroblast-derived dermal skin (HFDS) substitute, and Theraskin, a biologically active cryopreserved human skin allograft (HSA), to determine the relative number of diabetic foot ulcers (DFUs) healed (100% epithelialization without any drainage) and the number of grafts required by week 12. Secondary variables included the proportion of healed patients at weeks 16 and 20, time to healing during the study, and wound size progression. The 23 eligible participants (11 randomized to the HSA, 12 to the HFDS group) were recruited from two hospital-based outpatient wound care centers. Baseline patient (body mass index, age, gender, race, type and duration of diabetes, presence of neuropathy and/or peripheral arterial disease, tobacco use) and wound characteristics (size and duration) were recorded, and follow-up visits occurred every week for up to 20 weeks. Subjects included adults with diabetic foot ulcers one month or more in duration. Excluded were subjects with large ulcers (10 cm2 or greater), infection, Charcot foot, and inadequate circulation to the foot. Descriptive and multivariate regression analyses were used to compare wound outcomes. At baseline, no statistically significant differences between patients and wounds were observed. At week 12, seven (63.6%) patients in the HSA and four (33.3%) in the HFDS group were healed (P = 0.0498). At the end of the 20-week evaluation period, 90.91% of HSA versus 66.67% of HFDS were healed (P = 0.4282). Among the subset of wounds that healed during the first 12 weeks of treatment, an average of 4.36 (range 2–7) HSA grafts were applied versus 8.92 (range 6–12) in the HFDS subset (P <0.0001, SE 0.77584). Time to healing in the HSA group was significantly shorter (8.9 weeks) than in the HFDS group (12.5 weeks) (log-rank test, P = 0.0323). Limitations of this study include small sample size, omission of reporting certain important baseline variables and outcomes, and lack of blinding of persons assessing outcomes.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Sanders, et al. (2014) to be at moderate risk of bias.

Other references provided by the manufacturer of TheraSkin are to studies that are either unpublished or are in journals not indexed by the National Library of Medicine MEDLINE database of peer-reviewed journals (Soluble Systems, 2011; Lin, et al., 2011; Budny and Ley, 2013; Treadwell, 2011; DiDomenico, et al., 2011).

A draft guideline by the National Institute for Health and Clinical Excellence (NICE) on the use of skin substitutes in the inpatient management of diabetic foot problems stated that the evidence for the clinical effectiveness of wound dressings in treating diabetic foot problems was of low quality and that only low-quality evidence on dermagraft and graftskin demonstrated positive effects on complete wound healing (at least 50 % wound closure).  However, no positive effect was demonstrated on the critical outcome (reduction in amputation).  Furthermore, the guideline stated that in the absence of strong evidence on particular wound dressings, clinicians should use the wound dressings with the lowest acquisition cost, taking into account their clinical assessment of the wound, the experience and preferences of the patient, and the clinical circumstances.  In addition, the draft guideline stated that the use of skin substitute treatments for the inpatient management of diabetic foot problems should only be offered as part of a clinical trial (NICE, 2011).

Wilson et al (2016) noted that wounds with exposed bone or tendon continue to be a challenge for wound care physicians, and there is little research pertaining to the treatment of these particular wounds with allograft skin.  In a retrospective study, these researchers examined the safety and effectiveness of a biologically active cryo-preserved human skin allograft for treating wounds with exposed bone and/or tendon in the lower extremities.  A total of 15 patients with 15 wounds at a single hospital-based wound care center were included in the study; 11  wounds had exposed bone, 1 wound had exposed tendon, and 3 wounds had exposed bone and tendon.  Standard treatment principles with adjunctive cadaveric allograft application were performed on all wounds in the study.  In this study 14/15 (93.3 %) of the wounds healed completely.  The mean duration of days until coverage of the bone and/or tendon with granulation tissue was 36.14 (5.16 weeks) (range of 5 to 117 days).  Mean duration to complete healing of the wound was 133 days (19 weeks) (range of 53 to 311 days).  The mean number of grafts applied was 2.  There were no adverse events (AEs) directly related to the graft; and 0 major amputations and 1 minor amputation occurred.  The authors concluded that this study found biologically active cryo-preserved human skin allografts to be safe and effective in treating difficult wounds with exposed bone and/or tendon.  To the authors' knowledge, this was the largest study to-date focused on the utilization of allograft skin as an adjunct therapy for lower extremity wounds with exposed tendon and/or bone. 

The authors stated that this study was limited by its retrospective design; potential selection bias was inherent to a retrospective study.  There were no controls and, thus, no comparative analysis could be carried out.  The study was also limited by small sample size (n = 15).  However, this was the largest study utilizing human cadaveric skin allograft as an adjunct therapy for lower extremity ulcers with exposed tendon and/or bone.  Though wounds were of different etiology – diabetic foot ulcer, traumatic, surgical, and decubitus – this did not appear to change outcomes.  Some treatment modalities, such as the use of negative pressure wound therapy versus simple bolster dressing, differed between wounds, but no statistical difference was noted between the treatments.

Towler et al (2018) noted that chronic venous leg ulcers (VLUs) are responsible for significant morbidity and health care costs worldwide.  In a pilot study, these investigators evaluated the effectiveness 2 biologically active grafts, TheraSkin and Apligraf, in conjunction with compression therapy.  The study, not industry-sponsored, was designed and conducted as a prospective, head-to-head, single-site, randomized clinical trial to assess differences in healing rates, adverse outcomes, and treatment costs.  The healing rates were different but not statistically significant, there were no adverse outcomes, and TheraSkin averaged $2,495.33 and Apligraf averaged $4,316.67 per subject.  The authors concluded that the findings of this study suggested that TheraSkin may provide equivalent or superior outcomes to Apligraf while reducing costs.

A draft assessment of wound care products prepared for AHRQ (2019) judged this randomized controlled study by Towler et al (2018) to be at moderate risk of bias.

In a retrospective, propensity matched-cohort study, Gurtner and colleagues (2020) examined data from 2,074,000 lower extremity wounds across 644 institutions to determine the effectiveness of TheraSkin plus standard of care (SOC; n = 1,997) versus SOC alone (n = 1,997).  Multi-variate modelling comparing outcomes such as healing rates, percent area reductions (PARs), amputations, recidivism, treatment completion, and medical transfers were evaluated.  A higher proportion of wounds in the treatment group compared with the controls were more likely to close (68.3 % versus 60.3 %), particularly wounds with exposed structures (64 % versus 50.4 %) and with lower recidivism at 6 months (24.9 % versus 28.3 %).  The control group was 2.75 times more likely to require amputation than the treatment group.  The combination of propensity matching and logistic regression analysis on a particularly large database demonstrated that wounds treated with TheraSkin had higher healing rates, higher PARs (78.7 % versus 68.9 %), fewer amputations, lower recidivism, higher treatment completion (61.0 % versus 50.6 %), and lower medical transfers (16.1 % versus 23.5 %) than SOC alone.  This study considered data from complex wounds typically excluded from controlled trials and supported the idea that real-world evidence studies can be valid and reliable.

The authors stated that one drawback of this study was that the wounds treated with bioactive human skin allograft (BSA) were often of higher severity, resulting in application later during the entire course of treatment.  This may have potentially skewed healing rates and wound duration measures towards SOC.  Another drawback was that the database did not include specific measures of vascularity or hemoglobin A1c (HbA1c), and this may have contributed to the differences in the healing rates observed.  Furthermore, these researchers noted that a limitation that often exists in the registry data is that there may be variability in the data reported among the contributing clinics.  Diagnoses or procedures may be subject to coding error, for which the extent of miscoding or under-coding that could result in bias is unknown, and may also result in measurement error in ICD-9/10 or CPT based variables.  A benefit of selecting the 644 affiliated centers is that it ensures consistency in reporting as well as the clinical practice.

In a retrospective, matched-cohort study, Barbul et al (2020a) analyzed 1,556 patients with diabetic foot ulcers (DFUs) treated at 470 wound centers throughout the U.S. to determine the effectiveness of a cryo-preserved bioactive split-thickness skin allograft (TheraSkin) plus standard of care (SOC) when compared to SOC alone.  There were 778 patients treated with the graft in the treatment cohort, who were paired with 778 patients drawn from a pool of 126,864 candidates treated with SOC alone (controls), by using propensity matching to create nearly identical cohorts.  Both cohorts received standard wound care, including surgical debridement, moist wound care, and off-loading.  Logistic regression analysis of healing rates according to wound size, wound location, wound duration, volume reduction, exposed deep structures, and Wagner grade was carried out.  Amputation rates and recidivism at 3 months, 6 months, and 1 year after wound closure were analyzed.  Diabetic ulcers were 59 % more likely to close in the treatment cohort compared to the control cohort (p = 0.0045).  The healing rate with the graft was better than SOC across multiple subsets, but the most significant improvement was noted in the worst wounds that had a duration of 90 to 179 days prior to treatment (p = 0.0073), exposed deep structures (p = 0.036), and/or Wagner grade-4 ulcers (p = 0.04).  Furthermore, the decrease in recidivism was statistically significant at 3 months, 6 months, and 1 year, with and without initially exposed deep structures (p < 0.05).  The amputation rate in the treatment cohort was 41.7 % less than that of the control cohort at 20 weeks (0.9 % versus 1.5 %, respectively).  This study demonstrated that diabetic ulcers treated with a cryo-preserved bioactive split-thickness skin allograft were more likely to heal and remain closed compared to ulcers treated with SOC alone.

The authors stated that one drawback of this study was that all data were extracted retrospectively from electronic medical records (EMRs), which could lead to some potential inaccuracies if a provider did not document the condition and treatments of the wound properly.  These researchers had little direct insight to the level of compliance provided by study participants.  Another drawback was insufficient data were available in the EMRs to factor limb vascularity and HbA1c into the matching scheme.  It was possible that these factors may have varied between the cohorts.  Furthermore, the tendency toward treating patients with bioactive split‐thickness skin allograft (BSA) after failure with SOC may also have diminished the quality of the subject match.  Another consideration was the application regimen used by the clinicians treating with BSA.  Although the average number of grafts used was very similar to prior studies, it was unclear if the frequency of application and the use of dressing materials and cleansing agents were uniform from site to site.  Amputation rates among patients with DFUs was a reflection of the severity of the ulceration, speed of wound closure, vascular status, patient compliance, infection, and a host of other factors that play a role in wound healing.  Although rates can be measured comparatively using EMR data by creating treatment groups, absolute rates were far lower than those reported in prospective trials because it was hard to capture outcomes of patients transferred to other facilities in which procedures took place.  Finally, while these researchers conducted an exhaustive matching process to ensure the similarities between groups, all factors could not be measured.  Another potential drawback was the lack of direct comparison to other advanced treatment modalities for diabetic wounds.  For new biological products, the FDA requires direct comparison to current SOC.  From a payor perspective, such an analysis could prove helpful in determining reimbursement.  However, the current data does not allow for such a direct comparison.  Furthermore, other advanced therapies such as negative pressure wound therapy and hyperbaric oxygen therapy (HBOT) were used at the discretion of individual clinicians; their use did not statically alter the results of this study.

Barbul et al (2020b) examined differences in wound-related costs; product waste; lower-extremity amputations; and number of applications, hospitalizations, and emergency room (ER) visits among patients treated with 3 cellular and/or tissue-based products.  This retrospective intent-to-treat (ITT) matched-cohort study analyzed the full Medicare claims data-set from 2011 to 2014.  Patients who received either a bilayer cellular construct (BLCC), dermal skin substitute (DSS), or cryo-preserved human skin allograft (CHSA) were concurrently matched for Charlson Comorbidity Index (CCI), age, sex, and region, resulting in 14,546 study patients.  Key variables were reported at 60, 90, and 180 days after the 1st product application.  There were no statistically significant differences in the distribution of CCI, age, sex, and region among cohorts.  Wound-related costs and product wastage were lower for CHSA patients relative to both BLCC and DSS patients at all time intervals (p < 0.05).  Patients treated with CHSA received fewer product applications than DSS at 90 and 180 days (p < 0.05).  Amputations were significantly higher among patients treated with DSS than either CHSA or BLCC (p < .0001).  The authors concluded that these findings demonstrated that wound-related costs, product waste, amputations, and frequency of applications are lower for CHSA than DSS.  Wound-related costs and product waste were lower for CHSA compared with BLCC.  These researchers noted that although the cohorts were matched for CCI, a limitation of claims analysis in wound care studies is that there is no reliable and consistent way to measure wound severity.  Furthermore, chronic wounds often require other surgical interventions such as venous ablation or arterial intervention to achieve healing or prevent recidivism.  After cohort matching, this data-set was not large enough to conduct this type of sub-analysis; future real-world matched-cohort studies looking at timely surgical intervention and recidivism are needed.  Moreover, these investigators stated that future prospective research that combines cost, clinical outcomes, as well as patient-centered outcomes could provide insight into the use of advanced modalities in this challenging patient population and enhance the development of more appropriate quality measures and reimbursement models to ensure smarter spending for this growing and costly population.

Armstrong, et al. (2022) reported on a randomized, prospective study comparing the response of 100 subjects with non-healing DFUs of which 50 were treated with TheraSkin compared with 50 subjects treated with standard of care (SOC, collagen alginate dressing) at 12 weeks. Both groups received standardized care that included glucose monitoring, weekly debridement's as appropriate, and an offloading device. The primary endpoint was proportion of full-thickness wounds healed at 12 weeks, with secondary endpoints including differences in percent area reduction (PAR) at 12 weeks, changes in Semmes-Weinstein monofilament score, VAS pain, and w-QoL. The result illustrated in the intent-to-treat analysis at 12 weeks showed that 76% (38/50) of the TheraSkin-treated DFUs healed compared with 36% (18/50) treated with SOC alone (adjusted P = .00056). Mean PAR at 12 weeks was 77.8% in the TheraSkin group compared with 49.6% in the SOC group (adjusted P = .0019). In conclusion, adding TheraSkin to SOC appeared to significantly improve wound healing with a lower incidence of adverse events related to treatment compared with SOC alone.

TissueMend®

TissueMend (TEI Biosciences Inc., Boston, MA), marketed by Stryker Orthopaedics (Stryker Howmedica Osteonics, Kalamazoo, MI), is a remodelable collagen matrix derived from bovine skin intended for reinforcement of soft tissues repaired by sutures or suture anchors during tendon repair surgery, including reinforcement of the rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons.  There is a lack of evidence in the peer-reviewed medical literature to support it's clinical effectiveness.

TransCu O2 Continuous Diffusion of Oxygen [CDO] for Wound Healing

Niederauer, et al. (2015) examined planned interim data of a prospective, randomized, double-blind multi-center study comparing the clinical efficacy of the TransCu O2 device (EO2 Concepts) to standard moist wound therapy (MWT). The investigators explained that the therapy, known as continuous diffusion of oxygen (CDO), delivers pure oxygen to the wound at low flow rates, preserves patient mobility, showed significant benefits in animal studies and received FDA clearance in August 2009. The investigators summarized the results of a per protocol interim analysis of complete wound closure at 12 weeks in a double blind 2-arm clinical trial of 84 subjects randomized 1:1 to Active CDO versus Sham, conducted when 50% of the planned number of subjects completed 12 weeks of therapy (Active 21, Sham 21). The investigators also reported treatment comparisons with regard to days to wound closure, study period, and after excluding subjects who experienced fast closure or a small wound (<1.5 cm2) at screen. The investigators reported that complete wound closure at 12 weeks, the primary study endpoint, was not significantly associated with treatment per protocol [Active 11 (52.3%), Sham 8 (38.1%), RR 1.38 (95% CI 0.7, 2.7), p = 0.54]. 

