Commercial

Medical Policy

Title:

Bioengineered Skin Substitutes

Policy #:

11.08.20at

Policy

The scope of this policy includes the use of bioengineered skin substitutes for the treatment of lower extremity skin ulcers, second- and third-degree burns, epidermolysis bullosa, acute wounds, post-Mohs, and post-surgical use. The use of bioengineered skin substitutes for all other wounds is not discussed, and is beyond the scope of this policy. For the use of bioengineered skin substitutes for reconstructive breast surgery, see policy 11.08.15.

LOWER EXTREMITY SKIN ULCERS

MEDICALLY NECESSARY FOR LOWER EXTREMITY ULCERS

Chronic lower extremity wounds

Bioengineered skin substitutes, and their application, when used in the treatment of chronic lower extremity wounds, are considered medically necessary and, therefore, covered when ALL of the following are met:

The wound has a skin deficit at least 1.0 cm² in size
Partial- or full-thickness ulcers do not involve tendon, muscle, joint capsule or exhibit exposed bone or sinus tracts, and have a clean granular base
The wound is clean and free of infection, necrotic debris, or exudate, and without evidence of underlying osteomyelitis
The wound has adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by physical examination (e.g., Ankle-Brachial Index [ABI] no less than 0.60, toe pressure >30 mm Hg)
The requested bioengineered skin substitute is listed below in the applicable wound indication AND the criteria for that indication are met
ONE of the following is met:

Presence of a full-thickness skin loss ulcer that is the result of abscess, injury or trauma that has failed to respond* to appropriate control of infection, foreign body, tumor resection, or other disease process for a period of 4 weeks or longer
For diabetic lower extremity ulcers:

The individual’s medical record reflects a diagnosis of type 1 or type 2 diabetes and also reflects medical management for this condition
Presence of neuropathic diabetic foot ulcer(s) having failed to respond* to documented conservative wound-care measures of greater than 4 weeks, during which the individual is compliant with recommendations, and without evidence of underlying osteomyelitis or nidus of infection

For venous leg ulcers (VLU):

Presence of a venous stasis ulcer for at least 3 months but unresponsive* to appropriate wound care for at least 30 days with documented compliance

Diabetic lower extremity ulcers

The following bioengineered skin substitutes, and their application, when used in the treatment of chronic diabetic lower extremity ulcers, which have not adequately responded*, are considered medically necessary and, therefore, covered when provided in accordance with that product's US Food and Drug Administration (FDA)-labeled or cleared indication, and in accordance with that product's individualized application guidelines:

Affinity
AlloPatch HD
AlloPatch HD Pliable
AmnioBand Guardian
AmnioBand Membrane
AmnioBand Particulate
Apligraf
Biovance
DermACELL
DermACELL AWM
DermACELL AWM Porous
Dermagraft
EpiCord
EpiFix
Flex HD
Flex HD Pliable
Grafix Core
Grafix PL Core
Grafix PL Prime
Grafix Prime
Graftjacket/Graftjacket RTM
Integra Dermal Regeneration Template (DRT)
Integra Flowable Wound Matrix,
Integra Omnigraft Dermal Regeneration Matrix (also known as Omnigraft)
Kerecis MariGen
mVASC
NuShield
Oasis Wound Matrix
Stravix
Stravix PL
TheraSkin

Venous leg ulcers

The following bioengineered skin substitutes, and their application, when used in the treatment of chronic, partial- or full-thickness lower extremity skin ulcers due to venous insufficiency, which have not adequately responded*, are considered medically necessary and, therefore, covered when provided in accordance with that product's FDA-labeled or cleared indication, and in accordance with that product's individualized application guidelines:

AmnioBand Guardian
AmnioBand Membrane
AmnioBand Particulate
Apligraf
EpiFix
Oasis Wound Matrix

*Note: A failed response is defined as an ulcer or skin deficit that has failed to respond to documented appropriate wound-care measures, has increased in size or depth, or has not changed in baseline size or depth and has no indication that improvement is likely (such as granulation, epithelialization or progress towards closing).

EXPERIMENTAL/INVESTIGATIONAL FOR LOWER EXTREMITY ULCERS

All other uses of the bioengineered skin substitutes listed above (such as, but not limited to, acute wounds, post-Mohs, post-surgical use), and their applications, are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of these products cannot be established by review of the available published peer-reviewed literature.

EPIDERMOLYSIS BULLOSA / RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA

MEDICALLY NECESSARY FOR EPIDERMOLYSIS BULLOSA / RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA

OrCel

The use of OrCel, and its application, is considered medically necessary and, therefore, covered for the treatment of noninfected surgical wounds and donor sites associated with mitten hand deformities in individuals with recessive dystrophic epidermolysis bullosa when the following criteria are met:

Approval has been obtained for the use of OrCel in accordance with the humanitarian device exemption [HDE] specifications of the FDA

An HDE may only be used in facilities that have an institutional review board (IRB) to oversee the clinical application of such devices. The IRB must approve the application of the device to ensure that it will be used in accordance with the FDA-approved indication. In addition, documentation of IRB approval may be requested by the Company to ensure compliance with the HDE indication.

EXPERIMENTAL/INVESTIGATIONAL FOR EPIDERMOLYSIS BULLOSA / RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA

All other uses of the bioengineered skin substitute listed above (such as, but not limited to, acute wounds, post-Mohs, post-surgical use), and its application, are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of these products cannot be established by review of the available published peer-reviewed literature.

DEEP SECOND-DEGREE (PARTIAL-THICKNESS) BURNS AND THIRD-DEGREE (FULL-THICKNESS) BURNS

MEDICALLY NECESSARY FOR DEEP SECOND-DEGREE (PARTIAL-THICKNESS) BURNS AND THIRD-DEGREE (FULL-THICKNESS) BURNS

Biobrane/Biobrane Glove

The use of Biobrane/Biobrane Glove, and its application, is considered medically necessary and, therefore, covered for the treatment of deep second-degree (partial-thickness) burn wounds when ALL of the following medical necessity criteria are met:

The treatment is specific to noninfected partial-thickness burn wounds and donor site wounds
Initial excision of the burn wound is complete (i.e., eschar and nonviable tissue are removed)
Hemostasis is achieved
Sufficient autograft tissue is not available at the time of excision (e.g., inadequate amounts of donor autograft tissue available)
Autograft is not desirable due to the individual's physiologic condition (e.g., individual has multisystem injuries such that creating new wounds may cause undue stress)

Epicel

The use of Epicel, and its application, is considered medically necessary and, therefore, covered for the treatment of deep dermal or full-thickness burns when ALL of the following criteria are met:

The burns comprise 30 percent or greater of total body surface area
When used in conjunction with split-thickness autografts or alone in individuals for whom split-thickness autografts may not be an option due to the severity and extent of their burns
When provided in accordance with the HDE specifications of the FDA

An HDE may only be used in facilities that have an IRB to oversee the clinical application of such devices. The IRB must approve the application of the device to ensure that it will be used in accordance with the FDA-approved indication. In addition, documentation of IRB approval may be requested by the Company to ensure compliance with the HDE indication.

Integra Bilayer Matrix Wound Dressing (BMWD), Integra Dermal Regeneration Template, and Integra Meshed Bilayer Wound Matrix

The use of Integra Bilayer Matrix Wound Dressing, Integra Dermal Regeneration Template, and Integra Meshed Bilayer Wound Matrix, and their applications, are considered medically necessary and, therefore, covered for the treatment of second- and third-degree burn wounds when ALL of the following medical necessity criteria are met:

The treatment is specific to noninfected deep partial- and full-thickness burn wounds.
Initial excision of the burn wound is complete (i.e., eschar and nonviable tissue are removed).
Integra Dermal Regeneration Template must be applied on the same day as the initial excision of the recipient site.
Hemostasis is achieved.
Sufficient autograft tissue is not available at the time of excision (e.g., donor autograft tissue is thin and frail).
Autograft is not desirable due to the individual's physiologic condition (e.g., individual has multisystem injuries such that creating new wounds may cause undue stress).

OrCel

The use of OrCel (bilayered cellular matrix), and its application, is considered medically necessary and, therefore, covered for the treatment of fresh, clean split-thickness donor site wounds in individuals with second- and third-degree burns.

TransCyte

The use of TransCyte, and its application, is considered medically necessary and, therefore, covered for the treatment of second- and third-degree burn wounds when ALL of the following medical necessity criteria are met:

The treatment is specific to a temporary wound covering of one of the following:
- Noninfected deep partial-thickness and full-thickness burn wounds prior to autograft placement
- Noninfected mid-dermal to indeterminate depth burn wounds that may be expected to heal without autografting
Initial excision of the burn wound is complete (i.e., eschar and nonviable tissue is removed).
Hemostasis is achieved.

EXPERIMENTAL/INVESTIGATIONAL FOR DEEP SECOND-DEGREE (PARTIAL-THICKNESS) BURNS AND THIRD-DEGREE (FULL-THICKNESS) BURNS

ADDITIONAL COVERAGE LIMITATIONS FOR ALL ABOVE USES

FDA labeling for most skin substitutes include language suggesting multiple applications; however, it is not expected that every wound in every individual will require the maximum number of applications listed on the product label
It is expected that a specific skin substitute will be used for each documented wound, and in compliance with FDA assessments and guidelines for the specific skin substitute
Partial thickness loss with the retention of epithelial appendages is not a candidate for grafting or replacement, as epithelium will repopulate the deficit from the appendages, negating the benefit of overgrafting
Skin substitutes will be allowed for the episode of wound care in compliance with FDA guidelines for the specific product not to exceed 10 applications or treatments. In situations where more than one specific product is used, it is expected that the number of applications or treatments will still not exceed 10
Simultaneous use of more than one skin substitute for the treatment of a single wound within a 12-week period of time is considered not medically necessary. A change in skin substitute within the 12-week treatment period is covered, as long as the 10 application limit per wound is not exceeded
Repeat or alternative applications of skin substitutes are considered not medically necessary when a previous full course of applications was unsuccessful. Unsuccessful treatment is defined as an increase in size or depth of an ulcer or 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) for a period of 4 weeks past start of therapy
Retreatment of healed ulcers, those showing greater than 75 percent size reduction and smaller than 0.5 cm², is considered not medically necessary
Skin substitutes are contraindicated and considered not medically necessary in individuals with inadequate control of underlying conditions or exacerbating factors (e.g., uncontrolled diabetes, active infection, and active Charcot arthropathy of the ulcer extremity, vasculitis, or continued tobacco smoking without professional provider attempt to effect smoking cessation)
Skin substitutes are contraindicated in individuals with known hypersensitivity to any component of the specific skin substitute (e.g., allergy to avian, bovine, porcine, equine products)
Repeat use of surgical preparation services in conjunction with skin substitute application codes will be considered not medically necessary. It is expected that each wound will require the use of appropriate wound preparation code at least once at initiation of care prior to placement of the skin substitute
Re-treatment within 1 year of any given course of skin substitute treatment for a venous stasis ulcer or (diabetic) neuropathic foot ulcer is considered treatment failure and does not meet medically necessary criteria for re-treatment of that ulcer with a skin substitute procedure

REQUIRED DOCUMENTATION FOR ALL ABOVE USES

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to records from the health care professional's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Documentation (in the pre-service record) must be provided specifically addressing circumstances as to why the wound has failed to respond to standard wound care treatment of greater than 4 weeks; this documentation must reference specific interventions that have failed. Such record should include updated medication history, review of pertinent medical problems that may have occurred since the previous wound evaluation, and explanation of the planned skin replacement surgery with choice of skin substitute product. The procedure risks and complications should also be reviewed and documented. Documentation of smoking cessation counseling and cessation measures prescribed, if applicable, must also be documented in the individual's record.

In all wound management the ulcer must be free of infection and underlying osteomyelitis with documentation of the conditions that have been treated and resolved prior to the institution of skin substitute therapy.

Documentation of response requires measurements of the initial wound, measurements at the completion of at least 4 weeks of appropriate wound care, and measurements immediately prior to placement and with each subsequent placement of the skin substitute.

Prior to the application of the skin substitute for diabetic or venous insufficiency ulcers, it is expected that the medical record documentation will contain evidence of the following:

Documentation that conservative measures have failed or the medical record supports that the wound is so clinically severe that it requires immediate, aggressive therapy.
Documentation that the ulcer has failed to decrease in size and 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.
Documentation of venous insufficiency either by history of deep venous thrombosis in the affected leg, or documentation of valvular reflux by duplex ultrasound, venography, or air/photo plethysmography.

For the skin substitute for diabetic or venous insufficiency ulcers, it is expected that the medical record documentation will contain evidence of the following:

The individual's medical record must reflect the frequency of skin substitute application, and this record should be consistent with each individual's history and response to the skin substitute application and product safety criteria. Repeated application to the same wound within the same treatment period without signs of improvement may be denied.
Documentation that the skin substitute product was appropriately applied and immobilized in accordance with the manufacturer’s label instructions.

EXPERIMENTAL/INVESTIGATIONAL

The use of a bioengineered skin substitute, and its application, for indications not approved by the FDA, or in accordance with the manufacturer's package insert instructions/guidelines, are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this product cannot be established by review of the available published peer-reviewed literature.

