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Bio-Engineered Skin and Soft Tissue Substitutes Protocol (701113) Medical Benefit Preauthorization Yes Effective Date: 10/01/16 Next Review Date: 07/17 Review Dates: 03/12, 03/13, 03/14, 03/15, 07/15, 07/16 Preauthorization is required. The following Protocol contains medical necessity criteria that apply for this service. The criteria are also applicable to services provided in the local Medicare Advantage operating area for those members, unless separate Medicare Advantage criteria are indicated. If the criteria are not met, reimbursement will be denied and the patient cannot be billed. Please note that payment for covered services is subject to eligibility and the limitations noted in the patient’s contract at the time the services are rendered. Populations Individuals: • With conditions requiring surgical repair Individuals: • With chronic wounds Individuals: • With burns, skin grafts, or traumatic wounds Interventions Comparators Outcomes Interventions of interest are: Comparators of interest are: Relevant outcomes include: • Bio-engineered soft • Surgical repair alone • Symptoms • Morbid events tissue substitutes • Functional outcomes • Quality of life • Treatment-related morbidity Interventions of interest are: Comparators of interest are: Relevant outcomes include: • Bio-engineered skin • Standard wound care • Disease-specific survival • Symptoms substitutes • Change in disease status • Morbid events • Quality of life Interventions of interest are: Comparators of interest are: Relevant outcomes include: • Bio-engineered skin • Standard wound care • Symptoms • Morbid events substitutes • Functional outcomes • Quality of life • Treatment-related morbidity Description Bio-engineered skin and soft tissue substitutes may be derived from human tissue (autologous or allogeneic), nonhuman tissue (xenographic), synthetic materials, or a composite of these materials. Bio-engineered skin and soft tissue substitutes are being evaluated for a variety of conditions, including breast reconstruction and to aid healing of lower-extremity ulcers and severe burns. Acellular dermal matrix (ADM) products are also being evaluated for soft tissue repair. Summary of Evidence Surgical Repair In individuals who have conditions requiring surgical repair who receive bioengineered soft-tissue substitutes, the evidence incudes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, Page 1 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 functional outcomes, quality of life, and treatment-related morbidity. Overall, there are a limited number of soft-tissue substitutes, and the evidence is limited for any specific product. Following is a description of the evidence for specific indications. Breast Reconstruction Results from an RCT and systematic reviews in unselected populations of breast reconstruction patients found no benefit of ADM allograft compared to standard procedures for breast reconstruction. Reconstructions with ADM have been reported to have higher complication rates than reconstructions without ADM. However, in cases where there is limited breast tissue for coverage, including but not limited to when the use of ADM allows a single-stage reconstruction, the available noncomparative studies may be considered sufficient to permit conclusions about health outcomes that may inform patient decision making about reconstruction options. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. Interpositional Graft after Parotidectomy Two lower quality controlled trials were identified that demonstrated a reduction in the incidence of Frey syndrome with use of an interpositional ADM allograft. Neither study described the method of group assignment or blinding of patients and assessors. The evidence is insufficient to determine the effects of the technology on health outcomes. Tendon Repair One small RCT was identified that found improved outcomes with Graftjacket ADM allograft for rotator cuff repair. Although these results are promising, additional study with a larger number of subjects is needed. The evidence is insufficient to determine the effects of the technology on health outcomes. Fistula Repair One RCT was identified that used an ADM allograft that has not been cleared for marketing in the United States. The evidence is insufficient to determine the effects of the technology on health outcomes. Surgical Repair of Hernias or Parastomal Reinforcement Several comparative studies including RCTs show no difference in outcome between tissue-engineered skin substitutes and either standard synthetic mesh or no reinforcement. The evidence is sufficient to determine qualitatively that the technology is unlikely to improve the net health outcome. Oral Surgery One RCT and one nonrandomized cohort were identified on the use of an ADM allograft (AlloDerm) for root coverage therapy and oral cavity reconstruction following surgical removal of tumors. The studies show that although use of an ADM allograft (AlloDerm) may possibly result in less scar contracture, important health outcomes were not improved over the standard of care. The evidence is insufficient to determine the effects of the technology on health outcomes. Laryngoplasty The effect of micronized ADM (e.g., Cymetra) in laryngoplasty has been reported in case series. Longer term controlled study in a larger number of patients is needed to determine the durability of this procedure and to evaluate the safety of repeat injections. The evidence is insufficient to determine the effects of the technology on health outcomes. Tympanoplasty AlloDerm ADM has been compared with native tissue grafts in a non-RCT. There was no significant difference in Page 2 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 the success rate of the graft (88% for AlloDerm, 89% for fascia grafts, 96.7% for cartilage plus fascia), and there was no significant difference in hearing between the groups at follow-up. Longer-term controlled study in a larger number of patients is needed to determine the durability of this procedure. The evidence is insufficient to determine the effects of the technology on health outcomes. Chronic Wounds In individuals with chronic wounds who receive bioengineered skin substitutes, the evidence includes RCTs. Relevant outcomes include disease-specific survival, symptoms, change in disease status, morbid events, and quality of life. Overall, the number of bio-engineered skin substitutes is large, but the evidence is limited for any specific product. Relatively few products have been compared with the standard of care, and only for some indications. Comparative trials have been identified for use in lower-extremity ulcers (diabetic or venous) and for treatment of burns. In these trials, the healing rates improved roughly 15% to 20%. Several other products/ indications are supported by a U.S. Food and Drug Administration (FDA) humanitarian device exemption. Following is a description of the evidence for specific indications. Diabetic Lower-Extremity Ulcers • RCTs have demonstrated the efficacy of Apligraf, Dermagraft (living cell therapy), and Integra Dermal Regeneration Template (biosynthetic) over the standard of care. Several amniotic membrane products have also been shown to improve healing. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. • Additional study with a larger number of subjects is needed to evaluate the effect of human ADM products and xenogenic skin substitutes (e.g., Oasis Wound Matrix and PriMatrix) in comparison with the current standard of care. The evidence is insufficient to determine the effects of the technology on health outcomes. Lower-Extremity Ulcers due to Venous Insufficiency • RCTs have demonstrated the efficacy of Apligraf living cell therapy and xenogenic Oasis Wound Matrix over the standard of care. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. • In a moderately large RCT, Dermagraft was not shown to be more effective than controls in the primary or secondary end points for the entire population and was slightly more effective than controls (an 8%-15% increase in healing) only in subgroups of patients with ulcer duration of 12 months or less or size of 10 cm or less. The evidence is insufficient to determine the effects of the technology on health outcomes. • In a randomized comparison of EpiFix amniotic membrane versus standard of care that used a primary outcome measure of 40% wound healing, there was no difference between one or two applications of EpiFix and no difference between the experimental and controls groups in complete wound closure at four weeks. Additional study is needed. Additional study with a larger number of subjects is also needed to evaluate the effect of the xenogenic PriMatrix skin substitute in comparison with the current standard of care. The evidence is insufficient to determine the effects of the technology on health outcomes. Dystrophic Epidermolysis Bullosa OrCel (living cell therapy) has received FDA under a humanitarian device exemption. Although case series studies have shown good outcomes in this condition, as this is a rare disorder, it is unlikely that RCTs will be undertaken. The evidence is insufficient to determine the effects of the technology on health outcomes. Burns, Skin Grafts, and Traumatic Wounds In individuals with burns, skin grafts, and traumatic wounds who receive bio-engineered soft-tissue substitutes, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life, and treatment-related morbidity. Overall, there are a limited number of soft-tissue substitutes, Page 3 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 and the evidence is limited for any specific product. Following is a description of the evidence for specific indications. Ocular Burns An RCT of amniotic membrane transplantation did not demonstrate improved outcomes compared to medical therapy. The evidence is insufficient to determine the effects of the technology on health outcomes. Nonocular Burns Epicel (living cell therapy) is FDA-approved under a humanitarian device exemption for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30% or more. A case series showed permanent coverage of a mean of 26% of total BSA. The evidence is insufficient to determine the effects of the technology on health outcomes. Comparative studies have demonstrated improved outcomes for the biosynthetic skin substitute Integra Dermal Regeneration Template for the treatment of burns. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. Skin Grafts Keramatrix (xenogenic skin substitute) was compared with standard of care in a small RCT for healing of skin graft donor sites. Overall results are equivocal. Study in a larger number of patients/wounds is needed. The evidence is insufficient to determine the effects of the technology on health outcomes. Traumatic Wounds Use of biosynthetic Integra Dermal Regeneration Template has been reported in small case series (less than 20 patients) for the treatment of severe wounds with exposed bone, joint, and/or tendon. Controlled trials are needed to evaluate this product/indication. The evidence is insufficient to determine the effects of the technology on health outcomes. Clinical Input Clinical input was obtained on several occasions. The input considered ADM products to be medically necessary for breast reconstruction and for the various products to be similar in efficacy. Input in 2014 was mixed regarding the efficacy of amniotic membrane and xenogenic products. It was concluded that, given the extensive data from case series, as well as the clinical input obtained about the usefulness of this procedure in providing inferolateral support for breast reconstruction, this procedure was changed to medically necessary in breast reconstruction when there is insufficient tissue expander or implant coverage by the pectoralis major muscle and additional coverage is required; when there is viable but compromised or thin postmastectomy skin flaps that are at risk of dehiscence or necrosis; or when the inframammary fold and lateral mammary folds have been undermined during mastectomy and reestablishment of these landmarks is needed. Policy Breast reconstructive surgery using allogeneic acellular dermal matrix products* (including each of the following: AlloDerm®, AlloMaxTM, AlloMend®, DermaMatrixTM, FlexHD®, GraftJacket®; see Policy Guidlelines) may be considered medically necessary, • when there is insufficient tissue expander or implant coverage by the pectoralis major muscle and additional coverage is required, Page 4 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 • when there is viable but compromised or thin post-mastectomy skin flaps that are at risk of dehiscence or necrosis, or • the inframammary fold and lateral mammary folds have been undermined during mastectomy and reestablishment of these landmarks is needed. Treatment of chronic, noninfected, full-thickness diabetic lower extremity ulcers using the following tissueengineered skin substitutes may be considered medically necessary: • Apligraf®** • Dermagraft®** • Integra® Dermal Regeneration Template • Amniotic Membrane Graft* (including each of the following: Biovance®, Epifix®, Grafix™) Treatment of chronic, noninfected, partial- or full-thickness lower extremity skin ulcers due to venous insufficiency, which have not adequately responded following a one-month period of conventional ulcer therapy, using the following tissue-engineered skin substitutes may be considered medically necessary: • Apligraf®** • Oasis™ Wound Matrix*** Treatment of dystrophic epidermolysis bullosa using the following tissue-engineered skin substitutes may be considered medically necessary: • OrCel™ (for the treatment of mitten-hand deformity when standard wound therapy has failed and when provided in accordance with the humanitarian device exemption [HDE] specifications of the FDA)**** Treatment of second- and third-degree burns using the following tissue-engineered skin substitutes may be considered medically necessary: • Epicel® (for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30% or more when provided in accordance with the HDE specifications of the FDA)**** • Integra Dermal Regeneration Template™** *Banked Human Tissue **FDA premarket approval ***FDA 510(k) cleared ****FDA-approved under a humanitarian device exemption (HDE) All other uses of bio-engineered skin and soft tissue substitutes listed above are considered investigational. All other skin and soft tissue substitutes not listed above are considered investigational, including, but not limited to: • ACell® UBM Hydated Wound Dressing • Allowrap™ • Avaulta Plus™ • Alphaplex™ with MariGen Omega3™ • AxoGuard® Nerve Protector (AxoGen) • ACell® UBM Lyophilized Wound Dressing • Amniofix® • BioDfence/BioDfactor • Affinity™ • Aongen™ Collagen Matrix • CellerateRX® • AlloPatch HD™ • ArthroFlex™ (FlexGraft) • Clarix® Flo • AlloSkin™ • Atlas Wound Matrix • Collagen Sponge (Innocoll) • AlloSkin™ RT • Avagen Wound Dressing Page 5 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Collagen Wound Dressing (Oasis Research) • GraftJacket® Xpress, injectable • Oasis® Ultra Tri-Layer Matrix • GUARDIAN • Permacol™ • Collaguard® • HA Absorbent Wound Dressing • PriMatrix™ • CollaSorb™ • Helicoll • Primatrix™ Dermal Repair Scaffold • CollaWound™ • Hyalomatrix® (Laserskin®) • Puros® Dermis • Collexa® • Hyalomatrix® PA • Repliform® • Collieva® • hMatrix® • Repriza™ • Conexa™ • Integra™ Flowable Wound Matrix • Revitalon • Coreleader Colla-Pad • Integra™ Bilayer Wound Matrix • SIS Wound Dressing II • CorMatrix® • Jaloskin® • SS Matrix™ • CRXa™ • MariGen • Stimulen™ Collagen • Cymetra® • MatriDerm® • StrataGraft • Dermadapt™ Wound Dressing • MatriStem® Burn Matrix • Strattice™ (xenograft) • Dermapure • MatriStem® Micromatrix • Suprathel® • Dermavest™ • MatriStem® Wound Matrix • SurgiMend® • DressSkin • Matrix Collagen Wound Dressing • Talymed® • Durepair Regeneration Matrix® • Matrix HD™ • TenoGlide™ • Endoform Dermal Template™ • MediHoney® • TheraForm™ Standard/Sheet • ENDURAgen™ • Mediskin® • TheraSkin® • Excellagen • MemoDerm™ • Unite® Biomatrix • E-Z Derm™ • Neox® Flo • Veritas® Collagen Matrix • FortaDerm™ Wound Dressing • NuShield™ • GammaGraft • Oasis® Burn Matrix • Policy Guidelines Clinical input indicated that the various acellular dermal matrix (ADM) products used in breast reconstruction have similar efficacy. The products listed are those that have been identified for use in breast reconstruction. Additional ADM products may become available for this indication. Medicare Advantage Products are listed alphabetically. Please also note Medicare Advantage guidelines. AlloDerm® Regenerative Tissue Matrix AlloDerm® Regenerative Tissue Matrix is considered medically necessary for the following indications: • Abdominal wall reconstruction • Breast reconstruction after mastectomy for breast cancer Poor general medical condition or any pathology that would limit the blood supply and compromise healing should be considered when selecting patients for implanting AlloDerm® Regenerative Tissue Matrix as such conditions may compromise successful implantation. Apligraf® The patient must be competent