1. Osteogenic Protein-1 (OP-1) Implant

   Aetna considers the osteogenic protein-1 (OP-1) implant (also known as bone morphogenic, or morphogenetic protein-7, BMP-7) medically necessary for use as an alternative to autograft in recalcitrant long-bone non-unions where the (i) use of autograft is unfeasible (see I., A., below) and (ii) alternative treatments have failed (see I., B., below).

   1. Use of an autograft may be deemed unfeasible for any of the following reasons:

      1. Member has received a previous autograft and is not a candidate for further autograft procedures because the tissue is no longer available; or
      2. There is insufficient autogenous tissue for the intended purpose; or

      3. Member is deemed an unacceptable candidate for autograft for any of the following reasons:

         1. Obesity; or
         2. Advanced age (over 65 years of age); or
         3. Presence of morbidity (infection, or fracture) preventing harvesting at autograft donor site; or
         4. Excessive risk of anatomic disruption (including fracture) from harvesting autograft from donor site; or
         5. Member's bone is of poor quality (osteoporosis); or

         6. Member has concurrent medical conditions and co-morbidities that increase the risk of autograft.

   2. Alternative treatments should include the following, as appropriate:

      1. Cast immobilization or other non-operative approaches;
      2. Fixation (internal and external);
      3. Revision of fixation;
      4. Autograft;
      5. Cadaveric allograft;
      6. Compression;
      7. Dynamization;

      8. Bone growth stimulation (ultrasonic or electrical).

   3. The OP-1 Implant has no proven value in persons with any of the following contraindications:

      1. Persons with known hypersensitivity to the OP-1 Implant or to collagen;
      2. Persons who are skeletally immature (less than 18 years of age or no radiographic evidence of closure of epiphyses);
      3. Pregnant women;

      4. Persons with history of malignancy.

   4. Aetna considers the OP-1 Implant experimental and investigational if it is to be applied at the site of a resected tumor that is at or near the vicinity of the non-union because its use for these indications is less effective than bone autograft.

   5. Aetna considers the OP-1 Implant experimental and investigational for use in spinal fusion and for all indications other than those listed above because its effectiveness for these indications has not been established.

2. InFUSE Bone Graft (Bone Morphogenic Protein-2)

   Aetna considers the InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device medically necessary for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from the fourth lumbar vertebra (L4) to the first sacral vertebra (S1), in persons who meet the following criteria:

   1. Member has degenerative disc disease, defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies; and
   2. Member does not have greater than Grade I spondylolysthesis at the involved level; and
   3. Member has had at least six months of non-operative treatment prior to treatment with the InFUSE Bone Graft/LT-CAGE device; and
   4. InFUSE Bone Graft/LT-CAGE device is to be implanted via an anterior approach; and

   5. Use of allograft or cadaveric autograft is unfeasible for one of more of the reasons listed in Section I above.

   Aetna considers the InFUSE Bone Graft experimental and investigational for all other indications.

   Note: The InFUSE Bone Graft is also known as bone morphogenic, or morphogenetic protein-2, BMP-2.

3. Pro Osteon Porous Hydroxyapatite Bone Graft Substitute

   Aetna considers the Pro Osteon Porous Hydroxyapatite Bone Graft Substitute experimental and investigational for repair of metaphyseal fracture defects or repair of long bone cyst and tumor defects, because it has not been shown to be more effective than autograft or cadaveric allograft for these indications.

   Aetna considers the Pro Osteon Bone Graft Substitute experimental and investigational for use in spinal fusion, epiphyseal fractures or other indications because its effectiveness for these indications has not been established.

4. Platelet-Rich Plasma

   Aetna considers the use of platelet-rich plasma, alone or in conjunction with bone grafting materials, experimental and investigational for augmentation procedures (e.g., for dental implants and for maxillary sinus) or other indications other than thrombocytopenia because its effectiveness has not been established.

   See also CPB 244 - Wound Care (stating that autologous platelet-rich plasma is considered experimental and investigational for chronic wound healing).