All other skin substitutes not listed above, and their applications, are considered experimental/investigational and, therefore, not covered for all indications because the safety and/or effectiveness of these products cannot be established by review of the available published peer-reviewed literature. Refer to Attachment A for a list of skin substitutes, which are considered Experimental/Investigational for all indications. This list does not include all FDA-approved/regulated skin substitutes.

BILLING REQUIREMENTS

Application codes are not to be reported for application of non-graft wound dressings (e.g., gel, ointment, foam, liquid, or injected substances) or for a biologic implant for soft tissue reinforcement. Such products are considered part of other standard management procedures, if medically necessary, and not separately payable.

Guidelines

Chronic wounds are defined as wounds that do not respond to standard wound therapy for at least a 30-day period during organized comprehensive conservative therapy.

A non-healing wound (i.e., a "failed response") is defined as an ulcer or skin deficit that has failed to respond to documented appropriate wound-care measures, has increased in size or depth, or has not changed in baseline size or depth and has no indication that improvement is likely (such as granulation, epithelialization, or progress toward closing).

Appropriate wound therapy includes, but is not limited to:

control of edema, venous hypertension or lymphedema
control of any nidus of infection or colonization with bacterial or fungal elements
elimination of underlying cellulitis, osteomyelitis, foreign body or malignant process
appropriate debridement of necrotic tissue or foreign body (exposed bone or tendon)
for diabetic foot ulcers, appropriate non-weight bearing or off-loading pressure
for venous stasis ulcers, compression therapy provided with documented diligent use of multilayer dressings, compression stockings of higher than 20 mm Hg pressure, or pneumatic compression, and
provision of wound environment to promote healing (protection from trauma and contaminants, elimination of inciting or aggravating processes)

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, skin substitutes with US Food and Drug Administration (FDA) clearance/approval for use in the treatment of burns and chronic, non-healing wounds, are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in the medical policy are met.

Subject to the terms and conditions of the applicable benefit contract, devices that are used for the FDA-approved humanitarian device exemption (HDE) indications listed in this policy are covered under the medical benefits of the Company's products.

Subject to the terms and conditions of the applicable benefit contract, skin substitutes that do not meet the medical necessity criteria listed in the medical policy are not eligible for payment under the medical benefits of the Company’s products because they are considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are benefit contract exclusions for most plans of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION STATUS

There are numerous skin substitute products approved by the FDA for wound care.

Description

SKIN LAYERS

Skin is composed of two layers: the epidermis and the dermis. The outermost layer is called the epidermis, and immediately beneath the epidermis is the dermis. These layers are separated by a basement membrane, which helps stabilize the epidermis to the dermis. Because the epidermis contains no blood vessels, the underlying dermis is the supplier of nutrients to the skin. The dermis consists of a superficial papillary layer of loose connective tissue that contains capillaries, elastic fibers, reticular fibers, and some collagen. A deeper reticular layer of the dermis consists of dense connective tissue that contains larger blood vessels, interlaced elastic fibers, coarse branching collagen fibers, fibroblasts, mast cells, nerve endings, lymphatics, hair follicles, and sebaceous and sweat glands.

There are currently a wide variety of products available for soft tissue coverage to affect closure. These products may be derived from allogeneic, xenogeneic, synthetic sources or a combination of any or all of these types of materials. However, without the component of the recipient’s own distinct epithelium and cellular skin elements, permanent skin replacement or coverage by the graft cannot be accomplished.

SKIN GRAFTS

Historically, skin grafts have been employed to cover a skin deficit or replace lost tissue. Autologous skin grafts, also referred to as autografts, are permanent covers that use skin from different parts of the individual's body. These grafts consist of the epidermis and a dermal component of variable thickness. A split-thickness skin graft includes the entire epidermis and a portion of the dermis. A full-thickness skin graft removes all the layers of the skin. Although autologous skin grafts are the optimum choice for wound coverage, areas of skin for harvesting may be limited, particularly in cases of large burns; in addition, the procedures are invasive and painful. Allografts (which use skin from another human [e.g., a cadaver]) and xenografts (which use skin from another species [e.g., porcine or bovine]) may also be employed as temporary skin replacements, but they must later be covered by an autograft or the ingrowth of the individual's own skin.

SKIN SUBSTITUTES

Because of problems inherent with autografts, allografts, and xenografts, skin substitutes were developed. Skin substitutes (also referred to as tissue-engineered skin substitutes, human skin equivalents, or skin alternatives) are products that contain cells such as fibroblasts and keratinocytes in scaffolds of natural or synthetic matrices. The matrices provide a framework for mechanical stability and tissue infiltration. Cellular elements are predominantly derived from epidermal components, dermal components, or both in a composite graft. Skin substitutes are manufactured under a variety of trade names and marketed for various purposes.

Skin substitutes are classified into the following types:

Human skin allografts: derived from donated human skin (cadavers) that has been processed to remove the cellular components and retain the structural proteins of the dermis, and to avoid immunologic rejection. They are available in different forms to allow scaffolding, soft tissue filling, growth factors, and other bioavailable hormonal or enzymatic activity.
Allogeneic matrices: derived from human neonatal fibroblasts of the foreskin that may contain metabolically active or regenerative components primarily used for soft tissue support, though some have been approved for the treatment of full-thickness skin and soft tissue loss. Most are biodegradable and disappear after 3 to 4 weeks of implantation.
Composite matrices: derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen. These are also referred to as human skin equivalent but are unable to be used as autografts due to immunologic rejection or degradation of the living components by the host. Active cellular components continue to generate bioactive compounds and protein that may accelerate wound healing and epithelial regrowth.
Acellular matrices: derived from sources other than human skin and include the majority of skin substitutes. All are composed of allogeneic (i.e., from another human) or xenogeneic (i.e., from nonhuman species, such as bovine and porcine) derived collagen, membrane, or cellular remnants proposed to simulate or exaggerate the characteristics of human skin. All are proposed to promote healing by the creation of localized intensification of an array of hormonal and enzymatic activity to accelerate closure by migration of native dermal and epithelial components, rather than function as distinctly incorporated tissue closing the skin defect.

Although the precise mechanism by which these products enhance wound repair is not understood, it is thought that maintenance of a biochemically balanced moist wound environment, the structural support for tissue regeneration, and/or the application of cytokines and growth factors to the wound bed may contribute to the healing process. Skin substitutes were originally designed to cover acute extensive burns in individuals with insufficient autologous skin for grafting. However, the use of skin substitutes has since been expanded to include treatment of many other types of wounds.

REGULATION OF SKIN SUBSTITUTES

Based on the skin substitute's composition and origin, the US Food and Drug Administration (FDA) regulates skin substitutes under one of the following categories:

Human- and human/animal-derived products regulated through the premarket approval (PMA) process
Animal-derived products and synthetic products regulated through the 510(k) process
Human-derived products regulated as human cells, tissue, and cellular and tissue-based products (HCT/Ps)
Human- and human/animal-derived products regulated as a humanitarian use device (HUD) obtained through a humanitarian device exemption (HDE)

FDA PREMARKET APPROVAL
PMA is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or that present a potential, unreasonable risk of illness or injury. Because of the level of risk associated with Class III devices, the FDA has determined that general and special controls alone are insufficient to ensure the safety and effectiveness of Class III devices. Therefore, these devices require a PMA application in order to obtain marketing clearance.

PMA is the most stringent type of device marketing application required by the FDA. The applicant must receive FDA approval of its PMA application prior to marketing the device. PMA approval is based on a determination by the FDA that there is sufficient valid scientific evidence to ensure that the device is safe and effective for its intended use(s).

FDA PREMARKETING NOTIFICATION (510[K])
A Premarketing Notification (510[k]) is a process in which applicants must demonstrate that the device to be marketed (i.e., a Class II device) is "substantially equivalent" to a pre-existing legally marketed device (predicate) in terms of safety and effectiveness. The predicate must have been approved either via PMA or 510(k). This process is usually used when manufacturers make small changes to a previously approved device that are thought to improve effectiveness without compromising safety, thus allowing for expedited approval without costly and lengthy scientific studies confirming safety and effectiveness.

HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS
Cells and tissues taken from human donors and transplanted to a recipient are regulated under Public Health Services (PHS) 361 [21 Code of Federal Regulations (CFR) 1270 and 1271]. This regulation describes the rules concerning the use of human cells, tissues, and HCT/Ps for human medical purposes. The final rule, 21 CFR Part 1271, became effective on April 4, 2001, for human tissues intended for transplantation that are regulated under section 361 of the PHS Act and 21 CFR Part 1270. HCT/Ps are regulated by the Center for Biologics Evaluation and Research (CBER). CBER is responsible for regulating biological and related products including blood, vaccines, allergenics, tissues, and cellular and gene therapies. Establishments producing HCT/Ps must register with the FDA and list their HCT/Ps. HCT/Ps establishments are not required to demonstrate the safety or effectiveness of their products and the FDA does not evaluate the safety or effectiveness of these products.

HUMANITARIAN DEVICE EXEMPTION
In rare instances, certain medical devices intended to be used for humanitarian purposes are evaluated by the FDA through the HDE process. A device approved in this manner is designated as a HUD. A HUD designation permits the use of certain medical devices when there is no comparable device available to treat or diagnose a disease or condition affecting fewer than 4000 individuals annually. Because clinical investigation demonstrating the device's efficacy is not feasible (given the low prevalence of the disease in the population), an HDE grants manufacturers an exemption to the usual PMA process and allows marketing of the device only for the FDA-labeled HDE indication(s).

Under FDA requirements, a HUD may only be used after institutional review board (IRB) approval has been obtained for the use of the device in accordance with the FDA-labeled indication(s) under the HDE.

COMMON TYPES OF WOUNDS

BURNS
Burns are major threats that can lead to extensive tissue and fluid loss; they also provide openings for systemic infection. Burn severity is rated based on damage to skin layers. Superficial or first-degree burns involve only the outer layer of skin, the epidermis, and typically heal in 3 to 5 days. Partial-thickness or second-degree burns can be classified as superficial or deep. Superficial second-degree burns involve the entire epidermis and upper layers of the dermis, and should heal in 5 to 21 days without grafting. Deep second-degree burns involve the destruction of the entire epidermis and most of the dermis, and can quickly evolve into a full-thickness (or third-degree) burn. Deep second-degree burns will most likely need excision and skin grafting to heal. Full-thickness or third-degree burns involve the destruction of all layers of the skin, and often injure underlying subcutaneous adipose tissue as well. Conventional treatment for major burns consists of early staged surgical wound excision, in which eschar is removed and a granulating wound is exposed to serve as a bed for subsequent grafting and wound closure. Early burn wound excision has been shown to improve survival, decrease infection rates, decrease the formation of hypertrophic scars, and decrease the length of hospital stay.

DIABETIC FOOT ULCERATIONS
Diabetic foot ulcerations are common and occur in individuals who have type I or type II diabetes. The current standard of care (SOC) for diabetic ulcers includes removal of mechanical stress (e.g., non-weight-bearing regimen), sharp debridement when necessary, and wound care (e.g., saline-moistened dressings); however, because only 24 percent of these ulcers heal after 12 weeks of treatment, these regimens are not considered particularly effective.

VENOUS ULCERATIONS
Venous ulcerations are a result of a pathophysiologic process in the maintenance of tissue integrity. The standard therapy for venous ulcers is compression. Healing after initiation of compression therapy is predictive of long-term results. Ulcers that are not reduced by greater than 40 percent within 3 weeks of treatment are unlikely to heal and may require complex care.

EPIDERMOLYSIS BULLOSA/RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA
Epidermolysis bullosa is a family of genetic disorders that cause the skin to be very fragile and to blister easily after minor injury or friction, such as rubbing or scratching. The disease may occur in a relatively mild form, but it may also be disabling and sometimes fatal. Dystrophic epidermolysis bullosa (DEB) is one of the major forms of epidermolysis bullosa. DEB can be classified into three major types based on severity:

Autosomal recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens type (RDEB-HS): the most severe form of the condition (blisters are present over the whole body and affect mucous membranes; leads to severe scarring)
Autosomal recessive dystrophic epidermolysis bullosa, non-Hallopeau-Siemens type (non-HS RDEB): less severe than RDEB-HS (blisters are limited to the hands, feet, knees, and elbows, but may be widespread in more severe cases; scarring is limited to areas where blisters have occurred and are not as severe as in RDEB-HS)
Autosomal dominant type (DDEB): milder than the autosomal recessive forms (blisters limited to the hands, feet, knees, and elbows; blisters heal with scarring, but it is less severe).

Recessive dystrophic epidermolysis bullosa wounds have been treated with skin substitutes, one of which (OrCel) has been approved by the FDA under the HDE.

OTHER TYPES OF WOUNDS
Other wounds include, but are not limited to, partial- and full-thickness wounds, pressure ulcers, chronic vascular ulcers, surgical wounds (e.g., donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (e.g., abrasions, lacerations, skin tears), and draining wounds.