and/or have the support system required to participate in follow-up care associated with treatment of the wound with Apligraf®. Page 6 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Apligraf® will be considered medically necessary for the following: • • • When used with standard therapeutic compression for venous stasis ulcers (VSUs): o Only for ulcers that have failed to respond to documented conservative measures of greater than four (4) weeks in duration, that have at minimum included regular dressing changes, debridement of necrotic tissue and standard therapeutic compression. A “failed response” is defined as an ulcer that has increased in size or depth, or for which there has been no change in baseline size or depth and no sign of improvement or indication that improvement is likely, such as granulation, epithelialization, or progress towards closing. Documentation of response, or lack thereof, requires measurement of the ulcer at baseline, following cessation of conservative or conventional management. Documentation should also include measurement of the ulcer immediately prior to the placement of Apligraf®. o Only when adequate treatment of the underlying disease process(es) contributing to the ulcer, e.g., hypertension, is provided and documented in conjunction with the treatment; and o Only for ulcers that are free of infection, redness, drainage, underlying osteomyelitis, surround cellulitis, sinus tracts or tunnels, eschar or any necrotic material that could interfere with the adherence of Apligraf® and wound healing. When used with standard diabetic foot ulcer (DFU) care for neuropathic DFUs: o Only if the patient has the current medical diagnosis of either Type I or Type II diabetes mellitus; o Only if the patient does not have a current HbA1C reading exceeding 12%; o Only for full thickness ulcers of greater than three weeks in duration, which extend through the dermis but without tendon, muscle, capsule or bone exposure; o Only when adequate treatment of the underlying disease process(es) contributing to the ulcer, e.g., diabetes is provided and documented in conjunction with treatment; and o Only for ulcers located on the foot or toes that are free of infection, redness, drainage, underlying osteomyelitis, surrounding cellulitis, tunnels and tracts, eschar or any necrotic material that could interfere with the adherence of Apligraf®, and the process of wound healing. For both VSUs and DFUs all of the following must also be satisfied and documented: o The patient must have adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by physical examination (presence of acceptable peripheral pulses and/or Doppler toe signals and/or ankle-brachial index [ABI] of no less than 0.65 in the limb undergoing the procedure); o Dermal-epidermal tissue (DET) treatment must be used in conjunction with following standard conservative measures: Use of pressure-reducing footwear; A non-weight bearing regiment; Debridement of necrotic and callused tissue when necessary; and Acceptable methods of wound care, such as saline moistened dressings. The use of Apligraf® on ulcers with any of the following conditions is considered not medically necessary: • cellulitis; • osteomyelitis; • necrotic ulcer; Page 7 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes • draining wound; • bone exposed- wound bed; or • clinically significant wound healing impairment due to uncontrolled diabetes. Last Review Date: 07/16 The following uses of Apligraf® are considered not medically necessary: • Use of more than five applications for the same ulcer. (A single application for any particular ulcer is usually all that is required to affect wound healing in those wounds that are likely to be helped by this therapy. Treatment is usually expected to last no more than twelve (12) weeks and to involve a maximum of five applications); • Re-application more frequently than once per week for the same ulcer; • Re-application where initial application has resulted in no decrease in size or depth or increase in granulation tissue, epithelialization, or progress towards closing; • Re-treatment within one year following the last successful application; • Re-treatment of an ulcer following the unsuccessful treatment where it consisted of two failed applications. Dermagraft® Dermagraft® use is considered medically necessary in the following conditions: When used with standard diabetic foot ulcer care for neuropathic diabetic foot ulcers (DFUs): • Only if patient has a current medical diagnosis of Type I or Type II of diabetes mellitus; • Only if the patient does not have a current HbA1C reading exceeding 12%; • Only for full thickness ulcers that have been in existence for greater than six weeks; • Only for ulcers which have failed to respond to documented conservative treatment measures of greater than six weeks; • Only for ulcers located on the foot or toes that are free of infection, redness, drainage, underlying osteomyelitis, surrounding cellulitis, sinus tracts or tunnels, eschar or any necrotic material that could interfere with the adherence of Dermagraft®, and process of wound healing; • Only for ulcers which extend through the dermis but without tendon, muscle, capsule or bone exposure; • The patient must have adequate arterial blood supply as evidenced by ankle-brachial index (ABI) of 0.65 or greater in limb undergoing the procedure. Dermagraft® treatment must be used in conjunction with following standard conservative measures: • Use of pressure-reducing footwear; • A non-weight bearing regimen; • Debridement of necrotic and callused tissue when necessary; • Acceptable methods of wound care, such as saline moistened dressings; and • The patient must be competent and/or have the support system required to participate in follow-up care associated with treatment of the wound with Dermagraft®. The use of Dermagraft® on ulcers with any of the following conditions is considered not medically necessary: • cellulitis; Page 8 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes • osteomyelitis; • necrotic ulcer; • draining wound; • bone exposed-wound bed; or • clinically significant wound healing impairment due to uncontrolled diabetes. Last Review Date: 07/16 Dermagraft® should not be used on wounds that have signs of clinical infections. The following use of Dermagraft® is not medically necessary: • Continued reapplication of Dermagraft® when the treatment is unsuccessful after two applications as evidenced by increased wound size over two successive weeks. • Retreatment of the same ulcer using Dermagraft® within one year following the last successful or unsuccessful treatment . As long as reasonable healing progress is noted, reapplication may continue to a maximum of eight applications in 12 weeks. EpiFix® EpiFix® is considered medically necessary in the wound management for patients with neuropathic diabetic foot ulcers (DFUs) and non-infected partial and full-thickness skin ulcers due to venous insufficiency, i.e., venous stasis ulcers (VSUs) when the following criteria are met: A. When used with standard diabetic foot ulcer care for neuropathic DFUs: • Only if the patient has a current medical diagnosis of either Type I or Type II diabetes mellitus • Only If the patient does not have a current HbA1c reading above 12% • Only for partial or full thickness ulcers of greater than four weeks in duration, with documented failure of prior treatment to heal the wound • Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure • Ulcer exhibits no signs of infection Patient must have adequate circulation to the affected extremity, as evidenced by one of the following during the past 60 days: • TcPO2 with results greater than or equal to 30 mm HG; or • ABI with results of greater than or equal to 0.7 and less than or equal to 1.2; or • Doppler arterial waveforms which are triphasic or biphasic at the ankle of the affected leg. The following conservative measures must be in place: • Debridement of necrotic tissue; • Non-weight bearing regimen; • Use of pressure-reducing footwear. B. When used with standard therapeutic compression for venous stasis ulcers (VSUs): • Only for ulcers that have failed to respond to documented conservative measures of greater than four (4) weeks in duration, that have at minimum included regular dressing changes, debridement of necrotic Page 9 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 tissue and standard therapeutic compression. A “failed response” is defined as an ulcer that has increased in size or depth, or for which there has been no change in baseline size or depth