Tissue Engineered Skin Substitutes and Growth Factors

Medical Policy: 02.01.17 
Original Effective Date: May 1999 
Reviewed: September 2011 
Revised: January 2010 

Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

Description: 

Tissue engineered skin and platelet-derived growth factors represent significant advancements in wound healing.  A number of skin substitute products are commercially available, while still others are under development.  Skin substitutes are intended to promote the healing of such wounds as skin ulcers and burns by providing protection from infection and a biodegradable scaffold for dermal tissue regeneration.

Platelet-derived growth factor (PDGF) is produced by recombinant DNA technology and stimulates wound healing by promoting cell proliferation and enhancing the formation of granulation tissue.  PDGF is used in the treatment of lower extremity diabetic neuropathic ulcers and chronic pressure ulcers, typically lasts for 20 weeks and can be carried out by the patient or caregiver in the home setting.

The following summary of commercially available skin substitutes describes those products that have substantial relevant evidence on efficacy. This list demonstrated the wide range of types of products available:

AlloDerm® (LifeCell Corporation) is an acellular dermal matrix (allograft) derived from donated human skin tissue supplied by U.S American Association of Tissue Banks-compliant tissue banks suing the standards of the AATB and the U.S. Food and Drug Administration (FDA) guidelines. Acellular tissue matrix is a tissue-replacement product that is created from native human skin and processed so that the basement membrane and cellular matrix remain intact. Since AlloDerm® is regarded as minimally processed and not significantly changed in structure form the natural material; the FDA has classified it as banked human tissue.

AlloMax™ Surgical Graft (Bard Davol) is an acellular non-cross-linked human dermis allograft. It is classified as banked human tissue and does not require FDA approval. (AlloMax was previously marketed as NeoForm™).

Apligraft® (Organogenesis) is a bilayered cell therapy composed of an epidermal layer of living human keratinocytes and a dermal layer of living human fibroblasts. It was FDA-approved in 1998 for use in conjunction with compression therapy for the treatment of non-infected, partial and full-thickness skin ulcers due to venous insufficiency and in 2001 for full-thickness neuropathic diabetic lower extremity ulcers nonresponsive to standard wound therapy.

Biobrane®/Biobrane-L (Smith and Nephew) is a biosynthetic wound dressing constructed of a silicon film with a nylon fabric partially embedded into the film. The fabric creates a complex 3-dimensional structure of tri-filament thread which chemically binds collagen. Blood/sera clot in the nylon matrix, adhering the dressing to the wound until epithelialization occurs.

Dermagraft® (Advanced Tissue Sciences) is composed of cryopreserved human-derived fibroblasts and collagen applied to a bioabsorbable mesh. Dermagraft has been approved by the FDA for repair of diabetic foot ulcers and for use in the treatment of wounds related to dystrophic epidermolysis bullosa.

Epicel® (Genzyme Biosurgery) is a cultured epithelial autograft and is FDA –approved under a humanitarian device exemption (HDE) for the treatment of deep dermal or full-thickness burns comprising a total body surface area of greater than or equal to 30%.

GraftJacket® regenerative Tissue Matrix (KCI) is an acellular regenerative tissue matrix that has been processed from screened donated human skin supplied from U.S. tissue banks. The allograft is processed minimally to remove the epidermal and dermal cells while preserving dermal structure. It is regulated by the FDA as human tissue for transplantation.

Integra® Dermal regeneration Template (Integra LifeSciences) is a bovine, collagen/glycosaminoglycan dermal replacement covered by a silicone temporary epidermal substitute. It is FDA approved for use in post-excisional treatment of life-threatening full-thickness or deep partial-thickness thermal injury where sufficient autograft is not available at the time of excision or not desirable because of the physiological condition of the patient. Integra™ Matrix Wound Dressing and Integra™ meshed Bilayer Wound Matrix are substantially equivalent skin substitutes that are FDA 510(k) approved for other indications.

OASIS™ Wound Matrix (Cook Biotech) is a xenographic collagen scaffold derived from porcine small intestinal mucosa. It was cleared by the FDA’s 510(k) process in 2000 for the management of partial and full-thickness wounds including pressure ulcers, diabetic ulcers, chronic vascular ulcers, tunneled undermined wounds, surgical wounds, trauma wounds, and draining wounds.

OrCel™ (Forticel Bioscience) (formerly called 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 the FDA (pre-market approval) for healing donor site wounds in burn victim and under a humanitarian device exemption 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.

TransCyte™ (Advanced Tissue Sciences) consists of human dermal fibroblasts grown in nylon mesh, combined with a synthetic epidermal layer and was approved by the 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.

Regranex® Gel (Ortho-McNeil-Janssen) contains becaplermin, a human, platelet-derived growth factor, approved by the FDA in 1997 for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue and beyond and have an adequate blood supply. It is indicated as an adjunct to, and not a substitute for, good ulcer care practices. The FDA-approved label contains a warning about increased rate of mortality secondary to malignancy observed in patients treated with 3 or more tubes of Regranex® Gel; this observation occurred in a post-marketing retrospective cohort study. Regranex® Gel should only be used when the benefits are expected to outweigh the risks, and should be used with caution in patients with known malignancy.

Top

Prior Approval: 

Not applicable

Top

Policy: 

Breast reconstructive surgery using AlloDerm® may be considered medically necessary for any of the following:

• 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 post-mastectomy skin flaps that are at risk of dehiscence or necrosis
• the infra-mammary fold and lateral mammary folds have been undermined during mastectomy and re-establishment of these landmarks is needed 

Treatment of chronic, noninfected, full-thickness diabetic lower extremity ulcers using the following tissue-engineered skin substitutes may be considered medically necessary:

• Apligraf®
• Dermagraft®

Treatment of chronic, non-infected, 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:

• Dermagraft®
• 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 children with recessive epidermolysis bullosa who are undergoing reconstructive hand surgery using the following tissue-engineered skin substitute may be considered medically necessary:

• OrCel™

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 greater than or equal to 30% when provided in accordance with the HDE specifications of the FDA)
• Integra™
• TransCyte™

Treatment of fresh, clean, split-thickness donor site wounds in burn victims using the following tissue-engineered skin substitute may be considered medically necessary:

• OrCel™

As an adjunct to treatment of neuropathic diabetic foot ulcers of greater than three weeks duration which have failed to respond to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, joint capsule or bone exposure, the following tissue-engineered skin substitute may be considered medically necessary:

• Apligraf®

Treatment of full-thickness diabetic foot ulcers greater than 6 weeks duration that extend through the dermis but without tendon, muscle, joint capsule or bone exposure may be considered medically necessary with the following tissue-engineered skin substitute:

• Apligraf®

Regranex® Gel may be considered medically necessary as an adjunct to standard wound management for neuropathic diabetic lower extremity ulcers when the following criteria are met:

• Adequate tissue oxygenation, as measured by the transcutaneous partial pressure oxygen of 30 mm Hg or greater on the dorsum of the foot or at the margin of the ulcer
• Full-thickness ulcer extending through the dermis into the subcutaneous tissues
• Participation in a wound management program which includes sharp debridement, pressure relief, and infection control

Regranex® Gel may be considered medically necessary as an adjunct to standard wound management for pressure ulcers when the following criteria are met:

• Full-thickness ulcer extending through the dermis into the subcutaneous tissue
• Ulcer is in an anatomic location that can be offloaded for the duration of treatment
• Albumin concentration > 2.5g/dL
• Total lymphocyte count > 1,000/mm³

All other uses of the allogeneic skin substitutes listed above are considered investigational.

All other uses of Regranex® Gel are considered investigational.

All other skin substitutes not listed above are considered investigational, including, but not limited to:

• AlloPatch HD™
• AlloMax™
• AlloSkin™
• AlloSkin™ RT
• ArthroFlex™ (FlexGraft)
• Avaulta Plus™
• Biobrane®
• BioDfence/BioDfactor
• CellerateRX®
• Conexa™
• CorMatrix®
• CRXa™
• Cymetra®
• DermaMatrix Acellular Dermis
• Durepair Regeneration Matrix®
• Endoform Dermal Template™
• ENDURAgen™
• E-Z Derm™
• FlexHD® Acellular Hydrated Dermis
• GammaGraft
• GraftJacket® Regenerative Tissue Matrix
• GraftJacket® Xpress, injectable
• Hyalomatrix® PA
• Integra™ Flowable Wound Matrix
• Integra Dermal Regeneration Template
• MatriStem® Micromatrix
• MatriStem® Wound Matrix
• MatriStem® Burn Matrix
• Matrix HD™
• MediHoney®
• Mediskin®
• MemoDerm™
• PriMatrix
• Oasis® Burn Matrix
• Oasis® Ultra Tri-Layer Matrix
• Permacol™
• Repriza™
• Strattice™ (xenograft)
• SurgiMend®
• Talymed®
• TenoGlide™
• TheraSkin®Unite™
• Veritas® Collagen Matrix

Top

Procedure Codes and Billing Guidelines: 

• To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9 diagnostic codes.  
• HCPCS Q4100 Skin substitute, not otherwise specified
• HCPCS Q4101 Skin substitute, Apligraf, per sq cm
• HCPCS Q4102 Skin substitute, Oasis wound matrix, per sq cm
• HCPCS Q4103 Skin substitute, Oasis burn matrix, per sq cm
• HCPCS Q4104 Skin substitute, Integra bilayer matrix wound dressing (BMWD), per sq cm
• Q4105 Skin substitute, Integra dermal regeneration template (DRT), per sq cm
• Q4106 Skin substitute, Dermagraft, per sq cm
• Q4107 Skin substitute, GRAFTJACKET, per sq cm
• Q4108 Skin substitute, Integra matrix, per sq cm
• Q4109 Skin substitute, TissueMend, per sq cm
• Q4110 Skin substitute, PriMatrix, per sq cm
• Q4111 Skin substitute, GammaGraft, per sq cm
• Q4116 Skin substitute, AlloDerm, per square centimeter
• Q4122 DermACELL, per sq cm
• Q4123 AlloSkin RT, per sq cm
• Q4124 OASIS ultra tri-layer wound matrix, per sq cm
• Q4125 Arthroflex, per sq cm
• Q4126 MemoDerm, per sq cm
• Q4127 Talymed, per sq cm
• Q4128 FlexHD or AllopatchHD, per sq cm
• Q4129 Unite biomatrix, per sq cm
• Q4130 Strattice TM, per sq cm        
• G0440 Application of tissue cultured allogeneic skin substitute or dermal substitute; for use on lower limb, includes the site preparation and debridement if performed; first 25 sq cm or less
• G0441 Application of tissue cultured allogeneic skin substitute or dermal substitute; for use on lower limb, includes the site preparation and debridement if performed; each additional 25 sq cm                     
• S0157 may be used to report becaplermin gel (Regranex® )
• C9367 Skin substitute, Endoform Dermal Template, per sq cm
• C9365 Oasis Ultra Tri-Layer Matrix, per square centimeter
• 15170 Acellular dermal replacement, trunk, arms, legs; first 100 sq cm or less, or one percent of body area of infants and children
• 15171 Each additional 100 sq cm, or each additional one percent of body area of infants and children
• 15175 Acellular dermal replacement, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; first 100 sq cm or less, or one percent of body area of infants and children
• 15176 Each additional 100 sq cm, or each additional one percent of body area of infants and children, or part thereof
• 15271 Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area
• 15272 Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof (List separately in addition to code for primary procedure)
• 15273 Application of skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children
• 15274 Application of skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof (List separately in addition to code for primary procedure)
• 15275  Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area
• 15276 Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof (List separately in addition to code for primary procedure)
• 15277 Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children
• 15278 Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof (List separately in addition to code for primary procedure)             

Top

Selected References: 