PEER-REVIEWED LITERATURE

Bioengineered skin substitutes or cellular and tissue-based products (CTPs), referred to as skin substitutes by Centers for Medicare & Medicaid (CMS), the Current Procedural Terminology (CPT), and the Healthcare Common Procedure Coding manuals, have been developed to circumvent problems inherent with autografts, allografts, and xenografts. They are biologic covers for refractory wounds with full-thickness skin loss secondary to third-degree burns or other disease processes such as diabetic neuropathic ulcers and the skin loss of chronic venous stasis or venous hypertension. The production of these products generally involves the creation of immunologically inert biologic products containing protein, hormones or enzymes seeded into a matrix that may provide protein or growth factors proposed to stimulate or facilitate healing or promote epithelialization. A variety of biosynthetic and tissue-engineered skin substitution products marketed as human skin equivalents (HSE) or cellular or tissue-based products (CTP) are manufactured under an array of trade names and marketed for a variety of indications. All are procured, produced, manufactured, processed and promoted in sufficiently different manners to preclude direct product comparison for equivalency or superiority in randomized controlled trials (RCTs). Sufficient data are available to establish distinct inferiority to human skin autografts and preclude their designation as skin equivalence.

Bioengineered skin substitutes or CTPs are classified into the following types:

Human skin allografts derived from donated human skin (cadavers)
Allogeneic matrices derived from human tissue (fibroblasts or membrane)
Composite matrices derived from human keratinocytes, fibroblasts, and xenogeneic collagen
Acellular matrices derived from xenogeneic collagen or tissue
Human skin allografts bioengineered from human skin components and human tissue that have had intact cells removed or treated to avoid immunologic rejection. They are available in different forms, promoted to allow scaffolding, soft tissue filling, growth factors, and other bioavailable hormonal or enzymatic activity.
Allogeneic matrices are usually derived from human neonatal fibroblasts of the foreskin that may contain metabolically active or regenerative components primarily used for soft tissue support, although some have been approved for the treatment of full-thickness skin and soft tissue loss. Most are biodegradable and disappear 3 to 4 weeks after implantation.
Composite matrices are derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen. These are also referred to as xenogeneic human skin equivalent but are unable to elude an autograft due to immunologic rejection or degradation of the living components by the host. Active cellular components continue to generate bioactive compounds and protein that may accelerate wound healing and epithelial regrowth.
Acellular matrices are derived from other than human skin and include the majority of bioengineered skin substitutes. All are composed of allogeneic- or xenogeneic-derived collagen, membrane, or cellular remnants proposed to stimulate or exaggerate the characteristics of human skin. All propose to promote healing by the creation of localized intensification of an array of hormonal and enzymatic activity to accelerate closure by migration of native dermal and epithelial components, rather than function as distinctly incorporated tissue closing the skin defect.

Sui et al. (2024) conducted a systematic review of 15 RCTs to evaluate the effectiveness and safety of the application of dermal matrix therapy as an adjuvant treatment to SOC. Diabetic foot ulcers (DFUs) can lead to diabetic foot infection, lower leg amputation, and even death. Although SOC practices have been known as the gold standard for DFU care, SOC alone may not be enough to heal all DFUs and prevent recurrence. This study included 1524 individuals. Of them, 689 were treated with SOC alone, while 835 received SOC plus dermal matrix. Compared with the SOC group, a significantly shorter time (mean difference [MD], 2.84; 95 percent confidence interval [CI], 1.37–4.32; P<0.001) was required to achieve complete healing in the dermal matrix group. A significantly higher complete healing rate (odds ratio [OR], 0.40; 95 percent CI, 0.33–0.49; P<0.001) and lower overall (risk ratio [RR], 1.83; 95 percent CI, 1.15–2.93; P=0.011) and major (RR, 2.64; 95 percent CI, 1.30–5.36; P=0.007)] amputation risks were achieved in the dermal matrix group compared with the SOC group. No significant difference in the wound area, ulcer recurrence rate, and complication risk between the two groups was observed. Study limitations are that (1) a small sample size was included; (2) products among the manufacturers varied, which may have resulted in bias; (3) the trials were not blinded; (4) there was a lack of concealment to the investigator; and (5) follow-up times varied. The authors concluded that dermal matrix used as an adjuvant therapy in conjunction with SOC effectively improved the healing process of DFUs and reduced the amputation risk compared with SOC alone. This use of dermal matrix was also well tolerated by the individuals, with no additional risk of complications (Cazzell et al., 2017, 2019b, and Zelen et al., 2016, are included in this study.)

Alomairi et al. (2024) conducted a systematic review and meta-analysis to assess the application and effectiveness of human amniotic membrane (HAM) in the treatment of diabetic and venous leg ulcers to improve the management of chronic wounds. This review included 10 RCTs involving 633 individuals who were randomly assigned to either a treatment group receiving amniotic membrane (n=323) or a control group receiving SOC (n=310). HAM was used in all studies rather than synthetic types. Diabetes was the primary cause of the ulcer. The ulcers had a mean size of 4.3 cm² in the standard care group and 3.6 cm² in the amniotic membrane group. Findings revealed that HAM treatment significantly accelerated ulcer closure, with over 90 percent complete healing compared with standard care. The authors noted that several complications occurred during treatment. The follow-up was limited to 12 to 16 weeks, proving only short-term efficacy and exposing possible complications from the treatment itself. Study limitations include a limited number of RCTs, small sample sizes in some studies, and large population of older male individuals, which may have affected healing times. In addition, no standardized protocol for HAM preparation was followed, which possibly affected product quality. Many of the studies focused on individuals with diabetes with leg ulcers. Also, short-term follow-up across trials varied between 6 and 16 weeks, emphasizing the need to evaluate the long-term efficacy and safety of HAM. Additional research is needed, particularly focusing on a diverse array of cutaneous ulcers, given that most of the studies primarily addressed diabetic ulcers and often had small sample sizes (Serena et al., 2022, Serena et al., 2020, Snyder et al., 2016, Bianchi et al., 2018, DiDomenico et al., 2016, Lavery et al., 2014, Zelen et al., 2014, Tettelbach et al., 2019, Zelen et al., 2013, and Zelen et al., 2016, are all included in this review.)

A Hayes Health Technology Assessment for Skin Substitutes for Venous Leg Ulcers in Adults concluded that a low-quality body of evidence provided consistent evidence suggesting that acellular and cellular skin substitutes may improve healing of chronic venous leg ulcers when used in conjunction with standard wound care (SWC). The Hayes report gives a “C” rating for the use of acellular or cellular skin substitutes as an adjunct to SWC to treat adults with chronic, uninfected venous leg ulcers that have not healed with SWC alone. Evidence directly comparing different cellular skin substitutes with SWC alone and for skin substitute products or types is extremely limited and of very low quality. Skin substitutes appear to be safe, and no major safety concerns were reported. Additional large, well-designed clinical trials are needed to better evaluate the comparative effectiveness and safety of skin substitutes as adjuncts to SWC and as alternatives to other skin substitutes. The skin substitutes that were a part of the evidence base for this report included EPIFIX, TheraSkin, Talymed, and PriMatrix (Hayes, Skin Substitutes for Venous Leg Ulcers in Adults, 2020; updated 2023).

A Hayes report (2020; updated 2023) for acellular skin substitutes for chronic foot ulcers in adults with diabetes indicates that there is an overall low-quality body of evidence suggesting that acellular skin substitutes appear to heal more chronic DFUs than SWC alone and in a shorter period. While acellular skin substitutes appear to have some benefits over cellular skin substitutes, in terms of the incidence, time to healing, and possibly quality of life (QOL), no definitive conclusions can be drawn regarding comparative effectiveness and safety of these products due to the limited number of studies overall; this also includes the individual skin substitutes. Questions remain about the effect of acellular skin substitutes on the incidence of amputation and ulcer recurrence due to the limited number of studies on these outcomes. Evidence that directly compares different acellular skin substitutes or compares acellular with cellular skin substitutes is extremely limited and of very low quality, resulting in an inability determine whether any one product or product type is superior. The acellular skin substitutes that were part of the evidence base for this report include EPIFIX, EPICORD, AmnioBand, AmnioExcel, MatriStem MicroMatrix, and DermACELL (Hayes, Acellular Skin Substitutes for Chronic Foot Ulcers in Adults with Diabetes Mellitus, 2020; updated 2023).

A Hayes report (2020; updated 2023) for Cellular Skin Substitutes for Chronic Foot Ulcers in Adults with Diabetes indicates that there is an overall low-quality body of evidence that assesses the comparative effectiveness and safety of cellular skin substitutes incremental to SWC alone for the treatment of DFUs in individuals with diabetes. The overall quality of the bodies of evidence comparing cellular skin substitutes with other cellular skin substitutes and cellular skin substitutes with acellular skin substitutes as adjuncts to SWC are very low. Although cellular skin substitutes appear to benefit DFU healing over SWC alone, evidence on individual products to assess whether any cellular skin substitute is more effective than the others is insufficient. Large, well-designed clinical trials are needed to better evaluate the comparative effectiveness and safety of cellular skin substitutes as adjuncts to SWC and as alternatives to acellular skin substitutes. The cellular skin substitutes that were a part of the evidence base for this report include Affinity, GRAFIX, Matristem MicroMatrix, and TheraSkin (Hayes, Cellular Skin Substitutes for Chronic Foot Ulcers in Adults with Diabetes Mellitus, 2020; updated 2023).

In a technical brief prepared for the Agency for Healthcare Research and Quality (AHRQ), Snyder et al. (2020) evaluated skin substitutes for treating chronic wounds. Systematic reviews/meta-analyses, RCTs, and prospective, nonrandomized comparative studies that examined commercially available skin substitutes in individuals with DFUs, venous leg ulcers, pressure ulcers, and arterial leg ulcers were included in the review. Overall, 76 commercially available skin substitutes were identified and categorized based on the Davison-Kotler classification system. In total, 68 (89 percent) were categorized as acellular dermal substitutes, mostly replacements from human placental membranes and animal tissue sources. Three systematic reviews and 22 RCTs examined the use of 16 distinct skin substitutes, including acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes in DFUs, pressure ulcers, and venous leg ulcers. Overall, 21 ongoing clinical trials (all RCTs) examined an additional nine skin substitutes with comparable classifications. EPIFIX was reviewed in five studies. GRAFIX/GRAFIX PRIME, MatriStem Wound Matrix/MatriStem MicroMatrix, TheraSkin, and DermACELL were all reviewed in two studies each. The findings of the review included the following:

While 85 percent of studies examining acellular dermal substitutes described the experimental intervention as favorable over SOC for wound healing and shorter healing time, insufficient data are available to determine whether wound recurrence or other sequela are less frequent with acellular dermal substitutes. Only three studies compared cellular dermal substitutes with SOC. Clinical evidence for cellular dermal substitutes may be limited by the lack of robust, well-controlled clinical trials of these products in this category.
Of the six head-to-head, comparative studies, findings from five studies did not indicate significant differences between skin substitutes in outcomes measured at the latest follow-up (>12 weeks). The investigators concluded that the current evidence base may be insufficient to determine whether one skin substitute product is superior to another.
The investigators found little information on the long-term effects of using skin substitutes. Wound recurrence was seldom reported, and potential toxic and carcinogenic effects are not known. Information on amputations and hospitalizations due to infections is also missing. Before findings can be relied on, more data are needed on hospitalization, pain reduction, need for amputation, exudate, odor control, and return to baseline activities of daily living and function.
The investigators indicated that variation in study designs reduces the ability to compare outcomes across studies. For example, the investigators identified 20 different criteria in 38 (published and ongoing) studies that reported a wound size inclusion criterion. Sizes ranged from as small as 0.5 to 100 cm². Overall, 1 to 25 cm² was the most common range used as a wound size inclusion criterion. More than 4 weeks was the most common wound duration inclusion criterion (25 studies), while a few studies allowed up to 52 weeks. Only six published studies reported on wound recurrence after 12 weeks. Given the variation in these and other study design features, the investigators indicated that research in this field may benefit from a more standardized study design.
The investigators found that the industry sponsored 20 of 22 RCTs included in this report, which raises significant concerns about publication bias and selective outcome reporting; results unfavorable to the industry may not have been reported or published.

According to the investigators, this technical brief’s clearest implications are the lack of studies examining the efficacy of most skin substitute products and need for better-designed studies that provide more clinically relevant data. The investigators indicated that future studies may be improved by using a 4-week run-in period before study enrollment and at least a 12-week study period. Future studies should also report whether wounds recur during the 6-month follow-up.