and no sign of improvement or indication that improvement is likely, such as granulation, epithelialization, or progress towards closing. • Conservative methods of wound care include wound tissue hydration with saline, non-adherent dressings, moisture-donating or absorptive dressing (depending on amount of exudate), and compression wraps. • Documentation of response, or lack thereof, requires measurement of the ulcer at baseline, following cessation of conservative or conventional management. Documentation should also include measurement of the ulcer immediately prior to the placement of EpiFix®. • Only when adequate treatment of the underlying disease process(es) contributing to the ulcer, e.g. hypertension, is provided and documented in conjunction with the treatment; and • Only for ulcers that are free of infection, redness, drainage, underlying osteomyelitis, surrounding cellulitis, sinus tracts or tunnels, eschar or any necrotic material that could interfere with the adherence of Epifix® and wound healing. The use of EpiFix® on ulcers with any one of the following conditions is considered not medically necessary: • Osteomyelitis • Cellulitis • Necrotic tissue • Draining wound • Exposed bone • Active infection at wound site • Patients who are currently receiving radiation therapy or chemotherapy • Patients with an allergy to Gentamycin or Streptomycin • Patients whose index diabetic foot ulcer is greater than 25 cm2 • Treatment of the ulcer greater than twelve (12) weeks. The following treatments with EpiFix® are considered not medically necessary: • Reapplication of EpiFix® within one week for the same ulcer. (Treatment with EpiFix® occurs weekly, and is expected to last up to twelve (12) weeks.) • Re-treatment within one year following the last successful application with EpiFix®. • Re-treatment of an ulcer following the unsuccessful treatment where it consisted of two (2) failed EpiFix® applications. Grafix® Grafix® is considered medically necessary in the wound management for patients with diabetic foot ulcers (DFUs) when the following criteria are met: When used with standard diabetic foot ulcer care for DFUs: • Only if the patient has the current medical diagnosis of either Type I or Type II diabetes mellitus Page 10 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 • Only if the patient does not have a current HbA1c reading above 12% • Only for partial or full thickness ulcers of greater than four weeks in duration, with documented failure of prior treatment to heal the wound • Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure • Ulcer must exhibit no signs of infection Patient must have adequate circulation to the affected extremity, as evidenced by one of the following during the past 60 days: • TcPO2 with results ≥ 30mmHG; or • ABI with results of > 0.70 and < 1.20; or • Doppler arterial waveforms which are triphasic or biphasic at the ankle of the affected leg. The following conservative measures must be in place: • Debridement of necrotic tissue; • Non-weight bearing regimen; • Use of pressure-reducing footwear. The use of Grafix® on ulcers with any one of the following conditions is considered not medically necessary: • Osteomyelitis • Cellulitis • Necrotic tissue • Draining wound • Exposed bone • Active infection at wound site • Patients who are currently receiving radiation therapy or chemotherapy • Patients with an allergy to Gentamycin, Vancomycin and Amphotericin • Patients whose index diabetic foot ulcer is greater than 15 cm2 • Treatment of the ulcer greater than twelve (12) weeks These treatments with Grafix® are considered not medically necessary: • Reapplication of Grafix® within one week for the same ulcer. (Treatment with Grafix® occurs weekly, and is expected to last up to twelve (12) weeks). • Re-treatment within one year following the last successful application with Grafix®. • Re-treatment of an ulcer following the unsuccessful treatment where it consisted of two (2) failed Grafix® applications. GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair must be used in conjunction with the following standard conservative measures: • pressure-reducing footwear; Page 11 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes • non-weight bearing regimen; • debridement of necrotic and callused tissue when necessary; and • acceptable standard methods of wound care, such as saline moistened dressings. Last Review Date: 07/16 The patient must be competent and/or have the support system required to participate in follow-up care associated with treatment of the wound with GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair. GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair will be considered medically necessary for the following indications: • augmentation of repairs of large rotator cuff tears or ruptured calcaneal tendons; • treatment of neuropathic diabetic foot ulcers (DFU) with all the following conditions: o patient has a current medical diagnosis of either Type I or Type II diabetes mellitus; and o patient does not have a current HbA1C reading exceeding 12%; and o full thickness ulcers of greater than three weeks duration that extend through the dermis but without tendon, muscle, capsule or bone exposure; and o underlying disease process(es) contributing to the ulcer, e.g., diabetes, is adequately treated and documented; and o ulcers are located on the foot or toes and are free of infection, redness, drainage, underlying osteomyelitis, surrounding cellulitis, tunnels or tracts, eschar or any necrotic material that could interfere with the adherence of GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair and the process of wound healing; and o patient must have adequate arterial blood supply as evidenced by ankle-brachial index (ABI) of 0.65 or greater in the limb undergoing the procedure. The use of GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair on ulcers with any of the following conditions is considered not medically necessary: • cellulitis • osteomyelitis • necrotic ulcer • draining wound • bone exposed wound bed • clinically significant wound healing impairment due to uncontrolled diabetes, poor nutrition and/or general medical condition • autoimmune connective tissue disease. The following uses of GRAFTJACKET® matrix are considered not medically necessary: • Use of more than two applications for the same ulcer. (A single application for any particular ulcer is usually all that is required to achieve wound healing in those wounds that are likely to be helped by this therapy. Treatment is usually expected to last no more than twelve (12) weeks and to involve a maximum of two applications); • Re-application within three weeks for the same ulcer; Page 12 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 • Re-application where initial application has resulted in no decrease in size or depth or increase in granulation tissue, epithelialization, or progress towards closing; • Re-treatment within one year following the last successful application; • Re-treatment of an ulcer following two failed applications. GRAFTJACKET® XPRESS Flowable Soft Tissue Scaffold GRAFTJACKET® XPRESS Flowable Soft Tissue Scaffold is considered investigational. HYALOMATRIX® HYALOMATRIX® is considered medically necessary in the wound management for patients with neuropathic diabetic foot ulcers (DFUs) and non-infected partial and full-thickness skin ulcers due to venous insufficiency, i.e., venous stasis ulcers (VSUs) when the following criteria are met: When used with standard diabetic foot ulcer care for neuropathic DFUs: • Only if the patient has the current medical diagnosis of either Type I or Type II diabetes mellitus • Only if the patient does not have a current HbA1c reading above 12% • Only for partial or full thickness ulcers of greater than four weeks in duration, with documented failure of prior treatment to heal the wound • Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure • Ulcer must exhibit no signs of infection Patient must have adequate circulation to the affected extremity, as evidenced by one of the following during the past 60 days: • TcPO2 with results ≥ 30mmHG; or • ABI with results of ≥ 0.7 and ≤ 1.2; or • Doppler arterial waveforms which are triphasic or biphasic at the ankle of the affected leg. The following conservative measures must be in place: • Debridement of necrotic tissue; • Non-weight bearing regimen; • Use of pressure-reducing footwear. When used with standard therapeutic compression for venous stasis ulcers (VSUs): • Only for ulcers that have failed to respond to documented conservative