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Background
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 Food and Drug Administration (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 HUD 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 multi-center 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 multi-center 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 multi-center 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 % of the OP-1-treated nonunions and 85 % of patients receiving autogenous bone were judged by clinical criteria to have been treated successfully, and 75 % of OP-1 treated patients and 84 % 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 radio-stereometric follow-up analysis during 1 year. No significant difference was observed between the radio-stereometric 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. Vaccaro et al (2008) examined the safety and the clinical and radiographical efficacy of OP-1 (rhBMP-7) Putty as compared with an iliac crest bone autograft control in un-instrumented, single-level postero-lateral spinal arthrodesis. A total of 335 patients were randomized in 2:1 fashion to receive either OP-1 Putty or autograft for degenerative spondylolisthesis and symptomatic spinal stenosis. Patients were observed serially with radiographs, clinical examinations, and appropriate clinical indicators, including Oswestry Disability Index (ODI), Short-Form 36, and visual analog scale scores. Serum samples were examined at regular intervals to assess the presence of antibodies to OP-1. The primary end point, "overall success", was analyzed at 24 months. The study was extended to include additional imaging data and long-term clinical follow-up at 36+ months. At the 36+ month time point, CT scans were obtained in addition to plain radiographs to evaluate the presence and location of new bone formation. Modified overall success, including improvements in ODI, absence of re-treatment, neurological success, absence of device-related serious adverse events, angulation and translation success, and new bone formation by CT scan (at 36+ months), was then calculated using the 24-month primary clinical endpoints, updated retreatment data, and CT imaging and radiographical end points. OP-1 Putty was demonstrated to be statistically equivalent to autograft with respect to the primary end point of modified overall success. The use of OP-1 Putty when compared to autograft was associated with statistically lower intra-operative blood loss and shorter operative times. Although patients in the OP-1 Putty group demonstrated an early propensity for formation of anti-OP-1 antibodies, this resolved completely in all patients with no clinical sequelae. The authors concluded that OP-1 Putty is a safe and effective alternative to autograft in the setting of un-instrumented postero-lateral spinal arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis. Bone morphogenetic protein-2 (BMP-2) was 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 6 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 2 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 to S1 of at least 6 months duration that has not responded to non-operative treatments. The California Technology Assessment Forum 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.” In a study on occipito-cervical fusion using recombinant human BMP-2, Shahlaie and Kim (2008) stated that INFUSE should not be routinely used for occipito-cervical fusion. They noted that further studies are needed to determine if modified techniques such as intra-operative steroids and extended post-operative use of wound drains, can improve safety of its use in the posterior cervical region. 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 2 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 PRP 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 FDA 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. Platelet-rich plasma 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. In a randomized controlled trial, de Vos et al (2010) examined if a PRP injection would improve outcome in chronic mid-portion Achilles tendinopathy. A stratified, block-randomized, double-blind, placebo-controlled study at a single center of 54 randomized patients aged 18 to 70 years with chronic tendinopathy 2 to 7 cm above the Achilles tendon insertion were carried out. The trial was conducted between August 28, 2008, and January 29, 2009, with follow-up until July 16, 2009. Subjects received eccentric exercises (usual care) with either a PRP injection (PRP group) or saline injection (placebo group). Randomization was stratified by activity level. Main outcome measure was the validated Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire, which evaluated pain score and activity level; and was completed at baseline and 6, 12, and 24 weeks. The VISA-A score ranged from 0 to 100, with higher scores corresponding with less pain and increased