Álvaro-Afonso et al. (2020) reviewed the recent advances in dermoepidermal skin substitutes (DSSs) for the treatment of DFUs. The PubMed and Cochrane databases were systematically searched for systematic reviews published after 2013 and for RCTs. A retrospective evaluation of 28 RCTs was performed, without meta-analysis. Four of these used EPIFIX, including three that compared it with SOC, with two also reviewed in the Sui et al. systematic review reported above. Rates of complete wound closure and time to healing were examined for 17 commonly available DSSs. Healing rates after 12 weeks and time to complete closure of DFUs were heterogeneous among the 28 RCTs. The best healing rates at 12 weeks were accomplished with dermal cellular substitutes (EPIFIX, 100 percent; AmnioBand, 85 percent). The authors concluded that based on these studies, DSSs used in conjunction with standard care appear to improve the healing rates of DFUs compared with standard care alone. The authors indicated that new studies with more homogeneous samples are needed to ascertain the role of ulcer size, duration, depth, and/or type in the efficacy of DSSs. According to the authors, future RCTs should include individuals with severe comorbidities to be more representative of clinical reality. Gordon et al. (2019) conducted a systematic review to determine the efficacy of biological skin substitutes for healing DFUs. Some products included in this review were AmnioExcel, DermACELL, EPICORD, EPIFIX, GRAFIX, MatriStem, and TheraSkin. The main objective was to calculate a pooled risk ratio for the proportion of wounds completely closed by 12 weeks. Secondary objectives included a pooled risk ratio for the proportion of wounds completely closed by 6 weeks and the mean time to healing. Biological skin substitutes were organized both very specifically into product brand and more broadly by four main groups based on product composition: allografts/xenografts, cultured skin grafts, dermal substitutes, and biosynthetic dressings. Overall, 25 studies were identified that assessed the proportion of complete wound closure by 12 weeks. Wounds treated with biological dressings were 1.67 times more likely to heal by 12 weeks than those treated with SOC dressings (P<0.00001). Five studies assessed the proportion of complete wound closure by 6 weeks. Wounds treated with biological dressings were 2.81 times more likely to heal by 6 weeks than those treated with SOC dressings (P=0.0001). Descriptively, 29 of 31 studies that assessed time to healing favored biological dressings over SOC dressings. Cultured skin grafts did not show a statistical difference over SOC. The authors concluded that this systematic review provides supporting evidence that biological skin substitutes are more effective than SOC dressings at healing DFUs by 12 weeks. This review has several study limitations, one being that the individual products were assessed in only one or two studies. Complete wound healing was assessed at 12 weeks, but the mean time to healing in that time periods was not assessed. Finally, adverse effects of skin products were not mentioned. Future studies must address the relative benefits of different skin substitutes as well as the long-term implications of these products.

Abdominal Wall Reconstruction: Following a systematic review of 40 studies (37 retrospective reviews), Janis et al. (2012) concluded that there is a lack of high-level data to define the precise role of acellular dermal matrix (ADM) and guidelines for its use for abdominal reconstruction guidelines. Hernia recurrence, the primary outcome measure, ranged from 0 to 80 percent. Limitations of the studies included small, heterogeneous individual populations (n=5–240); short-term follow-ups (0–68 months); heterogeneity in surgical techniques; variable starting points of the studies; wide variety of clinical indications for reconstruction (e.g., ventral hernia; incisional hernia, abdominal compartment syndrome, tumor resection, fascial defects, contaminated abdominal wall); variety of positions of matrices; conflicting reports regarding superiority of underlay versus overlay techniques; variety in the number of matrix layers used; and use of matrices in combinations with other techniques making it difficult to evaluate the benefit of the matrix alone. Zhong et al. (2011) conducted a systematic review to evaluate the evidence on ADM used during abdominal wall reconstruction. Thirty case series (n=4) and retrospective reviews (n=26) met inclusion criteria. No RCTs or systematic reviews were found. Studies included the use of porcine ADM and human ADM. The outcomes studied included hernia recurrence, abdominal wall laxity, delayed wound healing, infection and seroma. The incidence of postoperative/recurrent hernia ranged from 0 to 80 percent, and the incidence of abdominal wall laxity was largely unreported. Delayed healing occurred in up to 64 percent of individuals with infection-related complications (e.g., surgical site infections, cellulitis, deep/intrabdominal abscesses) reported as high as 40 percent. Types of ADM, technique, and types of fascia repair and suture used varied. The authors concluded that there was a paucity of high-level evidence comparing ADM with other methods, interfering with the ability of physicians to make data-driven recommendations on clinical indications, surgical techniques and outcomes following ADM-assisted abdominal wall reconstruction.

Amniotic Allografts for Use in Bariatric and Gynecological Procedures: Abstracts included a Cochrane review (Bosteels et al., 2017) on antiadhesion therapy following operative hysteroscopy for treatment of female subfertility. Studies using HAM grafting versus no grafting were included. The authors concluded that the clinical effectiveness of antiadhesion treatment for improving key reproductive outcomes or for decreasing intrauterine adhesions (IUAs) following operative hysteroscopy in subfertile women remained uncertain. A pilot RCT (n=45) of women with severe adhesions allocated the women to one of three groups: insertion of intrauterine balloon only, fresh amnion graft, or dried amnion graft. Outcomes were significantly better with amnion graft than intrauterine balloon alone (P=0.003) and outcomes were better with fresh amnion than with dried amnion (P=0.01). Additional studies with larger individual populations are needed to validate the effectiveness of amniotic graft for this indication. No evidence was found to support the use of amniotic membrane in bariatric surgery.

Dural Sealants: Kinaci et al. (2018) conducted a systematic review of the literature to evaluate the efficacy of dural sealants in preventing cerebrospinal fluid (CSF) leakage following cranial surgery. Studies describing regular cranial procedures combined with the use of any dural sealant reporting CSF leakage were included. The primary outcome measure was CSF leakage of any origin. Secondary outcomes were incidental leakage through the skin, pseudomeningocele formation (subcutaneous or epidural collection of CSF) and surgical-site infection. Twenty studies (n=3682 procedures) met inclusion criteria and were primarily in the form of retrospective reviews and case series. Ten comparative studies (n=2321), including three RCTs, comparing sealant versus no sealant were included in the meta-analysis. There was no significant difference between the two groups in CSF leakage. Meta-analyses for secondary outcomes showed no significant difference between the number of incisional CSF leakages or in the pseudomeningocele formation. Surgical-site infection was seen less in the sealant group than the control group. The number of individuals with surgical-site infection in the sealant group was 10 of 1006 (1.0 percent) versus 60 of 1062 (5.6 percent) in the control group. Overall, adverse events were not reported and when they were, the direct relationship between sealant use and adverse event was not objectively confirmed. Author-noted limitations of this systematic review included lack of RCTs; individuals receiving rescue therapy in the control group with other types of sealants or grafts to obtain watertight closure were not excluded; high risk of bias in the comparative cohort studies; heterogeneity of the individual populations and sealants used; variation in the number of CSF leakages; and differentiation in leakage between supra- and infratentorial craniotomies could not be made. The authors concluded that studies with greater methodologic quality including RCTs are warranted.

Fibrin Sealants: Esposito et al. (2016) conducted a systematic review of the literature to investigate the safety and efficacy of fibrin sealants that are used as dural sealants to prevent and/or treat CSF leaks. Thirty-two studies enrolled 2935 individuals who were exposed to fibrin sealant. Seven studies that only included safety data were included and used for safety analysis. Three studies were RCTs. The remaining studies were prospective case series and retrospective reviews. The studies investigated fibrin glue for the treatment of acute intraoperative CSF leaks, prevention of postoperative CSF leaks, and treatment of persisting CSF leaks. Overall, few or no adverse events were reported in most of the studies. Limitations of the studies included limited number of RCTs, heterogeneity in the definition of postoperative CSF leak, limited number of studies (n=2) that discussed fibrin sealants for persistent CSF leaks, variations in surgical technique, variety of fibrin glues that were used did not allow comparison of products, heterogeneity in individual populations (e.g., age, sex, race, medical condition), and variation in use of secondary treatments (i.e., medical therapies, interventional strategies). Because of the limitations of the studies, firm conclusions could not be made regarding the benefit of fibrin sealants. Well-designed and powered randomized clinical trials are needed to support the safety and establish the efficacy of these sealants.

Fistula Plugs: Nasseri et al. (2016) conducted a systematic review to evaluate the evidence on the efficacy of anal fistula plugs (AFPs) in treating fistula-in-ano in individuals with Crohn’s disease. Twelve studies met inclusion criteria. Eight were nonrandomized prospective and four were retrospective reviews. Eighty-four individuals (n=1–20 per study), age between 18 and 72 years (median, 45 years) and follow-up between 3 and 24 months (median, 9 months) were included in the analysis. The total success rate (i.e., closure of the fistula tract) was achieved in 49 of 84 individuals. Two of five individuals had success with recurrent fistula. The overall success rate with Surgisis was 48 of 80 and one of four individuals for Gore Bio-A. Five studies reported a recurrence rate of 13.6 percent (3/22 individuals). The authors were unable to draw firm conclusions due to the limitations of the studies. The procedure appeared safe with little morbidity and low risk of incontinence. Limitations of the studies as noted by the authors included heterogeneity of study design; small individual population; lack of statistical significance in outcomes; grouping of fistulas in Crohn’s disease with other types of anal fistulas, thus introducing ambiguity; short-term follow-up and heterogeneity of follow-up times; and various confounding factors (e.g., use of steroids or immunosuppressants, previous use of seton stitch to aid in healing and variation in surgical technique) and lack of reporting of these factors. The authors noted that the outcomes may have been worse if longer follow-ups had been reported and that it was unclear whether failure occurred as a result of technical error or owing to the pathology of the fistula despite use of the correct surgical technique. In a systematic review, O’Riordan et al. (2012) identified 56 articles that investigated anal fistula plugs for the treatment of Crohn’s (n=42) and non-Crohn’s disease (n=488). Eight studies were retrospective, 10 were prospective cohorts, and two were RCTs. Individual population ranged between four and 60 individuals. Included studies involved individuals with and without Crohn’s disease that could be differentiated and a mean or median follow-up of 3 months or greater. The longest follow-up was 24.5 months. Individuals with rectovaginal, anovaginal, rectourethral, or ileal-pouch vaginal fistulas were excluded. Overall, plug extrusion rate was 8.7 percent (n=46). In individuals with non-Crohn’s disease, fistula closure ranged between 0.2 and 0.86. The overall success rate for individuals with Crohn’s was 54.8 percent (23 of 42 individuals) and 54.3 percent of individuals (265 of 488 individuals) without Crohn’s disease. Limitations of the study included heterogeneity of operative technique, perioperative care; operative position, and anesthesia type; and the retrospective and noncomparative study designs.

Hernia Repairs: Trippoli et al. (2018) conducted a systematic review of the literature to evaluate the differences in various biological products for the treatment of primary and incisional ventral hernias. Included studies met the following criteria: treatment of primary and incisional abdominal hernia; mesh derived from porcine dermis or porcine intestinal submucosa or bovine pericardium or bovine or fetal dermis; may or may not involve "cross-linking of collagen;" the end-point was 30-day follow-up of surgical site infection and/or relapse rate after follow-up of at least 12 months. The five available biological meshes of porcine derivative available in the market at the time of the analysis were Strattice, Permacol, Fortiva, Surgisis, and Xenmatrix. The four available bovine meshes were Peri-guard, Veritas, Bioripar, and Tutomesh. Eleven trials that evaluated five meshes met inclusion criteria. Nine studies were single-arm (prospective or retrospective), and two studies were based on a comparative design. The meshes included in the studies were Permacol (n=706), Strattice (n=324), Surgisis (n=44), Tutomesh (n=38) and Xenmatrix (n=22). No published studies were found investigating Fortiva, Veritas, Bioripar, and Tutomesh. Among all comparisons carried out within these biological meshes, one significant difference was found. Permacol (a crosslinked mesh) showed a lower recurrence rate at 12 months than Strattice (a non-cross-linked mesh) (P=0.001), suggesting that crosslinking may strengthen a mesh. Overall the studies generally showed a poor methodological quality. There was wide variability in the surgical wound infections between studies and the 12-month relapse rates (n=4 studies). Additional author-noted limitations of the studies included the limited available clinical information, small individual populations, short-term follow-ups, and uncontrolled study designs. Other limitations are the heterogeneity of the wound types and retrospective study designs. In conclusion, there is insufficient evidence in the published literature to support the use of biological mesh for hernia repair. Data do not indicate if a porcine versus bovine or cross-linked versus noncrosslinked mesh should be used. Individual selection criteria have not been established.

In a 2014 systematic review, Cross et al. reported that the data for biological mesh products in ventral hernia repair in contaminated fields were limited. Sixteen studies (n=554) met inclusion criteria. All of the studies were case series with the largest individual population being 116. Six different mesh products were used. The authors recommended that caution be used when considering the use of biological meshes because there is a paucity of controlled trials and none of the products are FDA approved for this indication.

Ferzoco (2013) conducted a systematic review to assess outcome in individuals who underwent repair of contaminated or infected ventral incisional hernias using a biologic mesh. The 11 studies that met inclusion criteria used the following products: AlloDerm (n=7), Surgisis (n=2); CollaMend (n=2), Permacol (n=2), Strattice (n=1), and Veritas (n=1). All studies were retrospective chart reviews and included a total of 677 individuals. Reported hernia recurrence varied widely and ranged between 0 and 50 percent. Wound dehiscence rates varied between 0 and 35.5 percent and mesh explantation ranged between 0 and 23 percent. Occurrence rates for seroma, fistula, evisceration, intrabdominal bleeding, repeat surgery, and hematoma were typically not reported. The most commonly reported reasons for a secondary surgical procedure included repair of recurrent hernia, mesh removal, drainage of seroma, and drainage of surgical site abscess. Prospective studies are needed to investigate the efficacy of biologic mesh in the treatment of infected ventral incisional hernias.