measures of greater than four (4) weeks in duration, that have at minimum included regular dressing changes, debridement of necrotic tissue and standard therapeutic compression. A “failed response” is defined as an ulcer that has increased in size or depth, or for which there has been no change in baseline size or depth and no sign of improvement or indication that improvement is likely, such as granulation, epithelialization, or progress towards closing. • Conservative methods of wound care include wound tissue hydration with saline, non-adherent dressings, moisture donating or absorptive dressing (depending on amount of exudate), and compression wraps. • Documentation of response, or lack thereof, requires measurement of the ulcer at baseline, following cessation of conservative or conventional management. Documentation should also include measurement of the ulcer immediately prior to the placement of HYALOMATRIX®. Page 13 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 • Only when adequate treatment of the underlying disease process(es) contributing to the ulcer, e.g. hypertension, is provided and documented in conjunction with the treatment; and • Only for ulcers that are free of infection, redness, drainage, underlying osteomyelitis, surrounding cellulitis, sinus tracts or tunnels, eschar or any necrotic material that could interfere with the adherence of HYALOMATRIX® and wound healing. The use of HYALOMATRIX® on ulcers with any one of the following conditions is considered not medically necessary: • Osteomyelitis • Cellulitis • Necrotic tissue • Excessively draining wound • Active infection at wound site • Treatment of the ulcer greater than twelve (12) weeks Treatment with HYALOMATRIX® is considered not medically necessary under the following conditions: • Reapplication within one week for the same ulcer. (Treatment with HYALOMATRIX® usually leads to the desired clinical response with two to three applications. Refractory ulcers may require up to six treatments, separated by as much as three weeks between applications.) • Re-treatment within one year following the last successful application. • Re-treatment of an ulcer following an unsuccessful treatment course which consisted of two failed applications. Integra®Omnigraft Dermal Regeneration Matrix Integra®Omnigraft Dermal Regeneration Matrix is considered medically necessary for the treatment of partial and full thickness neuropathic diabetic foot ulcers (DFUs) that are greater than six weeks in duration, with no capsule, tendon, or bone exposed and when used in conjunction with standard diabetic ulcer care. Integra®Omnigraft Dermal Regeneration Matrix is contraindicated for patients with clinically diagnosed infected wounds and in patients with a known sensitivity to bovine collagen or chondroitin materials. This product should be applied on the day of debridement, delaying the application may substantially impair the take of the material to the wound bed. Integra®Dermal Regeneration Template Integra®Dermal Regeneration Template will be considered medically necessary for the following: • The treatment is for post excisional treatment of life-threatening full-thickness or deep partial-thickness thermal injuries where sufficient autograft is not available at the time of excision or not desirable due to physiological condition of the patient; or • The treatment is indicated for the repair of scar contractures secondary to third degree burns when other therapies have failed, or when donor sites for repair are not sufficient or desirable due to the physiological condition of the patient. These scars must be documented to be disabling (e.g., by limiting elasticity and immobilizing the skin); and • The substitute skin product must be applied on the same day as the initial excision of the recipient site; and Page 14 of 29 Protocol • Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Each piece of this product is for a single use in a single patient only. The device is intended for one-time use. The use of this product in patients with chemical, radiation, or electrical burns should be limited and based on thorough evaluation of the wound by the surgeon. The wound must be documented to be suitable to excisional therapy and that there is likelihood that a viable wound bed will be created by excision. The product is contraindicated for patients with clinically diagnosed infected wounds. In the vast majority of patients, only one application of this skin substitute product would be required. Integra® Bilayer Wound Dressing Integra® Bilayer Wound Dressing is considered investigational. OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix should be used only in cases where the patient is competent and/or has a support system to participate in the follow-up care associated with its use. OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix will be considered medically necessary for the following indications: • Partial and full thickness wounds • Pressure ulcer • Venous stasis ulcers (VSUs) – when ALL the following conditions are met: • o The venous stasis ulcer has been present for greater than one month duration; o The venous stasis ulcer has failed to respond to documented conservative measures of at least four weeks duration. A “failed response” is defined as an ulcer that has increased in size or depth, for which there has been no change in baseline size or depth and no sign of improvement or indication that improvement is likely, such as granulation, epithelialization, or progress towards closing; o Documentation of response or lack thereof requires measurement of the ulcer at baseline and at completion of at least four weeks of standard conservative management. Documentation should also include measurement of the ulcer immediately prior to the placement of OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix and before each additional weekly placement; o Conservative methods of wound care include wound tissue hydration with saline, non-adherent dressings, moisture-donating or absorptive dressing (depending on amount of exudate), and compression wraps. Chronic vascular ulcers o • Ankle Brachial Index (ABI) when applicable must be greater than 0.7 mm HG, in the affected limb being treated. Neuropathic diabetic foot ulcers (DFUs) - when ALL the following conditions are met: o The patient is currently under management for either Type I or Type II diabetes mellitus; o The non-healing diabetic foot ulcer has been present for greater than one month and has a viable wound bed with granulation tissue present; o Standard conservative wound care measures have been tried. Conservative measures include removal of mechanical stress, debridement of necrotic tissue if present, and saline moistened dressings; o The ulcer is located on the foot or toes and there is no exposed bone, tendon, or fascia. Page 15 of 29 Protocol • Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, wound dehiscence). OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix is contraindicated in patients with the following history or conditions and would be considered not medically necessary: • for individuals with rheumatoid arthritis; • history of radiation therapy to the ulcer site; • for uncontrolled congestive heart failure; • for severe arterial disease; • for persons receiving corticosteroids or immunosuppressive therapies; • for individuals with a history of collagen vascular disease; • malnutrition (albumin); • known allergy to porcine-derived products; • ulcers that are clinically infected; • uncontrolled diabetes (HgbA1c greater than 12%); • previous organ transplant; • individuals undergoing hemodialysis; • wounds with signs of cellulitis, osteomyelitis, or necrotic or avascular ulcer beds; • for ulcers with exposed bone, tendon, or fascia; • insufficient blood supply to the ulcer (TcPO2 @ less than 30 mm Hg, toe or ankle brachial index less than 0.7 mm Hg); • active Charcot joint disease or Sickle Cell disease; • third degree burns. The application of OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix to human wounds requires reapplication every five to seven days. Once correctly applied, the wound should be assessed every five to seven days and if appropriate, additional applications of Oasis® should be performed. If wounds/ulcers managed with OASIS® Wound Matrix or OASIS® Ultra Tri-Layer Matrix do not evidence a measurable response after twelve weeks of applications, future applications are considered not medically necessary. Porcine (pig) skin dressings For Medicare Advantage porcine (pig) skin dressings may be medically