• The Medical Policy Reference Manual (MPRM) developed by the Blue Cross and Blue Shield Association Health Management Systems, based on Technology Evaluation Center (TEC) criteria.
• A review of the medical literature and recommendations from the Medical Policy Advisory Council (MPAC), which assists Wellmark’s medical directors in the development of medical policies.  MPAC is comprised of practicing physicians from Iowa and South Dakota.
• Trent JF, Kirsner RS. Tissue engineered skin: Apligraf, a bi-layered living skin equivalent. International Journal of Clinical Practice 1999 Sep; 52(6):408-413.
• Falanga V, Margolis D, Alvarez O, Auletta M, Naggiacomo F, Altman M, Jensen J, Sabolinski M, Hardin-Young J, and The Human Skin equivalent Investigators Group. Rapid healing of venous ulcers and lack of clinical rejection with an allogenic cultured human skin equivalent. The Archives of Dermatology 1998 March; 134:293-300.
• Veves A, Falanga V, Armstrong DG, Sabolinski ML; The Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 2001 Feb;24(2):290-5.
• Streit M, Barathen LR. Apligraf-a living human skin equivalent for the treatment of chronic wounds. International Journal of Artificial Organs 2000 Dec;23(12):831-3.
• Falanga VJ. Tissue engineering in wound repair. Advances in Skin Wound Care 2000 May-Jun;13(2 Suppl): 15-9.
• Gentzkow GD et. al. Improved healing of diabetic foot ulcer after grafting with a living human dermal replacement.  Wounds 1999;11(3):77-84.
• Gohari S, Gambla C, Healy M, Spaulding G, Gordon KB, Swan J, Cook B, West DP, Lapiere JC.  Evaluation of tissue-engineered skin (human skin substitute) and secondary intention healing in the treatment of full thickness wounds after Mohs micrographic or excisional surgery.  Dermatol Surg. 2002 Dec;28(12):1107-14; discussion 1114.
• Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis.  J Foot Ankle Surg. 2002 Sep-Oct;41(5):291-9.
• Wang HJ, Wan HL, Yang TS, Chen TM and Chang DM.  Acceleration f skin grafting healing by growth factor.  Burns 1996;vol 22(1):10-14.
• Embil JM, Papp K, Sibbald G et al.  Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy.  Wound Repair Regen. 2000 May-Jun;8(3):162-8.
• Bello YM, Phillis TJ.  Recent Advances in Wound Healing. JAMA 2000; 283,(6): 716-718.
• Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg. 2000 Sep;20(3):296-301.
• Sanchez AR, Sheridan PJ, Kupp LI. Is platelet-rich plasma the perfect enhancement factor? A current review. Int J Oral Maxillofac Implants. 2003 Jan-Feb;18(1):93-103.
• TARGET [database online]. Plymouth Meeting (PA): ECRI; January 2002; Bioengineered composite skin substitute for donor sites in burn victims. Available:http://www.ecri.org.
• ECRI. Bioengineered skin and dermal cell replacement for chronic diabetic ulcers. Plymouth Meeting (PA): ECRI Health Technology Assessment Information Service; 2002 Feb. 26 p. (Windows on medical technology; no. 65).
• ECRI. Acellular allograft membrane (GraftJacket) for ligament and tendon repair. Plymouth Meeting (PA): ECRI Health Technology Information Service; 2005 December 20. 6 p. (ECRI Custom Hotline Response). Also available: http://www.ecri.org
• Ehrenreich M, Ruszczak Z. Update on Tissue-Engineered Biological Dressings. Tissue Eng. 2006 Sep;12(9):2407-24.
• Pham C, Greenwood J, Cleland H et al. Bioenginnered skin substitutes for the management of burns: A systematic review. Burns. 2007 Dec;33(8):946-57.
• Carsin H, Ainaud P, Le Bever H et al. Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five year single-center experience with 30 patients. Burns. 2001 Jun;26(4):418-9.
• Barber C, Watt A, Pham C, Humphreys K et al. Influence of bioengineered skin substitutes on diabetic foot ulcer and venous leg ulcer outcomes. J Wound Care. 2008 Dec;17(12):517-27.
• ECRI Institute. AlloDerm versus Autograft for Tissue Regeneration. Plymouth Meeting (PA): ECRI Institute; 2008 Dec 19. 8 p. [ECRI hotine response]. Also available: http://www.ecri.org.
• ECRI Institute. Bioengineered Skin and Dermal Cell Replacement for Chronic Diabetic and Venous Ulcers. Plymouth Meeting (PA): ECRI Institute; 2009 Jan 16. 12 p. [ECRI hotine response]. Also available: http://www.ecri.org.
• ECRI Institute. Platelet-derived Growth Factors for Chronic, Nonhealing Wounds. Plymouth Meeting (PA): ECRI Institute; 2009 Feb 24. 10 p. [ECRI hotine response]. Also available: http://www.ecri.org.
• ECRI Institute. Porcine-derived Extracellular Matrix (OASIS Wound Matrix) for Wound Management. Plymouth Meeting (PA): ECRI Institute; 2009 April 24. 9p. [ECRI hotine response]. Also available: http://www.ecri.org.
• ECRI Institute. Skin Substitutes for Treatment of Burns. Plymouth Meeting (PA): ECRI Institute; 2009 May 12. 10 p. [ECRI hotine response]. Also available: http://www.ecri.org.
• Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound dressing in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology. Adv Skin Wound Care 2010; 23(1):34-8.

Top

Policy History: 

Date                                        Reason                              Action

September 2011                     Annual review                   Policy renewed

Top

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.