A subsequent report of this trial (Niederauer, et al., 2017) focused on the per protocol analysis of the previously described trial of the effect of CDO on the primary outcome of full wound closure by 12 weeks, as well as the secondary outcome of rate of wound closure. The investigators stated that, based upon the results of the planned interim analysis described above, the protocol was amended to change the minimum baseline wound size and run-in rate of wound closure inclusion/exclusion criteria. Subjects that failed these criteria were removed from the study. After removal of these subjects, the primary outcome of complete wound closure at 12 weeks for the completed trial was significantly associated with treatment per protocol, Active 23 (46.0%), Sham 11 (22.0%), RR 0.69 (95% CI 0.52, 0.93), P = .02.

As noted above, the planned interim analysis of the pivotal study, as reported by Niederauer, et al. (2015) found a lack of statistical significance for their primary endpoint, complete wound closure by 12 weeks. The manufacturer analyzed the interim data and discovered that, if one excludes smaller lesions at baseline and wounds that were rapidly healing during the two-week run-in period from the analysis, statistical significance could be achieved. These subjects with smaller lesions and more rapidly healing lesions during the run-in period were excluded from the subsequent report of the per protocol analysis of the completed trial by Niederauer, et al., 2017. By changing the minimum baseline wound size and run-in rate of wound closure inclusion/exclusion criteria and removing subjects that failed these criteria from the final analysis, the investigators introduced a significant source of bias. Thus, the results of this pivotal study would be considered hypothesis generating.  A subsequent report of the intention-to-treat analyhsis of this same study suffers from the same limitations (Niederauer, et al., 2018). A followup definitive study, which excludes subjects with smaller lesions and subjects with more rapidly healing lesions, is necessary to test the hypothesis that the TransCu O2 device is most effective in subjects with larger, more slowly healing lesions. 

If the results of such a second study are positive, it would however raise questions about the effectiveness of this product as used in clinical practice. The subjects of the pivotal study were highly selected, limited to those with superficial lesions (Class IA). In the pivotal study, the investigators selected subjects by assessing the rapidity of wound closure during the run-in period digital planimetric analysis. It is not clear whether a clinician in routine clinical practice would have the ability and willingness to limit the use of this product to persons with more slowly healing lesions by this measure. 

A systematic evidence review prepared for the International Working Group for the Diabetic Foot (Vas, et al., 2020) found that: "[t]he use of topical oxygen therapy or other gases does not seem to be more effective in ulcer healing when compared with best standard of care. Quality of evidence: low." Guidelines from this same organization (Rayman, et al., 2020) state that "We suggest not using topical oxygen therapy as a primary or adjunctive intervention in diabetic foot ulcers including those that are difficult to heal. (Weak; Low)."

In an exploratory study, Lavery et al (2020) examined continuous diffusion of oxygen therapy (CDOT) on cytokines, perfusion, and bacterial load in diabetic foot ulcers (DFUs).  These researchers evaluated 23 patients for 3 weeks.  Tissues biopsies were obtained at each visit to assess cytokines and quantitative bacterial cultures.  Perfusion was measured with hyperspectral imaging and transcutaneous oxygen.  They used paired-t tests to compare continuous variables and independent t tests to compare healers and non-healers.  There was an increase from baseline to week 1 in transforming growth factor‐β (TGF‐β) (p = 0.008), tumor necrosis factor‐α (TNF‐α) (p = 0.014), vascular endothelial growth factor (VEGF) (p = 0.008), platelet derived growth factor (PDGF) (p = 0.087), and insulin‐like growth factor‐1 (IGF‐1) (p = 0.058); baseline to week 2 in TGF‐β (p = 0.010), VEGF (p = 0.051), and interleukin-6 (IL‐6) (p = 0.031); and baseline to week 3 with TGF‐β (p = 0.055) and IL‐6 (p = 0.054).  There was a significant increase in transcutaneous oxygen after 1 week of treatment on both medial and lateral foot (p = 0.086 and 0.025); 53 % of the patients had at least a 50 % wound area reduction (healers).  At baseline, there were no differences in cytokines between healers and non-healers; however, there was an increase in CXCL8 (IL-8) after 1 week of treatment (p = 0.080) and IL‐6 after 3 weeks of treatment in non-healers (p = 0.099).  There were no differences in quantitative cultures in healers and non-healers. The authors concluded that this study evaluated a novel application of topical oxygen therapy that has had a successful randomized clinical trial in patients with DFUs.  Growth factors, cytokines, and perfusion were examined following therapy, similar to hyperbaric oxygen therapy (HBOT), although there was no difference in quantitative bacterial cultures.  These researchers stated that more studies with larger patient population are needed to examine the effectiveness of this therapy in chronic wound healing, and its potential to be used as an alternative to HBOT.

The authors stated that this study had several drawbacks.  This was a small prospective cohort study with only 23 patients and no control arm.  The duration of the study was only 3 weeks; thus, these researchers relied on surrogate markers for wound healing and only had 4 time-points to examine and compare changes in cytokines, perfusion, and bioburden.  Because this was an exploratory study, these investigators were only able to examine a limited number of cytokines.  Furthermore, these researchers did not measure the duration of therapy in minutes or hours.  The device was intended to be used continuously; however, there were inevitably times the device came off while the patient was sleeping or during the day, and because all of our study subjects had severe diabetic sensory neuropathy, the problem was often not identified immediately.  These findings should not be generalized to other products or approaches that deliver topical oxygen or other types of wounds.  The device used in this study delivered continuous topical oxygen.  There are several products that provide intermittent topical oxygen therapy, usually once-daily.  The duration of some therapies was relatively short, and all the topical oxygen therapy devices use different doses.  These investigators stated that a large RCT that examines changes in wound area reduction and cytokines in active and sham treatment groups would give clinicians better insights regarding the effect of continuous topical oxygen on and timing and the expression of cytokines.

TransCyte

According to the manufacturer, Organogenesis Inc., TransCyte is a human fibroblast-derived temporary wound cover consisting of polymer membrane and donated neonatal human fibroblast cells cultured under aseptic conditions in vitro on a nylon mesh (CMS, 2017). As fibroblasts proliferate within the nylon mesh, they secrete human dermal collagen, matrix proteins and growth factors. Following freezing, no cellular metabolic activity remains; however, the tissue matrix and bound growth factors are left intact. TransCyte provides a temporary protective barrier for the wound. TransCyte is intended for use as a temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in patients who require such a covering prior to autograft placement. TransCyte is also intended for the treatment of mid-dermal to indeterminate depth burn wounds that typically require debridement and that may be expected to heal without autografting. TransCyte is applied to a wound using sutures or other fixation method based on the size of the wound being treated. It is supplied in a cassette containing two aseptically processed sheets, each approximately 5 inches by 7.5 inches.

TransCyte was granted premarket approval (PMA) by the FDA in 1997 for "for use as a temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in patients who require such a covering prior to autograft placement." TranCyte was not indicated for chronic wounds.  TransCyte consists of human dermal fibroblasts grown on nylon mesh, combined with a synthetic epidermal layer.  TransCyte can be used as a temporary covering over full thickness and some partial-thickness burns until autografting is possible.  It can also be used as a temporary covering for some burn wounds that heal without autografting.  TransCyte is packaged and shipped in a cryo-preserved state to burn treatment centers.  The surgeon then thaws the product and stretches it over a burn site.  In about 7 to 14 days, the TransCyte starts peeling off, and the surgeon trims it away as it peels.

TruSkin

According to the manufacturer Orsis Therapeutics Inc., TruSkin is a split-thickness cryopreserved human skin allograft, intended for the replacement or reconstruction of inadequate or damaged integumental tissue. The manufacturer states that TruSkin, an advanced skin substitute, is an easy-to-use, off-the-shelf alternative to fresh skin allograft. TruSkin addresses biological deficiencies in the wound, assists in epithelialization, and aids in preserving surrounding tissue. The key differentiating feature of TruSkin from all other preserved skin allografts is the proprietary processing, which retains all components of fresh skin in their native state, including: collagen-rich skin Extracellular Matrix (ECM), endogenous bioactive factors, and endogenous living skin cells. The applicant claims that TruSkin is indicated for patients with acute and chronic wounds, who have limited treatment options and are at great risk for wound-related morbidities and mortality. TruSkin offers patients an alternative to invasive procedures, including autologous skin grafting or limb amputation. The quantity and size of the product used will vary based upon wound size and physician recommendation. Application of TruSkin is recommended weekly or bi-weekly for up to 12 weeks or until the wound is closed. TruSkin is supplied as a graft in two sizes: 32 cm ² and 8cm².

Unite Biomatrix

Unite Biomatrix (Synovis Orthopedic and Woundcare, Inc.) is a wound biomodulating decellularized extracellular matrix (ECM) that is sourced from equine pericardium (Snyder, et al., 2012). Unite Biomatrix is a non-reconstituted collagen dressing used to maintain the wound bed in the healing phase thereby allowing for health granulation tissue and wound closure. Unite Biomatrix is indicated for local management of moderately to heavily exudating wounds. Unite Biomatrix was cleared by the FDA in 2011 based upon a 510(k) "For the management of moderately to severely exudating wounds, including: partial and full thickness wounds, draining wounds, pressure sores/ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (e.g., abrasions, lacerations, partial thickness [second-degree] burns, skin tears), surgical wounds (e.g., donor sites/grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, dehisced surgical incisions)."

It is applied to the debrided wound bed without promoting an inflammatory response, while maintaining integrity as the wound heals. To apply, cut the rinsed Unite Biomatrix to a size slightly larger than the outline of the wound area and secure in place by sutures or staples. As healing occurs, sections of the matrix may gradually peel and may be removed during dressing changes. Additional Unite Biomatrix may be applied to discrete areas of the wound that have not yet healed satisfactorily. Unite Biomatrix is packaged in a chemical solution and is available pre-fenestrated or non-fenestrated. Unite Biomatrix differs from other products in that it is composed of decellularized equine pericardial implants. The use of equine-derived decellularized collagen products (e.g., OrthADAPT™ and Unite™) has not been established as shown by the lack of evidence on the subject.

Vendaje

Vendaje is a dehydrated human amniotic membrane consisting of the amnion layer that is sterile for single homologous use. Additionally, Vende is a structural tissue allograft that is utilized as a skin substitute serving as a protective barrier via resorption into the wound and repairs superficial dermal and soft tissue wounds. By providing a scaffold of extracellular matrix proteins, active growth factors and cytokines, this critical components facilitate healing and infection control. More specifically, the amniotic membrane provides a vapor barrier preventing undesirable water loss from excessive evaporation at the wound with a resultant decrease in pain and inflammation. The product is applied topically by placing the membrane over the wound or within the surgical site. It is held in place by hydrostatic tension. Venjade is available in sizes of 1x1 cm, 2x2 cm, 2x4 cm, 4x4 cm, 4x6cm, 4x8 cm, and 6x6 cm with dosage determined by wound size (CMS, 2021c).

Veritas® Collagen Matrix

Veritas Collagen Matrix (Synovis Surgical Innovations, St. Paul, MN ) was cleared by the FDA via the 510(k) process in 2000.  It is an implantable surgical patch comprised of non-crosslinked bovine pericardium.  Veritas Collagen Matrix undergoes proprietary processing that allows neo-collagen formation and neo-vascularization of the implanted device and permits replacement of the device with host tissue, or remodeling.  Veritas Collagen Matrix is intended for use as an implant for the surgical repair of soft tissue deficiencies, this includes but is not limited to the following:
  1. buttressing and reinforcing staple lines during lung resection (e.g., wedge resection, blebectomy, lobectomy, bullectomy, bronchila resection, segmentectomy, pneumonectomy/pneumectomy, pneumoreduction) and other incisions and excisions of the lung and bronchus;
  2. reinforcement of the gastric staple line during the bariatric surgical procedures of gastric bypass and gastric banding; and
  3. abdominal and thoracic wall repair, muscle flap reinforcement, rectal and vaginal prolapse repair, urinary incontinence treatment, reconstruction of the pelvic floor, and repair of hernias (e.g., diaphragmatic, femoral, incisional, inguinal, lumbar, paracolostomy, scrotal, umbilical). 

Veritas Collagen Matrix received an additional 510(k) clearance by the FDA in 2006 and is intended to minimize tissue attachment to the device in case of direct contact with viscera.  There is insufficient scientific evidence regarding the effectiveness of Veritas Collagen Matrix for use as an implant for the surgical repair of soft tissue deficiencies or for any other indication.

Viaflow and Viaflow C Flowable Placental Tissue Matrices

Viaflow and Viaflow C Flowable Placental Tissue Matrices are pre-mixed, tissue matrix allografts, processed from human placental tissues.  The fluid tissue combination contains collagens, growth factors, and other key biologic components. 

  • 2 configurations available: Ambient temperature (Viaflow) and Cryopreserved (Viaflow C)
  • 5-year shelf life at ambient temperature (Viaflow)
  • 5-year shelf life at -40o C (Viaflow)
  • Flowable through a 23-G needle
  • Target defects quickly and precisely
  • Easily mixable with carriers.

The placental extracellular matrix (ECM) supports healing by modulating correct tissue reconstruction rather than scar tissue formation.  This ECM includes growth factors, fibronectin, laminin, hyaluronic acid, proteoglycans, and other proteins.

Lullove (2015) noted that damaged connective tissue commonly leads to lower extremity injuries.  These injuries can result in inflammation, reduced mobility, and chronic pain.  Conservative treatment may include orthotics, off-loading the injury, physical therapy, and/or non-steroidal anti-inflammatory drugs (NSAIDs).  If conservative treatment fails, surgical intervention may be required.  Even after successful surgery, these procedures often result in reduced joint mobility and tendon or ligament strength.  A novel flowable tissue matrix allograft, derived from human placental connective tissue, has recently been made available for minimally invasive treatment of damaged or inadequate tissue  (PX50®, Human Regenerative Technologies LLC, Redondo Beach, CA).  Based on the universal role of connective tissue in the body, and its reported anti-microbial, anti-adhesive, and anti-inflammatory properties, these researchers assessed the effects of using this placental tissue matrix in the treatment of a series of lower extremity injuries.  In this pilot study, 9 of 10 patients reported pain levels of 2 or less by week 4 using the visual analog scale (VAS) pain scale.  This short-term pilot study showed that injectable, flowable amniotic allografts can be used for orthopedic sports injuries of the lower extremities.  Moreover, they stated that further research would be needed to compare the use of amniotic allograft tissue injections versus corticosteroid injections head-to-head, and further larger studies, including randomized controlled trials, may elucidate the reasons for these differences.

VIM Human Amniotic Membrane

VIM human amniotic membrane is a marginally modified allograft sheet of human amnion that is eventually sterilized. VIM human amniotic membrane allograft originates from human tissue and is for homologous use. The proprietary processing of VIM human amniotic membrane allograft results in the preservation of structural and signaling proteins such as collagen, glycoproteins, proteoglycans, cytokines, and growth factors, that are important to biochemical and biomechanical processes occurring at a cellular level. Specifically, VIM human amniotic membrane allograft is indicated for discretionary homologous use by the physician when human amniotic membrane might be beneficial as a wound covering or barrier. This product requires topical application and is held in place with usual attachment and sterile dressings. Additionally, this product is supplied as sterile 2x2 cm and 4x4 cm sizes which may be further cut to size (CMS, 2021c).

WoundEx

According to the manufacturer, Human Regenerative Technologies, LLC., WoundEx consists of placental connective tissue matrix intended to replace or supplement damaged or inadequate connective tissue (CMS, 2017). WoundEx membrane allograft consists of dehydrated and decellularized human amniotic membrane that has been processed with proprietary HydraTek technology. "WoundEx Thin Membrane is designed as a single layer wound covering for common wounds, and WoundEx Thick Membrane is designed as a thicker single layer wound covering, for deeper wounds where more tissue bulk is required." WoundEx membrane is intended to be used as a wound covering in the treatment of chronic and acute wounds. Both the thin and thick membranes are supplied in the following sizes: 1 x1 cm; 2 X 2 cm; 2 X 4 cm; 4 X 4 cm 4 X 6 cm and 4 X 8 Cm. WoundEx is stored at ambient temperature and has a 5-year shelf life.

WoundEx Flow

WoundEx Flow (Skye Biologics) consists of placental connective tissue matrix intended to replace or supplement damaged or inadequate connective tissue (CMS, 2017). WoundEx membrane allograft consists of dehydrated and decellularized human amniotic membrane that has been processed with proprietary HydraTek technology. WoundEx Flow is supplied in single use: 0.5cc, 1.0 cc, 1.5 cc, 2.0 vials. WoundEx Flow is stored at ambient temperature and has a 5-year shelf life.

WoundFix and BioWound

According to the manufacturer, Human Regenerative Technologies, LLC., WoundFix Membrane and BioWound Membrane are single-layer wound coverings for common wounds. These are intended for use as a wound covering, surgical covering, wrap or barrier, application to partial-and full-thickness, acute and chronic wounds such as, traumatic and complex wounds, burns, surgical and Mohs surgery sites and diabetic, venous, arterial, pressure and other ulcers, including with exposed tendon, muscle, bone, or other vital structures. These products are supplied in single use packaging in sizes ranging from .786 to 486 sq. cm.

WoundFix Plus and BioWound Plus

According to the Human Regenerative Technologies, LLC.,  WoundFix Plus and BioWound Plus membranes are single layer wound coverings composed of human, chorion-based membranes (CMS, 2019). The products are intended for use as a wound covering, surgical covering, wrap or barrier, application to partial-and full-thickness, acute and chronic wounds such as traumatic and complex wounds, burns, surgical and Mohs surgery sites and diabetic, venous, arterial, pressure and other ulcers, including with exposed tendon, muscle, bone, or other vital structures. Typically, one application is applied per wound; however, the product may be reapplied if necessary. WoundFix Plus and BioWound Plus membrane are supplied in single use packaging in sizes ranging from .786 to 192 sq. cm.

WoundFix XPlus Membrane and BioWound XPlus

According to the manufacturer, Human Regenerative Technologies, LLC.,WoundFix XPlus Membrane and BioWound XPlus Membrane are single layer human placental tissue-based membranes intended to be used as a wound covering, surgical covering, wrap or barrier, application to partial-and full-thickness, acute and chronic wounds such as, traumatic and complex wounds, burns, surgical and Mohs surgery sites and diabetic, venous, arterial, pressure and other ulcers, including with exposed tendon, muscle, bone, or other vital structures (CMS, 2019). WoundFix XPlus Membrane and BioWound XPlus Membrane are supplied in single-use packaging, in 6 sq. cm and 12 sq. cm. sizes.

WoundPlus Membrane or E-Graft

WoundPlus Membrane or E-Graft consists of dehydrated and devitalized human derived amniotic membrane and has been processed with the HydraTek technology. WoundPlus Membrane is a single layer amnion-only membrane allograft that is designed to act as a barrier, wrap or cover for acute and chronic wounds. Health care practitioners use sterile forceps to apply WoundPlus Membrane topically to the wound for single patient use. The healthcare practitioner, at their discretion, determines application duration.. Dosing or sizing is wound size dependent. This allograft product is supplied in a sterilized single one-time use packaging and available in various sizes and is stored at ambient temperature with a 5-year shelf life (CMS, 2023a).

Xcell Amino Matrix

Xcell Amino Matrix is a lyophilized amniotic membrane allograft which undergoes aseptic processing to retain the native extracellular matrix and endogenous proteins. This allograft product is designed to act as a barrier and provide protective coverage from the surrounding environment for acute and chronic wounds such as partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds and draining wounds. Xcell Amino Matrix is available in various sizes and directly applied to the wound site as a per square centimeter dosage (CMS, 2023a).

XCellerate

XCellerate (Precise Bioscience) is a lyophilized amniotic membrane allograft that is aseptically processed to preserve the native extracellular matrix and endogenous proteins that can be used as a biological barrier or wound cover. XCellerate is a human cellular and tissue-based product. Each allograft is restricted to homologous use in procedures on a single occasion by a licensed physician or surgeon. It is used for the treatment of non-healing wounds and burn injuries. XCellerate Amniotic Membrane Allograft delivers cytokines, proteins and growth factors to help regenerate soft tissue. The amniotic membrane allograft is immune-privileged and possesses little or no risk of foreign body reaction, which can lead to fibrosis and graft failure. XCellerate Amniotic Membrane Allograft is available in the following size: 2 x 2 cm, 2 x 4 cm, 4 x 4 cm, 4 x 7 cm and 6 mm, 9 mm, 12 mm discs. It is applied over a wound or burn site following wound preparation in multiple sites of care. XCellerate is provided in a sterile sealed package and is intended for single use.

There is a lack of evidence regarding the effectiveness of the XCellerate allograft.

XCelliStem

XCelliStem consists of a blend of multiple extracellular matrix (ECM) source material, spleen and lung. This composition of multiple ECM sources is in stark contrast to all current products derived from a single ECM source. The multiple ECM sources and their varying collection of components (e.g., collagen, elastin, fibronectin, laminin, glycosaminoglycans [GAGs], proteoglycans, and other proteins) within in each ECM in XCelliStem provide a myriad of signaling molecules and numerous binding sites within their structure. Collective capabilities of XCelliStem’s composition include the following activities within the tissue: binding to existing native ECM material, binding to cells, signaling cell attraction, cell mobility, cell growth, and cell differentiation. Furthermore, the signaling molecules participate in progenitor cell recruitment to the site, and regulation of progenitor cell activity at the site.

XCM Biologic Tissue Matrix

XCM Biologic Tissue Matrix is a sterile, non-cross-linked 3-D matrix derived from porcine dermis. It provides a support structure for cellular migration and as such the matrix is incorporated into the surrounding tissue. It is "indicated for use in general surgical procedures for the reinforcement and repair of soft tissue where weakness exists including, but not limited to: defect of the thoracic wall, suture line reinforcement, and muscle flap reinforcement; urogynecological surgical reinforcement including but not limited to, rectal and vaginal prolapse, reconstruction of the pelvic floor, hernia repair; soft tissue reconstructive procedures including plastic and reconstructive surgical application, and for reinforcement of the soft tissues, which are repaired by suture or suture anchors, including but not limited to, rotator cuff, patellar, Achilles, biceps, quadriceps and other tendons." XCM Biologic Tissue Matrix is supplied sterile (hydrated) in a foil liner pouch. It does not require refrigeration, or any preparation before use. 

Xelma

Xelma is an extracellular matrix (ECM) protein to provide cell adhesion proteins in order to initiate healing in hard-to-heal wounds.

XWrap Dry or Hydro Plus

XWrapDry or Hydro is a resorbable, chorion-free, human amnion allogfaft, used as a covering for soft tissue defects and wounds.

Zenith Amniotic Membrane

Zenith Amniotic Membrane is a dehydrated amniotic membrane allograft. This product works as a barrier and covering for acute and chronic non-healing wounds and burn injuries. Specifically, Zenith Amniotic Membrane is indicated for the treatment of acute and chronic non-healing wounds inclusive but not limited to non-infected partial or full-thickness diabetic foot ulcers, venous leg ulcers, pressure ulcers, surgical wounds, and burn injuries unresponsive to conventional therapy. Serving as a biological barrier and wound cover, Zenith Amniotic Membrane functions to protect chronic non-healing wounds and burn injuries from the outside environment throughout the healing duration. It is applied over the wound or burn site following wound preparation in a physician’s office or outpatient setting. The product is sterile single use and is available in sizes of 1x1 cm, 2 cm x 2 cm, 2 cm x 3 cm, 4 cm x 4 cm, 4 cm x 6 cm, 4 cm x 8 cm, 8 cm x 8 cm, 10 cm x 10 cm, 10 cm x 12 cm, and 10 cm x 20 cm (CMS, 2021c).

Miscellaneous

Isaacs et al (2008) compared a variety of potentially useful artificial and biological sealants applied to sutured nerve repairs to decrease gapping at the repaired site.  A total of 57 fresh-frozen cadaveric nerve specimens were transected and repaired with two 8-0 nylon epineural sutures placed 180 degrees apart.  The specimens were divided into 5 groups.  Four groups received augmentation of the repair with application of either autologous fibrin glue, Tisseel fibrin glue, Evicel fibrin glue, or DuraSeal polyethylene glycol-based hydrogel sealant, and the 5th group had no glue.  Each nerve construct was mounted in a servo-hydraulic materials testing machine and stretched at a constant 5 mm/min displacement rate until failure.  A non-contact video analysis permitted normalization of stretch within the repair region.  Statistical analysis was performed via analysis of variance followed by Tukey-Kramer post hoc pair-wise comparison when indicated.  Resistance to gapping as measured through normalized stiffness (N/mm/mm) was greater for the Tisseel group, Evicel group, and DuraSeal group versus the no-glue group only.  The stiffness of the autologous group approached significance versus the no-glue group.  There were no significant differences in stiffness between any of the nerve glue groups.  There was no statistical difference for the peak load at failure between any of the groups.  The authors concluded that avoidance of gapping at the nerve repair site is crucial in achieving successful nerve regeneration.  Commercially available tissue sealants (Tisseel, Evicel, and DuraSeal), when used to augment 2-suture nerve repairs, as in the authors' protocol, help prevent this initial gapping.  None of the tissue sealants tested, however, increased the ultimate load to complete failure of the repair.

Miscellaneous Wound Care Products

  • The use of porcine-derived decellularized collagen products (e.g., Collamend, Cuffpatch™, Pelvicol®, Pelvisoft®, and Strattice) has been proposed for use in various surgical procedures and in the treatment of dermal wounds.  Currently, there is insufficient evidence to allow for proper evaluation regarding the effectiveness of this technology.
  • The use of porcine-derived polypropylene composite wound dressing (e.g., Avaulta Plus™) in the clinical setting has not been established.  Until comparative studies of this product have been made available, a thorough evaluation of its safety and effectiveness can not be completed.

Other Human Amniotic Membrane Products

Abdul and colleagues (2020) performed a systematic review and meta-analysis of human amniotic membrane as option for graft donor sites. The investigators cited four studies (i.e., Saleh et al, Singh et al, Zidan et al, and Loefebellian et al) comparing human amniotic membrane with routine dressings for split-thickness skin grafts (STSGs) with primary outcomes measured as wound healing and infection rate. Secondary outcomes included severity of pain, discharge from donor site, number of dressing changes, pruritis, and comfort.

Salehi et al performed a single center randomized control trial in India consisting of 42 patients with burn wounds of second or third degrees deep and a total burn surface are from 20% to 40% undergoing STSG. Post-excision of donor sites, all donor sites were randomly covered either by amniotic membrane or conventional dressing such as gauze soaked with topical Vaseline. The intervention and control groups were located in a single patient, therefore performing a blinded procedure was not possible in this study.

Singh et al conducted a single center prospective randomized clinical trial in India consisting of 30 patients with ulcers undergoing STSG. Post-excision of donor sites, all donor sites were randomly covered either with gamma-irradiated amniotic membrane dressing or paraffin gauze dressings. Insufficient details of randomization was noted in this study.

Zidan et al performed a single center prospective randomized controlled trial in Egypt consisting of 40 patients with thermal burns or trauma undergoing STSG. Post-excision of donor sites, all donor sites were randomly covered either with human amniotic membrane (HAM) preserved in 98% glycerol or chlorhexidine-soaked paraffin gauze with cotton gauze. Insufficient information was provided regarding randomization in this study.

Loefebellian et al performed a randomized controlled trial in Germany consisting of 45 patients undergoing STSG. Patients were placed into three groups where post-excision of donor sites, included group A covered with allogenic HAM, group B with polyurethane (PU) foam and group C with PU foil and consecutive paraffin gauze. Insufficient information was provided regarding randomization in this study.

In their discussion, Abdul and colleagues (2020) noted HAM dressings displayed a superior effect in comparison to routine dressings with regard to wound healing time and the proportion of wounds healed by day 12 in the STSG donor site. Would healing time showed a significant (P < .0001) improvement in the HAM group versus the control groups. Likewise, there was a significant (P = .01) enhancement in the proportion of wounds healed by day 12 in the HAM group. However, there was no significant (P = .27) difference in the analysis of infection rates. Additionally, HAM proved to more effective than routine dressings with regard to secondary outcomes. In the HAM group, patients experienced less pain upon removal of dressings and less discharge from the donor site compared with the non-HAM group. The HAM group was associated with less pruritis, dressing changes, and discomfort than the non-HAM group. Although, the results of this review suggest that HAM dressings provide better outcomes in regard to STSG donor site healing in comparison to routine dressings, limitations were noted. The evidence was limited and based only on 4 studies with a small patient sample of 157 patients in addition to other short-comings previously stated. The authors indicated that further randomized controlled trials are warranted to support this current study.

Kogan and colleagues (2018) conducted a review of the safety and efficacy of amniotic membrane adjuncts in wound healing. The investigators looked at clinical trials from 2013 to 2017 involving amnion/chorion membranes studied in the treatment of burns, diabetic foot ulcers, fistulas, ocular defects, venous leg ulcers, in addition to other wounds. Although the clinical trials demonstrated that patients treated with amniotic membrane products showed increased rates of wound healing compared with standard of care, the investigators stated that additional trials are warranted to examine more amnion/chorion membrane products.

Thompson and colleagues (2019) conducted a prospective, randomized controlled trial comparing two treatments for diabetic foot ulcer: group A, total contact cast and human amniotic allograft versus group B, total contact cast and standard wound care. The study consisted of 13 adult patients with type 1 or 2 diabetes and a diabetic foot ulcer located on the plantar surface larger than 0.5 cm in area. Additionally, these patients had to have not demonstrated a 50% reduction in would area following 4 weeks of standard treatment for inclusion in this study. Patients in group A, with a higher mean hemoglobin A1c at study outset, experienced a longer mean time to closure (29.50) days compared with group B (26.20 days). The 90-day recurrence rates were different for the two groups, with only one recurrence for group A (14.29%) but five recurring ulcers in group B (83.33%). The investigators noted that significance was not established due to sample size but further investigation with human amniotic allograft is warranted.