necessary as an occlusive dressing for burns, donor sites of a homograft, and decubiti and other ulcers. The following are examples of products that are derived from porcine, and because FDA approval is integral to the uses they are deemed reasonable and necessary for, it should be considered: • Oasis™ Wound Matrix (medically necessary indications below) • Permacol™ PrimatrixTM Dermal Repair Scaffold PrimatrixTM Dermal Repair Scaffold will be considered medically necessary for the following: Page 16 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 • Partial thickness wounds • Full thickness wounds with or without exposed bone and/or exposed tendon – when ALL the following conditions are met: o The wound has been determined and documented to be full thickness with or without exposed underlying structures. o The wound has been adequately debrided of necrotic and/or non-viable tissue and results in a bleeding wound bed. o PriMatrix is adequately applied and secured in a manner that maintains contact with the wound bed. o A moist wound environment is maintained but excessive fluid/exudates accumulation is managed by means of appropriate dressing. o The patient must have adequate arterial blood supply to support tissue growth. • Pressure ulcers • Diabetic ulcers – when ALL the following conditions are met: • o The type 1 or type 2 diabetic is under current medical management; and o The diabetic foot ulcer has been present for a minimum of 30 days duration. o The diabetic foot ulcer must have failed to respond to documented conservative measures including aggressive sharp or surgical debridement of necrotic tissue, saline moistened dressings and a nonweight bearing regime. Medical record documentation will contain evidence that the conservative measures have failed as evidenced by an ulcer that has increased in size and/or depth or that there has been no change in baseline size or depth with no sign of improvement or no indication that improvement is likely. o The patient must have adequate arterial blood supply to support tissue growth. o The ulcer must be free of infection and underlying osteomyelitis. Venous ulcers – when ALL the following conditions are met: o The venous stasis ulcer has been present for greater than two months duration and has been refractory to the conservative treatment measures described below for greater than one month. o The venous stasis ulcer must have failed to respond to documented conservative measures including aggressive sharp or surgical debridement of necrotic tissue, saline moistened dressings and compression dressing. Medical record documentation will contain evidence that the conservative measures have failed as evidenced by an ulcer that has increased in size and/or depth or that there has been no change in baseline size or depth with no sign of improvement or no indication that improvement is likely. o PriMatrix is applied in conjunction with adequate compression dressing. o The patient must have adequate arterial blood supply to support tissue growth. • Surgical wounds (donor sites/grafts, post-Mohs surgery, podiatric, wound dehiscence) • Trauma wounds • Tunneled/undermined wounds • Draining wounds. Page 17 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 PrimatrixTM Dermal Repair Scaffold is contraindicated and therefore will be considered not medically necessary for the following: • Use in third-degree burns. Reapplication is required. Once correctly applied, the wound should be assessed every five to seven days and if appropriate, additional applications of PriMatrix™ Dermal Repair Scaffold should be performed. Treatment courses in studies provided by the manufacturer typically varied between seven and thirteen weeks duration and involved a maximum of five applications no less than two weeks apart. TheraSKIN® TheraSKIN® will be considered medically necessary for the same VSU and DFU criteria as Apligraf® above, except conservative measures would have been required for six (6) weeks VSUs. The use of Theraskin on ulcers with any of the following conditions is considered not medically necessary: • cellulitis; • osteomyelitis; • necrotic ulcer; • draining wound; or • clinically significant wound healing impairment due to uncontrolled diabetes. The following treatments with Theraskin are considered not medically necessary: • The use of more than five applications for the same ulcer. (Treatment with TheraSkin® is usually expected to last no more than twelve (12) weeks and to involve a maximum of five TheraSkin® applications for any ulcer that initially qualifies for treatment.) • Re-application of TheraSkin® within one week for the same ulcer. • Re-application of TheraSkin® where initial application has resulted in no decrease in size or depth or increase in granulation tissue, epithelialization, or progress towards closing. • Re-treatment within one year following the last successful application with TheraSkin®. • Re-treatment of an ulcer following the unsuccessful treatment where it consisted of two failed TheraSkin® applications. Medicare Advantage Policy Guidelines In addition to the specific products discussed above, this is general information regarding biologic products for wound treatment and surgical interventions. Types of wound coverings, skin substitutes, or other tissue substitutes: 1. Dermal and/or epidermal, (substitute) tissue of human origin or non-human origin, with or without bioengineered or processed elements, with or without metabolically active elements, solid or injectable; 2. Allograft skin for temporary wound closure; 3. Xenograft, skin (dermal), for temporary wound closure; 4. Tissue cultured epidermal autograft; 5. Tissue cultured allogeneic skin substitute; Page 18 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 6. Tissue cultured allogeneic dermal substitute; and 7. Biologic Wound Dressings. The Food and Drug Administration (FDA) distinguishes between products according to function (wound management, e.g., wound dressings and wound treatment, e.g., bioactive skin substitutes.) The former (Class II) requires 510(k) pre-market notification for FDA clearance while the latter (Class III) requires pre-market approval. Human tissue products (acellular) require no FDA clearance or approval and are intended for homologous use only. [Title 21 Code of Federal Regulations (CFR), Section 1271.10(a) 2005] Medicare Advantage considers Class II or Human Tissue products investigational unless otherwise specified in the biologic product criteria above. Medicare Advantage will consider the use of Class III products medically necessary when used in keeping with the FDA’s approved indications for those products unless otherwise specified in the criteria above. Also refer to the general business policy statements above when otherwise not specifically addressed in this Medicare Advantage section and not contradictory to these general statements. For example, general business policy statements and regulatory status sections above provide some FDA information for the following which are not discussed separately in this Medicare Advantage criteria section: Epicel®, OrCel™, TransCyte™, and for Dermagraft® for wounds related to dystrophic epidermolysis bullosa. Background Bio-engineered skin and soft tissue substitutes may be either acellular or cellular. Acellular products (e.g., dermis with cellular material removed) contain a matrix or scaffold composed of materials such as collagen, hyaluronic acid, and fibronectin. Acellular dermal matrix products can differ in a number of ways, including as species source (human, bovine, porcine), tissue source (e.g., dermis, pericardium, intestinal mucosa), additives (e.g., antibiotics, surfactants), hydration (wet, freeze dried) and required preparation (multiple rinses, rehydration). Cellular products contain living cells such as fibroblasts and keratinocytes within a matrix. The cells contained within the matrix may be autologous, allogeneic, or derived from other species (e.g., bovine, porcine). Skin substitutes may also be composed of dermal cells, epidermal cells, or a combination of dermal and epidermal cells and may provide growth factors to stimulate healing. Tissue-engineered skin substitutes can be used as either temporary or permanent wound coverings. There are a large number of potential applications for artificial skin and soft tissue products. One large category is nonhealing wounds, which potentially encompasses diabetic neuropathic ulcers, vascular insufficiency ulcers, and pressure ulcers. A substantial minority of such wounds do not heal adequately with standard wound care, leading to prolonged morbidity and increased risk of mortality. For example, nonhealing lower-extremity wounds represent an ongoing risk for infection, sepsis, limb amputation, and death. Bio-engineered skin and soft tissue substitutes have the potential to improve rates of healing and reduce secondary complications. The preferred outcomes for the healing of lower-extremity ulcers and burn wounds are the percentage of patients with complete wound healing and the time to complete wound healing.1 The percentage of patients with 50% wound healing and time to 50% wound healing have also been considered to be appropriate outcomes for these conditions.2 The percent change in wound area at four weeks is predictive of complete healing at 12 weeks in patients with diabetic foot ulcers.3 Thus, minimal improvement at 30 days can be considered as an indicator that a wound is unlikely to heal in patients with comorbidities that are known to affect wound healing. Page 19 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Other situations in which bio-engineered skin products might substitute for living skin grafts include certain postsurgical states (e.g., breast reconstruction) in which skin coverage is inadequate for the procedure performed, or for surgical wounds in patients with compromised ability to heal. Second- and third-degree burns are another situation in which artificial skin products may substitute for auto- or allografts. Certain primary dermatologic conditions that involve large areas of skin breakdown, (e.g., bullous diseases) may also be conditions in which artificial skin products can be considered as substitutes for skin grafts. Acellular dermal matrix products are also being evaluated in the repair of other soft tissues including rotator cuff repair, following oral and facial surgery, hernias, and other conditions. Regulatory Status A large number of artificial skin products are commercially available or in development. The following summary of commercially available skin substitutes describes those products that have substantial relevant evidence on efficacy. Information on other artificial skin and soft tissue substitutes that are available in the United States may be found in a 2012 Technology Assessment from the Agency for Healthcare Research and Quality.4 Acellular Dermal Matrix Products Allograft ADM products derived from donated human skin tissue are supplied by tissue banks compliant with standards of the American Association of Tissue Banks (AATB) and U.S. Food and Drug Administration (FDA) guidelines. The processing removes the cellular components (i.e., epidermis and all viable dermal cells) that can lead to rejection and infection. ADM products from human skin tissue are regarded as minimally processed and not significantly changed in structure from the natural material; FDA classifies it as banked human tissue and therefore, does not require FDA approval. • AlloDerm® (LifeCell Corp.) is an ADM (allograft) tissue-replacement product that is created from native human skin and processed so that the basement membrane and cellular matrix remain intact. Originally, AlloDerm required refrigeration and rehydration before use. It is currently available in a ready-to-use product that is stored at room temperature. An injectable micronized form of AlloDerm (Cymetra) is available. • AlloMax™ Surgical Graft (Bard Davol) is an acellular non-cross-linked human dermis allograft. (AlloMax was previously marketed as NeoForm™.) • FlexHD® (Ethicon) is an acellular hydrated dermis derived from donated human allograft skin. The Musculoskeletal Transplant Foundation acquires and processes the tissue. • DermACELL™ (LifeNet Health) is an allogeneic ADM processed with proprietary technologies MATRACELL® and PRESERVON®. • DermaMatrix™ (Synthes) is a freeze-dried ADM derived from donated human skin tissue. DermaMatrix Acellular Dermis is processed by the Musculoskeletal Transplant Foundation® (MTF®). • DermaPure™ (Tissue Regenix Wound Care) is a single-layer decellularized human dermal allograft for the treatment of acute and chronic wounds. • Graftjacket® Regenerative Tissue Matrix (also called Graftjacket Skin Substitute, KCI) is an acellular regenerative tissue matrix that has been processed from human skin supplied from U.S. tissue banks. The allograft is minimally processed to remove the epidermal and dermal cells, while preserving dermal structure. Graftjacket Xpress® is an injectable product. FDA product code: FTM, OXF. Page 20 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Xenogenic Products Keramatrix® (Keraplast Research) is an open-cell foam comprised of freeze-dried keratin that is derived from acellular animal protein. In 2009, it was cleared for marketing by FDA through the 510(k) marketing process under the name of Keratec. The wound dressings are indicated in the management of the following types of dry, light, and moderately exudating partial and full-thickness wounds, pressure (stage I-IV) and venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers, donor sites, and grafts. Helicoll (Encol) is an acellular collagen matrix from bovine dermis. In 2004, it was cleared by FDA through the 510(k) process for topical wound management that includes partial and full-thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (e.g., abrasions, lacerations, seconddegree burns, skin tears), and surgical wounds including donor sites/grafts. Permacol™ (Covidien) is xenogeneic and composed of cross-linked porcine dermal collagen. Cross-linking improves the tensile strength and long-term durability, but decreases pliability. PriMatrix™ (TEI Biosciences) is a xenogeneic ADM processed from fetal bovine dermis. It was cleared for marketing by FDA through the 510(k) process for partial- and full-thickness wounds; diabetic, pressure, and venous stasis ulcers; surgical wounds; and tunneling, draining, and traumatic wounds. FDA product code: KGN. SurgiMend® PRS (TEI Biosciences) is a xenogeneic ADM processed from fetal bovine dermis. This product is currently undergoing an FDA-regulated investigational device exemption (IDE) trial for breast reconstruction. Strattice™ Reconstructive Tissue Matrix (LifeCell Corp.) is a xenogenic non-cross-linked porcine-derived ADM. There are pliable and firm versions, which are stored at room temperature and come fully hydrated. OASIS™ Wound Matrix (Cook Biotech) is a xenogeneic collagen scaffold derived from porcine small intestinal mucosa. In 2000, it was cleared for marketing by FDA through the 510(k) process for the management of partialand full-thickness wounds including pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled undermined wounds, surgical wounds, trauma wounds, and draining wounds. FDA Product code: KGN. Amniotic Membrane Products Amniotic membrane consists of two conjoined layers, the amnion and chorion, and forms the innermost lining of the amniotic sac or placenta.5 It is harvested immediately after birth, cleaned, sterilized, and either fresh frozen or dehydrated. Human amniotic membrane is considered to be minimally processed and not significantly changed in structure from the natural material; FDA classifies it as banked human tissue and, therefore, it does not require FDA approval. Amniotic membrane sheet products include Affinity™ (NuTech Medical), AlloWrap™ (AlloSource), AmnioBand and GUARDIAN (Musculoskeletal Transplant Foundation), AmnioGraft® (Bio-Tissue), BioDfence™ and BioDDryFlex® (both from BioD), Biovance® (Alliqua Biomedical), Dermavest™ and Plurivest™ (Aedicell), EpiFix® (dehydrated-MiMedix) Neox®1000 (Amniox® Medical), Grafix® Prime and Grafix® Core (cryopreserved, Osiris), NuShield™ (NuTech Medical), Revitalon™ (previously known as AmnioClear, Medline Industries). Injectable amniotic membrane products, such as AmnioFix® (MiMedix), are not discussed in this Protocol. Living Cell Therapy Apligraf® (Organogenesis) is a bilayered living cell therapy composed of an epidermal layer of living human keratinocytes and a dermal layer of living human fibroblasts. Apligraf® is supplied as needed, in one size, with a shelf-life of 10 days. In 1998, it was approved by FDA for use in conjunction with compression therapy for the treatment of noninfected, partial- and full-thickness skin ulcers due to venous insufficiency and in 2001 for fullthickness neuropathic diabetic lower-extremity ulcers nonresponsive to standard wound therapy. FDA product code: FTM. Page 21 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Dermagraft® (Organogenesis) is composed of cryopreserved human-derived fibroblasts and collagen derived from newborn human foreskin and cultured on a bioabsorbable polyglactin mesh scaffold. Dermagraft has been approved by FDA for repair of diabetic foot ulcers. FDA product code: PFC. TheraSkin® (Soluble Systems) is a cryopreserved human skin allograft composed of living fibroblasts and keratinocytes and an extracellular matrix in epidermal and dermal layers. TheraSkin® is derived from human skin allograft in compliance with the AATB and FDA guidelines. It is considered a minimally processed human cell, tissue, and cellular- and tissue-based product by the FDA. Epicel® (Genzyme Biosurgery) is a cultured epithelial autograft and is FDA-approved under an HDE for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30% or more. It may be used in conjunction with split-thickness autografts or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. FDA product code: OCE. OrCel™ (Forticell Bioscience; formerly Composite Cultured Skin) is an absorbable allogeneic bilayered cellular matrix, made of bovine collagen, in which human dermal cells have been cultured. It was approved by FDA premarket approval for healing donor site wounds in burn victims and under an HDE for use in patients with recessive dystrophic epidermolysis bullosa undergoing hand reconstruction surgery to close and heal wounds created by the surgery, including those at donor sites. FDA product code: ODS. Biosynthetic Products Biobrane®/Biobrane-L (Smith and Nephew) is a biosynthetic wound dressing constructed of a silicon film with a nylon fabric partially imbedded into the film. The fabric creates a complex three-dimensional structure of trifilament thread, which chemically binds collagen. Blood/sera clot in the nylon matrix, adhering the dressing to the wound until epithelialization occurs. FDA product code: FRO. Integra® Dermal Regeneration Template (marketed as Omnigraft Dermal Regeneration Matrix, Integra LifeSciences) is a bovine, collagen/glycosaminoglycan dermal replacement covered by a silicone temporary epidermal substitute. It was approved by FDA for use in postexcisional treatment of life- threatening fullthickness or deep partial-thickness thermal injury where sufficient autograft is not available at the time of excision or not desirable because of the physiologic condition of the patient. Integra™ Matrix Wound Dressing and Integra™ meshed Bilayer Wound Matrix are substantially equivalent skin substitutes approved by FDA through the 510(k) process for other indications. Integra® Bilayer Wound Matrix (Integra LifeSciences) is designed to be used in conjunction with negative pressure wound therapy. The meshed bilayer provides a flexible wound covering and allows drainage of wound exudate. FDA product code: MDD. TransCyte™ (Advanced Tissue Sciences) consists of human dermal fibroblasts grown on nylon mesh, combined with a synthetic epidermal layer and was approved by FDA in 1997. TransCyte is intended to be used as a temporary covering over burns until autografting is possible. It can also be used as a temporary covering for some burn wounds that heal without autografting. Synthetic Products Suprathel® (PolyMedics Innovations) is a synthetic copolymer membrane fabricated from a tripolymer of polylactide, trimethylene carbonate, and s-caprolactone. It is used to provide temporary coverage of superficial dermal burns and wounds. Suprathel® is covered with gauze and a dressing that is left in place until the wound has healed. Related Protocol Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions Page 22 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 Services that are the subject of a clinical trial do not meet our Technology Assessment Protocol criteria and are considered investigational. For explanation of experimental and investigational, please refer to the Technology Assessment Protocol. It is expected that only appropriate and medically necessary services will be rendered. We reserve the right to conduct prepayment and postpayment reviews to assess the medical appropriateness of the above-referenced procedures. Some of this Protocol may not pertain to the patients you provide care to, as it may relate to products that are not available in your geographic area. References We are not responsible for the continuing viability of web site addresses that may be listed in any references below. 1. U.S. Food and Drug Administration. Guidance for industry: Chronic cutaneous ulcer and burn wounds. 2006; http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071324. pdf. Accessed December 23, 2015. 2. European Wound Management Association. Outcomes in controlled and comparative studies on nonhealing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care 2010; 19(6): 239-268. Accessed December 23, 2015. 3. Sheehan P, Jones P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. Jun 2003; 26(6):1879-1882. PMID 12766127 4. Snyder DL, Sullivan N, Schoelles KM. Skin Substitutes for Treating Chronic Wounds. Research conducted by the ECRI Institute Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract Number: HHSA 290-2007-10063). 2012; http://www.ahrq.gov/research/findings/ta/skinsubs/HCPR0610_skinsubst-final.pdf. Accessed November, 2014. 5. Zelen CM, Snyder RJ, Serena TE, et al. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. Jan 2015; 32(1):135-146. PMID 25440424 6. Davila AA, Seth AK, Wang E, et al. Human acellular dermis versus submuscular tissue expander breast reconstruction: a multivariate analysis of short-term complications. Arch Plast Surg. Jan 2013; 40(1):19-27. PMID 23362476 7. Ho G, Nguyen TJ, Shahabi A, et al. A systematic review and meta-analysis of complications associated with acellular dermal matrix-assisted breast reconstruction. Ann Plast Surg. Apr 2012; 68(4):346-356. PMID 22421476 8. Kim JY, Davila AA, Persing S, et al. A meta-analysis of human acellular dermis and submuscular tissue expander breast reconstruction. Plast Reconstr Surg. Jan 2012; 129(1):28-41. PMID 22186498 9. Govshievich A, Somogyi RB, Brown MH. Conservative mastectomies and immediate reconstruction with the use of ADMs. Gland Surg. Dec 2015; 4(6):453-462. PMID 26644999 10. Hunsicker LM, Ashikari AY, Berry C, et al. Short-Term Complications Associated With Acellular Dermal Matrix-Assisted Direct-to-Implant Breast Reconstruction. Ann Plast Surg. Feb 5 2016. PMID 26849284 Page 23 of 29 Protocol Bio-Engineered Skin and Soft Tissue Substitutes Last Review Date: 07/16 11. Salzberg CA, Ashikari AY, Koch RM, et al. An 8-year experience of direct-to-implant immediate breast reconstruction using human acellular dermal matrix (AlloDerm). Plast Reconstr Surg. Feb 2011; 127(2):514524. PMID 21285756 12. McCarthy CM, Lee CN, Halvorson EG, et al. The use of acellular dermal matrices in two-stage expander/ implant reconstruction: a multicenter, blinded, randomized controlled trial. Plast Reconstr Surg. Nov 2012; 130(5 Suppl 2):57S-66S. PMID 23096987 13. Preminger BA, McCarthy CM, Hu QY, et al. The influence of AlloDerm on expander dynamics and complications in the setting of immediate tissue expander/implant reconstruction: a matched-cohort study. Ann Plast Surg. May 2008; 60(5):510-513. PMID 18434824 14. Liu DZ, Mathes DW, Neligan PC, et al. Comparison of outcomes using AlloDerm versus FlexHD for implantbased breast reconstruction. Ann Plast Surg. May 2014; 72(5):503-507. PMID 23636114 15. Seth AK, Persing S, Connor CM, et al. A comparative analysis of cryopreserved versus prehydrated human acellular dermal matrices in tissue expander breast reconstruction. Ann Plast Surg. Jun 2013; 70(6):632635. PMID 23429218 16. Brooke S, Mesa J, Uluer M, et al. 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Complications of alloderm and dermamatrix for parotidectomy reconstruction. Head Neck. Jan 2012; 34(1):88-93. PMID 21469246 21. Barber FA, Burns JP, Deutsch A, et al. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. Jan 2012; 28(1):8-15. PMID 21978432 22. ba-bai-ke-re AMM, Wen H, Huang HG, et al. Randomized controlled trial of minimally invasive surgery using acellular dermal matrix for complex anorectal fistula. World J Gastroenterol. Jul 14 2010; 16(26):3279-3286. PMID 20614483 23. Bellows CF, Smith A, Malsbury J, et al. Repair of incisional hernias with biological prosthesis: a systematic review of current evidence. Am J Surg. Jan 2013; 205(1):85-101. PMID 22867726 24. Zhong T, Janis JE, Ahmad J, et al. Outcomes after abdominal wall reconstruction using acellular dermal matrix: a systematic review. J Plast Reconstr Aesthet Surg. Dec 2011; 64(12):1562-1571. PMID 21624851 25. 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