Beale et al. (2012) conducted a systematic review to evaluate the use of biological mesh in the repair of ventral hernias in adults. Twenty-nine studies met inclusion criteria (n=1257). Four studies used Permacol (n=64), three used Surgisis (n=87), and 23 used AlloDerm (n=1106). Primary outcomes were hernia recurrence and surgical site occurrences (hematoma, seroma, wound infection, dehiscence or graft removal). Device-specific recurrence rates were 20.8 percent for AlloDerm, 10.9 percent for Permacol, and 8.0 percent for Surgisis. The surgical site occurrence rate (e.g., hematoma, seroma, wound, infection, dehiscence, or need for graft removal) was 31.4 percent for AlloDerm, 25 percent for Permacol, and 40.2 percent. The authors noted that it was difficult to identify a uniformly accepted technique for the placement of the biologic mesh. Limitations of the studies included retrospective study design (n=27 studies), heterogeneity of surgical technique and placement of the product, lack of reporting of hernia recurrence and complication rates, paucity of data, and older studies. Well-designed, prospective RCTs with large individual populations and long-term follow-up are needed to evaluate biological mesh for ventral hernia repair.

Kissane and Itani (2012) conducted a systematic review to evaluate ADM for complex ventral incisional hernia repair. Eight single-center studies (n=635) met inclusion criteria and used either AlloDerm (n=461), Surgisis (“Sis-ECM” mesh) (n=91), or Strattice (n=80). One study was prospective and used Strattice in a one-stage repair of infected or contaminated hernias. Seven studies were retrospective in design. There was a recurrence rate of 21 percent after 25.8 months; the highest rate was observed in the AlloDerm individuals. Total percentage of complications (e.g., wound-related, eventration, mesh rejection) in the AlloDerm hernia repairs was 40.4 percent. Other complications included seroma formation, postoperative peritonitis, subfascial abscesses, intra-abdominal hematoma, and mesh reaction. Because of the heterogeneity of the individual population, ventral incisional hernia grades, type of meshes used, surgical techniques, and length of follow-up, a meta-analysis could not performed. Other limitations of the studies included minimal reporting of individual inclusion criteria and demographics, diverse individual comorbidities, retrospective study designs, lack of controls, and short-term follow-up (mean, 25.8 months).

Smart et al. (2012) conducted a systematic review to assess the clinical outcomes of biological meshes used in abdominal wall hernia repairs. Forty-five RCTs, case series, and retrospective reviews met inclusion criteria including 23 studies on AlloDerm, seven on Surgisis, 10 on Permacol, and seven on other meshes. Most articles were retrospective reviews or uncontrolled prospective case series with small heterogeneous, individual populations, poorly described methodology, and short-term follow-ups (3–52 months). AlloDerm recurrence rates ranged from 0 to 100 percent and were inferior compared to polypropylene and Surgisis. In infected fields, recurrence rates were high at short and medium-term follow-up. Concerns were reported regarding bulging at the repair site and stretching of the graft. "There is little evidence to support the use of AlloDerm in most of the situation where a biological mesh is indicated." The recurrence rates with Permacol were 0 to 15 percent. Outcomes in Permacol studies were conflicting and “important methodological weaknesses exist” representing a low level of evidence. Outcomes with Surgisis were also conflicting. Some studies reported a recurrence rate of 0 to 5.3 percent regardless of whether the surgery was performed in a clean or infected field, whereas other studies reported a recurrence rate as high as 39 percent in dirty fields. One study was terminated early due to the high recurrence rates in a Surgisis group with clean cases. According to the authors, insufficient or minimal data in the form of retrospective reviews were found for Veritas, Xenmatrix, CollaMend, and Strattice, and only case reports were found for Allomax, FlexHD, FortaGen, Peri-Guard, SurgiMend and Tutopatch.

Hyaluronic Acid: Shaharudin and Aziz (2016) conducted a systematic review to assess the evidence on the effectiveness of hyaluronic acid compared to placebo or other agents for promoting chronic wound healing. Nine RCTs (n=865) met inclusion criteria. The authors noted that there was better quality of evidence for mixed arterial and venous ulcers than for venous leg ulcers and DFUs. Overall, the studies provided little evidence regarding the claimed effects of hyaluronic acid for this indication. Some mixed evidence suggested that hyaluronic acid reduced the intensity of pain for mixed arterial and venous ulcers. There is insufficient evidence to support the use of hyaluronic acid for the treatment of chronic wound healing.

Laryngotracheal and Pharyngeal Reconstruction: Hui et al. (2017) conducted a systematic review to evaluate the safety and efficacy of acellular dermal matrices in laryngotracheal and pharyngeal reconstruction. Eleven studies (n=170) including three retrospective review, five case series, and three case reports met inclusion criteria. Eight studies reported on ADM use in oncological reconstruction. Seven studies used AlloDerm, three studies used Heal-All Oral Biofilm (Zhenghai Biotech, Yantai, China) and one case report used Permacol. Follow-ups varied between 2 weeks and 42 months. The methodology of the studies was poor. Other limitations included the small individual populations, and heterogeneity of surgical procedures and diagnosis. Overall, the studies provided incomplete descriptive detail concerning perioperative radiation dosing and scheduling, the surgeon’s experience using dermal grafts, graft thickness, and defect size. The authors stated that because of the limited number and heterogeneity of the cases, conclusions could not be made regarding the impact of ADM use on postoperative stricture and stenosis rates in tracheal or pharyngeal reconstruction.

Orthopedic Sports Medicine: Riboh et al. (2016) conducted a systematic review of the literature to assess the evidence for amniotic membrane products used in orthopedic sports medicine. Eighty articles were considered relevant to the study. Fifty-five of the articles were narrative and 25 articles described preclinical and clinical trials of amniotic products for orthopedic sports medicine. The primary indications explored included cartilage restoration, ligament and tendon healing, nonoperative treatment of knee osteoarthritis, and plantar fasciitis. Because of the low quality of the studies, a systematic review summary and meta-analysis for the use of these products for this indication could not be conducted. According to the authors the current body of evidence is heavily biased toward in vitro and animal studies, with little to no human clinical data.

Tendon and Ligament Repairs: Chen et al. (2009) conducted a systematic review of biological and synthetic scaffolds used for tendon and ligament repairs. Of 378 identified articles, 47 clinical trials met inclusion criteria. Of the 47 articles, 16 clinical trials included four commercial biological scaffolds (i.e., five included the use of Restore, six used GraftJacket, four used Zimmer [formerly Permacol], and one study included both Restore and GraftJacket. After a review of the data, the authors reported the following:

Restore – “Restore or scaffolds from small intestine submucosal are ineffective in the reinforcement of large rotator cuff tears and currently not recommended for use in cuff tendon repair.” They identified other scaffolds made from small intestine submucosal (i.e., Oasis, Surgisis, and CuffPatch™ [Organogenesis, Inc., Canton, MA]) and stated that “extra care should be taken to monitor adverse events when applied in individuals.”
GraftJacket – “Satisfactory results have been described using GraftJacket for skin lesion and abdominal wall repair.” No reports of inflammatory response, edema or postoperative infection have been reported, and individuals seemed to tolerate it well. However, recurrent tears were noted in 30 percent of individuals in two studies.
Zimmer (Permacol) – Two retrospective reviews (n=10 each) reported increased pain relief and range-of-motion following implantation, but two other smaller studies reported recurrent tears, aggravated pain and decrease range-of-motion. Foreign body reaction was noted in several of the individuals.
TissueMend – No published animal or clinical studies were found. They noted that TissueMend has been reported to contain higher genetic materials compared to other products which raise concern regarding human application.
OrthADAPT – No published animal or clinical studies could be found

According to Chen et al., the studies in this systematic review were primarily in the form of case reports, case series, or retrospective reviews and limited by small individual populations (n=1–30), short-term follow-ups (3 months–5 years) and lack of comparison to established methods of treatment. One of the major concerns with these products is biocompatibility and inflammatory response associated with foreign body rejection. The authors also noted that many scaffolds were FDA approved without proper animal studies or evidence-based clinical trials.

For individuals who are undergoing breast reconstruction who receive allogeneic ADM products, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, functional outcomes, QOL, and treatment-related morbidity. A systematic review found no difference in overall complication rates with ADM allograft compared with standard procedures for breast reconstruction. Reconstructions with ADM have been reported to have higher seroma, infection, and necrosis rates than reconstructions without ADM. However, capsular contracture and malposition of implants may be reduced. Thus, in cases where there is limited tissue coverage, the available evidence may inform individual decision making about reconstruction options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are undergoing tendon repair who receive GraftJacket, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, QOL, and treatment-related morbidity. The RCT identified found improved outcomes with the GraftJacket ADM allograft for rotator cuff repair. Although these results were positive, additional studies with a larger number of individuals is needed to evaluate the consistency of the effect. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are undergoing surgical repair of hernias or parastomal reinforcement who receive acellular collagen–based scaffolds, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, QOL, and treatment-related morbidity. Several comparative studies including RCTs have shown no difference in outcomes between tissue-engineered skin substitutes and either standard synthetic mesh or no reinforcement. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have diabetic lower extremity ulcers who receive AlloPatch, Apligraf, Dermagraft, Integra, mVASC, or TheraSkin, the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, and QOL. RCTs reporting complete wound healing outcomes with at least 12 weeks of follow-up have demonstrated the efficacy of AlloPatch (reticular ADM), Apligraf, and Dermagraft (living cell therapy), Integra (biosynthetic), mVASC, TheraSkin, and Omega3 Wound (Kerecis) over the SOC. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have diabetic lower extremity ulcers who receive bioengineered skin substitutes other than AlloPatch, Apligraf, Dermagraft, Integra, mVASC, TheraSkin, or Omega3 Wound, the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, and QOL. Results from a multicenter RCT showed some benefit of DermACELL that was primarily for the subgroup of individuals who only required a single application of the ADM. Studies are needed to further define the population who might benefit from this treatment. Additional study with a larger number of subjects is needed to evaluate the effect of GraftJacket, DermACELL, Cytal, PriMatrix, and Oasis Wound Matrix, compared with current SOC or other advanced wound therapies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have lower extremity ulcers due to venous insufficiency who receive Apligraf or Oasis Wound Matrix, the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, and QOL. RCTs have demonstrated the efficacy of Apligraf living cell therapy and xenogeneic Oasis Wound Matrix over the SOC. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have lower extremity ulcers due to venous insufficiency who receive bioengineered skin substitutes other than Apligraf or Oasis Wound Matrix, the evidence includes RCTs. Relevant outcomes are disease-specific survival, symptoms, change in disease status, morbid events, and QOL. In a moderately large RCT, Dermagraft was not shown to be more effective than controls for the primary or secondary endpoints in the entire population and was only slightly more effective than controls (an 8 percent to 15 percent increase in healing) in subgroups of individuals with ulcer durations of 12 months or less or size of 10 cm or less. Additional studies with a larger number of subjects is needed to evaluate the effect of the xenogeneic PriMatrix skin substitute versus the current SOC. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have deep dermal burns who receive bioengineered skin substitutes (i.e., Epicel, Integra Dermal Regeneration Template), the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related morbidity. Overall, few skin substitutes have been approved, and the evidence is limited for each product. Epicel (living cell therapy) has received FDA approval under a HDE for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30 percent or more. Comparative studies have demonstrated improved outcomes for biosynthetic skin substitute Integra Dermal Regeneration Template for the treatment of burns.

Epicel (Vericel Corporation, Cambridge, MA) is a cultured epidermal autograft (CEA) that is FDA approved under the HDE process for individuals who have deep dermal or full-thickness burns comprising a total body surface area of greater than or equal to 30 percent (Vericel Corporation, 2025). It may be used in conjunction with split-thickness autografts or alone in individuals for whom split thickness autografts may not be an option (FDA, 2007). Epicel is FDA approved as a HDE device. Prospective comparative studies and case series support Epicel for the treatment of burns (Carson et al., 2003; Munster, 1996). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have deep dermal burns who are treated with the ReCell autologous cell harvesting device, the evidence includes RCTs. One RCT evaluated ReCell as an adjunct to meshed autologous skin grafting and the other compared ReCell head-to-head with skin grafting. Although the ReCell device was comparable to standard care on outcomes such as complete wound closure, confidence in the strength of the overall body of evidence is limited by individual study limitations and heterogeneity of populations, interventions, and outcome measures across studies. Additional RCT evidence in the intended use population is needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have dystrophic epidermolysis bullosa who receive OrCel, the evidence includes a case series. Relevant outcomes are symptoms, change in disease status, morbid events, and QOL. OrCel was approved under a humanitarian drug exemption for use in individuals with dystrophic epidermolysis bullosa undergoing hand reconstruction surgery, to close and heal wounds created by the surgery, including those at donor sites. Outcomes have been reported in a small series (e.g., five individuals). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

OrCel (Forticell Bioscience, Inc., New York, NY) is an allogeneic, bilayered cellular matrix, type I bovine collagen sponge with FDA PMA approval for the treatment of split-thickness donor site wounds in burn individuals. There is limited evidence to support the efficacy of Orcel compared to the SOC for the treatment of split-thickness donor sites. Therefore, OrCel is considered investigational for this indication. FDA-HDE approval (H990013) was granted for OrCel for use as an adjunct in the treatment of mitten-hand deformity surgery of epidermolysis bullosa. Published studies are in the form of case series with small individual populations (n=7). There is insufficient evidence to support the use of Orcel for any indication. In a matched-pairs study conducted by Still et al. (2003), the use of OrCel was compared to treatment with Biobrane L. Eighty-two severely burned individuals each had two designated split thickness donor sites of equivalent surface area and depth. Sites were randomized to receive a single treatment of either OrCel or the standard dressing, Biobrane-L. Sites were evaluated for wound closure. The researchers found a statistically significant decrease in healing time with the use of OrCel compared to Biobrane L. There was a decrease in scarring associated with the use of OrCel, although it was not statistically significant. Additional clinical trials are needed to validate the findings of this study.