activity. Treatment group effects were evaluated using general linear models on the basis of intention-to-treat. After randomization into the PRP group (n = 27) or placebo group (n = 27), there was complete follow-up of all patients. The mean VISA-A score improved significantly after 24 weeks in the PRP group by 21.7 points (95 % confidence interval [CI]: 13.0 to 30.5) and in the placebo group by 20.5 points (95 % CI: 11.6 to 29.4). The increase was not significantly different between both groups (adjusted between-group difference from baseline to 24 weeks, -0.9; 95 % CI: -12.4 to 10.6). This CI did not include the pre-defined relevant difference of 12 points in favor of PRP treatment. The authors concluded that among patients with chronic Achilles tendinopathy who were treated with eccentric exercises, a PRP injection compared with a saline injection did not result in greater improvement in pain and activity. In a decision memorandum, the Centers for Medicare & Medicaid Services (CMS, 2008) determined that the evidence is inadequate to conclude that autologous PRP for the treatment of chronic non-healing cutaneous wounds, acute surgical wounds when the autologous PRP is applied directly to the closed incision, or dehiscent wounds improves health outcomes. Therefore, CMS determined that PRP is not reasonable and necessary for the treatment of these indications. Consequently, CMS issued a non-coverage determination for acute surgical wounds when the autologous PRP is applied directly to the closed incision and for dehiscent wounds. CMS also maintained the current non-coverage for chronic, non-healing cutaneous wounds. In a systematic review on the safety and effectiveness of the use of autologous PRP for tissue regeneration, Martínez-Zapata et al (2009) concluded that PRP improves the gingival recession but not the clinical attachment level in chronic periodontitis. In the complete healing process of chronic skin ulcers, the results are inconclusive. There are little data regarding the safety of PRP. There are several methodological limitations and, consequently, future research should focus on strong and well-designed RCTs that evaluate the safety and effectiveness of PRP. Guidelines from the Work Loss Data Institute (2008) on work-related disorders of the elbow state that platelet-rich plasma and autologous blood donation are under study and are not specifically recommended. An assessment by the Institute for Clinical Effectiveness and Health Policy (IECS, 2008) concluded that, "although in vitro, PRP has demonstrated to release growth factors and to improve tendon structure, so far, there is no evidence supporting its use in human beings."
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 pubo-vaginal 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. A guidance document from the National Institute for Health and Clinical Excellence (NICE, 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. Schwandner and Fuerst (2009) analyzed the efficacy of the Surgisis(R) AFP(TM) anal fistula plug and the Surgisis(R) mesh for the closure of complex fistulas in Crohn's disease. All patients with peri-anal Crohn's disease suffering from trans-sphincteric and recto-vaginal fistulas who underwent surgery using the Surgisis(R) anal fistula plug or the Surgisis(R) mesh were prospectively enrolled in this study. Inclusion criteria included trans-sphincteric single-tract fistulas and recto-vaginal fistulas. Surgery was performed using a standardized technique, including irrigation of the fistula tract, placement and internal fixation of the Surgisis(R) anal fistula plug, and combined trans-anal/trans-vaginal excision of recto-vaginal fistula with trans-vaginal placement of the mesh. Success was defined as closure of both internal and external (peri-anal or vaginal) openings, absence of drainage without further intervention, and absence of abscess formation. Follow-up information was obtained from clinical examination 3, 6, 9, and 12 months post-operatively. Within the observation period, a total of 16 procedures were performed. After a mean follow-up of 9 months and 1 patient lost to follow-up, the overall success rate was 75 %. For trans-sphincteric fistulas, the success rate was 77 %, whereas it was 66 % in recto-vaginal fistulas associated with Crohn's disease. All 4 patients with failure had re-operation. Rate of stoma reversal in those patients who had fecal diversion was 66 %. No deterioration of continence was documented. The authors concluded that the short-term success rates are promising; further analysis is needed to explain the definite role of this technique in comparison with traditional surgical techniques. Safar et al (2009) analyzed the efficacy of the Cook Surgisis AFP anal fistula plug for the management of complex anal fistulas. This was a retrospective review of all patients prospectively entered into a database at the authors' institution who underwent treatment for complex anal fistulas using Cook Surgisis AFP anal fistula plug between July 2005 and July 2006. Patient's demographics, fistula etiology, and success rates were recorded. The plug was placed in accordance with the inventor's guidelines. Success was defined as closure of all external openings, absence of drainage without further intervention, and absence of abscess formation. A total of 35 patients underwent 39 plug insertions (22 men; mean age of 46 (range of 15 to 79) years). Three patients were lost to follow-up, therefore, 36 procedures to be analyzed. The fistula etiology was crypto-glandular in 31 (88.6 %) patients and Crohn's disease associated in the other 4 (11.4 %). There were 11 smokers and 3 patients with diabetes. The mean follow-up was 126 days (standard = 69.4). The overall success rate was 5 of 36 (13.9 %). One of the 4 Crohn's disease-associated fistulas healed (25 %) and 4 of 32 (12.5 %) procedures resulted in healing of crypto-glandular fistulas. In 17 patients, further procedures were necessary as a result of failure of treatment with the plug. The reasons for failure were infection requiring drainage and seton placement in 8 patients (25.8 %), plug dislodgement in 3 (9.7 %), persistent drainage/tract and need for other procedures in 20 patients (64.5 %). The authors concluded that the success rate for Surgisis AFP anal fistula plug for the treatment of complex anal fistulas was (13.9 %), which is much lower than previously described. They stated that further analysis is needed to explain significant differences in outcomes. Bone Void Fillers for Nonunions Minimally invasive injectable graft (MIIG) (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 FDA through the 510(k) process since it is substantially equivalent to other bone void fillers on the market. Integra Mozaik Osteoconductive Scaffold (OS) putty (Integra LifeSciences Corp., Plainsboro, NJ) is a synthetic bone void filler manufactured from beta tri-calcium phosphate and type I bovine collagen. Combined with bone marrow aspirate, Integra Mozaik OS is intended for use as a bone void filler of the skeletal system in the extremities, spine,and pelvis. Integra Mozaik OS putty was cleared by the FDA through the 510(k) process since it is substantially equivalent to another bone void filler on the market. According to the FDA 510(k) letter to the manufacturer, it is specifically indicated for use in the treatment of surgically treated osseous defects or osseous defects created from traumatic injury to the bone. Following placement in the body void or gap (defect), Integra Mozaik putty is resorbed and replaced with bone during the healing process. There is insufficient evidence to support the use of MIIG, Integra Mozaik OS putty, or other bone void fillers as a treatment for delayed union or nonunions. Furthermore, 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. A retrospective case series examined the use of AlloMatrix injectable putty in nonunions in multiple bone types (Wilkins and Kelly, 2003). The nonunions were also treated using standard internal/external fixation techniques. The publication did not report prior treatment or the duration of the nonunions prior to the AlloMatrix putty treatment. A technology assessment prepared by the ECRI Institute (Schoelles et al, 2005) for the Agency for Healthcare Research and Quality, commenting on this study, stated that "[w]ithout this information, interpretation of the results is difficult". The study also did not report whether all consecutively treated patients were included or if dropouts occurred during the treatment period. The reported healing rate was 30 of 35 (85 %) in an average of 3.5 months, but healing rates per bone type were not reported. A subsequent study by Ziran and colleagues (2007) reported on an unacceptably high rate of complications with the use of Allomatrix for nonunions. A consecutive series of patients requiring bone grafting for atrophic/avascular nonunions were retrospectively studied. Patients were monitored for healing and adverse effects, which included local or systemic reactions, wound problems, infection, and any secondary surgery caused by graft complications. The investigators reported that over half of the patients (51 %) developed post-operative drainage. Of the 41 patients, 13 (32 %) had drainage that required surgical intervention and 14 (34 %) developed a deep infection. Eleven patients with deep infections also required surgical treatment of drainage. In addition, 19 (46 %) patients did not heal and required secondary surgical intervention. The investigators reported that there were correlations between infection and a history of previously treated infection (p < 0.007), as well as wound drainage (p < 0.001). Failure of treatment correlated to the presence of a post-operative infection (p < 0.001). Other analyses were not performed because of the small sample size, which was because of early termination of the study. The investigators concluded that the use of Allomatrix putty as an alternative for autogenous bone graft in the treatment of nonunions resulted in an unacceptably high rate of complications. The investigators stated: "[a]lthough we recommend further study, we do not recommend the use of Allomatrix for the treatment of nonunions, especially if there is a large volumetric defect or a history of any prior contamination of the tissue bed". 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. Mclain et al (2005) noted that successful arthrodesis in challenging clinical scenarios is facilitated when the site is augmented with autograft bone. The iliac crest has long been the preferred source of autograft material, but graft harvest is associated with frequent complications and pain. Connective tissue progenitor cells aspirated from the iliac crest and concentrated with allograft matrix and demineralized bone matrix provide a promising alternative to traditional autograft harvest. The vertebral body, an even larger reservoir of myeloproliferative cells, should provide progenitor cell concentrations similar to those of the iliac crest. In this study, a total of 21 adults (11 men and 10 women with a mean age of 59 +/- 14 years) undergoing posterior lumbar arthrodesis and pedicle screw instrumentation underwent transpedicular aspiration of connective tissue progenitor cells. Aspirates were obtained from two depths within the vertebral body and were quantified relative to matched, bilateral aspirates from the iliac crest that were obtained from the same patient at the same time. Histochemical analysis was used to determine the prevalence of vertebral progenitor cells relative to the depth of aspiration, the vertebral level, age, and gender, as compared with the iliac crest standard. The cell count, progenitor cell concentration (cells/cc marrow), and progenitor cell prevalence (cells/million cells) were calculated. Aspirates of vertebral marrow demonstrated comparable or greater concentrations of progenitor cells compared with matched controls from the iliac crest. Progenitor cell concentrations were consistently higher than matched controls from the iliac crest (p = 0.05). The concentration of osteogenic progenitor cells was, on the average, 71 % higher in the vertebral aspirates than in the paired iliac crest samples (p = 0.05). With the numbers available, there were no significant differences relative to vertebral body level, the side aspirated, the depth of aspiration, or gender. An age-related decline in cellularity was suggested for the iliac crest aspirates. The authors concluded that the vertebral body is a suitable site for aspiration of bone marrow for graft augmentation during spinal arthrodesis. They also stated that future clinical studies will attempt to confirm the ability to obtain fusion using only this source of connective tissue progenitor cells. Anderson and colleagues (2005) reviewed the rationale and discussed the results of cellular strategies that have been proposed or investigated for disc degeneration. These investigators noted that although substantial work remains, the future of cellular therapies for symptomatic disc degeneration appears promising. They concluded that continued research is warranted to further define the optimal cell type, scaffolds, and adjuvants that will allow successful disc repair in human patients. Risbud and colleagues (2006) evaluated the osteogenic potential of MSCs isolated from the bone marrow of the human vertebral body (VB). Marrow samples from VB of patients undergoing lumbar spinal surgery were collected; marrow was also harvested from the iliac crest (IC). Progenitor cells were isolated and the number of colony forming unit-fibroblastic (CFU-F) determined. The osteogenic potential of the cells was characterized using biochemical and molecular biology techniques. Both the VB and IC marrow generated small, medium, and large sized CFU-F. Higher numbers of CFU-F were obtained from the VB marrow than the IC (p < 0.05). Progenitor cells from both anatomic sites expressed comparable levels of CD166, CD105, CD49a, and CD63. Moreover, progenitor cells from the VB exhibited an increased level of alkaline phosphatase activity. MSCs of the VB and the IC displayed similar levels of expression of Runx-2, collagen Type I, CD44, ALCAM, and ostecalcin. The level of expression of bone sialoprotein was higher in MSC from the IC than the VB. VB and IC cells mineralized their extracellular matrix to a similar extent. The authors concluded that their findings show that CFU-F frequency is higher in the marrow of the VB than the IC. Progenitor cells isolated from both sites respond in a similar manner to an osteogenic stimulus and express common immunophenotypes. Based on these findings, these researchers proposed that progenitor cells from the lumbar vertebral marrow would be suitable candidate for osseous graft supplementation in spinal fusion procedures. They stated that studies must now be conducted using animal models to ascertain if cells of the VB are as effective as those of the IC for the fusion applications. 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. Miscellaneous Interventions: Cheng et al (2010) had previously isolated and identified stem cells from human anterior cruciate ligament (ACL). The purpose of this study was to evaluate the differences in proliferation, differentiation, and extracellular matrix (ECM) formation abilities between bone marrow stem cells (BMSCs) and ACL-derived stem cells (LSCs) from the same donors when cultured with different growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta1). Ligament tissues and bone marrow aspirate were obtained from patients undergoing total knee arthroplasty and ACL reconstruction surgeries. Proliferation, colony formation, and population doubling capacity as well as multi-lineage differentiation potentials of LSCs and BMSCs were compared. Gene expression and ECM production for ligament engineering were also evaluated. It was found that BMSCs possessed better osteogenic differentiation potential than LSCs, while similar adipogenic and chondrogenic differentiation abilities were observed. Proliferation rates of both LSCs and BMSCs were enhanced by bFGF and TGF-beta1. TGF-beta1 treatment significantly increased the expression of type I collagen, type III collagen, fibronectin, and alpha-smooth muscle actin in LSCs, but TGF-beta1 only up-regulated type I collagen and tenascin-c in BMSCs. Protein quantification further confirmed the results of differential gene expression and suggested that LSCs and BMSCs increase ECM production upon TGF-beta1 treatment. In summary, in comparison with BMSCs, LSCs proliferate faster and maintain an undifferentiated state with bFGF treatment, whereas under TGF-beta1 treatment, LSCs up-regulate major tendinous gene expression and produce a robust amount of ligament ECM protein, making LSCs a potential cell source in future applications of ACL tissue engineering. Steinert et al (2011) noted that when ruptured, the ACL of the human knee has limited regenerative potential. However, the goal of this report was to show that the cells that migrate out of the human ACL constitute a rich population of progenitor cells and these researchers hypothesized that they display mesenchymal stem cell (MSC) characteristics when compared with adherent cells derived from bone marrow or collagenase digests from ACL. They showed that ACL outgrowth cells are adherent, fibroblastic cells with a surface immunophenotype strongly positive for cluster of differentiation (CD)29, CD44, CD49c, CD73, CD90, CD97, CD105, CD146, and CD166, weakly positive for CD106 and CD14, but negative for CD11c, CD31, CD34, CD40, CD45, CD53, CD74, CD133, CD144, and CD163. Staining for STRO-1 was seen by immunohistochemistry but not flow cytometry. Under suitable culture conditions, the ACL outgrowth-derived MSCs differentiated into chondrocytes, osteoblasts, and adipocytes and showed capacity to self-renew in an in vitro assay of ligamentogenesis. MSCs derived from collagenase digests of ACL tissue and human bone marrow were analyzed in parallel and displayed similar, but not identical, properties. In situ staining of the ACL suggests that the MSCs reside both aligned with the collagenous matrix of the ligament and adjacent to small blood vessels. The authors concluded that the cells that emigrate from damaged ACLs are MSCs and that they have the potential to provide the basis for a superior, biological repair of this ligament. According to information from the manufacturer, BIO MatrX Structure is a highly porous, synthetic bone graft substitute that sets hard upon implantation for a complete defect fill. The manufacturer states that the resulting osteoconductive scaffold provides inter-connected porosity and high surface area to facilitate cell mediated remodeling and new bone growth. BIO MatrX Generate is a combination of osteoconductive nano-crystalline calcium phosphate and Demineralized Bone Matrix (DBM) that is tested for osteoinductive potential by lot, after sterilization, in an in-vivo athymic nude rodent muscle pouch model. The viscous putty sets hard after closure providing an osteoconductive scaffold to facilitate new bone growth. The manufacturer states that both materials are FDA-cleared to be hydrated with saline or blood; and are indicated as bone void fillers of the pelvis, extremities and the postero-lateral spine. The use of minced cartilage techniques are in the early stages of development. According to the manufacturer, DeNovo NT was developed as a consequence of the need for expanded treatment options for the treatment of cartilage lesions. DeNovo NT (natural tissue) graft and DeNovo ET live chondral engineered tissue graft (Neocartilage) are produced by ISTO Technologies (St. Louis, MO), and exclusively distributed by Zimmer, Inc. (Warsaw, IN). DeNovo NT consists of manually minced cartilage tissue pieces obtained from juvenile allograft donor joints. The tissue fragments are mixed intra-operatively with fibrin glue before implantation. It is thought that mincing the tissue helps with cell migration. As there are no chemicals used and minimal manipulation, it is regulated as an allograft tissue rather than a biological implant. Thus, the allograft tissue does not require FDA approval for marketing. DeNovo NT is currently available in the U.S. Neocartilage uses juvenile allogeneic cartilage cells that are isolated and expanded in-vitro, similar to other ACI techniques. Neocartilage is currently being studied in human clinical trials under an FDA-approved investigational new drug (IND) application. The FDA approved ISTO's IND application in 2006, which allowed them to pursue clinical trials of the product in humans. There are no studies evaluating the DeNovo ET tissue graft in the published medical literature. There are no studies evaluating the DeNovo NT graft in the published medical literature. The manufacturer of DeNovo NT has initiated a post-market, multi-center, longitudinal data collection study to collect clinical outcomes of subjects implanted with DeNovo NT. Data are to be obtained either retrospectively or prospectively from patients implanted or to be implanted with DeNovo NT for the treatment of lesion in the ankle. Data to be collected include details of the operative procedure as well as subjects' pain, function, activity levels, and healthcare resource use through a 5-year post-operative follow-up period. Four U.S. sites are participating in this manufacturer-sponsored observational study with 25 subjects; the study began in 2006 and is expected to be completed in 2013. Ky et al (2008) evaluated the effectivness of the Surgisis (Anal Fistula Plug) in multiple patients and presented early clinical results along with notable clinical observations from their experience. This was a prospective analysis of all patients who received the Anal Fistula Plug for treatment of anorectal fistulas between April 2006 and February 2007. All tracts were irrigated with peroxide, the plug was inserted in the tract, and buried at the internal opening with 2-0 vicryl and mucosal advancement flap. Statistical analysis was performed with Fisher's exact test. A total of 45 patients were treated with the Anal Fistula Plug and 1 patient was lost to follow-up. There were 27 males and 17 females with average age of 44.1 years treated for simple (n = 24) or complex (n = 20) fistulas. Preliminary results indicated an 84 % healing rate by 3 to 8 weeks post-operatively, which progressively declined from 72.7 % at 8 weeks to 62.4 % at 12 weeks and 54.6 % at a median follow-up of 6.5 (range of 3 to 13) months. Long-term Anal Fistula Plug closure rate was significantly higher in patients with simple than complex fistulas (70.8 versus 35 %; p < 0.02) and with non-Crohn's disease versus Crohn's disease (66.7 versus 26.6 %; p < 0.02). Patients with 2 successive plug placements had significantly lower closure rates than patients who underwent placement of the plug once (12.5 versus 63.9 %; p < 0.02). No significant difference in closure rates were found between patients with 1 versus multiple fistula tracts. Post-operative complications included peri-anal abscess in 5 patients (3 Crohn's disease, 2 non-Crohn's disease). The authors concluded that Anal Fistula Plug is most successful in the treatment of simple anorectal fistulas but is associated with a high failure rate in complex fistula and particularly in patients with Crohn's disease. Repeat plug placement is associated with increased failure. Given the relatively low morbidity associated with the procedure, Anal Fistula Plug should be considered as a first-line treatment for patients with simple fistulas and as an alternative in selected patients with complex fistulas. Drawbacks of this study were: (i) small sample size, (ii) short duration of follow-up, and (iii) high failure rate. Buchberg et al (2010) compared the Cook Surgisis AFP plug and the newer Gore Bio-A plug in the management of complex anal fistulas. A retrospective chart review of patients treated with Cook and Gore fistula plugs between August 2007 and December 2009 was performed. Success was defined as closure of all external openings and absence of drainage and abscess formation. Twelve Cook patients underwent 16 plug insertions and 10 Gore patients underwent 11 plug insertions. The overall procedural success rate in the Gore group was 54.5 % (6 of 11) versus 12.5 % (2 of 16) in the Cook group. The reasons for failure were unknown in the majority of patients and plug dislodgement in 2 patients. These short-term results with the Gore fistula plug suggested a higher procedural success rate in comparison to the Cook plug. The authors concluded that patients should be cautioned regarding potentially high failure rates; however, longer follow-up and a larger patient population are needed to confirm significant differences in fistula plug efficacy.
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