References

The above policy is based on the following references:

General References

  1. Adams E. Bibliography: Collagen-based Dressings for Chronic Wound Management. Boston, MA: Veterans Health Administration Technology Assessment Program (VATAP): January 2003.
  2. Agency for Healthcare Research and Quality (AHRQ). Overview of wound care technologies. Technology Assessment. Rockville, MD: AHRQ; 2003.
  3. Agency for Healthcare Research and Quality's (AHRQ). Technology Assessment Program: Skin substitutes for treating chronic wounds. Draft technical brief. Rockville, MD: AHRQ; January 28, 2019. Available at: https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/drafts-for-review/skin-substitutes_draft.pdf. Accessed February 13, 2019.
  4. Barber C, Watt A, Pham C, et al. Bioengineered skin substitutes for the management of wounds: A systematic review. ASERNIP-S Report No. 52. Stepney, Australia: Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S); August 2006. 
  5. Bowering K, Embil JM. Foot care. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.
  6. Bradley M, Cullum N, Nelson EA, et al. Systematic reviews of wound care management: (2) dressings and topical agents used in the healing of chronic wounds. Health Tech Assess. 1999;(17 Pt 2):1-35.
  7. Buchberger B, Follmann M, Freyer D, et al. The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): A health technology assessment (HTA). Exp Clin Endocrinol Diabetes. 2011;119(8):472-479.
  8. Canadian Agency for Drugs and Technologies in Health. Non-adherent versus traditional dressings for wound care: Comparative effectiveness, safety, and guidelines. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2011.
  9. Centers for Medicare & Medicaid Services (CMS). Agenda for Health Common Procedures Coding System (HCPCS). Public Meeting for Code Applications for Non-Drug and Non-Biological Items and Services Submitted to CMS’ 1st 2021 Biannual HCPCS Coding Cycle. Baltimore, MD: CMS; July 7, 2021a.
  10. Centers for Medicare & Medicaid Services (CMS). Agenda for Healthcare Common Procedure Coding System (HCPCS). Public Meeting for Code Applications for Non-Drug and Non-Biological Items and Services Submitted to CMS’ 2nd 2021 Biannual HCPCS Coding Cycle. Baltimore, MD: CMS; December 2, 2021b.
  11. Centers for Medicare & Medicaid Services (CMS). Centers for Medicare & Medicaid Services' (CMS') First Biannual 2022 Healthcare Common Procedure Coding System (HCPCS) Public Meeting Agenda. Baltimore, MD: CMS; June 9, 2022a.
  12. Centers for Medicare & Medicaid Services (CMS). Centers for Medicare & Medicaid Services' (CMS') First Biannual 2022 Healthcare Common Procedure Coding System (HCPCS) Public Meeting Agenda. Baltimore, MD: CMS; November 30, 2022b.
  13. Centers for Medicare & Medicaid Services (CMS). Healthcare Common Procedure Coding System (HCPCS). Application Summaries and Coding Recommendations. First Quarter, 2022 HCPCS Coding Cycle. Baltimore, MD: CMS; July 1, 2022c.
  14. Centers for Medicare & Medicaid Services (CMS). Healthcare Common Procedure Coding System (HCPCS) Application Summaries and Coding Recommendations. First Quarter, 2023 HCPCS Coding Cycle. Baltimore, MD: CMS; July 1, 2023a.
  15. Centers for Medicare & Medicaid Services (CMS). Healthcare Common Procedure Coding System (HCPCS). Application Summaries and Coding Recommendations. Fourth Quarter, 2021 HCPCS Coding Cycle. Baltimore, MD: CMS; March 30, 2022d.
  16. Centers for Medicare & Medicaid Services (CMS). Healthcare Common Procedure Coding System (HCPCS). Application Summaries and Coding Decisions Second Quarter 2021 Coding Cycle for Drug and Biological Products. Baltimore, MD: CMS; September 30, 2021c.
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  28. Centers for Medicare & Medicaid Services (CMS). Healthcare Common Procedure Coding System (HCPCS). Application Summaries for Drugs, Biologicals and Radiopharmaceuticals. Baltimore, MD: CMS; May 18, 2017.
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  43. Ho C, Tran K, Hux M, et al. Artificial skin grafts in chronic wound care: A meta-analysis of clinical efficacy and a review of cost-effectiveness. Technology Report No 52. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2005. 
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  48. Jones JE, Nelson EA, Al-Hity A. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2013;(1):CD001737.
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  50. Lipsky BA, Berendt AR, Cornia PB, et al.; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54:e132-e173.
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  53. National Institute for Health and Clinical Excellence (NICE) Diabetic foot problems: Inpatient management of diabetic foot problems. NICE Clinical Guideline 119. London, UK: NICE; March 2011.
  54. National Institute for Health and Clinical Excellence (NICE). Diabetic foot problems: Evidence Update. Evidence Update 33. London, UK: NICE; March 2013.
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  57. Nicolau I, Xie X, McGregor M, Dendukuri N. Evaluation of acellular dermal matrix for breast reconstruction: An update. Report No. 59. Montreal, QC: Technology Assessment Unit of the McGill University Health Centre (MUHC); 2012.
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  61. Pham CT. Bioengineered skin substitutes for the management of burns: A systematic review. ASERNIP-S Report No. 46. Stepney, Australia: Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S); July 2006. 
  62. Reddy M. Pressure ulcers. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; June 2010.
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  65. Snyder DL, Sullivan N, Margolis D, et al. Skin substitutes for treating chronic wounds. Technology Assessment Report. Prepared by the ECRI Institute Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Contract No. HHSA 290-2015-00005-I. Project ID: WNDT0818. Rockville, MD: AHRQ; February 2, 2020.
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Affinity

  1. McQuilling JP, Vines JB, Mowry KC, et al. In vitro assessment of a novel, hypothermically stored amniotic membrane for use in a chronic wound environment. Int Wound J. 2017;14(6):993-1005.
  2. Mowry KC, Bonvallet PP, Bellis SL. Enhanced skin regeneration using a novel amniotic-derived tissue graft. Wounds. 2017;29(9):277-285. 
  3. Sabo M, Moore S, Yaakov R, et al. Fresh hypothermically stored amniotic allograft in the treatment of chronic nonhealing ulcers: A prospective case series. Chronic Wound Care Manage Res. 2018;5:1-4.
  4. Serena TE, Yaakov R, Moore S, et al. A randomized controlled clinical trial of a hypothermically stored amniotic membrane for use in diabetic foot ulcers. J Comp Eff Res. 2020;9(1):23-34.

AlloDerm

  1. Australia and New Zealand Horizon Scanning Network (ANZHSN). Alloderm  for deep superficial and full-thickness burns. Horizon Scanning Prioritising Summary. Adelaide, SA: Royal Australasian College of Surgeons, Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S); updated February 2007.
  2. Aycock J, Fichera A, Colwell JC, Song DH. Parastomal hernia repair with acellular dermal matrix. J Wound Ostomy Cont Nurs. 2007;34(5):521-523.
  3. Beale EW, Hoxworth RE, Livingston EH, Trussler AP. The role of biologic mesh in abdominal wall reconstruction: A systematic review of the current literature. Am J Surg. 2012;204(4):510-517.
  4. Bindingnavele V, Gaon M, Ota KS, et al. Use of acellular cadaveric dermis and tissue expansion in postmastectomy breast reconstruction. J Plast Reconstr Aesthet Surg. 2007;60(11):1214-1218.
  5. Bluebond-Langner R, Keifa ES, Mithani S, et al. Recurrent abdominal laxity following interpositional human acellular dermal matrix. Ann Plast Surg. 2008;60(1):76-80.
  6. Bochicchio GV, De Castro GP, Bochicchio KM, et al. Comparison study of acellular dermal matrices in complicated hernia surgery. J Am Coll Surg. 2013;217(4):606-613.
  7. Breuing KH, Colwell AS. Inferolateral AlloDerm hammock for implant coverage in breast reconstruction. Ann Plast Surg. 2007;59(3):250-255.
  8. Brooke S, Mesa J, Uluer M, et al. Complications in tissue expander breast reconstruction: A comparison of AlloDerm, DermaMatrix, and FlexHD acellular inferior pole dermal slings. Ann Plast Surg. 2012;69(4):347-349.
  9. Buinewicz B, Rosen B. Acellular cadaveric dermis (AlloDerm): A new alternative for abdominal hernia repair. Ann Plast Surg. 2004;52(2):188-194.
  10. Butler CE, Langstein HN, Kronowitz SJ. Pelvic, abdominal, and chest wall reconstruction with AlloDerm in patients at increased risk for mesh-related complications. Plast Reconstr Surg. 2005;116(5):1263-1277.
  11. Butterfield JL. 440 Consecutive immediate, implant-based, single-surgeon breast reconstructions in 281 patients: A comparison of early outcomes and costs between SurgiMend fetal bovine and AlloDerm human cadaveric acellular dermal matrices. Plast Reconstr Surg. 2013;131(5):940-951.
  12. Champagne BJ. Operative management of anorectal fistulas. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2021.
  13. Deneve JL, Turaga KK, Marzban SS, et al. Single-institution outcome experience using AlloDerm® as temporary coverage or definitive reconstruction for cutaneous and soft tissue malignancy defects. Am Surg. 2013;79(5):476-482.
  14. Diaz JJ Jr, Guy J, Berkes MB, et al. Acellular dermal allograft for ventral hernia repair in the compromised surgical field. Am Surg. 2006;72(12):1181-1188.
  15. Efsandiari S, Dendukuri N, McGregor M. Clinical efficacy and cost of Allogenic Acellular Dermal Matrix (AADM) in implant-based breast reconstruction of post mastectomy cancer patients. Report No. 40. Montreal, QC: Technology Assessment Unit of the McGill University Health Centre (MUHC); 2009.
  16. Ellis CV, Kulber DA. Acellular dermal matrices in hand reconstruction. Plast Reconstr Surg. 2012;130(5 Suppl 2):256S-269S.
  17. Espinosa-de-los-Monteros A, de la Torre JI, Marrero I, et al. Utilization of human cadaveric acellular dermis for abdominal hernia reconstruction. Ann Plast Surg. 2007;58(3):264-267.
  18. Gamboa-Bobadilla GM. Implant breast reconstruction using acellular dermal matrix. Ann Plast Surg. 2006;56(1):22-25.
  19. Garramone CE, Lam B. Use of AlloDerm in primary nipple reconstruction to improve long-term nippleprojection. Plast Reconstr Surg. 2007;119(6):1663-1668.
  20. Germani RM, Vivero R, Herzallah IR, Casiano RR. Endoscopic reconstruction of large anterior skull base defects using acellular dermal allograft. Am J Rhinol. 2007;21(5):615-618.
  21. Glasberg SB, D'Amico RA. Use of regenerative human acellular tissue (AlloDerm) to reconstruct the abdominal wall following pedicle TRAM flap breast reconstruction surgery. Plast Reconstr Surg. 2006;118(1):8-15.
  22. Gordley K, Cole P, Hicks J, Hollier L. A comparative, long term assessment of soft tissue substitutes: AlloDerm, Enduragen, and Dermamatrix. J Plast Reconstr Aesthet Surg. 2009;62(6):849-850.
  23. Gore DC. Utility of acellular allograft dermis in the care of elderly burn patients. J Surg Res. 2005;125(1):37-41.
  24. Gupta A, Zahriya K, Mullens PL, et al. Ventral herniorrhaphy: Experience with two different biosynthetic mesh materials, Surgisis and Alloderm. Hernia. 2006;10(5):419-425.
  25. Guy JS, Miller R, Morris JA Jr, et al. Early one-stage closure in patients with abdominal compartment syndrome: Fascial replacement with human acellular dermis and bipedicle flaps. Am Surg. 2003;69(12):1025-1029.
  26. Harirchian S, Baredes S. Use of AlloDerm in primary reconstruction after resection of squamous cell carcinoma of the lip and oral commissure. Am J Otolaryngol. 2013;34(5):611-613.
  27. Harth KC, Krpata DM, Chawla A, et al. Biologic mesh use practice patterns in abdominal wall reconstruction: A lack of consensus among surgeons. Hernia. 2013;17(1):13-20.
  28. Hiles M, Record Ritchie RD, Altizer AM. Are biologic grafts effective for hernia repair?: A systematic review of the literature. Surg Innov. 2009;16(1):26-37.
  29. Holton LH 3rd, Kim D, Silverman RP, et al. Human acellular dermal matrix for repair of abdominal wall defects: Review of clinical experience and experimental data. J Long Term Eff Med Implants. 2005;15(5):547-558.
  30. Janis JE, O'Neill AC, Ahmad J, et al.  Acellular dermal matrices in abdominal wall reconstruction: A systematic review of the current evidence. Plast Reconstr Surg. 2012;130(5 Suppl 2):183S-193S.
  31. Jansen LA, De Caigny P, Guay NA, et al. The evidence base for the acellular dermal matrix AlloDerm: A systematic review. Ann Plast Surg. 2013;70(5):587-594.
  32. Jin J, Rosen MJ, Blatnik J, et al. Use of acellular dermal matrix for complicated ventral hernia repair: Does technique affect outcomes? J Am Coll Surg. 2007;205(5):654-660.
  33. Kim H, Bruen K, Vargo D. Acellular dermal matrix in the management of high-risk abdominal wall defects. Am J Surg. 2006;192(6):705-709.
  34. Kissane NA, Itani KM. A decade of ventral incisional hernia repairs with biologic acellular dermal matrix: What have we learned? Plast Reconstr Surg. 2012;130(5 Suppl 2):194S-202S.
  35. Kolker AR, Brown DJ, Redstone JS, et al. Multilayer reconstruction of abdominal wall defects with acellular dermal allograft (AlloDerm) and component separation. Ann Plast Surg. 2005;55(1):36-42.
  36. Lattari V, Jones LM, Varcelotti JR, et al. The use of a permanent dermal allograft in full-thickness burns of the hand and foot: A report of three cases. J Burn Care Rehabil. 1997;18(2):147-155.
  37. Lee JM, Seo YJ, Shim DB, et al. Surgical outcomes of tympanoplasty using a sterile acellular dermal allograft: A prospective randomised controlled study. Acta Otorhinolaryngol Ital. 2018;38(6):554-562.
  38. Li C, Yang X, Pan J, et al. Graft for prevention of Frey syndrome after parotidectomy: A systematic review and meta-analysis of randomized controlled trials. J Oral Maxillofac Surg. 2013;71(2):419-427.
  39. Liu DZ, Mathes DW, Neligan PC, et al. Comparison of outcomes using AlloDerm versus FlexHD for implant-based breast reconstruction. Ann Plast Surg. 2014;72(5):503-507.
  40. Lorenz RR, Dean RL, Hurley DB, et al. Endoscopic reconstruction of anterior and middle cranial fossa defects using acellular dermal allograft. Laryngoscope. 2003;113(3):496-501.
  41. Lydiatt WM, Quivey JM. Salivary gland tumors: Treatment of locoregional disease. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2012. 
  42. Lynch MP, Chung MT, Rinker BD. Dermal autografts as a substitute for acellular dermal matrices (ADM) in tissue expander breast reconstruction: A prospective comparative study. J Plast Reconstr Aesthet Surg. 2013;66(11):1534-1542.
  43. McCarthy CM, Lee CN, Halvorson EG, et al. The use of acellular dermal matrices in two-stage expander/implant reconstruction: A multicenter, blinded, randomized controlled trial. Plast Reconstr Surg. 2012;130(5 Suppl 2):57S-66S.
  44. Memorial Sloan Kettering Cancer Center (MSKCC). Tissue expander/implant reconstruction: A single-blinded, randomized, controlled trial. ClinicalTrials.gov. Identifier NCT00639106. Bethesda, MD: National Library of Medicine; February 18, 2009.
  45. Mendenhall SD, Anderson LA, Ying J, et al. The BREASTrial: Stage I. Outcomes from the time of tissue expander and acellular dermal matrix placement to definitive reconstruction. Plast Reconstr Surg. 2015;135(1):29e-42e.
  46. Patel KM, Bhanot P. Complications of acellular dermal matrices in abdominal wall reconstruction. Plast Reconstr Surg. 2012;130(5 Suppl 2):216S-224S.
  47. Patel MR, Stadler ME, Snyderman CH, et al. How to choose? Endoscopic skull base reconstructive options and limitations. Skull Base. 2010;20(6):397-404.
  48. Patton JH Jr, Berry S, Kralovich KA. Use of human acellular dermal matrix in complex and contaminated abdominal wall reconstructions. Am J Surg. 2007;193(3):360-363.
  49. Preminger BA, McCarthy CM, Hu QY, et al. The influence of AlloDerm on expander dynamics and complications in the setting of immediate tissue expander/implant reconstruction: A matched-cohort study. Ann Plast Surg. 2008;60(5):510-513.
  50. Ricci JA, Treiser MD, Tao R, et al. Predictors of complications and comparison of outcomes using SurgiMend fetal bovine and AlloDerm human cadaveric acellular dermal matrices in 
    implant-based breast reconstruction. Plast Reconstr Surg. 2016;138(4):583e-591e.
  51. Salzberg CA. Nonexpansive immediate breast reconstruction using human acellular tissue matrix graft (AlloDerm). Ann Plast Surg. 2006;57(1):1-5.
  52. Scott BG, Welsh FJ, Pham HQ, et al. Early aggressive closure of the open abdomen. J Trauma. 2006;60(1):17-22.
  53. Shridharani SM, Tufaro AP. A systematic review of acelluar dermal matrices in head and neck reconstruction. Plast Reconstr Surg. 2012;130(5 Suppl 2):35S-43S.
  54. Slater NJ, van der Kolk M, Hendriks T, et al. Biologic grafts for ventral hernia repair: A systematic review. Am J Surg. 2013;205(2):220-230.
  55. Sobti N, Liao EC. Surgeon-controlled study and meta-analysis comparing FlexHD and AlloDerm in immediate breast reconstruction outcomes. Plast Reconstr Surg. 2016;138(5):959-967.
  56. Spear SL, Parikh PM, Reisin E, Menon NG. Acellular dermis-assisted breast reconstruction. Aesthetic Plast Surg. 2008;32(3):418-425.
  57. Tsai CC, Lin SD, Lai CS, Lin TM. The use of composite acellular allodermis-ultrathin autograft on joint area in major burn patients--one year follow-up. Kaohsiung J Med Sci. 1999;15(11):651-658.
  58. Vertrees A, Greer L, Pickett C, et al. Modern management of complex open abdominal wounds of war: A 5-year experience. J Am Coll Surg. 2008;207(6):801-809.
  59. Walters J, Cazzell S, Pham H, et al. Healing rates in a multicenter assessment of a sterile, room temperature, acellular dermal matrix versus conventional care wound management and an active comparator in the treatment of full-thickness diabetic foot ulcers. Eplasty. 2016;16:e10.
  60. Weber PC, Lambert PR, Cunningham CD, 3rd, et al. Use of Alloderm in the neurotologic setting. Am J Otolaryngol. 2002;23(3):148-152.
  61. Yonehiro L, Burleson G, Sauer V. Use of a new acellular dermal matrix for treatment of nonhealing wounds in the lower extremities of patients with diabetes. Wounds. 2013;25(12):340-344.
  62. Zelen CM, Orgill DP, Serena T, et al. A prospective, randomised, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allogenic human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J. 2017b;14(2):307-315.
  63. Zeng XT, Tang XJ, Wang XJ, et al. AlloDerm implants for prevention of Frey syndrome after parotidectomy: A systematic review and meta-analysis. Mol Med Report. 2012;5(4):974-980.
  64. Zhong T, Janis JE, Ahmad J, Hofer SO. Outcomes after abdominal wall reconstruction using acellular dermal matrix: A systematic review. J Plast Reconstr Aesthet Surg. 2011;64(12):1562-1571.
  65. Zienowicz RJ, Karacaoglu E. Implant-based breast reconstruction with allograft. Plast Reconstr Surg. 2007;120(2):373-381.