The data on skin substitute usage for managing Mohs micrographic surgery (MMS) wounds remain limited. The most commonly used skin substitute for this purported indication within reliable data sources had been porcine collagen. Bovine collagen, Integra, Hyalofill, amnion/chorion-derived grafts, and allogeneic epidermal-dermal composite grafts are also reported in limited capacity and in a significantly lower quality—relative to porcine collagen—within peer-reviewed and published literature. Common factors influencing skin substitute selection appear to be cost, healing efficacy, cosmetic outcome, individual comfort, and ease of use. There are pertinent published articles in the available literature that did not specify individual and wound characteristics. Comprehensive review and assessment of evidence lead to the deduction that skin substitute usage in MMS reconstruction is not well-guided. Blinded RCTs comparing the efficacy of skin substitutes and traditional repair methods are imperative for establishing evidence-based guidelines on skin substitute usage following MMS.

For example, the peer-reviewed and published evidence for Integra consists of low-quality retrospective data of different biased and limited designs, which preclude making any definitive deductions about the safety and effectiveness of this technology. There is a paucity of reliable evidence for Integra for post-Mohs surgery; however, the overall data for multiple versions of this product for several other purported indications (e.g., Bascone et al., 2023; Maus et al., 2021; Othman et al., 2021; Mogedas-Vegara et al., 2021; Locurcio et al., 2023; Reece et al., 2023; Bassetto et al., 2025) also present with insufficiencies in evidence regarding sustained and relevant health improvements. The retrospective study design of pertinent publications confers heterogeneous bias in data collection. A smaller sample size and nonparametrically distributed data in these studies in the failure groups very likely limits the ability to detect clinically significant findings, such as the differences in wound age, and larger studies are warranted. Furthermore, the length of stay could not adequately be captured in these studies due to many subjects being involved in immediate, ambulatory procedures. In the available data, specific individual factors were underpowered for the detection of correlation with failure. For example, increased age, smoking history, and diabetes are known obstacles to wound healing and the small number of subjects with a positive history of each may have resulted in a lack of identification as correlative risk factors for failure. Furthermore, the small sample sizes in the failure groups also confer bias to any documented results.

Among others, one of the reported main drawbacks of Integra is the need to perform a second intervention to carry out a split-thickness skin graft. Soft tissue defects created by wide local excision are capable of producing bigger depth discrepancies and larger dermal violations than those created by MMS. Thus, it is possible for the chances of contour deformity to be greater if Integra is applied in this setting, in addition to an increased latency period to second-stage reconstruction while waiting for the defect to fill in with granulation tissue. It was acknowledged in the clinical research that in the facial region, deeper defects (which suffer a great loss in cartilage) sometimes require more adequate structural support and tissue bulk from a free or local flap, to overcome more severe contracture. Limitations of studies also include failure to include analysis of adjuvant therapy and its effect on construct durability. Individuals receiving adjuvant therapy in studies were few in number and had insufficient follow-up or escalation of reconstruction, making meaningful analyses difficult. Furthermore, certain variables were surgeon dependent in studies (choice of dressing modality, clinical evaluation of graft take). Larger, prospective studies with randomization and analysis of adjuvant therapies are needed. Additionally, studies fail to include a matched individual group receiving flap reconstruction, analyze cosmetic outcomes, and address related clinical factors. It should be noted that, typically, there was differential skin graft adherence between the full-thickness wound groups (which necessitated burring of outer-table bone prior to Integra placement) and the partial-thickness cohorts. Therefore, larger studies would be useful to clarify this difference and corroborate any encouraging clinical outcomes that continue to only be reported in low-quality reliable evidence.

Helicoll^® HeliColl (EnColl Corporation, Fremont, CA) is a semi-occlusive, self-adhering, acellular, type 1 collagen graft proposed for wound care (EnColl, 2026). It is derived from a bovine or ovine source. The product is FDA 510(k) approved for topical wound management including partial and full thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence). It was approved as a predicate device to existing similar products. According to EnColl, healing occurs within one to four applications. HeliColl comes in multiple sizes ranging from 1 square cm to 50 square cm (WoundSource, 2025; Dhanraj, 2015; FDA, 2004). Data supporting the safety and efficacy of HeliColl is lacking. There are limited studies related to Helicoll for wound treatments, second-degree burns, and chronic ulcers. Therefore, it is not possible to determine whether Helicoll has a beneficial effect on health outcomes. Helicoll (MCT Medical Solutions LLC) is a semiocclusive, self-adhering collagen sheet that is used for wound treatments, second-degree burns, and chronic ulcers. This biodegradable skin substitute is made from animal tissues. In an evidence-based review, McNamara et al. (2020) discussed the principles of pediatric wound management and new treatments that were published in the literature to date. Databases were searched for relevant sources, including PubMed, Embase, Web of Science, and DynaMed. The findings noted that amniotic membrane living skin equivalent is a cellular matrix that has been reportedly successful in treating pediatric wounds and is currently under investigation in randomized clinical trials. The authors indicated that Helicoll, an acellular matrix, shows promise in children with recessive dystrophic epidermolysis bullosa. According to the authors, there have been promising results in many studies to date, but RCTs that involve larger sample sizes are necessary to (1) determine the specific role that these advanced products play in pediatric wounds, and (2) identify their safety and efficacy. Dhanraj et al. (2015) conducted a prospective RCT to compare Helicoll, a type I pure collagen dressing, with OPSITE dressing and with scarlet red dressing in the treatment of standardized STSG donor sites. Overall, 30 participants, over a 3-month period, underwent various reconstructive procedures, necessitating the use of STSGs. Following a simple randomized clinical protocol, the analysis of data included donor site pain, the healing time of the donor site, the initial absorption of the applied dressing, and the rate of infection with the three different dressings. Compared with the OPSITE and scarlet red dressing groups, participants in the Helicoll group reported significantly less pain and a decreased infection rate, and they required no dressing change. The healing time of the donor site in the Helicoll group was shorter than that in the scarlet red group; however, it was comparable to that in the OPSITE group. The authors concluded that Helicoll, as a donor site dressing, is successful in providing pain-free mobility, with a measurable healing rate. Study limitations include a small study population and the fact that only one wound type (STSG donor site) was evaluated.

Integra Flowable Wound Matrix (Integra Lifesciences, Princeton, NJ) is a granulated, acellular bovine tendon collagen and glycosaminoglycan device that is 510(k) FDA (K072113) approved for the treatment of advanced wound care. The granulates are reconstituted with saline to form a gel-like substance. The matrix is considered “substantially equivalent in function and intended use to Integra Matrix Wound Dressing” and is approved for the treatment of “partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining wounds” (Integra LifeSciences, 2026; FDA, 2007). The skin substitute is packaged in a syringe and intended for one time use. There is insufficient evidence in the published peer-reviewed scientific literature supporting the efficacy of Integra Flowable Wound Matrix. Campitiello et al. (2017) conducted a randomized, placebo-controlled trial to evaluate the efficacy of Integra Flowable Wound Matrix (n=23) compared with a wet dressing (n=23) for the treatment of DFUs with irregular geometries (tunneling or cavity lesions). Inclusion criteria were diabetic individuals, age greater than 18 years, who had grade 3 Wagner classification DFUs with an ankle-brachial index (ABI) of 0.5 or greater. Antibiotic therapy was started 7 to 10 days prior to surgery and continued until the wound had healed. The primary objective of the study was to determine the percentage of individuals with wound closure (100 percent re-epithelialization). Secondary outcome measures included the time to healing and safety (number of major amputations and hospitalizations). Wounds were cleaned and necrotic tissue was removed until normal healthy tissues appeared. After mixing the dry granular collagen with saline solution, the matrix was applied to the lesion, until completely filled. The edge of the wound was sutured. Wounds in the control group were covered with a sterile saline-moistened gauze before the dressing was applied. Compression dressings and offloading devices were used by both groups. Individuals were followed until complete wound healing had occurred or for up to six weeks. Healing was determined by clinical examination and complete healing was defined as 100 percent re-epithelialization in the absence of discharge. At 6 weeks, complete healing had occurred in significantly more Integra individuals (n=20; 86.95 percent) than control group individuals (n=12; 52.17 percent) (P=0.001). Healing time was significantly shorter in the study group, for which the surgical breach was closed by primary intention, compared with the control group, for which the surgical breach healed by secondary intention. The biomaterial allowed closure of wound by primary intention, reducing the healing time. Minor amputations were performed in nine study group subjects and eight control group subjects. Major amputations (P=0.0019) and re-hospitalization rates (P=0.028) were significantly fewer in the Integra group. Limitations of the study include the small individual population and short-term follow-up. The authors concluded that additional studies are needed with large individual populations and long-term follow-up to validate these findings.

Integra Reinforcement Matrix (Integra LifeSciences, Princeton, NJ) is an acellular porcine dermal matrix proposed for use in the reconstruction of soft tissue deficiencies. Per Lifesciences, the matrix is “intended for implantation to reinforce soft tissue where weakness exists and for surgical repair of damaged or ruptured soft tissue, including reinforcement of the rotator cuff, patellar, Achilles, biceps, quadriceps, or other tendons. Integra Reinforcement Matrix is not intended to replace normal body structure or provide full mechanical strength. Sutures used to repair the tear and sutures or bone anchors used to attach the tissue to the bone provide biomechanical strength for the tendon repair.” The Integra Reinforcement Matrix is available in 4×7 cm and 5×10 cm. There is insufficient evidence in the published peer-reviewed literature to support the safety and effectiveness of this matrix.

Membrane Wrap (BioLab Holdings Inc., Mesa, AZ) is a dual-layered dehydrated human amnion membrane allograft composed primarily of a connective tissue matrix. It is proposed to be minimally manipulated, preserving the natural growth factors and cytokines that are present in amniotic tissue. The product is proposed for chronic and postsurgical wound healing including the treatment of nonhealing acute and chronic wounds (diabetic, venous, mixed, venous-arterial, pressure ulcers), complex and/or open surgical wounds and burns, for children and adults. It is available in various sizes (BioLab Holdings, 2025). Membrane Graft is a similar product by BioLab proposed for the same indications (CMS, May 2019). There is insufficient evidence to support the clinical effectiveness of these products. Membrane Graft and Membrane Wrap (BioLab Sciences, Inc.) are human amniotic allograft membranes that are intended to be used to repair tissue deficits and to reduce healing time for chronic wounds and postsurgical wounds; Membrane Wrap-Hydro (BioLab Sciences, Inc.) is a hydrated human amnion membrane that is indicated for chronic and acute wounds. The product serves as a protective covering from the surrounding environment for acute and chronic wounds. Membrane Wrap-Lite (BioLab Sciences, Inc.) is a human amnion single-layer allograft that is indicated for acute and chronic wounds. There are few published studies that address the use of Membrane Graft, Membrane Wrap, Membrane Wrap-Hydro, and Membrane Wrap-Lite. Therefore, it is not possible to determine whether these products have a beneficial effect on health outcomes.

While the published data discuss presence and potential of positive outcomes, they predominately draw from small, retrospective studies or case reports, which are not sufficient reliable evidence to draw definitive conclusions regarding effectiveness of skin substitutes. There is also a scarcity of data comparing skin substitutes with each other or controls. Prospective, randomized, and controlled study designs with sufficient power and appropriate objective clinical outcomes with long-term follow-ups remain warranted.

PROFESSIONAL SOCIETIES/ORGANIZATIONS

In 2016, the American Society of Colon and Rectal Surgeons published clinical practice guidelines for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula (Vogel et al., 2016). The guidelines state that the fistula plug is a relatively ineffective treatment for fistula-in-ano. The guidelines did not include the use of collagen plug for rectovaginal fistulas owing to the prohibitively poor success of this intervention.

Based on data from a prospective, multicenter registry of 245 individuals who underwent surgical intervention for anal fistula, the New England Regional Society of the American Society of Colon and Rectal Surgeons (Hyman et al., 2009) reported that the best healing rates occurred following fistulotomy (87 percent) and the worst healing rates occurred following anal fistula plug (32 percent) (P=0.001). They stated that RCTs comparing various treatment options for anal fistulas “are clearly needed.”

The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) (Daly et al., 2024) guidelines for hiatal hernia repair are based on a systematic review of the evidence in the published peer-reviewed scientific literature. One objective was to assess the benefits and harms associated with the surgical management options of using mesh versus no mesh. Large hiatal hernias were defined as those measuring more than 2 cm in any direction. The guideline panel deferred making a recommendation on the routine use because the evidence was lacking. They concluded that the use of mesh must be a joint decision between surgeon and individual; large, well-designed RCTs comparing type of mesh used and orientation of the mesh are required to better establish the safety and long-term outcomes of mesh use at the hiatus.

The Society for Vascular Surgery/American Podiatric Medical Association/Society for Vascular Medicine (SVS/APMA/SVM) published a joint evidence-based guideline for the management of individuals with diabetes, including treatment of diabetes-related chronic foot ulcers (Hingorani et al., 2016). These organizations recommended the following:

Standard wound therapy for diabetic ulcers includes moist dressings, offloading, and debridement.
For DFUs that fail to demonstrate improvement (>50 percent wound area reduction) after a minimum of 4 weeks of standard wound therapy, adjunctive wound therapy options include biologics (platelet-derived growth factor, living cellular therapy, extracellular matrix products, or amniotic membrane products). The choice of adjuvant therapy is based on clinical findings, availability of therapy, and cost-effectiveness; there is no recommendation on ordering of therapy choice. Reevaluation of vascular status, infection control, and offloading is recommended to ensure optimization before initiation of adjunctive wound therapy (grade 1B).
Consider living cellular therapy using a bilayered keratinocyte/fibroblast construct or a fibroblast-seeded matrix for treatment of DFUs when the individual is recalcitrant to standard therapy (grade 2B).
Consider the use of extracellular matrix products using acellular human dermis or porcine small intestinal submucosal tissue as an adjunctive therapy for DFUs when the individual is recalcitrant to standard therapy (grade 2C).

Wound Healing Society (WHS): The WHS has published updated evidence-based guidelines on the treatment of diabetic ulcers. Regarding the use of skin substitutes, the WHS concluded the following:

Cellular, bioengineered skin substitutes increase the incidence of healing and decrease the time to heal (level I – unchanged).
ADM products have been shown to increase the incidence of healing and decrease the time to heal (level I – unchanged).
Human amniotic tissue membranes have been shown to increase the incidence of healing and decrease the time to heal (level I).
Synthetic skin equivalents have been shown to increase the incidence of healing and decrease the time to heal (level II).
The strength of evidence used in the previous guidelines has been retained:

Level I: Meta-analysis or at least two RCTs supporting the intervention of the guideline. Another route would be multiple laboratory or animal experiments, with at least two clinical series supporting the laboratory results.
Level II: Less than level I, but at least one RCT and at least two significant clinical series or expert opinion papers, with literature reviews supporting the intervention. Experimental evidence that is quite convincing but not yet supported by adequate human experience.
Level III: Suggestive data of proof of principle but lacking sufficient data such as meta-analysis, RCT, or multiple clinical series (Lavery et al., 2016; updated 2023). In an evidence-based guideline for venous ulcers, the WHS stated that there is evidence that a bilayered living human skin equivalent, used in conjunction with compression bandaging, increases the incidence and speed of healing for venous ulcers compared with compression and a simple dressing (level I evidence). The WHS recommends adequate wound bed preparation and control of excess bioburden levels prior to application of a biologically active dressing. They also noted that cultured epithelial autografts or allografts have not been demonstrated to improve stable healing of venous ulcers (level I). The WHS also stated that there is level II evidence that a porcine small intestinal submucosal construct may enhance healing of venous ulcers (Marston et al., 2016).

The NICE clinical guideline on diabetic foot problems considers dermal or skin substitutes as an adjunct to standard care when treating DFUs only when healing has not progressed and on the advice of the multidisciplinary foot care service. Their recommendation does not specify which dermal or skin substitutes are considered to be effective (NICE, 2015; updated October 2019).

In 2023, the International Working Group on the Diabetic Foot (IWGDF) updated their evidence-based guidelines on wound healing interventions to promote healing of foot ulcers in persons with diabetes. This is an update of their 2019 guideline (Hu et al., 2023). All recommendations should be considered adjunctive to best SOC when best SOC alone has failed to heal the ulcers. This should include sharp debridement and basic wound dressings, which according to the IWGDF Practical Guidelines, should be dressings to absorb exudate and maintain a moist wound healing environment. The IWGDF made the following suggestions:

Do not use cellular skin substitute products as a routine adjunct therapy to SOC for wound healing in individuals with diabetes-related foot ulcers (conditional; low).
Do not use acellular skin substitute products as a routine adjunct therapy to SOC for wound healing in individuals with diabetes-related foot ulcers (conditional; low).
Do not use autologous skin graft skin substitute products as an adjunct therapy for wound healing in individuals with diabetes-related foot ulcers (strong; low).
With the exception of an autologous leucocyte, platelet, and fibrin patch, do not use autologous platelet therapy (including blood bank–derived platelets) as an adjunct therapy to SOC (conditional; low).
Consider the use of an autologous leucocyte, platelet, and fibrin patch for diabetes-related foot ulcers as an adjunctive therapy to SOC where best SOC alone has been ineffective and where the resources and expertise exist for the regular venipuncture required (conditional; moderate).
Do not use other cell therapy as an adjunct therapy to SOC for wound healing in people with diabetes-related foot ulcers (conditional; low).
Do not use growth factor therapy as an adjunct therapy to SOC for wound healing in people with diabetes-related foot ulcers (conditional; low).
Consider the use of placental-derived products as an adjunct therapy to SOC for wound healing in people with diabetes-related foot ulcers in whom SOC alone has failed (conditional; low).

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Novitas Solutions, Inc. Local Coverage Determination (LCD) 35041: Application of bioengineered skin substitutes to lower extremity chronic non-healing wounds. [Novitas Web site]. Original: 10/01/2015 (Revised 09/26/2019). Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=35041&ver=113. Accessed April 3, 2026.

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Serena TE, Carter MJ, Le LT, et al; EpiFix VLU Study Group. A multi-center, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. 2014;22(6):688-693.

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Shah AP. Using amniotic membrane allografts in the treatment of neuropathic foot ulcers. J Am Podiatr Med Assoc. 2014;104(2):198-202.

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Sibbald RG, Zuker R, Coutts P, et al. Using a dermal skin substitute in the treatment of chronic wounds secondary to recessive dystrophic epidermolysis bullosa: a case series. Ostomy Wound Manage. 2005;51(11):22-46.

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Stiefel D, Schiestl C, Meuli M. Integra Artificial Skin for burn scar revision in adolescents and children. Burns. 2010;36(1):114-120.

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Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

15011, 15012, 15013, 15014, 15015, 15016, 15017, 15018, 15150, 15151, 15152, 15155, 15156, 15157, 15271, 15272, 15273, 15274, 15275, 15276, 15277, 15278

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

MEDICALLY NECESSARY

A2019 Kerecis omega3 marigen shield, per square centimeter (add-on, list separately in addition to primary procedure)

A2043 Biobrane, per square centimeter (add-on, list separately in addition to primary procedure)

A2044 Biobrane glove, each

C9363 Skin substitute (Integra Meshed Bilayer Wound Matrix), per square cm

G0681 Application of a premarket approval (pma), 510(k), 361 human cells, tissues or cellular and tissue-based products (hct/p) non-sheet form skin substitute for a wound surface area up to 100 sq cm; first 25 sq cm or less of wound surface area

G0682 Application of a premarket approval (pma), 510(k), 361 human cells, tissues or cellular and tissue-based products (hct/p) non-sheet form skin substitute for a 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)

G0683 Application of a premarket approval (pma), 510(k), 361 human cells, tissues or cellular and tissue-based products (hct/p) non-sheet form skin substitute graft for a wound surface greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children

G0684 Application of a premarket approval (pma), 510(k), 361 human cells, tissues or cellular and tissue-based products (hct/p) non-sheet form skin substitute graft for a wound surface 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)

Q4101 Apligraf, per square centimeter (add-on, list separately in addition to primary procedure)

Q4102 Oasis wound matrix, per square centimeter (add-on, list separately in addition to primary procedure)

Q4104 Integra bilayer matrix wound dressing (bmwd), per square centimeter (add-on, list separately in addition to primary procedure)

Q4105 Integra dermal regeneration template (drt) or integra omnigraft dermal regeneration matrix, per square centimeter (add-on, list separately in addition to primary procedure)

Q4107 Graftjacket, per square centimeter (add-on, list separately in addition to primary procedure)

Q4114 Integra flowable wound matrix, injectable, 1 cc

Q4121 Theraskin, per square centimeter (add-on, list separately in addition to primary procedure)

Q4122 Dermacell, dermacell awm or dermacell awm porous, per square centimeter (add-on, list separately in addition to primary procedure)

Q4128 Flex hd, or allopatch hd, per square centimeter (add-on, list separately in addition to primary procedure)

Q4132 Grafix core and grafixpl core, per square centimeter (add-on, list separately in addition to primary procedure)

Q4133 Grafix prime, grafixpl prime, stravix and stravixpl, per square centimeter (add-on, list separately in addition to primary procedure)

Q4151 Amnioband or guardian, per square centimeter (add-on, list separately in addition to primary procedure)

Q4154 Biovance, per square centimeter (add-on, list separately in addition to primary procedure)

Q4159 Affinity, per square centimeter (add-on, list separately in addition to primary procedure)

Q4160 Nushield, per square centimeter (add-on, list separately in addition to primary procedure)

Q4168 AmnioBand, 1 mg

Q4182 Transcyte, per square centimeter (add-on, list separately in addition to primary procedure)

Q4186 Epifix, per square centimeter (add-on, list separately in addition to primary procedure)

Q4187 Epicord, per square centimeter (add-on, list separately in addition to primary procedure)

THE FOLLOWING CODE IS USED TO REPRESENT EPICEL

A4100 Skin substitute, fda cleared as a device, not otherwise specified (list in addition to primary procedure)

THE FOLLOWING CODE IS USED TO REPRESENT DERMAGRAFT AND ORCEL

Q4431 Pma skin substitute product, not otherwise specified (list in addition to primary procedure)

THE FOLLOWING CODE IS USED TO REPRESENT 510(K) SKIN SUBSTITUTE PRODUCTS

Q4432 510(k) skin substitute product, not otherwise specified (list in addition to primary procedure)

THE FOLLOWING CODE IS USED TO REPRESENT MVASC

Q4433 361 hct/p skin substitute product, not otherwise specified (list in addition to primary procedure)

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 11.08.20at:

10/01/2026

This version of the policy will become effective 10/01/2026.

The list of bioengineered skin substitutes medically necessary for the indications of lower extremity skin ulcers (diabetic foot ulcers and venous leg ulcers), epidermolysis bullosa, and second- and third-degree burns was revised based on review of the available published peer-reviewed literature.
Medically necessary criteria for the use of bioengineered skin substitutes for the indication of chronic lower extremity wounds, required documentation, and billing requirements were revised.
A note with the definition of a failed response was added for additional clarity.
Experimental/investigational statements were revised. These include the statement that the use of bioengineered skin substitutes other than those specified in the policy (such as, but not limited to, acute wounds, post-Moh's, post-surgical use) are considered experimental/investigational.
Experimental/investigational statements were added under each applicable indication.
Attachment A was revised to include bioengineered skin substitutes that are always experimental/investigational for all indications.
The Company's coverage position has changed from Medically Necessary to Experimental/Investigational for the applicable HCPCS code for any bioengineered skin substitute listed on Attachment A.
The effective date for the following HCPCS codes was revised to 01/01/2026: G0681, G0682, G0683, G0684
The following HCPCS codes have been added to Attachment A of this policy as always Experimental/Investigational:
A2046, A2047, A2048, A2049, A2050, Q4207, Q4223, Q4243
The following HCPCS codes have been revised on Attachment A of this policy: A2040, A2041, A2042, A2043, A2045, Q4298, Q4299

Revisions From 11.08.20as:

04/01/2026

This policy has been identified for the HCPCS code update, effective 04/01/2026.

The following HCPCS codes have been added to this policy: A2040, A2041, A2042, A2043, A2044, A2045, G0681, G0682, G0683, G0684, Q4418, Q4419, Q4421, Q4422, Q4423, Q4424, Q4425, Q4426, Q4427, Q4428, Q4429, Q4435, Q4436, Q4437, Q4438, Q4439, Q4440.

The narratives of the following HCPCS codes have been revised in this policy: A2014, A2037.

Revisions From 11.08.20ar:

01/01/2026

This policy has been identified for the HCPCS code update, effective 01/01/2026.

The following HCPCS codes have been added to this policy: Q4398, Q4399, Q4400, Q4401, Q4402, Q4403, Q4404, Q4405, Q4406, Q4407, Q4408, Q4409, Q4410, Q4411, Q4412, Q4413, Q4414, Q4415, Q4416, Q4417, Q4420, Q4431, Q4432, Q4433.

The following HCPCS codes have been terminated (effective 01/01/2026) and removed from this policy: C5271, C5272, C5273, C5274, C5275, C5276, C5277, C5278, Q4100, Q4106.

As a result of HCPCS code Q4100 being terminated, Epicel is now represented by HCPCS code A4100.

As a result of HCPCS code Q4100 being terminated, Biobrane and Orcel are now represented by new HCPCS code Q4431.

The narratives of the following HCPCS codes have been revised in this policy: A2001, A2002, A2007, A2008, A2009, A2010, A2011, A2012, A2013, A2015, A2016, A2018, A2019, A2021, A2022, A2024, A2025, A2027, A2031, A2032, A2034, A2036, A2038, A2039, A4100, Q4101, Q4102, Q4103, Q4104, Q4105, Q4107, Q4108, Q4110, Q4111, Q4115, Q4117, Q4121, Q4122, Q4123, Q4124, Q4126, Q4127, Q4128, Q4132, Q4133, Q4134, Q4135, Q4136, Q4137, Q4140, Q4141, Q4146, Q4147, Q4148, Q4151, Q4152, Q4153, Q4154, Q4156, Q4157, Q4158, Q4159, Q4160, Q4161, Q4163, Q4164, Q4165, Q4166, Q4167, Q4169, Q4170, Q4173, Q4175, Q4176, Q4178, Q4179, Q4180, Q4181, Q4182, Q4183, Q4184, Q4186, Q4187, Q4188, Q4190, Q4191, Q4193, Q4194, Q4195, Q4196, Q4197, Q4198, Q4199, Q4200, Q4201, Q4203, Q4204, Q4205, Q4208, Q4209, Q4211, Q4214, Q4216, Q4217, Q4218, Q4219, Q4220, Q4221, Q4222, Q4224, Q4225, Q4227, Q4229, Q4232, Q4234, Q4235, Q4236, Q4237, Q4238, Q4239, Q4247, Q4248, Q4249, Q4250, Q4251, Q4252, Q4253, Q4254, Q4255, Q4256, Q4257, Q4258, Q4259, Q4260, Q4261, Q4262, Q4263, Q4264, Q4265, Q4266, Q4267, Q4268, Q4269, Q4270, Q4271, Q4272, Q4273, Q4274, Q4275, Q4276, Q4278, Q4279, Q4280, Q4281, Q4282, Q4283, Q4284, Q4287, Q4288, Q4289, Q4290, Q4291, Q4292, Q4293, Q4294, Q4295, Q4296, Q4297, Q4298, Q4299, Q4300, Q4301, Q4302, Q4303, Q4304, Q4305, Q4306, Q4307, Q4308, Q4309, Q4311, Q4312, Q4314, Q4317, Q4318, Q4319, Q4320, Q4321, Q4322, Q4325, Q4326, Q4327, Q4328, Q4329, Q4330, Q4331, Q4332, Q4333, Q4336, Q4337, Q4338, Q4339, Q4340, Q4341, Q4342, Q4344, Q4345, Q4354, Q4355, Q4356, Q4357, Q4358, Q4359, Q4361, Q4362, Q4363, Q4364, Q4365, Q4366, Q4367, Q4368, Q4370, Q4371, Q4372, Q4373, Q4375, Q4376, Q4377, Q4378, Q4379, Q4380, Q4382, Q4383, Q4384, Q4385, Q4386, Q4387, Q4388, Q4389, Q4390, Q4392, Q4393, Q4394, Q4395, Q4396, Q4397.

Revisions From 11.08.20aq:

12/19/2025	This policy has been reissued in accordance with the Company's annual review process.
10/01/2025	This policy has been identified for the HCPCS code update, effective 10/01/2025. The following HCPCS codes have been added to this policy as Medically Necessary: A2036, A2037, A2038, A2039, Q4383, Q4384, Q4385, Q4386, Q4387, Q4388, Q4389, Q4390, Q4392, Q4393, Q4394, Q4395, Q4396, Q4397.

Revisions From 11.08.20ap:

07/01/2025

This policy has been identified for the HCPCS code update, effective 07/01/2025.

The following HCPCS codes have been added to this policy as Medically Necessary:
Q4368, Q4370, Q4371, Q4372, Q4373, Q4375, Q4376, Q4377, Q4378, Q4379, Q4380, Q4382.

Revisions From 11.08.20ao:

04/01/2025

This policy has been identified for the HCPCS code update, effective 04/01/2025.

The following HCPCS codes have been added to this policy as Medically Necessary:
A2030, A2031, A2032, A2033, A2034, A2035, Q4354, Q4355, Q4356, Q4357, Q4358, Q4359, Q4361, Q4362, Q4363, Q4364, Q4365, Q4366, Q4367.

Myriad Matrix was removed from the list of skin substitutes reported using HCPCS Code Q4100.

The following HCPCS code has been termed and removed from this policy: Q4231.

Revisions From 11.08.20an:

01/01/2025

This policy has been identified for the CPT and HCPCS code update, effective 01/01/2025.

The following CPT codes have been added to this policy as Medically Necessary:
15011, 15012, 15013, 15014, 15015, 15016,15017, 15018

The following HCPCS code hasbeen added to this policy as Medically Necessary:
C8002

Revisions From 11.08.20am:

10/01/2024

This policy has been identified for the HCPCS code update, effective 10/01/2024.

The following HCPCS codes have been added to this policy as Medically Necessary: A2027, A2028, Q4336, Q4337, Q4338, Q4339, Q4340, Q4341, Q4342, Q4344, Q4345.

The following HCPCS code narrative has been revised within this policy: A2024

Revisions From 11.08.20al:

07/01/2024

This policy has been identified for the HCPCS code update, effective 07/01/2024.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4311, Q4312, Q4314, Q4317, Q4318, Q4319, Q4320, Q4321, Q4322, Q4325, Q4326, Q4327, Q4328, Q4329, Q4330, Q4331, Q4332, Q4333

The following HCPCS codes have been removed from this policy: Q4210, Q4277

Revisions From 11.08.20ak:

04/01/2024

This policy has been identified for the HCPCS code update, effective 04/01/2024.

The following HCPCS codes have been added to this policy as Medically Necessary: A2026, Q4305, Q4306, Q4307, Q4308, Q4309 Q4310

The following HCPCS codes have been removed from this policy: Q4244

Revisions From 11.08.20aj:

01/02/2024

This version of the policy will become effective 01/02/2024.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4279, Q4287, Q4288, Q4289, Q4290, Q4291, Q4292, Q4293, Q4294, Q4295, Q4296, Q4297, Q4298, Q4299, Q4300, Q4301, Q4302, Q4303, Q4304

The following HCPCS narrative has been revised in this policy: Q4225

Revisions From 11.08.20ai:

01/01/2024

This version of the policy will become effective 01/01/2024.

The following HCPCS code has been deleted from this policy:

Q4233 Surfactor or NuDyn, per 0.5 cc

The Company's coverage position has changed from Medically Necessary to Experimental/Investigational for Q4233 Surfactor or NuDyn, per 0.5 cc

Revisions to Attachment A listing Skin Substitutes, which are represented by a specific HCPCS code, and their approved indications

The following skin substitutes were added to Attachment A of this policy: Barrera sl or Barrera dl, Biovance tri-layer or biovance 3l, Complete ft, Complete sl, Cygnus dual, Dermabind sl, Epieffect, Esano aaa, Esano ac, Esano aca, Innovaburn or innovamatrix xl, Innovamatrix pd, Kerecis omega3 marigen shield, Miro3d, Neomatrix, Neostim, Orion, Resolve matrix, Surgraft ft, Surgraft xt, Woundplus membrane or e-graft, and Xcell amino matrix.
The following skin subtitutes were removed from Attachement A of this Policy: Surfactor and NuDyn

Revisions From 11.08.20ah:

10/01/2023

This policy has been identified for the HCPCS code update, effective 10/01/2023.

The following HCPCS codes have been added to this policy as Medically Necessary: A2022, A2023, A2024, and A2025

Revisions From 11.08.20ag:

07/01/2023

This policy has been identified for the HCPCS code update, effective 07/01/2023.

The following HCPCS codes have been added to this policy as Medically Necessary:
Q4272, Q4273, Q4274, Q4275, Q4276. Q4277, Q4278, Q4280, Q4281, Q4282, Q4283, Q4284

Revisions From 11.08.20af:

04/01/2023

This policy has been identified for the HCPCS code update, effective 04/01/2023.

The following HCPCS codes have been added to this policy as Medically Necessary: A2019, A2021, Q4265, Q4266, Q4267, Q4268, Q4269, Q4270, Q4271

Revisions From 11.08.20ae:

01/01/2023

This version of the policy will become effective 01/01/2023.

The following medical criteria was revised:

The wound has adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by physical examination (e.g., Ankle-Brachial Index (ABI) between 0.60 and 1.4, toe pressure > 30 mm Hg)

The following 01/01/2023 HCPCS codes were added to the policy: Q4236, Q4262, Q4263, Q4264

The following skin substitute was added under HCPCS Code Q4100 in the coding table: Myriad Matrix

The following HCPCS code has been deleted effective 01/01/2023: C1849

Revisions to Attachment A listing Skin Substitutes, which are represented by a specific HCPCS code, and their approved indications

The following skin substitutes were added to Attachment A of this policy: Amniobind, Apis, CarePATCH, Celera Dual Layer, Celera Dual Membrane, Cocoon Dual-Layer and Single-Layer Membranes, Dual Layer Impax Membrane, Enverse, Human health factor 10 amniotic patch (HHF10-P), Innovamatrix AC, Innovamatrix FS, Mlg-Complete, Mirragen Advanced Wound Matrix, Myriad Matrix, Omeza Collagen Matrix, Permeaderm B, Permeaderm C, Phoenix Wound Matrix, Relese, Restrata, Signature Apatch, Supra SDRM, Suprathel, SurGraft TL, Symphony, Tag, Theragenesis, and XCellistem.

Revisions From 11.08.20ad:

10/01/2022

This policy has been identified for the HCPCS code update, effective 10/01/2022.

The following HCPCS codes have been added to this policy as Medically Necessary: A2014, A2015, A2016, A2018

The following HCPCS narrative has been revised in this policy: Q4128

Revisions From 11.08.20ac:

07/01/2022

This policy has been identified for the HCPCS code update, effective 07/01/2022.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4259, Q4260, Q4261

The following HCPCS narrative has been revised in this policy: A2004

Revisions From 11.08.20ab:

04/01/2022

This policy has been identified for the HCPCS code update, effective 04/01/2022.

The following HCPCS codes have been added to this policy as Medically Necessary: A2011, A2012, A2013, Q4224, Q4225, Q4256, Q4257, Q4258

The following code is used to represent skin substitutes that are FDA cleared as a device, and has been added to this policy: A4100

Revisions From 11.08.20aa:

01/01/2022

This policy has been identified for the HCPCS code update, effective 01/01/2022.

The following HCPCS codes have been added to this policy as Medically Necessary: A2001, A2002, A2003, A2004, A2007, A2008, A2009, A2010, Q4199

____________________________________________________________________

NOTE: On 01/04/2022, this policy was updated with the following coding changes effective 01/01/2022.

CMS made a correction and the following HCPCS code was removed from the 01/01/2022 release: A2003.

As a result, HCPCS code A2003 was removed from this policy.

Revisions From 11.08.20z:

12/20/2021

This version of the policy will become effective 12/20/2021.

Revisions to Attachment A listing Skin Substitutes, which are represented by a specific HCPCS code, and their approved indications

The following skin substitutes were added to Attachment A of this policy: Vendaje, VIM Amniotic Membrane, Zenith Amniotic Membrane
The following skin substitute were removed from Attachment A of this policy because they are no longer manufactured or used: BioNextPATCH, carePATCH

Revisions From 11.08.20y:

10/01/2021

This policy has been identified for the HCPCS code update, effective 10/01/2021.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4251, Q4252, Q4253

The following HCPCS codes have been removed from this policy: Q4228, Q4236

Revisions From 11.08.20x:

12/21/2020

This version of the policy will become effective 12/21/2020.

NOTABLE REVISIONS TO THE POLICY

Billing Requirements

The following skin substitutes were added to the list of skin substitutes in which application codes are not to be reported: Amniotext, Axolotl Ambient, Axolotl Cryo, Cogenex Flowable Amnion, Corplex P, CoreText, Fluid Flow, Fluid GF, NuDyn, Procenta, ProText, and SurFactor.

Coding

The following HCPCS codes have been removed from this policy because the products they describe are classified as Bandages/Surgical Dressings, not Skin Substitutes: A6460, A6461

Revisions to Attachment A listing Skin Substitutes, which are represented by a specific HCPCS code, and their approved indications

The following skin substitutes were added to Attachment A of this policy:

AltiPly, AmnioAMP-MP, AmnioCore, Amnio-Maxx, Amnio-Maxx Lite, Amnion Bio, Axobiomembrane, Amniorepair, Amniotext, