Bioengineered Skin and Soft Tissue Substitutes

POLICY NUMBER

A.7.01.113

DESCRIPTION

Bioengineered 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. Bioengineered skin and soft tissue substitutes are being evaluated for a variety of conditions, including breast reconstruction and healing lower-extremity ulcers and severe burns. Acellular dermal matrix (ADM) products are also being evaluated for soft tissue repair.

Skin and Soft Tissue Substitutes

Bioengineered skin and soft tissue substitutes may be either acellular or cellular. Acellular products (eg, dermis with cellular material removed) contain a matrix or scaffold composed of materials such as collagen, hyaluronic acid, and fibronectin. Acellular dermal matrix (ADM) products can differ in a number of ways, including by species source (human, bovine, porcine), tissue source (eg dermis, pericardium, intestinal mucosa), additives (eg 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 (eg, 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. Bioengineered skin substitutes can be used as either temporary or permanent wound coverings.

ApplicationsThere 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. Bioengineered skin and soft tissue substitutes have the potential to improve rates of healing and reduce secondary complications.

Other situations in which bioengineered skin products might substitute for living skin grafts include certain postsurgical states (eg, 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 indication in which artificial skin products may substitute for auto- or allografts. Certain primary dermatologic conditions that involve large areas of skin breakdown (eg, 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.

The U.S. Food and Drug Administration (FDA) does not refer to any single product or class of products as “skin substitutes." Products in this policy cover products that do not require FDA approval or clearance as well as a number of products cleared through the 510(k) pathway with a variety of FDA product codes. A large number of artificial skin and soft-tissue products are commercially available or in development. Commercial availability is not a reflection of a product's regulatory status. The following section summarizes a subset of commercially available skin and soft-tissue substitutes. This is not a complete list of all commercially available products. Information on additional products is available in a 2020 Technical Brief on skin substitutes for treating chronic wounds that was commissioned by the Agency for Healthcare Research and Quality.

Acellular Dermal Matrix Products

Allograft acellular dermal matrix (ADM) products derived from donated cadaveric human skin tissue are supplied by tissue banks compliant with standards of the American Association of Tissue Banks and U.S. Food and Drug Administration (FDA) guidelines. The processing removes the cellular components (ie, epidermis, 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; The FDA classifies ADM products as banked human tissue and therefore, not requiring FDA approval for homologous use.

In 2017, the FDA published clarification of what is considered minimal manipulation and homologous use for human cells, tissues, and cellular and tissue-based products (HCT/Ps).

HCT/Ps are defined as human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. If an HCT/P does not meet the criteria below and does not qualify for any of the stated exceptions, the HCT/P will be regulated as a drug, device, and/or biological product and applicable regulations and premarket review will be required.

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria:

1. "The HCT/P is minimally manipulated;

2. The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;

3. The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and

4. Either:

   1. The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or

   2. The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:

      1. Is for autologous use;

      2. Is for allogeneic use in a first-degree or second-degree blood relative; or

      3. Is for reproductive use."

• AlloDerm® (LifeCell Corp.) is an ADM (allograft) tissue-replacement product 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 stored at room temperature. An injectable micronized form of AlloDerm® (Cymetra) is available.

• AlloPatch® (Musculoskeletal Transplant Foundation) is an acellular human dermis allograft derived from the reticular layer of the dermis and marketed for wound care. This product is also marketed as FlexHD® for postmastectomy breast reconstruction.

• Cortiva® (previously marketed as AlloMax™ Surgical Graft and before that NeoForm™) is an acellular non-cross-linked human dermis allograft.

• FlexHD® and the newer formulation FlexHD® Pliable™ (Musculoskeletal Transplant Foundation) are acellular hydrated reticular dermis allograft derived from donated human skin.

• 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.

• 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.

• mVASC® (MicroVascular Tissues, Inc.) is a microvascular tissue structural allograft made of small blood vessels and extracellular matrix, inherent non-viable cells, and associated biological signaling factors harvested from subcutaneous tissue of cadaveric human donors.

• TheraSkin® (LifeNet Health) is a cryopreserved split-thickness 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 supplied by tissue banks compliant with the American Association of Tissue Banks and FDA guidelines. It is considered a minimally processed human cell, tissue, and cellular- and tissue-based product by the FDA.

Although frequently used by surgeons for breast reconstruction, the FDA does not consider this homologous use and has not cleared or approved any surgical mesh device (synthetic, animal collagen-derived, or human collagen-derived) for use in breast surgery. The indication of surgical mesh for general use in “Plastic and reconstructive surgery” was cleared by the FDA before surgical mesh was described for breast reconstruction in 2005. The FDA states that the specific use of surgical mesh in breast procedures represents a new intended use and that a substantial equivalence evaluation via 510(k) review is not appropriate and a pre-market approval evaluation is required.

In March 2019, the FDA held an Advisory Committee meeting on breast implants, at which time the panel noted that while there is data about ADM for breast reconstruction, the FDA has not yet determined the safety and effectiveness of ADM use for breast reconstruction. The panel recommended that patients are informed and also recommended studies to assess the benefit and risk of ADM use in breast reconstruction.

In March 2021, the FDA issued a Safety Communication to inform patients, caregivers, and health care providers that certain ADM products used in implant-based breast reconstruction may have a higher chance for complications or problems. An FDA analysis of patient-level data from real-world use of ADMs for implant-based breast reconstruction suggested that 2 ADMs—FlexHD and Allomax—may have a higher risk profile than others.

In October 2021, an FDA advisory panel on general and plastic surgery voted against recommending FDA approval of the SurgiMend mesh for the specific indication of breast reconstruction. The advisory panel concluded that the benefits of using the device did not outweigh the risks.

FDA product codes: FTM, OXF.

Xenogenic Products

Cytal™ (previously called MatriStem®) Wound Matrix, Multilayer Wound Matrix, Pelvic Floor Matrix, MicroMatrix, and Burn Matrix (all manufactured by ACell) are composed of porcine-derived urinary bladder matrix.

Helicoll (Encol) is an acellular collagen matrix derived from bovine dermis. In 2004, it was cleared by the 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 (eg, abrasions, lacerations, second-degree burns, skin tears), and surgical wounds including donor sites/grafts.

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 the FDA through the 510(k) 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 to IV) and venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers, donor sites, and grafts.

Kerecis™ Omega3 Wound (Kerecis) is an ADM derived from fish skin. It has a high content of omega 3 fatty acids and is intended for use in burn wounds, chronic wounds, and other applications.

Oasis™ Wound Matrix (Cook Biotech) is a collagen scaffold (extracellular matrix) derived from porcine small intestinal submucosa. In 2000, it was cleared for marketing by the FDA through the 510(k) process for the management of partial- and full-thickness wounds, including pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled undermined wounds, surgical wounds, trauma wounds, and draining wounds.

Permacol™ (Covidien) is xenogeneic and composed of cross-linked porcine dermal collagen. Cross-linking improves tensile strength and long-term durability, but decreases pliability.

PriMatrix™ (TEI Biosciences; a subsidiary of Integra Life Sciences) is a xenogeneic ADM processed from fetal bovine dermis. It was cleared for marketing by the 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.

SurgiMend® PRS (TEI Biosciences; a subsidiary of Integra Life Sciences) is a xenogeneic ADM processed from fetal and neonatal bovine dermis.

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.

FDA Product codes: KGN, FTL, FTM.

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 1 size, with a shelf-life of 10 days. In 1998, it was approved by the 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 full-thickness neuropathic diabetic lower-extremity ulcers nonresponsive to standard wound therapy.

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 the FDA for repair of diabetic foot ulcers.

Epicel® (Genzyme Biosurgery) is an epithelial autograft composed of a patient's own keratinocytes cultured ex vivo and 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. 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.

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 the FDA premarket approval for healing donor site wounds in burn victims 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.

FDA product codes: FTM, PFC, OCE, ODS.

Autologous Cell Harvesting Device

Recell® (Avita Medical) was initially approved by the FDA in September 2018 under the premarket approval (PMA) process (PMA BP170122). It is an autologous cell harvesting device indicated for the treatment of acute partial-thickness thermal burn wound when used by an appropriately-licensed healthcare professional at the patient’s point of care to prepare autologous RES Regenerative Epidermal Suspension. The initial indication was for use in patients 18 years of age and older in combination with meshed autografting. Subsequently, indications were expanded to include direct application to acute partial-thickness thermal burn wounds in patients 18 years of age and older or application in combination with meshed autografting for acute full-thickness thermal burn wounds in pediatric as well as adult patients and for full-thickness skin defects after traumatic avulsion (e.g., degloving) or surgical excision (e.g., necrotizing tissue infection) or resection (e.g., skin cancer) in patients 15 years of age and older.

FDA product code: QCZ.

Biosynthetic Products

Biobrane®/Biobrane-L (Smith & 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 trifilament thread, which chemically binds collagen. Blood/sera clot in the nylon matrix, adhering the dressing to the wound until epithelialization occurs.

Integra® Dermal Regeneration Template (also 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 the FDA for use in the postexcisional 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 physiologic condition of the patient and for certain diabetic foot ulcers. Integra® Matrix Wound Dressing and Integra® Meshed Bilayer Wound Matrix are substantially equivalent skin substitutes and were cleared for marketing by the FDA through the 510(k) process for other indications. Integra® Bilayer Matrix Wound Dressing (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.

TransCyte™ (Advanced Tissue Sciences) consists of human dermal fibroblasts grown on nylon mesh, combined with a synthetic epidermal layer, and was approved by the FDA in 1997. TransCyte is intended 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.

FDA product codes: FRO, MDD, MGR.

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.

Nerve Wraps

Nerve wraps can be used for peripheral nerve repair. They are often made from biocompatible materials like collagen, designed to encase injured peripheral nerves. It provides a barrier between the nerve and surrounding tissue, minimizing scarring and promoting a conducive environment for nerve healing. Their application is ideal for cases where the nerve is intact, but needs protection from scarring or compression. Nerve conduits, addressed in the Peripheral Nerve Injury Repair Using Synthetic Conduits or Processed Nerve Allografts , would be more suitable in cases of severed nerves.

AxoGuard® nerve connector (Axogen, Inc) is an implant derived from small intestine submucosa designed to protect injured and compressed nerves. Other FDA 510K approved nerve wraps include: Flexibile Collagen Nerve Cuff (Collagen Matrix, Inc), Mochida Nerve Cuff (Mochida Pharmaceutical Co.), NervAlign Nerve Cuff (Renerve, Ltd), Nerve tape (BioCircuit Technologies, Inc), Neurawrap (Integra LifeSciences, Corp), NeuroMend (Stryker Orthopedics), NeuroShield (Monarch bioimplants, GmBH), Reinforce flexible Collagen Nerve Cuff (Collagen Matrix, Inc), and Versawrap nerve protector (Alafair Biosciences, Inc).

POLICY

Breast reconstructive surgery using allogeneic acellular dermal matrix products* (including each of the following: AlloDerm®, Cortiva® [AlloMax™], DermACELL™, DermaMatrix™, FlexHD®, FlexHD® Pliable™; see Policy Guidelines) may be considered medically necessary:

• 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

• 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:

• AlloPatch®*

• Apligraf®**

• Dermagraft®**

• Integra® Omnigraft™ Dermal Regeneration Matrix (also known as Omnigraft™) and Integra Flowable Wound Matrix

• mVASC®

• TheraSkin®.

Treatment of chronic, noninfected, partial- or full-thickness lower-extremity skin ulcers due to venous insufficiency, which have not adequately responded following a 1-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 greater than or equal to 30% when provided in accordance with the HDE specifications of the FDA)****

• Integra® Dermal Regeneration Template**.

*Banked human tissue.** FDA premarket approval.*** FDA 510(k) clearance.**** FDA-approved under a humanitarian device exemption.

All other uses of the 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/Lyophilized Wound Dressing

• AlloSkin™

• AlloSkin™ RT

• Apis®

• Aongen™ Collagen Matrix

• Architect® ECM, PX, FX

• Artacent® Wound

• ArthroFlex™ (Flex Graft)

• AxoGuard® Nerve Protector (AxoGen)

• Biobrane®/Biobrane-L

• Bio-ConneKt® Wound Matrix

• CollaCare®

• CollaCare® Dental

• Collagen Wound Dressing (Oasis Research)

• CollaGUARD®

• CollaMend™

• CollaWound™

• Coll-e-derm

• Collexa®

• Collieva®

• Conexa™

• Coreleader Colla-Pad

• CorMatrix®

• Cymetra™ (Micronized AlloDerm)™

• Cytal™ (previously MatriStem®)

• DeNovoSkin™

• Dermadapt™ Wound Dressing

• Derma-gide

• DermaPure™

• DermaSpan™

• DressSkin

• Durepair Regeneration Matrix®

• Endoform Dermal Template™

• ENDURAGen™

• Excellagen®

• ExpressGraft™

• E-Z Derm™

• Flexibile Collagen Nerve Cuff (Collagen Matrix, Inc)

• FlowerDerm™

• Foundation Dermal Regeneration Scaffold (DRS) Solo

• GammaGraft

• Geistlich Derma-Gide™

• GraftJacket® Xpress, injectable

• Helicoll™

• hMatrix®

• Hyalomatrix®

• Hyalomatrix® PA

• InnovaMatrix®

• Integra™ Bilayer Wound Matrix

• Integra® Matrix Wound Dressing (previously Avagen)

• InteguPly®

• Keramatrix®

• Kerecis™ Omega3

• Keroxx™

• MatriDerm®

• MatriStem

• Matrix HD™

• MicroMatrix®

• Miro3D Fibers Wound Matrix

• MiroTract Wound Matrix

• Miroderm®

• Mediskin®

• MemoDerm™

• Microderm® biologic wound matrix

• Microlyte matrix®

• Mochida Nerve Cuff (Mochida Pharmaceutical Co.)

• MyOwn skin

• Myriad matrix

• Myriad morcells

• NervAlign Nerve Cuff (Renerve, Ltd)

• Nerve tape (BioCircuit Technologies, Inc)

• Neurawrap (Integra LifeSciences, Corp)

• NeuroMend (Stryker Orthopedics)

• NeuroShield (Monarch bioimplants, GmBH)

• Novosorb™ Biodegradable Temporizing Matrix (BMT)

• Oasis® Burn Matrix

• Oasis® Ultra

• Ologen™ Collagen Matrix

• Omega3 Wound (originally Merigen wound dressing)

• Omeza® Collagen Matrix

• Permacol™

• PermeaDerm® B

• PermeaDerm® C

• PermeaDerm® Glove

• Phoenix™ Wound Matrix

• PriMatrix™

• PriMatrix™ Dermal Repair Scaffold

• Progenamatrix™

• Puracol® and Puracol® Plus Collagen Wound Dressings

• PuraPly™ Wound Matrix (previously FortaDerm™)

• PuraPly™ AM (Antimicrobial Wound Matrix)

• Puros® Dermis

• RegenePro™

• Reinforce flexible Collagen Nerve Cuff (Collagen Matrix, Inc)

• Repliform®

• ReCell®

• Repriza™

• Restrata®

• Restrata MiniMatrix

• SkinTE™

• StrataGraft®

• Strattice™

• SUPRA SDRM®

• Suprathel®

• SurgiMend®

• Symphony™

• Talymed®

• TenoGlide™

• TenSIX™ Acellular Dermal Matrix

• TissueMend

• TheraForm™ Standard/Sheet

• TheraGenesis®

• TransCyte™

• TruSkin™

• Tutomesh™ Fenestrated Bovine Pericardium

• Veritas® Collagen Matrix

• Versawrap nerve protector (Alafair Biosciences, Inc)

• Xcellistem®

• XCM Biologic® Tissue Matrix

• XenMatrix™ AB.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

There is no standard definition of “skin substitute." Products in this policy cover products that do not require U.S. Food and Drug Administration (FDA) approval or clearance as well as a number of products cleared through the 510(k) pathway with a variety of FDA product codes. The FDA product codes that include these products are not limited to skin substitute products and may include other indications not related to wounds. The list of products named in this policy is not a complete list of all commercially available products.

Note: Amniotic and placental products are reviewed in the Amniotic Membrane and Amniotic Fluid  medical policy.

Synthetic conduits and processed nerve allografts are reviewed in the Peripheral Nerve Injury Repair Using Synthetic Conduits or Processed Nerve Allografts medical policy.

See the Agency for Healthcare Research and Quality Technology Review by Snyder and colleagues (2020) for detailed description of skin substitute products for treatment of chronic wounds.

The Women’s Health and Cancer Rights Act (WHCRA) helps protect many women with breast cancer who choose to have their breasts rebuilt (reconstructed) after a mastectomy. Mastectomy is surgery to remove all or part of the breast. This federal law requires most group insurance plans that cover mastectomies to also cover breast reconstruction. It was signed into law on October 21, 1998. The United States Departments of Labor and Health and Human Services oversee this law.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

5/2001: Approved by Medical Policy Advisory Committee (MPAC).

4/10/2002: Code Reference section updated, HCPCS J7340 added.

4/18/2002: Type of Service and Place of Service deleted.

5/30/2002: Code Reference section updated, ICD-9 280.82, 459.81, 459.89, 707.0, 707.10, 707.11, 707.12, 707.13, 707.14, 707.15, 707.19, 707.8, 707.9, 891.0, 891.1, 891.2, 892.0, 892.1, 892.2, 893.0, 893.1, 893.2, 894.0, 894.1, 894.2 added.

8/1/2003: ICD-9 diagnosis code 433.9 typo corrected, ICD-9 diagnosis code ranges 443.0-443.9, 707.0-707.9, 891.0-894.2 listed separately.

2/12/2004: Code Reference section updated; ICD-9 diagnosis code 443.0, 443.1, 443.21, 443.22, 443.23, 443.24, 443.29, 443.81, 443.89, 443.9 deleted; HCPCS C1305, Q0185 deleted.

3/22/2005: Code Reference section updated, ICD-9 diagnosis code 707.0 5^th digit with effective date of 10/1/2004 added, HCPCS J7343 with effective date of 1/1/2005 added.

8/1/2005: Code Reference section updated, CPT 15342, 15343 added, ICD-9 diagnosis code 250.80, 250.81 with note "use additional code to identify any associated ulceration (i.e., 707.10-707.9)" added, ICD-9 diagnosis 707.10-707.9 description revised, ICD-9 diagnosis code 891.0, 891.1, 891.2, 892.0, 892.1, 892.2, 893.0, 893.1, 893.2, 894.0, 894.1, 894.2 deleted.

03/08/2006: Coding updated. CPT/HCPCS 2006 revisions added to policy.

11/16/2006: Policy updated. Updates approved by Medical Policy Advisory Committee (MPAC). Added ICD-9 code 756.81.

12/27/2006: Code Reference section updated per the 2007 CPT/HCPCS revisions.

5/14/07: Policy reviewed, no changes.

12/17/07: Coding updated. CPT/HCPCS 2008 revisions added to policy.

9/3/2008: Added ICD-9 codes 250.60 - 250.63.

9/22/2008: Annual ICD-9 updates effective 10-1-2008 applied.

12/24/2008: Code reference section updated per 2009 CPT/HCPCS revisions.

6/30/2009: New HCPC codes Q4115 and Q4116 added to covered table.

03/09/2011: Removed the following deleted codes from the Code Reference section: 15342, 15343, J7340, J7343, J7345 - J7349.

04/24/2013: Policy reviewed; no changes.

11/03/2014: Policy title changed from "Apligraf for Wound Healing" to "Bio-Engineered Skin and Soft Tissue Substitutes." Policy description updated to reflect scope of policy. Policy statement updated to list medically necessary products and their covered indications, as well as the products that are considered investigational.

12/31/2014: Added the following new 2015 HCPCS codes to the Code Reference section: Q4150, Q4151, Q4152, Q4153, Q4154, Q4155, Q4156, Q4157, Q4158, Q4159, and Q4160.

04/30/2015: Policy statement revised to add that EpiFix is considered medically necessary for treatment of diabetic foot ulcers. Updated listing of investigational skin and soft tissue substitutes in the policy statement. Policy guidelines updated to add medically necessary and investigational definitions. Code Reference section updated to add CPT Codes 15271, 15272, 15273, 15274, 15275, 15276, 15277, and 15278 to the Covered Codes table. Added HCPCS codes Q4128 and Q4131 to the Covered Codes table. Removed deleted procedure codes Q4109, 15170, 15171, 15175, 15176, 15340, 15341, 15360, 15361, 15365, and 15366 from the Code Reference section. HCPCS codes Q4103, Q4104, Q4108, Q4110, Q4111, and Q4115 moved to the Investigational Codes section and also added HCPCS codes Q4112 - Q4114, and Q4117 - Q4127, and Q4129 - Q4149 to the Investigational Codes table per the investigational policy statement. Added ICD-9 diagnosis codes 174.0 - 174.9, 233.0, 941.30 - 941.39, 941.40 - 941.49, 941.50 - 941.59, 942.30 - 942.39, 942.40 - 942.49, 942.50 - 942.59, 943.30 - 943.39, 943.40 - 943.49, 943.50 - 943.59, 944.30 - 944.38, 944.40 - 944.48, 944.50 - 944.58, 945.30 - 945.39, 945.40 - 945.49, 945.50 - 945.59, 946.3 - 946.5, 948.00 - 948.99, 949.3 - 949.5, V10.3, and V45.71 to the Covered Codes table. Removed diagnosis code 756.81 from the Covered Codes table. Deleted outdated references from the Sources section.

08/31/2015: Medical policy revised to add ICD-10 codes.

12/31/2015: Code Reference section updated to add new 2016 HCPCS codes Q4161, Q4162, Q4163, Q4164, and Q4165 to the investigational codes table. Code description revised for HCPCS code Q4153.

05/31/2016: Policy number added.

12/31/2016: Policy description updated regarding artificial skin and soft tissue substitutes. Policy statement regarding treament of diabetic lower-extremity ulcers updated to add Integra® Dermal Regeneration Template and Amniotic Membrane Graft (including Biovance® and Grafix™) as medically necessary. Removed TransCyte™ as medically necessary for treatment of second and third degree burns, as it is no longer commercially available. Investigational list of skin and soft tissue substitutes updated to add, remove, and revise product names. Policy guidelines updated for clarification regarding acellular dermal matrix products. Code Reference section updated to move the following HCPCS codes from investigational to covered, effective 01/01/2017: Q4132, Q4133, and Q4154. Added new 2017 HCPCS codes Q4166, Q4167, Q4168, Q4169, Q4170, Q4171, Q4172, Q4173, Q4174, and Q4175 to the investigational codes table. Revised code descriptions for HCPCS codes Q4105 and Q4131.

09/29/2017: Code Reference section updated to add new ICD-10 diagnosis codes L97.105, L97.106, L97.108, L97.115, L97.116, L97.118, L97.125, L97.126, L97.128, L97.205, L97.206, L97.208, L97.215, L97.216, L97.218, L97.225, L97.226, L97.228, L97.305, L97.306, L97.308, L97.315, L97.316, L97.318, L97.325, L97.326, L97.328, L97.405, L97.406, L97.408, L97.415, L97.416, L97.418, L97.425, L97.426, L97.428, L97.505, L97.506, L97.508, L97.515, L97.516, L97.518, L97.525, L97.526, L97.528, L97.805, L97.806, L97.808, L97.815, L97.816, L97.818, L97.825, L97.826, L97.828, L97.905, L97.906, L97.908, L97.915, L97.916, L97.918, L97.925, L97.926, L97.928, L98.415, L98.416, L98.418, L98.426, L98.428, L98.495, L98.496, and L98.498. Effective 10/01/2017.

02/26/2018: Code Reference section updated to add new HCPCS codes Q4176, Q4177, Q4178, Q4179, Q4180, Q4181, and Q4182. Revised descriptions for HCPCS codes Q4132, Q4133, Q4148, Q4156, Q4158, Q4162, and Q4163. Removed deleted HCPCS codes Q4119, Q4120, and Q4129.

04/20/2018: Policy description updated regarding acellular dermal matrix and xenogenic products. Moved information regarding amniotic membrane grafts to the Amniotic Membrane and Amniotic Fluid Injections policy. Medically necessary statement regarding breast reconstructive surgery updated to include AlloMend®, DermACELL™, and FlexHD® Pliable™. AlloMax was renamed to Cortiva. Medically necessary criteria for treatment of diabetic lower-extremity ulcers updated to add AlloPatch®, Omnigraft, and Integra Flowable Wound Matrix. Investigational list of skin and soft tissue substitutes updated to remove the following that are now addressed in the Amniotic Membrane and Amniotic Fluid Injections policy: Affinity™, AlloWrap™, AmnioBand®/Guardian, AMNIOEXCEL®, AmnioFix®, AMNIOMATRIX®, BioDDryFlex®, BioDfence/BioDfactor, Clarix®, Clarix® Flo, Dermavest™, GUARDIAN, Neox® Flo, Neox® Cord, Neox® Wound Allograft, NuShield™, Plurivest™, and Revitalon™. Investigational list of skin and soft tissue substitutes updated to remove the following due to product name changes or discontinuation: CellerateRX® (CRXa™), MatriStem® Burn Matrix, MatriStem® Micromatrix, MatriStem® Wound Matrix, and Unite™Biomatrix. Added the following as investigational: Biobrane®/Biobrane-L, Cytal™, Helicoll™, Keramatrix®, Kerecis™, Microderm® biologic wound matrix, PuraPly™ Wound Matrix (previously FortaDerm™), PuraPly™ AM (Antimicrobial Wound Matrix), TransCyte™, and TruSkin™. Policy guidelines updated to add the link to the Amniotic Membrane and Amniotic Fluid Injections medical policy. Code Reference section updated to remove the following HCPCS codes that are now addressed in the Amniotic Membrane and Amniotic Fluid Injections policy: Q4131, Q4132, Q4133, Q4154, Q4137, Q4138, Q4139, Q4140, Q4145, Q4148, Q4150, Q4151, Q4153, Q4155, Q4156, Q4157, Q4159, Q4160, Q4162, Q4163, Q4168, Q4169, Q4170, Q4171, Q4173, and Q4174. Moved HCPCS codes Q4114 and Q4122 from investigational to covered.

12/20/2018: Code Reference section updated to add new HCPCS codes Q4189, Q4192, Q4195, Q4196, Q4197, Q4202, and Q4203, effective 01/01/2019.

03/20/2019: Policy description updated regarding Xenogenic products. Policy statements unchanged.

09/17/2019: Code Reference section updated to add new HCPCS codes Q4208, Q4209, Q4210, Q4211, Q4212, Q4213, Q4214, Q4215, Q4216, Q4217, Q4218, Q4219, Q4220, Q4222, and Q4226. Added new ICD-10 diagnosis codes L89.006, L89.016, L89.026, L89.106, L89.116, L89.126, L89.136, L89.146, L89.156, L89.206, L89.216, L89.226, L89.306, L89.316, L89.326, L89.46, L89.506, L89.516, L89.526, L89.606, L89.616, L89.626, L89.816, L89.896, and L89.96. Revised code description for HCPCS codes Q4122 and Q4165. Effective 10/01/2019.

02/13/2020: Policy description updated regarding clarification of what is considered minimal manipulation and homologous use for human cells, tissues, and cellular and tissue-based products. Xenogenic products updated. Policy statements unchanged. Code Reference section updated to remove deleted HCPCS code Q4172.

06/08/2020: Code Reference section updated to remove HCPCS codes Q4126, Q4189, Q4208, Q4211, Q4212, Q4213, Q4214, Q4215, Q4217, and Q4218.

06/26/2020: Code Reference section updated to revise code description for HCPCS code Q4176 and to add new HCPCS codes C1849 and C4238, effective 07/01/2020.

12/16/2021: Code Reference section updated to add new HCPCS codes A2001, A2002, A2003, A2004, A2005, A2006, A2007, A2008, A2009, A2010, and Q4199, effective 01/01/2022.

03/28/2022: Code Reference section updated to add new 04/01/2022 HCPCS codes A2011, A2012, A2013, and A4100.

05/01/2022: Policy description updated regarding acellular dermal matrix products for breast reconstruction. Investigational list of skin and soft tissue substitutes updated to add and remove products. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Conditions" and "Medically Necessary" to "medical necessity." Code Reference section updated to add HCPCS codes A6460, A6461, C9354, C9356, C9358, C9360, C9363, C9364, Q4126, Q4193, and Q4200 as investigational. The following HCPCS codes were removed from this policy and added to Medical Policy Number 7.01.149: Q4176, Q4177, Q4178, Q4180, Q4181, Q4192, Q4209, Q4210, Q4216, Q4219, Q4220, and Q4238.

06/28/2022: Code Reference section updated to revise code description for HCPCS code A2004, effective 07/01/2022.

09/30/2022: Code Reference section updated to revise HCPCS code Q4128 and to add new HCPCS codes A2014, A2015, A2016, A2017, and A2018, effective 10/01/2022.

12/28/2022: Code Reference section updated to make note of deleted HCPCS code.

01/16/2023: Code Reference section updated to remove HCPCS codes A2001 and Q4199.

02/16/2023: Policy description updated regarding autologous cell harvesting device. Investigational statement updated to add ReCell®.

03/31/2023: Code Reference section updated to add new HCPCS codes A2019, A2020, and A2021 as investigational, effective 04/01/2023.

09/25/2023: Code Reference section updated to add new HCPCS codes A2022, A2023, A2024, and A2025, effective 10/01/2023.

03/27/2024: Code Reference section updated to add new HCPCS code A2026, effective 04/01/2024. Removed deleted HCPCS code C1849.

08/01/2024: Policy description updated regarding products. Medically necessary statement regarding diabetic lower-extremity ulcers updated to add mVASC® and TheraSkin® to the list of products. Policy statement updated to add investigational products. Policy Guidelines updated regarding products discussed in this policy and women with breast cancer. Code Reference section updated to move HCPCS code Q4121 from the Investigational Codes table to the Covered Codes table. Added HCPCS code C1832 to the Investigational Codes table.

10/01/2024: Code Reference section updated to revise the code description for HCPCS code A2024. Added new HCPCS codes A2027, A2028, A2029, Q4343, and Q4345.

12/18/2024: Code Reference section updated to add new CPT codes 15011, 15012, 15013, 15014, 15015, 15016, 15017, 15018 and HCPCS codes C8002, Q4346, Q4350, and Q4353 effective 01/01/2025.

04/01/2025: Code Reference section updated to add new HCPCS codes A2030, A2031, A2032, A2033, and A2034, effective 04/01/2025.

07/15/2025: Policy description updated regarding nerve wraps. First medically necessary policy statement regarding breast reconstructive surgery updated to remove AlloMend® and GraftJacket®. Policy statement regarding all other skin and soft tissue substitutes revised to update list of investigational products. Policy Guidelines updated regarding synthetic conduits, processed nerve allografts, and skin substitute products for treatment of chronic wounds. Code Reference section updated to remove deleted HCPCS code A2003 and add HCPCS code Q4371 to the Investigational Codes table. HCPCS code Q4107 moved from the Covered Codes table to the Investigational Codes table.

10/01/2025: Code Reference section updated to add new HCPCS codes A2036, A2037, A2038, A2039, Q4385, Q4395, Q4396, Q4397 and ICD-10 diagnosis codes C50.A0, C50.A1, and C50.A2.

01/01/2026: Code Reference section updated to add new HCPCS codes Q4431, Q4432, and Q4433.

SOURCE(S)

Blue Cross Blue Shield Association policy #7.01.113

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

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