5. Porcine Intestinal Submucosa Surgical Mesh

   Aetna considers a surgical mesh composed of porcine intestinal submucosa experimental and investigational because its clinical value in rotator cuff repair surgery, repair of anorectal fistula, and for other indications has not been established.

6. Bone Void Fillers for Nonunions

   Aetna considers bone void fillers experimental and investigational for the treatment of delayed unions or nonunions because they have not been proven effective for this indication. Note: Bone void fillers (e.g., Opteform, a demineralized bone matrix-based allograft) are most commonly used in orthopedic surgery for filling osteochondral defects; their use as such is considered an integral part of the surgical procedure.

7. Mesenchymal Stem Cell Therapy
   
   Aetna considers the use of mesenchymal stem cell therapy for spinal fusion and other orthopedic indications (e.g., long bone nonunions) experimental and investigational because there is insufficient evidence to support its use especially its safety and long-term outcomes.

Osteogenic proteins, also referred to as bone morphogenetic, or morphogenic proteins (BMPs), are a family of bone-matrix polypeptides isolated from a variety of mammalian species. Implantation of OPs induces a sequence of cellular events that lead to the formation of new bone. Some of the potential clinical applications of OPs are: (i) as a bone graft substitute to promote spinal fusion and to aid in the incorporation of metal implants, (ii) to improve the performance of autograft and allograft bone, and (iii) as an agent for osteochondral defects.

Recombinantly produced human osteogenic protein-1 (OP-1), also known as BMP-7, was developed by Stryker Biotech (Hopkinton, MA), a division of Stryker Corporation. The OP-1 Implant was approved by the FDA as a Humanitarian Use Device (HUD). As defined in the Federal Food, Drug and Cosmetic Act (21 CFR 814.124), a HUD “is a device that is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or is manifested in fewer than 4,000 individuals in the United States per year.” The FDA developed the Humanitarian Use Device categorization to provide an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting small patient populations.

The manufacturer submitted to the FDA results from a multicenter Long Bone Treatment Study, where 10 patients with long bone nonunions having prior failed autograft were treated with OP-1 implant. Seven of the 10 patients had clinical healing (pain and function), and 2 of 10 had radiographic healing (bridging in 3 or 4 cortices).

The manufacturer also submitted the results of the multicenter Tibial Nonunion Study, where a subset of 14 patients with prior failed autograft was treated with the OP-1 Implant, and 13 patients were treated with autograft.Twelve of patients receiving the OP-1 Implant had clinical resolution (pain and function) of their nonunion, and 8 patients had radiographic healing (bridging in three views). By comparison, 12 of 13 patients receiving autograft had clinical resolution of their nonunion, and 12 of 13 had radiographic healing. The FDA concluded that, although the OP-1 implant was an effective treatment for nonunions, the implant was not as effective as autograft. Therefore, the FDA product labeling states that the OP-1 bone morphogenic protein is indicated “for use as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed” (emphasis added).

Friedlaender et al. (2001) reported on the results of a randomized, controlled, single blind multicenter clinical trial where 122 patients with 124 tibial nonunions were assigned to either OP-1 Implant or bone autograft. The OP-1 Implant was found to be less effective than bone autograft. After 9 months of treatment, 81 percent of the OP-1-treated nonunions and 85 percent of patients receiving autogenous bone were judged by clinical criteria to have been treated successfully, and 75 percent of OP-1 treated patients and 84 percent of autograft-treated patients had healed fractures by radiographic criteria.

In a randomized study, Johnsson et al (2002) examined whether OP-1 (BMP-7) in the OP-1 Implant yields better stabilizing bony fusion than autograft bone in patients undergoing posterolateral fusion between L5 and S1. A total of 20 patients were randomized to fusion with either OP-1 Implant (n = 10) or autograft bone from the iliac crest (n = 10). The patients were instructed to keep the trunk straight for 5 months after surgery with the aid of a soft lumbar brace. At surgery 0.8-mm metallic markers were positioned in L5 and the sacrum, enabling radiostereometric follow-up analysis during 1 year. No significant difference was observed between the radiostereometric and radiographic results of fusion with the OP-1 Implant and fusion with autograft bone. Thus, the OP-1 Implant did not yield better stabilizing bony fusion than autograft bone.

Sandhu et al (2003) stated that OP-1 has been studied in limited pilot studies of posterolateral fusion. It is unclear whether the addition of OP-1 ensures arthrodesis in this application.

Bone morphogenetic protein-2 (BMP-2) is approved by the FDA as a bone graft substitute in anterior lumbar interbody fusions. It has also been used off-label in anterior cervical fusions. Smucker and colleagues (2006) examined if BMP-2 is associated with an increased incidence of clinically relevant post-operative pre-vertebral swelling problems in patients undergoing anterior cervical fusions. A total of 234 consecutive patients (aged 12 to 82 years) undergoing anterior cervical fusion with and without BMP-2 over a 2-year period at one institution comprised the study population. The incidence of clinically relevant pre-vertebral swelling was calculated. The populations were compared and statistical significance was determined. A total of 234 patients met the study criteria, 69 of whom underwent anterior cervical spine fusions using BMP-2; 27.5 % of those patients in the BMP-2 group had a clinically significant swelling event versus only 3.6 % of patients in the non-BMP-2 group. This difference was statistically significant (p < 0.0001) and remained so after controlling for other significant predictors of swelling. The authors concluded that off-label use of BMP-2 in the anterior cervical spine is associated with an increased rate of clinically relevant swelling events.

In a systemic review, Mussano et al (2007) examined if BMPs are more effective in treating bone defects than traditional techniques, such as grafting autologous bone. An electronic search was made in the databases of MEDLINE, EMBASE (through MeSH and Emtree), and the Cochrane Central Register of Controlled Trials with no linguistic restrictions. Randomized controlled trials (RCTs) that compared bone regeneration achieved through BMPs versus that obtained by traditional methods entered the study. The 17 publications that met the criteria, divided into subgroups by type of bone, were tabulated by salient characteristics and evaluated through the items proposed by van Tulder et al. However, as the studies differed widely (in terms of site, sample size, dosage of active principle, carrier, clinical and radiological data recording), it was possible to carry out a meta-analysis of clinical and radiological outcome only for the subgroup that evaluated the vertebrae, where it was observed that BMPs offer a slightly but statistically significant greater efficacy than do traditional techniques. The authors concluded that the use of BMPs at the vertebrae can eliminate the need for surgery to harvest autologous bone. The only large study carried out on the other sites suggested that BMPs should be used at a concentration of 1.5 mg/ml to treat fractures of the tibia. The authors stated that further RCTs of good methodological quality are needed to clarify the effectiveness of BMPs in clinical practice.

The Pro Osteon Bone Graft Substitute (Interpore International) is a hydroxyapatite bone allograft material made from marine coral. The product was approved by the FDA in 1992 as a bone void filler for repair of metaphyseal defects and long bone cyst and tumor defects. The product is to be used in conjunction with rigid internal fixation, as the Pro Osteon does not possess sufficient strength to support the reduction of a defect site prior to hard tissue ingrowth. External stabilization is not sufficient.

Pro Osteon coralline hydroxyapatite is not indicated for spinal fusion or fractures of the epiphyseal plate. A prospective randomized controlled clinical study directly compared coralline hydroxyapatite to iliac crest grafts in spinal fusion and found that the coralline graft “does not possess adequate structural integrity to resist axial loading and maintain disc height or segmental lordosis during cervical interbody fusion” (McConnell, et al., 2003).

The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device (Medtronic Sofamor Danek) includes recombinant human bone morphogenic protein 2 (rhBMP-2) in a collagen absorbable sponge and a tapered titanium spinal cage, and has been approved for spinal fusion in persons with single-level degenerative disc disease from L4 to S1, where the patient has had at least six months of nonoperative treatment, and the device is to be used via an anterior approach. Studies submitted to the FDA compared the InFUSE Bone Graft to autogenous iliac crest bone graft in patients with degenerative lumbar disc disease. These studies showed clinically equivalent fusion rates between the two groups, with similar outcomes in terms of back pain, leg pain, disability and neurological status. The primary advantage of use of the device is that it does not require harvesting of autologous bone.

The California Technology Assessment Forum (CTAF) (Feldman, 2005) concluded that rhBMP-2 carried on a collagen sponge used in conjunction with an FDA approved device meets CTAF criteria for the treatment of patients undergoing single level anterior lumbar interbody spinal fusion for symptomatic single level degenerative disease at L4-S1 of at least six months duration that has not responded to non-operative treatments. CTAF concluded that all other uses of rhBMP-2 including its use in cervical spinal fusions and for treatment of open tibial fracture do not meet CTAF criteria.

An evidence review prepared for the Ontario Ministry of Health and Long-Term Care (2004) found that “[t]he largest number of spinal fusion cases using BMP devices has been for anterior lumbar interbody fusion. Although radiologic fusion occurs at a consistently faster rate among recipients of the BMP device than among recipients of autologous bone grafts, clinical outcomes (pain and disability) appear no different. Regardless of technique, improvements in pain and disability are reported by similar proportions of participants in all the arms of all the trials.”

Platelet-Rich Plasma

Regeneration of guided bone is an established procedure used in implant dentistry to increase the quality and quantity of the host bone in sites of localized alveolar defects. Improvement in the osteo-inductive properties of currently available grafting materials is needed because of the lack of predictability in osseous regenerative procedures with these materials. Platelet-rich plasma (PRP), a modification of fibrin glue derived from autologous blood, is being used to deliver growth factors in high concentration to areas requiring osseous grafting. Growth factors released from the platelets include platelet-derived growth factor, transforming growth factor beta, platelet-derived epidermal growth factor, platelet-derived angiogenesis factor, insulin-like growth factor 1, and platelet factor 4. These factors signal the local mesenchymal and epithelial cells to migrate, divide, and increase collagen and matrix synthesis. PRP, as an adjunctive material with bone grafts during augmentation procedures, has been suggested to increase quality of bone regeneration and the rate of bone deposition.

In a randomized controlled study (n = 10), Kassolis and Reynolds (2005) compared bone formation after sub-antral maxillary sinus augmentation with freeze-dried bone allograft (FDBA) plus PRP versus FDBA plus resorbable membrane. The authors reported that the combination of FDBA and PRP enhanced the rate of formation of bone compared with FDBA and membrane, when used in sub-antral sinus augmentation. The investigators concluded, however, that more studies are needed to determine if such incremental enhancements in bone formation affect clinical outcome.

In a randomized controlled study, Camargo, et al. (2005) compared the clinical effectiveness of a combination therapy consisting of bovine porous bone mineral (BPBM), guided tissue regeneration (GTR), and PRP in the regeneration of periodontal intra-bony defects in humans. Twenty-eight paired intra-bony defects were surgically treated using a split-mouth design. Defects were treated with BPBM, GTR, and PRP (experimental), or with open-flap debridement (control). Clinical parameters evaluated included changes in attachment level, pocket depth, and defect fill as revealed by re-entry at 6 months. Pre-operative pocket depths, attachment levels, and trans-operative bone measurements were similar for the two groups. Post-surgical measurements taken at 6 months revealed that both treatment modalities significantly decreased pocket depth and increased clinical attachment and defect fill compared to baseline. The differences between the experimental and control groups were 2.22 (+/-0.39) mm on buccal and 2.12 (+/-0.34) mm on lingual sites for pocket depth, 3.05 (+/-0.51) mm on buccal and 2.88 (+/-0.46) mm on lingual sites for gain in clinical attachment, and 3.46 (+/-0.96) mm on buccal and 3.42 (+/-0.02) mm on lingual sites for defect fill. These differences between groups were statistically significant in favor of the experimental defects. The combined therapy was also clinically more effective than open-flap debridement. The authors stated that the superiority of the experimental group could not be attributed solely to the surgical intervention and was likely a result of the BPBM/GTR/ PRP application. The authors concluded that combining BPBM, GTR, and PRP was an effective modality of regenerative treatment for intra-bony defects in patients with advanced periodontitis.

Lekovic and colleagues (2003) examined the effectiveness of PRP, BPBM and GTR used in combination as regenerative treatment for grade II molar furcation defects in humans (n = 52). These investigators concluded that the PRP/BPBM/GTR combined technique is an effective modality of regenerative treatment for mandibular grade II furcation defects. Moreover, they stated that further studies are necessary to elucidate the role played by each component of the combined therapy in achieving these results.

Recent reviews have reached contradictory findings regarding the effectiveness of platelet-rich plasma for bone grafting. Marx (2004) stated that PRP remains the only effective growth factor preparation available to oral and maxillofacial surgeons as well as other dental specialists for outpatient use. In contrast, Freymiller and Aghaloo (2004) stated:

"Practitioners involved with bone grafting have high hopes that PRP will be proven to be of benefit in bone graft healing. However, at this early stage of investigation, the results are inconclusive. There is still much to learn regarding PRP before this adjunctive material should be considered for routine use. Unfortunately, this has not been the case because an entire industry has developed to manufacture the equipment and supplies needed for surgeons to prepare PRP in the office or operating room. Courses are being offered throughout the United States touting the benefits of PRP. Considering the meager volume and contradictory nature of the currently available evidence, there appears to be a disproportionate use of PRP in clinical practice."

These authors concluded that more research (especially well-designed, rigorous, standardized human trials) is needed before evidence-based surgeons can feel confident in recommending this procedure/material to their patients.

These conclusions are in agreement with the observations of Sanchez, et al. (2003) and Grageda (2004). Sanchez et al (2003) stated that “there is clearly a lack of scientific evidence to support the use of PRP in combination with bone grafts during augmentation procedures. This novel and potentially promising technique requires well-designed, controlled trials to provide evidence of effectiveness.” Grageda (2004) stated that since the introduction of PRP, several investigators have examined its effectiveness using various bone grafting materials. There have been different protocols as well as different types of clinical cases. The author concluded that “there is an urgent need not just for more, but for standardized research studies in this subject to provide evidence-based dentistry to patients. Without the standardization of these protocols, it will be extremely difficult to ascertain whether PRP enhances bone healing when it is used alone or in conjunction with bone grafting materials.

A systematic evidence review of surgical techniques for placing dental implants prepared for the Cochrane Collaboration (Coulthard, et al., 2003) concluded that there is no strong evidence that the use of PRP or other variations in surgical technique described in the review for placing implants have superior success rates.

Devices to prepare PRP have been cleared by the U.S. Food and Drug Administration based on 510(k) premarket notification. The FDA has required that the product labeling for one such device state that “[t]he Platelet Rich Plasma prepared by this device has not been evaluated for any clinical indications” (Golding, 2004).

Recent studies also produced contradictory findings on the clinical value of PRP. While Okuda et al (2005) reported that treatment with a combination of PRP and porous hydroxyapatite (HA) compared to HA with saline led to a significantly more favorable clinical improvement in intra-bony periodontal defects (n = 70), and Sammartino et al (2005) found that PRP is effective in inducing and accelerating bone regeneration for the treatment of periodontal defects at the distal root of the mandibular second molar after surgical extraction of a mesioangular, deeply impacted mandibular third molar (n = 18), results from other studies indicated that PRP does not provide any added benefits.

In a randomized controlled study (n = 24), Huang et al (2005) examined the effects of PRP in combination with coronally advanced flap (CAF) for the treatment of gingival recession. These investigators concluded that the application of PRP in CAF root coverage procedure provides no clinically measurable enhancements on the final therapeutic outcomes of CAF in Miller's Class I recession defects. Furthermore, in a controlled clinical trial (n = 10), Monov et al (2005) found that the instillation of PRP during implant placement in the lower anterior mandible did not add additional benefit. These findings are in agreement with the observation of Raghoebard et al (2005) who noted that no beneficial effect of PRP on wound healing and bone remodeling of autologous bone grafts used for augmentation of the floor of the maxillary sinus.

In a review on the role of PRP in sinus augmentation, Boyapati and Wang (2006) stated that although the lateral wall sinus lift is a predictable clinical procedure to increase vertical bone height resulting in implant success rates comparable to that of native bone, the issue of extended healing periods remains troublesome. Clinicians and researchers have investigated several methods, including addition of growth factors and peptides, to reduce this healing time and enhance bone formation within the subantral environment. PRP is an autologous blood product containing high concentrations of several growth factors and adhesive glycoproteins. The incorporation of PRP into the sinus graft has been proposed as a method to shorten healing time, enhance wound healing, and improve bone quality. These investigators noted that currently, the literature is conflicting with respect to the adjunctive use of PRP in sinus augmentation. Factors that may contribute to this variability include variable/inappropriate study design, under-powered studies, differing platelet yields, and differing graft materials used. In addition, methods of quantifying bone regeneration and wound healing differ between studies. Currently, because of limited scientific evidence, the adjunctive use of PRP in sinus augmentation cannot be recommended. The authors stated that further prospective clinical studies are urgently needed.

Porcine Intestinal Submucosa Surgical Mesh

The rotator cuff is comprised of four muscles (i.e., infraspinatus, subscapularis, supraspinatus and teres minor) that originate from the scapula. The tendons of these muscles form a single tendon unit, which inserts onto the greater tuberosity of the humerus. These “structures” combine to form a “cuff” over the head of the humerus. The rotator cuff helps to lift and rotate the arm as well as to stabilize the ball of the shoulder within the joint.

Tears of the rotator cuff tendons are one of the most common causes of pain, loss of motion, and disability in adults. Traditional treatments include conservative interventions (e.g., rest and limited overhead activity, use of a sling, non-steroidal anti-inflammatory drugs, oral glucocorticoid, strengthening exercise and physical therapy, intra-articular or subacromial glucocorticosteroid injection), and surgery (arthroscopic or open). Non-surgical treatments, which may take several weeks or months, produce pain relief in approximately 50 % of patients and no improvement in strength at long-term follow-up, whereas surgical intervention results in pain relief in about 85 % of patients and a better return of strength (Ruotolo and Nottage, 2002). Following rotator cuff repair surgery, the arm is immobilized to allow the tear to heal. The length of immobilization is usually dependent on the severity of the tear. Furthermore, patients' commitment/compliance to rehabilitation is important to attain a good surgical outcome.

Recent developments in rotator cuff repair surgery include newer arthroscopic and mini-open surgical techniques. These new techniques are intended to allow for smaller, less painful incisions and faster recovery time. Many of these advances use dissolvable anchors, which hold sutures in place or hold sutures down to bone until the repair has healed and then are absorbed by the body. There is also ongoing research on orthobiologic tissue implants that is intended to enhance healing and promote growth of new tissue.

A surgical mesh composed of porcine small intestinal submucosa (Restore Orthobiologic Soft Tissue Implant, DePuy Orthopaedics, Inc., Warsaw, IN) was cleared for marketing based on a (FDA) 510(k) premarket notification in December 2000. The implant is manufactured from 10 layers of small intestine submucosa derived from porcine small intestine and is mainly composed of water and collagen. According to the FDA, this surgical mesh implant is intended for use in general surgical procedures for reinforcement of soft tissue where weakness exists. The device is intended to act as a resorbable scaffold that initially has sufficient strength to assist with a soft tissue repair, but then resorbs and is replaced by the patient's own tissue. In addition, the implant is intended for use in the specific application of reinforcement of the soft tissues, which are repaired by suture or suture anchors, limited to the supraspinatus, during rotator cuff surgery. According to the manufacturer, this surgical mesh implant is intended to give the surgeon a less invasive treatment when the rotator cuff tissue is of poor quality or the repair needs reinforcement.

Although the Restore orthobiologic implant has been cleared by the FDA for marketing, there is a lack of adequate evidence on the effectiveness of this implant in rotator cuff repair. Malcarney, et al. (2005) presented a case series of 25 patients who underwent rotator cuff repair by one surgeon using this implant to augment the repaired tendon or fill a defect. Four of 25 patients (16 %) experienced an overt inflammatory reaction at a mean of 13 days post-operatively. All patients underwent open irrigation and debridement of the rotator cuff and the implant. The authors concluded that these porcine surgical mesh implants should be used with caution and with the understanding that an early post-operative non-specific inflammatory reaction can occur that may cause breakdown of the repair. Furthermore, these investigators stated that more studies are needed to further characterize the reaction and determine which patients are susceptible.

Zheng, et al. (2005) stated that the small intestinal submucosa (SIS) that is used in this implant is not an acellular collagenous matrix, and contains porcine DNA. They suggested that further studies should be conducted to evaluate the clinical safety and effectiveness of SIS implant biomaterials.

The most frequent side effects encountered in soft tissue repair include infection, adhesions, sterile effusion, instability, increased stiffness post-operatively, and general risks associated with surgery and anesthesia such as neurological, cardiac, and respiratory deficit. Potential device-related risks include stretching or tearing of the device, stiffness, chronic synovitis or effusion, prolonged post-operative rehabilitation, delayed or failed incorporation of the device as well as immunological reaction. Moreover, the porcine surgical mesh implant is contraindicated in patients with massive chronic rotator cuff tears that cannot be mobilized, or where the muscle tissue has undergone substantial fatty degeneration.

Fibrin glue has been used to treat anorectal fistulas in an attempt to avoid more radical surgical intervention. Fibrin glue treatment is simple and repeatable; failure does not compromise further treatment options; and sphincter function is preserved. However, reported success rates vary widely. Suturable bioprosthetic plugs (Surgisis, Cook Surgical, Inc.) have been employed to close the primary opening of fistula tracts. Surgisis is a new 4- or 8-ply bioactive, prosthetic mesh for hernia repair derived from porcine SIS. In a review on resorbable extra-cellular matrix grafts in urological reconstruction, Santucci and Barber (2005) noted that recent problems with inflammation following 8-ply pubovaginal sling use and failures after 1- and 4-ply SIS repair of Peyronie's disease underscore the need for research before wide adoption.

In a prospective cohort study, Johnson and Armstrong (2006) compared fibrin glue versus the anal fistula plug. Patients with high trans-sphincteric fistulas, or deeper, were prospectively enrolled. Patients with Crohn's disease or superficial fistulas were excluded. Age, gender, number and type of fistula tracts, and previous fistula surgeries were compared between groups. Under general anesthesia and in prone jack-knife position, the tract was irrigated with hydrogen peroxide. Fistula tracts were occluded by fibrin glue versus closure of the primary opening using a Surgisis anal fistula plug. A total of 25 patients were prospectively enrolled: 10 patients underwent fibrin glue closure, and 15 used a fistula plug. Patient's age, gender, fistula tract characteristics, and number of previous closure attempts was similar in both groups. In the fibrin glue group, 6 patients (60 %) had persistence of one or more fistulas at 3 months, compared with 2 patients (13 %) in the plug group (p < 0.05, Fisher exact test). The authors concluded that closure of the primary opening of a fistula tract using a suturable biologic anal fistula plug is an effective method of treating anorectal fistulas. The method seems to be more reliable than fibrin glue closure. The greater efficacy of the fistula plug may be the result of the ability to suture the plug in the primary opening, therefore, closing the primary opening more effectively. These investigators noted that further prospective, long-term studies are warranted.

An Interventional Procedure Consultation Document by the National Institute for Health and Clinical Excellence (2006) found insufficient evidence to support the use of porcine intestinal submucosa plugs for repair of anorectal fistula. The NICE assessment concluded: "Current evidence suggests that there are no major safety concerns associated with the closure of anal fistula (fistula in ano) using a suturable bioprosthetic plug. However, evidence on the efficacy of the procedure is not adequate for it to be used without special arrangements for consent and for audit or research." The specialist advisors to NICE commented that there was uncertainty about recurrence rates and the long-term outcomes of this procedure.

Bone Void Fillers for Nonunions

Minimally invasive injectable graft (Wright Medical Technology, Inc., Arlington, TN) is an example of a bone void filler, and is a paste made with calcium sulphate (plaster of Paris). It is injected into osseous defects that are created surgically or as a result of trauma. The paste cures in situ, resorbs, and then is replaced with bone during the healing process. The cured paste provides a temporary support media for bone fragments during the surgical procedure but does not provide structural support during the healing process. Injection of MIIG is usually performed in conjunction with another procedure, such as reduction of a fracture. Minimally invasive injectable graft was cleared by the United States Food and Drug Administration through the 510(k) process since it is substantially equivalent to other bone void fillers on the market. However, there is insufficient evidence to support the use of MIIG or other bone void fillers as a treatment for delayed union or nonunions. A technology assessment prepared by ECRI for Agency for Healthcare Research and Quality (2005) concluded that there is no reliable evidence to support the use of calcium sulphate or other bone void fillers as treatments for delayed fracture healing.

Mesenchymal Stem Cell

Mesenchymal stem cells or MSCs are multipotent stem cells that can differentiate into a variety of cell types. Mesenchymal stem cells have been classically obtained from the bone marrow, and have been shown to differentiate into various cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, and neuronal cells.

Helm and colleagues (2001) stated that although autologous bone remains the gold standard for stimulating bone repair and regeneration, the advent in molecular biology as well as bioengineering techniques has produced materials that exhibit potent osteogenic activities. Recombinant human osteogenic growth factors (e.g., BMP) are now produced in highly concentrated and pure forms and have been shown to be extremely potent bone-inducing agents when delivered in vivo in rats, dogs, primates, and humans. They noted that the delivery of MSCs, derived from adult bone marrow, to regions requiring bone formation is also compelling, and it has been shown to be successful in inducing osteogenesis in many pre-clinical animal studies. Finally, the identification of biological and non-biological scaffolding materials is a crucial component of future bone graft substitutes, not only as a delivery vehicle for bone growth factors and MSCs, but also as an osteo-conductive matrix to stimulate bone deposition directly.

Recently, MSCs has been studied for its use in orthopedic application (e.g., healing long bone defects, intervertebral disc repair and regeneration as well as spinal arthrodesis procedures). Acosta et al (2005) noted that although important obstacles to the survival and proliferation of MSCs within the degenerating intervertebral disc need to be overcome, the potential for this therapy to slow or reverse the degenerative process remains substantial. Leung et al (2006) stated that in the past several years, significant progress has been made in the field of stem cell regeneration of the intervertebral disc. Autogenic MSCs in animal models can arrest intervertebral disc degeneration or even partially regenerate it, and the effect is suggested to be dependent on the severity of degeneration. Mesenchymal stem cells are able to escape alloantigen recognition which is an advantage for allogenic transplantation. A number of injectable scaffolds have been described and various methods to pre-modulate MSCs' activity have been tested. They noted that more work is needed to address the use of MSCs in large animal models as well as the fate of the implanted MSCs, especially the long-term outcomes.

Minamide et al (2007) examined the ability of BMP and basic fibroblast growth factor (FGF) to enhance the effectiveness of bone marrow-derived MSCs in lumbar arthrodesis. They found that MSCs cultured with BMP-2 and basic FGF act as a substitute for autograft in lumbar arthrodesis. This technique may yield a more consistent quality of fusion bone as compared to that with autograft. They stated that these results are encouraging and warrant further studies with the suitable dose of BMP-2 and basic FGF, and may provide a rational basis for their clinical application.

Further investigation is needed to study the value of MSC therapy in orthopedic applications before it can be used in the clinical setting.