Alloderm and Strattice for Surgical Repair of Complex Abdominal Wall Wounds

  1. Booth JH, Garvey PB, Baumann DP, et al. Primary fascial closure with mesh reinforcement is superior to bridged mesh repair for abdominal wall reconstruction. J Am Coll Surg. 2013;217(6):999-1009.
  2. Garvey PB, Giordano SA, Baumann DP, et al. Long-term outcomes after abdominal wall reconstruction with acellular dermal matrix. J Am Coll Surg. 2017;224(3):341-350.
  3. Giordano S, Garvey PB, Baumann DP, et al. Primary fascial closure with biologic mesh reinforcement results in lesser complication and recurrence rates than bridged biologic mesh repair for abdominal wall reconstruction: A propensity score analysis. Surgery. 2017a;161(2):499-508.
  4. Giordano S, Schaverien M, Garvey PB, et al. Advanced age does not affect abdominal wall reconstruction outcomes using acellular dermal matrix: A comparative study using propensity score analysis. Am J Surg. 2017b;213(6):1046-1052.
  5. Mericli AF, Garvey PB, Giordano S, et al. Abdominal wall reconstruction with concomitant ostomy-associated hernia repair: Outcomes and propensity score analysis. J Am Coll Surg. 2017;224(3):351-361. 
  6. Romain B, Story F, Meyer N, et al. Comparative study between biologic porcine dermal meshes: Risk factors of postoperative morbidity and recurrence. J Wound Care. 2016;25(6):320-325.
  7. Sbitany H, Kwon E, Chern H, et al. Outcomes analysis of biologic mesh use for abdominal wall reconstruction in clean-contaminated and contaminated ventral hernia repair. Ann Plast Surg. 2015;75(2):201-204.

Allomax

  1. Alicuben ET, Worrell SG, DeMeester SR. Impact of crural relaxing incisions, Collis gastroplasty, and non-cross-linked human dermal mesh crural reinforcement on early hiatal hernia recurrence rates. J Am Coll Surg. 2014;219(5):988-992.
  2. Brosious JP, Wong N, Fowler G, et al. Evaluation of AlloMax acellular dermal matrix for objective collagen deposition. J Reconstr Microsurg. 2014;30(1):31-34.
  3. Chauviere MV, Schutter RJ, Steigelman MB, et al. Comparison of AlloDerm and AlloMax tissue incorporation in rats. Ann Plast Surg 2014;73(3):282-285.
  4. Roth JS, Brathwaite C, Hacker K, et al. Complex ventral hernia repair with a human acellular dermal matrix. Hernia.2015;19(2):247-252.

AlloPatch 

  1. Agrawal H, Tholpady S, Capito A, et al. Macrophage phenotypes correspond with remodeling outcomes of various acellular dermal matrices. Open J Regen Med. 2012;1(3):51-59.
  2. Agrawal V. Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft. Int J Shoulder Surg. 2012;6(2):36-44.
  3. Barber FA, Aziz-Jacobo J. Biomechanical testing of commercially available soft-tissue augmentation materials. Arthroscopy. 2009;25(11):1233-1239.
  4. Dasgupta A, Orgill D, Galiano RD, et al. A novel reticular dermal graft leverages architectural and biological properties to support wound repair. Plast Reconstr Surg Glob Open. 2016;4(10):e1065.
  5. Musculoskeletal Transplant Foundation (MTF). AlloPatch Pliable allograft dermal matrix. Donated human tissue. Package Insert. PI –112 Rev1, 01/2015. RM –2065. Edison, NJ: MTF; 2015. 
  6. Zelen CM, Orgill DP, Serena T, et al. A prospective, randomised, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allogenic human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J. 2017b;14(2):307-315.
  7. Zelen CM, Orgill DP, Serena T, et al. Human reticular acellular dermal matrix in the healing of chronic diabetic foot ulcerations that failed standard conservative treatment: A retrospective crossover study. Wounds. 2017a;29(2):39-45.
  8. Zelen CM, Orgill DP, Serena TE, et al. An aseptically processed, acellular, reticular, allogenic human dermis improves healing in diabetic foot ulcers: A prospective, randomised, controlled, multicentre follow-up trial. Int Wound J. 2018;15(5):731-739. 

Alloskin /Allosource

  1. Fagotti L, Soares E, Bolia IK, et al. Early outcomes after arthroscopic hip capsular reconstruction using iliotibial band allograft versus dermal allograft. Arthroscopy. 2019;35(3):778-786.
  2. ISBI Practice Guidelines Committee; Steering Subcommittee; Advisory Subcommittee. ISBI practice guidelines for burn care. Burns. 2016;42(5):953-1021.
  3. Li HY, Xiao SC, Zhu SH, et al. Successful treatment of a patient with an extraordinarily large deep burn. Med Sci Monit. 2011;17(4):CS47-CS51.
  4. Moravvej H, Hormozi AK, Hosseini SN, et al. Comparison of the application of allogeneic fibroblast and autologous mesh grafting with the conventional method in the treatment of third-degree burns. J Burn Care Res. 2016;37(1):e90-e95.

AmnioBand and Guardian 

  1. DiDomenico LA, Orgill DP, Galiano RD, et al. A retrospective crossover study of the use of aseptically processed placental membrane in the treatment of chronic diabetic foot ulcers. Wounds. 2017;29(10):311–316.
  2. DiDomenico LA, Orgill DP, Galiano RD, et al. Aseptically processed placental membrane improves healing of diabetic foot ulcerations: Prospective, randomized clinical trial. Plast Reconstr Surg Glob Open. 2016;4(10):e1095. 
  3. DiDomenico LA, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective, randomised, multi‐centre clinical trial in 80 patients. Int Wound J. 2018;15(6):950-957.
  4. Glat P, Orgill DP, Galiano R, et al. Placental membrane provides improved healing efficacy and lower cost versus a tissue-engineered human skin in the treatment of diabetic foot ulcerations. Plast Reconstr Surg Glob Open. 2019;7(8):e2371.
  5. Musculoskeletal Transplant Foundation (MTF). AmnioBand Membrane allograft placental matrix. Donated human tissue. Package Insert. PI -108 Rev 3, 8/2016. RM-2017. Edison, NJ: MTF; 2015.
  6. Serena TE, Orgill DP, Armstrong DG, et al.  A multicenter, randomized, controlled, clinical trial evaluating dehydrated human amniotic membrane in the treatment of venous leg ulcers. Plast Reconstr Surg. 2022;150(5):1128-1136.

AmnioExcel

  1. Snyder RJ, Shimozaki K, Tallis A, et al. A prospective, randomized, multicenter, controlled evaluation of the use of dehydrated amniotic membrane allograft compared to standard of care for the closure of chronic diabetic foot ulcer. Wounds. 2016;28(3):70-77.

Amniotic-Derived Products

  1. Duerr RA, Ackermann J, Gomoll AH. Amniotic-derived treatments and formulations. Clin Sports Med. 2019;38(1):45-59.
  2. Hannon CP, Yanke AB, Farr J. Amniotic tissue modulation of knee pain - A focus on osteoarthritis. J Knee Surg. 2019;32(1):26-36.
  3. Muttini A, Barboni B, Valbonetti L, et al. Amniotic epithelial stem cells: Salient features and possible therapeutic role. Sports Med Arthrosc Rev. 2018;26(2):70-74.
  4. Riboh JC, Saltzman BM, Yanke AB, Cole BJ. Human amniotic membrane-derived products in sports medicine: Basic science, early results, and potential clinical applications. Am J Sports Med. 2016;44(9):2425-2434.
  5. Sultan AA, Samuel LT, Roth A, et al. Operative applications of placental tissue matrix in orthopaedic sports injuries: A review of the literature. Surg Technol Int. 2019;34:397-402. 

Amniotic Fluid Injection

  1. Abbasian B, Kazemini H, Esmaeili A, Adibi S. Effect of bovine amniotic fluid on intra-abdominal adhesion in diabetic male rats. J Diabetes Complications. 2011;25(1):39-43.
  2. Castro-Combs J, Noguera G, Cano M, et al. Corneal wound healing is modulated by topical application of amniotic fluid in an ex vivo organ culture model. Exp Eye Res. 2008;87(1):56-63.
  3. Kerimoğlu S, Livaoğlu M, Sönmez B, et al. Effects of human amniotic fluid on fracture healing in rat tibia. J Surg Res. 2009;152(2):281-287.
  4. Ozgenel GY, Samli B, Ozcan M. Effects of human amniotic fluid on peritendinous adhesion formation and tendon healing after flexor tendon surgery in rabbits. J Hand Surg Am. 2001;26(2):332-339.
  5. Tahmasebi S, Tahamtan M, Tahamtan Y. Prevention by rat amniotic fluid of adhesions after laparatomy in a rat model. Int J Surg. 2012;10(1):16-19.

Amniox

  1. Cooke M, Tan EK, Mandrycky C, et al. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-474,
  2. Swan J. Use of cryopreserved, particulate human amniotic membrane and umbilical cord (AM/UC) tissue: A case series study for application in the healing of chronic wounds. Surg Technol Int. 2014;25:73-78.

Apis

  1. U.S. Food and Drug Administration (FDA). Apis. 510K no.K182725. Silver Spring, MD: FDA; May 31, 2019.

Apligraf

  1. Agence d'Evaluation des technologies et des Modes d'Intervention en Sante (AETMIS). The treatment of venous leg ulcers and optimal use of Apligraf (TM). CETS 2000-5 RE. Montreal, QC: AETMIS; 2000.
  2. Alvarez OM, Fahey CB, Auletta MJ, et al. A novel treatment for venous leg ulcers. J Foot Ankle Surg. 1998;37(4):319-324.
  3. Australia and New Zealand Horizon Scanning Network (ANZHSN). Apligraf for burn injuries. Horizon Scanning Prioritising Summary. Adelaide, SA: Royal Australasian College of Surgeons, Australian Safety and Efficacy Registry of New Interventional Procedures - Surgical (ASERNIP-S); updated February 2007.
  4. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Graftskin for the treatment of skin ulcers. TEC Assessment Program. Chicago, IL: BCBSA; November 2001;16(12). 
  5. Brem H, Balledux J, Bloom T, et al. Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent: A new paradigm in wound healing. Arch Surg. 2000;135(6):627-634.
  6. Buchberger B, Follmann M, Freyer D, et al. The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): A health technology assessment (HTA). Exp Clin Endocrinol Diabetes. 2011;119(8):472-479.
  7. Carlson M, Faria K, Shamis Y, et al. Epidermal stem cells are preserved during commercial-scale manufacture of a bilayered, living cellular construct (Apligraf®). Tissue Eng Part A. 2011;17(3-4):487-493.
  8. Coulomb B, Friteau L, Baruch J, et al. Advantage of the presence of living dermal fibroblasts within in vitro reconstructed skin for grafting in humans. Plast Reconstr Surg. 1998;101(7):1891-1903.
  9. De SK, Reis ED, Kerstein MD.  Wound treatment with human skin equivalent. J Am Podiatr Med Assoc. 2002;92(1):19-23.
  10. DeCarbo WT. Special segment: soft tissue matrices--Apligraf bilayered skin substitute to augment healing of chronic wounds in diabetic patients. Foot Ankle Spec. 2009;2(6):299-302.
  11. DiDomenico L, Emch KJ, Landsman AR, et al. A prospective comparison of diabetic foot ulcers treated with either cryopreserved skin allograft or bioengineered skin substitute. Wounds. 2011;23(7):184-189.
  12. Dolynchuk K, Hull P, Guenther L, et al. The role of Apligraf in the treatment of venous leg ulcers. Ostomy Wound Manage. 1999;45(1):34-43. 
  13. Eaglstein WH, Falanga V. Tissue engineering and the development of Apligraf, a human skin equivalent. Cutis. 1998;62(1 Suppl):1-8.
  14. Eaglstein WH, Falanga V. Tissue engineering and the development of Apligraf, a human skin equivalent. Clin Ther. 1997;19(5):894-905. 
  15. Eaglstein WH, Falanga V. Tissue engineering for skin: An update. J Am Acad Dermatol. 1998;39(6):1007-1010. 
  16. Eaglstein WH, Iriondo M, Laszlo K. A composite skin substitute (graftskin) for surgical wounds. A clinical experience. Dermatol Surg. 1995;21(10):839-843.
  17. Edmonds M, Bates M, Doxford M, et al. New treatments in ulcer healing and wound infection. Diabetes Metab Res Rev. 2000;16 Suppl 1:S51-S54. 
  18. Edmonds M; European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009;8(1):11-18.
  19. Fahey C. Experience with a new human skin equivalent for healing venous leg ulcers. J Vasc Nurs. 1998;16(1):11-15. 
  20. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human skin equivalent investigators group. Arch Dermatol. 1998;134(3):293-300.
  21. Ho C, Tran K, Hux M, et al. Artificial skin grafts in chronic wound care: A meta-analysis of clinical efficacy and a review of cost-effectiveness. Technology Report No 52. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2005. 
  22. Hu S, Kirsner RS, Falanga V, et al. Evaluation of Apligraf(R) persistence and basement membrane restoration in donor site wounds: A pilot study. Wound Repair Regen. 2006;14(4):427-433.
  23. Jansen DA, Asgari MM, Atillasoy ES, Milstone LM. Clinical and in vitro responses of bilayered skin construct (graftskin) to meshing. Arch Dermatol. 2002;138(6):843-844.
  24. Kirsner RS, Eaglstein WH, Kerdel FA. Split-thickness skin grafting for lower extremity ulcerations. Dermatol Surg. 1997;23(2):85-93. 
  25. Kirsner RS, Falanga V, Eaglstein WH. The development of bioengineered skin. Trends Biotechnol. 1998;16(6):246-249.
  26. Kirsner RS, Fastenau J, Falabella A, et al. Clinical and economic outcomes with graftskin for hard-to-heal venous leg ulcers: A single-center experience. Dermatol Surg. 2002;28(1):81-82.
  27. Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res. 2009;9:115.
  28. Mundy L, Parrella A. Apligraf (R): For the treatment of diabetic foot and venous leg ulcers. Horizon Scanning Prioritising Summary - Volume 7. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2004.
  29. Novartis Pharmaceuticals Corporation. Apligraf (graftskin). Product Labeling. East Hanover, NJ; Novartis; June 2002. 
  30. Paquette D, Falanga V. Leg ulcers. Clin Geriatr Med. 2002;18(1):77-88, vi.
  31. Rice JB, Desai U, Ristovska L, et al. Economic outcomes among Medicare patients receiving bioengineered cellular technologies for treatment of diabetic foot ulcers. J Med Econ. 2015;18(8):586-595.
  32. Sams HH, Chen J, King LE. Graftskin treatment of difficult to heal diabetic foot ulcers: One center's experience. Dermatol Surg. 2002;28(8):698-703.
  33. Shealy FG Jr, DeLoach ED. Experience with the use of apligraf to heal complicated surgical and nonsurgical wounds in a private practice setting. Adv Skin Wound Care. 2006;19(6):310-322.
  34. Sorensen JC. Living skin equivalents and their application in wound healing. Clin Podiatr Med Surg. 1998;15(1):129-137.
  35. Steinberg JS, Edmonds M, Hurley DP Jr, King WN. Confirmatory data from EU study supports Apligraf for the treatment of neuropathic diabetic foot ulcers. J Am Podiatr Med Assoc. 2010;100(1):73-77.
  36. Swedish Council on Technology Assessment in Health Care (SBU). Transplantation of cultured skin (Apligraf) in treating venous leg ulcers - early assessment briefs (Alert). Stockholm, Sweden: SBU; 2003.
  37. Veves A, Falanga V, Armstrong DG, et al. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: A prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295.
  38. Waymack P, Duff RG, Sabolinski M. The effect of a tissue engineered bilayered living skin analog, over meshed split-thickness autografts on the healing of excised burn wounds. The Apligraf Burn Study Group. Burns. 2000;26(7):609-619. 
  39. Zaulyanov L, Kirsner RS. A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clin Interv Aging. 2007;2(1):93-98.

Artelon

  1. Bell R, Desai S, House H, et al. A retrospective multicenter study of the Artelon® carpometacarpal joint implant. Hand (N Y). 2011;6(4):364-372.
  2. Clarke S, Hagberg W, Kaufmann RA, et al. Complications with the use of Artelon in thumb CMC joint arthritis. Hand (N Y). 2011;6(3):282-286.
  3. Ehrl D, Erne H. Poor outcomes from use of the Artelon® biodegradable implant for the treatment of thumb carpo-metacarpal joint and scapho-trapezio-trapezoid osteoarthritis: A short report and brief review of literature. J Hand Surg Eur Vol. 2015;40(9):1009-1012. 
  4. Giuffrida AY, Gyuricza C, Perino G, Weiland AJ. Foreign body reaction to artelon spacer: Case report. J Hand Surg Am. 2009;34(8):1388-1392.
  5. Giza E, Frizzell L, Farac R, et al. Augmented tendon Achilles repair using a tissue reinforcement scaffold: A biomechanical study. Foot Ankle Int. 2011;32(5):S545-S549.
  6. Huang YC, Jazayeri L, Le W, Yao J. Failure of artelon interposition arthroplasty after partial trapeziectomy: A case report with histologic and immunohistochemical analysis. Am J Orthop (Belle Mead NJ). 2015;44(4):E117-E122.
  7. Huss FR, Nyman E, Gustafson CJ, et al. Characterization of a new degradable polymer scaffold for regeneration of the dermis: In vitro and in vivo human studies. Organogenesis. 2008;4(3):195-200.
  8. Jorheim M, Isaxon I, Flondell M, et al. Short-term outcomes of trapeziometacarpal artelon implant compared with tendon suspension interposition arthroplasty for osteoarthritis: A matched cohort study. J Hand Surg Am. 2009;34(8):1381-1387.
  9. Nilsson A, Liljensten E, Bergström C, Sollerman C. Results from a degradable TMC joint Spacer (Artelon) compared with tendon arthroplasty. J Hand Surg Am. 2005;30(2):380-389.
  10. Nilsson A, Wiig M, Alnehill H, et al. The Artelon CMC spacer compared with tendon interposition arthroplasty. Acta Orthop. 2010;81(2):237-244.
  11. Park MJ, Lee AT, Yao J. Treatment of thumb carpometacarpal arthritis with arthroscopic hemitrapeziectomy and interposition arthroplasty. Orthopedics. 2012;35(12):e1759-e1764.
  12. Robinson PM, Muir LT. Foreign body reaction associated with Artelon: Report of three cases. J Hand Surg Am. 2011;36(1):116-120.
  13. Vermeulen GM, Slijper H, Feitz R, et al. Surgical management of primary thumb carpometacarpal osteoarthritis: A systematic review. J Hand Surg Am. 2011;36(1):157-169.
  14. Vitale MA, Taylor F, Ross M, Moran SL. Trapezium prosthetic arthroplasty (silicone, Artelon, metal, and pyrocarbon). Hand Clin. 2013;29(1):37-55.
  15. Wajon A, Vinycomb T, Carr E, et al. Surgery for thumb (trapeziometacarpal joint) osteoarthritis. Cochrane Database Syst Rev. 2015;(2):CD004631.

Arthroflex

  1. Beitzel K, Chowaniec DM, McCarthy MB, et al. Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone. Am J Sports Med. 2012;40(5):1148-1154.
  2. Beitzel K, McCarthy MB, Cote MP, et al. Properties of biologic scaffolds and their response to mesenchymal stem cells. Arthroscopy. 2014;30(3):289-298.
  3. Denard PJ, Brady PC, Adams CR, et al. Preliminary results of arthroscopic superior capsule reconstruction with dermal allograft. Arthroscopy. 2018;34(1):93-99
  4. Dimock RAC, Malik S, Consigliere P, et al. Superior capsule Rreconstruction: What do we know? Arch Bone Jt Surg. 2019;7(1):3-11.
  5. Ehsan A, Lee DG, Bakker AJ, Huang JI. Scapholunate ligament reconstruction using an acellular dermal matrix: A mechanical study. J Hand Surg Am. 2012;37(8):1538-1542.
  6. Gilot GJ, Alvarez-Pinzon AM, Barcksdale L, et al. Outcome of large to massive rotator cuff tears repaired with and without extracellular matrix augmentation: A prospective comparative study. Arthroscopy. 2015;31(8):1459-1465
  7. Gilot GJ, Attia AK, Alvarez AM. Arthroscopic repair of rotator cuff tears using extracellular matrix graft. Arthrosc Tech. 2014;3(4):e487-e489
  8. Hirahara AM, Adams CR. Arthroscopic superior capsular reconstruction for treatment of massive irreparable rotator cuff tears. Arthrosc Tech. 2015;4(6):e637-e641
  9. Hirahara AM, Andersen WJ, Panero AJ. Superior capsular reconstruction: Clinical outcomes after minimum 2-year follow-up. Am J Orthop (Belle Mead NJ). 2017;46(6):266-278
  10. Makovicka JL, Chung AS, Patel KA, et al. Superior capsule reconstruction for irreparable rotator cuff tears: A systematic review of biomechanical and clinical outcomes by graft type. J Shoulder Elbow Surg. 2020;29(2):392-401
  11. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470
  12. Morris A, Samsell B, Dorsch K, et al. Use of acellular dermal matrix for reconstruction of massive rotator cuff tears in an older population. Orthop Muscular Syst. 2018;7:3
  13. Pennington WT, Bartz BA, Pauli JM, et al. Arthroscopic superior capsular reconstruction with acellular dermal allograft for the treatment of massive irreparable rotator cuff tears: Short-term clinical outcomes and the radiographic parameter of superior capsular distance. Arthroscopy. 2018;34(6):1764-1773
  14. Tokish JM, Beicker C. Superior capsule reconstruction technique using an acellular dermal allograft. Arthrosc Tech. 2015;4(6):e833-e839.
  15. Zastrow RK, London DA, Parsons BO, Cagle PJ. Superior capsule reconstruction for irreparable rotator cuff tears: A systematic review. Arthroscopy. 2019;35(8):2525-2534.

Artiss

  1. Foster K, Greenhalgh D, Gamelli R et al; FS 4IU VH S/D Clinical Study Group. Efficacy and safety of a fibrin sealant for adherence of autologous skin grafts to burn wounds: Results of a phase 3 clinical study. J Burn Care Res. 2008;29(2):293-303.
  2. U.S. Food and Drug Administration (FDA). FDA approves new medical adhesive to treat burn patients. FDA News. Rockville, MD: FDA; March 19, 2008.

Autologous Platelet-Derived Growth Factors (e.g., Procuren)

  1. Bergstrom N, Bennett MA, Carlson CE, et al. Treatment of pressure ulcers. Clinical Practice Guideline No. 15. AHCPR Pub. No. 95-0652. Rockville, MD: Agency for Healthcare Policy and Research (AHCPR); December 1994. 
  2. Browne AC, Sibbald RG. The diabetic neuropathic ulcer: An overview. Ostomy Wound Manage. 1999;45(1A Suppl):6S-22S. 
  3. Center for Medicare and Medicaid Services (CMS). Decision memo for autologous blood-derived products for chronic non-healing wounds (CAG-00190N). Baltimore, MD: CMS; December 15, 2003. 
  4. Center for Medicare and Medicaid Services (CMS). Medlearn Matters: Information for Medical Providers. Autologous blood-derived products for chronic non-healing wounds (MM3384). Baltimore, MD: CMS; July 23, 2004. 
  5. Center for Medicare and Medicaid Services (CMS). Proposed decision memo for autologous blood derived products for chronic non-healing wounds (CAG-00190R2). Baltimore, MD: CMS; December 20, 2007.  
  6. Centers for Medicare & Medicaid Services (CMS). National coverage determination (NCD) for blood derived products for chronic non-healing wounds (270.3). Baltimore, MD: CMS; August 2, 2012.
  7. Evans JM, Andrews KL, Chutka DS, et al. Pressure ulcers: Prevention and management. Mayo Clin Proc. 1995;70(8):789-799. 
  8. Ganio C, Tenewitz FE, Wilson RC, Moyles BG. The treatment of chronic nonhealing wounds using autologous platelet-derived growth factors. J Foot Ankle Surg. 1993;32(3):263-268. 
  9. Gillam AJ, Da Camara CC. Treatment of wounds with procuren. Ann Pharmacother. 1993;27(10):1201-1203. 
  10. Graham A. The use of growth factors in clinical practice. J Wound Care. 1998;7(10):536-540. 
  11. Hafner J, Brunner U, Burg G. [Treatment guidelines for venous leg ulcers: Causal therapy initiation and local wound treatment]. Ther Umsch. 1996;53(4):304-308. 
  12. He C, Hughes MA, Cherry GW, Arnold F. Effects of chronic wound fluid on the bioactivity of platelet-derived growth factor in serum-free medium and its direct effect on fibroblast growth. Wound Repair Regen. 1999;7(2):97-105. 
  13. Herndon DN, Nguyen TT, Gilpin DA. Growth factors. Local and systemic. Arch Surg. 1993;128(11):1227-1233. 
  14. Hom DB. Growth factors and wound healing in otolaryngology. Otolaryngol Head Neck Surg. 1994;110:560-564. 
  15. Hotta SS, Holohan TV. Procuren: A platelet-derived wound healing formula. Health Technology Review No. 2. AHCPR Pub. No. 92-0065. Rockville, MD: Agency for Healthcare Policy and Research (AHCPR); July 1992. 
  16. Kirsner RS, Warriner R, Michela M, et al. Advanced biological therapies for diabetic foot ulcers. Arch Dermatol. 2010;146(8):857-862.
  17. Lutz S. Mixed views on wound product. Mod Healthcare. 1991;21(50):34, 36.
  18. Martinez-Zapata MJ,  Martí-Carvajal AJ,  Solà I,  et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;(10):CD006899.
  19. Meyer-Ingold W. Wound therapy: Growth factors as agents to promote healing. Trends Biotechnol. 1993;11(9):387-392. 
  20. Nelson EA, Jones J. Venous leg ulcers. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; September 2007.
  21. No authors listed.  A discussion of CHAMPUS policy. Federal Register. 1995;60(96):26705-26709. 
  22. No authors listed.  Procuren: A platelet-derived wound healing formula. American Medical Association Technology News. 1994;7(5):8-10. 
  23. Robinson CJ. Growth factors: Therapeutic advances in wound healing. Ann Med. 1993;25(6):535-538. 
  24. Robson MC, Mustoe TA, Hunt TK. The future of recombinant growth factors in wound healing. Am J Surg. 1998;176(2A Suppl):80S-82S. 
  25. Rudkin GH, Miller TA. Growth factors in surgery. Plast Reconstr Surg. 1996;97(2):469-476.
  26. Sobiczewska E, Szmigielski S. The role of selected cell growth factors in the wound healing process. Przegl Lek. 1997;54(9):634-638. 
  27. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg. 1996;183(1):61-64.
  28. Steed DL. Modifying the wound healing response with exogenous growth factors. Clin Plast Surg. 1998;25(3):397-405. 
  29. Steenfos HH. Growth factors and wound healing. Scand J Plast Reconstr Surg Hand Surg. 1994;28(2):95-105. 
  30. Wasiak J, Cleland H, Campbell F. Dressings for superficial and partial thickness burns. Cochrane Database Syst Rev. 2008;(4):CD002106.

Avaulta

  1. Auzin M, Teune TM, Hogewoning CJ. Bladder polyps following Avaulta anterior mesh vaginal wall repair. Int Urogynecol J. 2012;23(12):1797-1799.
  2. Bondili A, Deguara C, Cooper J. Medium-term effects of a monofilament polypropylene mesh for pelvic organ prolapse and sexual function symptoms. J Obstet Gynaecol. 2012;32(3):285-290.
  3. Cervigni M, Natale F, La Penna C, et al. Collagen-coated polypropylene mesh in vaginal prolapse surgery: An observational study. Eur J Obstet Gynecol Reprod Biol. 2011;156(2):223-227.
  4. Culligan PJ, Littman PM, Salamon CG, et al. Evaluation of a transvaginal mesh delivery system for the correction of pelvic organ prolapse: Subjective and objective findings at least 1 year after surgery. Am J Obstet Gynecol. 2010;203(5):506.e1-e6.
  5. Dass AK, Lo TS, Khanuengkitkong S, Tan YL. A delayed type of ureteric injury developed after transobturator mesh procedure for massive prolapse. Female Pelvic Med Reconstr Surg. 2013;19(3):179-180.
  6. Thomin A, Touboul C, Hequet D, et al. Genital prolapse repair with Avaulta Plus(®) mesh: Functional results and quality of life. Prog Urol. 2013;23(4):270-275. 
  7. Vollebregt A, Fischer K, Gietelink D, van der Vaart CH. Primary surgical repair of anterior vaginal prolapse: A randomised trial comparing anatomical and functional outcome between anterior colporrhaphy and trocar-guided transobturator anterior mesh. BJOG. 2011;118(12):1518-1527.

Avotermin

  1. Bush J, Duncan JA, Bond JS, et al. Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial. Plast Reconstr Surg. 2010;126(5):1604-1615.
  2. Ferguson MW, Duncan J, Bond J, et al. Prophylactic administration of avotermin for improvement of skin scarring: Three double-blind, placebo-controlled, phase I/II studies. Lancet. 2009;373(9671):1264-1274.
  3. McCollum PT, Bush JA, James G, et al. Randomized phase II clinical trial of avotermin versus placebo for scar improvement. Br J Surg. 2011;98(7):925-934.
  4. Occleston NL, O'Kane S, Laverty HG, et al. Discovery and development of avotermin (recombinant human transforming growth factor beta 3): A new class of prophylactic therapeutic for the improvement of scarring. Wound Repair Regen. 2011;19 Suppl 1:s38-s48.
  5. So K, McGrouther DA, Bush JA, et al. Avotermin for scar improvement following scar revision surgery: A randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial. Plast Reconstr Surg. 2011;128(1):163-172.

Axogen

  1. Brooks DN, Weber RV, Chao JD, et al. Processed nerve allografts for peripheral nerve reconstruction: A multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery. 2012;32(1):1-14.
  2. Danish SF, Samdani A, Hanna A, et al. Experience with acellular human dura and bovine collagen matrix for duraplasty after posterior fossa decompression for Chiari malformations. J Neurosurg. 2006;104(1 Suppl):16-20.
  3. Guo Y, Chen G, Tian G, Tapia C. Sensory recovery following decellularized nerve allograft transplantation for digital nerve repair. J Plast Surg Hand Surg. 2013;47(6):451-453.
  4. Moore AM, MacEwan M, Santosa KB, et al. Acellular nerve allografts in peripheral nerve regeneration: A comparative study. Muscle Nerve. 2011;44(2):221-234.
  5. Narotam PK, José S, Nathoo N, et al. Collagen matrix (DuraGen) in dural repair: Analysis of a new modified technique. Spine (Phila Pa 1976). 2004;29(24):2861-2867; discussion 2868-2869.
  6. Peled ZM. Treatment of a patient with small fiber pathology using nerve biopsy and grafting: A case report. J Reconstr Microsurg. 2013;29(8):551-554.
  7. Sade B, Oya S, Lee JH. Non-watertight dural reconstruction in meningioma surgery: Results in 439 consecutive patients and a review of the literature. Clinical article. J Neurosurg. 2011;114(3):714-718.
  8. Whitlock EL, Tuffaha SH, Luciano JP, et al. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve. 2009;39(6):787-799.
  9. Williams LE, Vannemreddy PS, Watson KS, Slavin KV. The need in dural graft suturing in Chiari I malformation decompression: A prospective, single-blind, randomized trial comparing sutured and sutureless duraplasty materials. Surg Neurol Int. 2013;4:26. 

Biobrane Biosynthetic Dressing

  1. Austin RE, Merchant N, Shahrokhi S, Jeschke MG. A comparison of Biobrane™ and cadaveric allograft for temporizing the acute burn wound: Cost and procedural time. Burns. 2015;41(4):749-753.
  2. Barret JP, Dziewulski P, Ramzy PI, et al. Biobrane versus 1% silver sulfadiazine in second-degree pediatric burns. Plast Reconstr Surg. 2000;105(1):62-65.
  3. Bishop JF. Pediatric considerations in the use of Biobrane in burn wound management. J Burn Care Rehabil. 1995;16(3 Pt 1):331-333; discussion 333-334.
  4. Cassidy C, St Peter SD, Lacey S, et al. Biobrane versus duoderm for the treatment of intermediate thickness burns in children: A prospective, randomized trial. Burns. 2005;31(7):890-893.
  5. Ehrenreich M, Ruszczak Z. Tissue-engineered temporary wound coverings. Important options for the clinician. Acta Dermatovenerol Alp Panonica Adriat. 2006;15(1):5-13.
  6. Farroha A, Frew Q, El-Muttardi N, et al. Use of Biobrane to dress split-thickness skin graft adjacent to skin graft donor sites or partial-thickness burns. J Burn Care Res. 2013;34(5):e308.
  7. Frew Q, Philp B, Shelley O, et al. The use of Biobrane(®) as a delivery method for cultured epithelial autograft in burn patients. Burns. 2013;39(5):876-880. 
  8. Greenwood JE. A randomized, prospective study of the treatment of superficial partial-thickness burns: AWBAT-S versus Biobrane. Eplasty. 2011;11:e10.
  9. Hubik DJ, Wasiak J, Paul E, Cleland H. Biobrane: A retrospective analysis of outcomes at a specialist adult burns centre. Burns. 2011;37(4):594-600.
  10. Krezdorn N, Könneker S, Paprottka FJ, et al. Biobrane versus topical agents in the treatment of adult scald burns. Burns. 2017;43(1):195-199.
  11. Lesher AP, Curry RH, Evans J, et al. Effectiveness of Biobrane for treatment of partial-thickness burns in children. J Pediatr Surg. 2011;46(9):1759-1763.
  12. Pham C, Greenwood J, Cleland H, Woodruff P, Maddern G. Bioengineered skin substitutes for the management of burns: A systematic review. Burns. 2007;33(8):946-957.
  13. Phillips LG, Robson MC, Smith DJ, et al. Uses and abuses of a biosynthetic dressing for partial skin thickness burns. Burns. 1989;15(4):254-256.
  14. Rahmanian-Schwarz A, Beiderwieden A, Willkomm LM, et al. A clinical evaluation of Biobrane(®) and Suprathel(®) in acute burns and reconstructive surgery. Burns. 2011;37(8):1343-1348.
  15. Smith DJ Jr. Use of Biobrane in wound management. J Burn Care Rehabil. 1995;16(3 Pt 1):317-320.
  16. Vloemans AF, Hermans MH, van der Wal MB, et al. Optimal treatment of partial thickness burns in children: A systematic review. Burns. 2014;40(2):177-190.
  17. Wiechula R. Post harvest management of split thickness skin graft donor sites: A systematic review. Systematic Review No. 13. Adelaide, SA: Joanna Briggs Institute for Evidence Based Nursing and Midwifery; 2001.

Bio-ConnecKt Wound Matrix

  1. Centers for Medicare & Medicaid Services (CMS) Agenda for Health Common Procedures Coding System (HCPCS). Public Meeting for Code Applications for Non-Drug and Non-Biological Items and Services Submitted to CMS’ 1st 2021 Biannual HCPCS Coding Cycle. Baltimore, MD: CMS; July 7, 2021.

BioDfactor Human Amnion Allograft

  1. Gutierrez-Moreno S, Alsina-Gibert M, Sampietro-Colom L, et al. Cost-benefit analysis of amniotic membrane transplantation for venous ulcers of the legs that are refractory to conventional treatment. Actas Dermosifiliogr. 2011;102(4):284-288.
  2. Koike T, Yasuo M, Shimane T, et al. Cultured epithelial grafting using human amniotic membrane: The potential for using human amniotic epithelial cells as a cultured oral epithelium sheet. Arch Oral Biol. 2011;56(10):1170-1176.

Bionect

  1. Brown TJ, Alcorn D, Fraser JR. Absorption of hyaluronan applied to the surface of intact skin. J Invest Dermatol. 1999 Nov;113(5):740-6.
  2. Gariboldi S, Palazzo M, Zanobbio L, et al. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J Immunol. 2008;181(3):2103-10.
  3. Greco RM, Iocono JA, Ehrlich HP. Hyaluronic acid stimulates human fibroblast proliferation within a collagen matrix. J Cell Physiol. 1998;177(3):465-73.
  4. Prescribing information for Bionect (hyaluronic acid sodium salt, 0.2%). Charleston, SC: Innocutis Holdings, LLC; June 2014.
  5. Schlesinger T, Rowland Powell C. Efficacy and safety of a low molecular weight hyaluronic Acid topical gel in the treatment of facial seborrheic dermatitis final report. J Clin Aesthet Dermatol. 2014;7(5):15-8.
  6. Shaharudin A, Aziz Z. Effectiveness of hyaluronic acid and its derivatives on chronic wounds: a systematic review. J Wound Care. 2016;25(10):585-592.
  7. Weindl G, Schaller M, Schäfer-Korting M, et al. Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. 2004;17(5):207-13.

Biovance

  1. Letendre S, LaPorta G, O'Donnell E, et al. Pilot trial of biovance collagen-based wound covering for diabetic ulcers. Adv Skin Wound Care. 2009;22(4):161-166.

CellECT

  1. Delibaltov DL, Gaur U, Kim J, et al. CellECT: Cell evolution capturing tool. BMC Bioinformatics. 2016;17:88.
  2. Englund MC, Caisander G, Noaksson K, et al. The establishment of 20 different human embryonic stem cell lines and subclones; a report on derivation, culture, characterisation and banking. In Vitro Cell Dev Biol Anim. 2010;46(3-4):217-230.
  3. Lee K, Goodman SB. Cell therapy for secondary osteonecrosis of the femoral condyles using the Cellect DBM System: A preliminary report. J Arthroplasty. 2009;24(1):43-48.

CellerateRx

  1. Newman MI, Baratta LG, Swartz K. Activated, type I collagen (CellerateRx) and its effectiveness in healing recalcitrant diabetic wounds: A case presentation. Adv Skin Wound Care. 2008;21(8):370-374.

CollaMend

  1. Chavarriaga LF, Lin E, Losken A, et al. Management of complex abdominal wall defects using acellular porcine dermal collagen. Am Surg. 2010;76(1):96-100.
  2. Coccolini F, Lotti M, Bertoli P, et al. Thoracic wall reconstruction with Collamend® in trauma: Report of a case and review of the literature. World J Emerg Surg. 2012;7(1):39. 
  3. Harth KC, Rosen MJ. Major complications associated with xenograft biologic mesh implantation in abdominal wall reconstruction. Surg Innov. 2009;16(4):324-329. 
  4. Shah BC, Tiwari MM, Goede MR, et al. Not all biologics are equal! Hernia. 2011;15(2):165-171.

Conexa

  1. Xu H, Sandor M, Qi S, et al. Implantation of a porcine acellular dermal graft in a primate model of rotator cuff repair. J Shoulder Elbow Surg. 2012;21(5):580-588.

Cook Medical Anal Fistula Plug

  1. Filgate R, Thomas A, Ballal M. Treatment of foregut fistula with biologic plugs. Surg Endosc. 2015;29(7):2006-2012.

Cormatrix

  1. Bibevski S, Scholl FG. Feasibility and early effectiveness of a custom, hand-made systemic atrioventricular valve using porcine extracellular matrix (CorMatrix) in a 4-month-old infant. Ann Thorac Surg. 2015;99(2):710-712.
  2. Brinster DR, Patel JA. The use of CorMatrix extracellular matrix for aortic root enlargement. J Cardiothorac Surg. 2014;9(1):178.
  3. Deorsola L, Pace Napoleone C, Abbruzzese PA. Repair of an unusual aortic coarctation using an extracellular matrix patch. Ann Thorac Surg. 2014;97(3):1059-1061.
  4. DuBose JJ, Azizzadeh A. Utilization of a tubularized CorMatrix extracellular matrix for repair of an arteriovenous fistula aneurysm. Ann Vasc Surg. 2015;29(2):366.e1-e4.
  5. Gerdisch MW, Boyd WD, Harlan JL, et al. Early experience treating tricuspid valve endocarditis with a novel extracellular matrix cylinder reconstruction. J Thorac Cardiovasc Surg. 2014;148(6):3042-3048.
  6. Gerdisch MW, Shea RJ, Barron MD. Clinical experience with CorMatrix extracellular matrix in the surgical treatment of mitral valve disease. J Thorac Cardiovasc Surg. 2014;148(4):1370-1378.
  7. Gilbert CL, Gnanapragasam J, Benhaggen R, Novick WM. Novel use of extracellular matrix graft for creation of pulmonary valved conduit. World J Pediatr Congenit Heart Surg. 2011;2(3):495-501.
  8. Quarti A, Nardone S, Colaneri M, et al. Preliminary experience in the use of an extracellular matrix to repair congenital heart diseases. Interact Cardiovasc Thorac Surg. 2011;13(6):569-572.
  9. Slachman FN. Constructive remodeling of CorMatrix extracellular matrix after aortic root repair in a 90-year-old woman. Ann Thorac Surg. 2014;97(5):e129-e131.
  10. Szczeklik M, Gupta P, Amersey R, Lall KS. Reconstruction of the right atrium and superior vena cava with extracellular matrix. J Card Surg. 2015;30(4):351-354.
  11. Wallen J, Rao V. Extensive tricuspid valve repair after endocarditis using CorMatrix extracellular matrix. Ann Thorac Surg. 2014;97(3):1048-1050.
  12. Yanagawa B, Rao V, Yau TM, Cusimano RJ. Initial experience with intraventricular repair using CorMatrix extracellular matrix. Innovations (Phila). 2013;8(5):348-352. 
  13. Yanagawa B, Rao V, Yau TM, Cusimano RJ. Potential myocardial regeneration with CorMatrix ECM: A case report. J Thorac Cardiovasc Surg. 2014;147(4):e41-e43. 
  14. Yeen WC, Faber C, Caldeira C, et al. Reconstruction of pulmonary venous conduit with CorMatrix in lung transplant. Asian Cardiovasc Thorac Ann. 2013;21(3):360-362.
  15. Zaidi AH, Nathan M, Emani S, et al. Preliminary experience with porcine intestinal submucosa (CorMatrix) for valve reconstruction in congenital heart disease: Histologic evaluation of explanted valves. J Thorac Cardiovasc Surg. 2014;148(5):2216-2224, 2225.

Cuffpatch

  1. Barber FA, Herbert MA, Coons DA. Tendon augmentation grafts: Biomechanical failure loads and failure patterns. Arthroscopy. 2006;22(5):534-538.
  2. Coons DA, Alan Barber F. Tendon graft substitutes-rotator cuff patches. Sports Med Arthrosc. 2006;14(3):185-190.
  3. Derwin KA, Baker AR, Spragg RK, et al. Commercial extracellular matrix scaffolds for rotator cuff tendon repair. Biomechanical, biochemical, and cellular properties. J Bone Joint Surg Am. 2006;88(12):2665-2672.
  4. Johnson W, Inamasu J, Yantzer B, et al. Comparative in vitro biomechanical evaluation of two soft tissue defect products. J Biomed Mater Res B Appl Biomater. 2007.
  5. Karlsson M, Lindgren M, Jarnhed-Andersson I, Tarpila E. Dressing the split-thickness skin graft donor site: A randomized clinical trial. Adv Skin Wound Care. 2014;27(1):20-25.
  6. Valentin JE, Badylak JS, McCabe GP, Badylak SF. Extracellular matrix bioscaffolds for orthopaedic applications. A comparative histologic study. J Bone Joint Surg Am. 2006;88(12):2673-2686.

Cymetra

  1. Allam RC. Micronized, particulate dermal matrix to manage a non-healing pressure ulcer with undermined wound edges: A case report. Ostomy Wound Manage. 2007;53(4):78-82.
  2. Apte RS, Solomon SD, Gehlbach P. Acute choroidal infarction following subcutaneous injection of micronized dermal matrix in the forehead region. Retina. 2003;23(4):552-554.
  3. Banta MN, Eaglstein WH, Kirsner RS. Healing of refractory sinus tracts by dermal matrix injection with Cymetra. Dermatol Surg. 2003;29(8):863-866.
  4. Hirsch RJ, Cohen JL. Soft tissue augmentation. Cutis. 2006;78(3):165-172.
  5. Homicz MR, Watson D. Review of injectable materials for soft tissue augmentation. Facial Plast Surg. 2004;20(1):21-29.
  6. Levy D, Banta MR, Kirsner RS. Refractory pyoderma gangrenosum peristomal ulcer and sinus tract treated with micronized cadaveric dermis. J Am Acad Dermatol. 2005;52(6):1104.
  7. Maloney BP, Murphy BA, Cole HP 3rd. Cymetra. Facial Plast Surg. 2004;20(2):129-134.
  8. Narins RS, Bowman PH. Injectable skin fillers. Clin Plast Surg. 2005;32(2):151-162.
  9. Sclafani AP, Romo T 3rd, Jacono AA. Rejuvenation of the aging lip with an injectable acellular dermal graft (Cymetra). Arch Facial Plast Surg. 2002;4(4):252-257.

Dehydrated Human Amniotic Membrane Allograft (e.g., BioFix, FlowerPatch)

  1. Massee M, Chinn K, Lei J, et al. Dehydrated human amnion/chorion membrane regulates stem cell activity in vitro. J Biomed Mater Res B Appl Biomater. 2016;104(7):1495-1503.
  2. Willett NJ, Thote T, Lin AS, et al. Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development. Arthritis Res Ther. 2014;16(1):R47.

DermACELL

  1. Bullocks JM. DermACELL: A novel and biocompatible acellular dermal matrix in tissue expander and implant-based breast reconstruction. Eur J Plast Surg. 2014;37(10):529-538. 
  2. Capito AE, Tholpady SS, Agrawal H, et al. Evaluation of host tissue integration, revascularization, and cellular infiltration within various dermal substrates. Ann Plast Surg. 2012;68(5):495-500.
  3. Cazzell S. A randomized controlled trial comparing a human acellular dermal matrix versus conventional care for the treatment of venous leg ulcers. Wounds. 2019;31(3):68-74.
  4. Cazzell S, Vayser D, Pham H, et al. A randomized clinical trial of a human acellular dermal matrix demonstrated superior healing rates for chronic diabetic foot ulcers over conventional care and an active acellular dermal matrix comparator. Wound Repair Regen. 2017;25(3):483-497.  
  5. Chen SG, Tzeng YS, Wang CH. Treatment of severe burn with DermACELL(®), an acellular dermal matrix. Int J Burns Trauma. 2012;2(2):105-109.
  6. Cheng A, Saint-Cyr M. Comparison of different ADM materials in breast surgery. Clin Plast Surg. 2012;39(2):167-175.
  7. Robb GL, Gurtner GC. Letter to the editor. Healing rates in a multicenter assessment of a sterile, room temperature, acellular dermal matrix versus conventional care wound management and an active comparator in the treatment of full-thickness diabetic foot ulcers. Eplasty. 2016;16:229. 
  8. Roussalis JL. Novel use of an acellular dermal matrix allograft to treat a chronic scalp wound with bone exposure: A case study. Int J Burns Trauma. 2014;4(2):49-52. 
  9. Shitrit SB, Ramon Y, Bertasi G. Use of a novel acellular dermal matrix allograft to treat complex trauma wound: A case study. Int J Burns Trauma. 2014;4(2):62-65.
  10. Vashi C. Clinical outcomes for breast cancer patients undergoing mastectomy and reconstruction with use of DermACELL, a sterile, room temperature acellular dermal matrix. Plast Surg Int. 2014;2014:704323.
  11. Walters J, Cazzell S, Pham H, et al. Healing rates in a multicenter assessment of a sterile, room temperature, acellular dermal matrix versus conventional care wound management and an active comparator in the treatment of full-thickness diabetic foot ulcers. Eplasty. 2016;16:e10.

DermaClose

  1. Bajoghli AA, Yoo JY, Faria DT. Utilization of a new tissue expander in the closure of a large Mohs surgical defect. J Drugs Dermatol. 2010;9(2):149-151.
  2. Durden F Jr, Tiwari P, Kocak E. Can the DermaClose device contribute to periwound tissue ischemia and necrosis: A case presentation and discussion? Plast Surg Nurs. 2012;32(3):132-133.
  3. Reinard KA, Zakaria HM, Qatanani A, et al. Preoperative external tissue expansion for complex cranial reconstructions. J Neurosurg. 2016;125(4):861-868.
  4. Santiago GF, Bograd B, Basile PL, et al. Soft tissue injury management with a continuous external tissue expander. Ann Plast Surg. 2012;69(4):418-421.

Derma-Gide

  1. Armstrong DG, Orgill DP, Galiano RD, et al. An observational pilot study using a purified reconstituted bilayer matrix to treat non‐healing diabetic foot ulcers. Int Wound J. 2020;17(4):966-973.
  2. Armstrong DG, Orgill DP, Galiano RD, et al. Functional properties of a purified reconstituted bilayer matrix design support natural wound healing activities. Plast Reconstr Surg Glob Open. 2021;9(5):e3596.
  3. Armstrong DG, Orgill DP, Galiano RG, et al. Use of a purified reconstituted bilayer matrix in the management of chronic diabetic foot ulcers improves patient outcomes vs standard of care: Results of a prospective randomised controlled multi-centre clinical trial. Int Wound J. 2022;19(5):1197-1209.

Dermagraft

  1. Advanced Tissue Sciences, Inc. Dermagraft interactive wound dressing. Summary of Safety and Effectiveness Data. Premarket Approval Application No. P000036. Rockville, MD: U.S. Food and Drug Administration; September 28, 2001. 
  2. Bowering CK. Dermagraft in the treatment of diabetic foot ulcers. J Cutan Med Surg. 1998;3 Suppl 1:S1-29-32. 
  3. Browne AC, Vearncombe M, Sibbald RG. High bacterial load in asymptomatic diabetic patients with neurotrophic ulcers retards wound healing after application of Dermagraft. Ostomy Wound Manage. 2001;47(10):44-49. 
  4. Buchberger B, Follmann M, Freyer D, et al. The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): A health technology assessment (HTA). Exp Clin Endocrinol Diabetes. 2011;119(8):472-479.
  5. Eaglstein WH. Dermagraft treatment of diabetic ulcers. J Dermatol. 1998;25(12):803-804. 
  6. Edmonds ME, Foster AV, McColgan M. 'Dermagraft': A new treatment for diabetic foot ulcers. Diabet Med 1997;14:1010-1011. 
  7. Frykberg RG, Marston WA, Cardinal M. The incidence of lower-extremity amputation and bone resection in diabetic foot ulcer patients treated with a human fibroblast-derived dermal substitute. Adv Skin Wound Care. 2015;28(1):17-20.
  8. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996;19(4):350-354.
  9. Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg. 2002;41(5):291-299.
  10. Hansbrough JF, Mozingo DW, Kealey GP, et al. Clinical trials of a biosynthetic temporary skin replacement, Dermagraft-Transitional Covering, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds. J Burn Care Rehabil. 1997;18(1 Pt 1):43-51.
  11. Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int Wound J. 2013;10(2):132-137.
  12. Jiang WG, Harding KG. Enhancement of wound tissue expansion and angiogenesis by matrix-embedded fibroblast (dermagraft), a role of hepatocyte growth factor/scatter factor. Int J Mol Med. 1998;2(2):203-210.
  13. Kashefsky H, Marston W. Total contact casting combined with human fibroblast-derived dermal tissue in 15 DFU patients. J Wound Care. 2012;21(5):236, 238, 240, 242-243.
  14. Krishnamoorthy L, Harding K, Griffiths D, et al. The clinical and histological effects of Dermagraft in the healing of chronic venous leg ulcers. Phlebology. 2003;18(1):12-22.
  15. Landsman A, Roukis TS, DeFronzo DJ, et al. Living cells or collagen matrix: Which is more beneficial in the treatment of diabetic foot ulcers? Wounds. 2008;20(5):111-116.
  16. Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res. 2009;9:115.
  17. Marston WA, Hanft J, Norwood P, et al. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: Results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701-1705.
  18. Marston WA. Dermagraft, a bioengineered human dermal equivalent for the treatment of chronic nonhealing diabetic foot ulcer. Expert Rev Med Devices. 2004;1(1):21-31.
  19. Mundy L, Merlin T, Parrella A. Dermagraft (R): Dermal substitute wound cover for patients with dystrophic epidermolysis bullosa. Horizon Scanning Prioritising Summary - Volume 6. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2004.
  20. Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs. 1997;21(11):1203-1210. 
  21. Newton DJ, Khan F, Belch JJ, et al. Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. J Foot Ankle Surg. 2002;41(4):233-237.
  22. Purdue GF, Hunt JL, Still JM Jr, et al. A multicenter clinical trial of a biosynthetic skin replacement, Dermagraft-TC, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds. J Burn Care Rehabil. 1997;18(1 Pt 1):52-57.
  23. Truong AT, Kowal-Vern A, Latenser BA, et al. Comparison of dermal substitutes in wound healing utilizing a nude mouse model. J Burns Wounds. 2005;4:e4. 
  24. U.S. Food and Drug Administration (FDA). Dermagraft, Human Fibroblast-Derived Dermal Substitute. Treatment of wounds related to dystrophic epidermolysis bullosa. Summary of Safety and Probable Benefit. Humanitarian Device Exemption No. H020004. Rockville, MD: FDA; July 7, 2003.
  25. Warriner RA 3rd, Cardinal M; TIDE Investigators. Human fibroblast-derived dermal substitute: Results from a treatment investigational device exemption (TIDE) study in diabetic foot ulcers. Adv Skin Wound Care. 2011;24(7):306-311.

Dermamatrix

  1. Athavale SM, Phillips S, Mangus B, et al. Complications of alloderm and dermamatrix for parotidectomy reconstruction. Head Neck. 2012;34(1):88-93. 
  2. Kathju S, Lasko LA, Medich DS. Perineal hernia repair with acellular dermal graft and suture anchor fixation. Hernia. 2011;15(3):357-360.
  3. Lee EW, Berbos Z, Zaldivar RA, et al. Use of DermaMatrix graft in oculoplastic surgery. Ophthal Plast Reconstr Surg. 2010;26(3):153-154.
  4. Sahoo S, DeLozier KR, Erdemir A, Derwin KA. Clinically relevant mechanical testing of hernia graft constructs. J Mech Behav Biomed Mater. 2015;41:177-188.

Duragen

  1. Alfieri A, Schettino R, Taborelli A, et al. Endoscopic endonasal treatment of a spontaneous temporosphenoidal encephalocele with a detachable silicone balloon. Case report. J Neurosurg. 2002;97(5):1212-1216.2:
  2. Bowers CA, Brimley C, Cole C, et al. AlloDerm for duraplasty in Chiari malformation: Superior outcomes. Acta Neurochir (Wien). 2015;157(3):507-511.
  3. Braca JA 3rd, Marzo S, Prabhu VC. Cerebrospinal fluid leakage from tegmen tympani defects repaired via the middle cranial fossa approach. J Neurol Surg B Skull Base. 2013;74(2):103-107.
  4. Danish SF, Samdani A, Hanna A, et al. Experience with acellular human dura and bovine collagen matrix for duraplasty after posterior fossa decompression for Chiari malformations. J Neurosurg. 2006;104(1 Suppl):16-20.
  5. Grigoryants V, Jane JA Jr, Lin KY. Salvage of a complicated myelomeningocele using collagen (Duragen) and dermal (Alloderm) matrix substitutes. Case report and review of the literature. Pediatr Neurosurg. 2007;43(6):512-515. 
  6. Harvey RJ, Nogueira JF, Schlosser RJ, et al. Closure of large skull base defects after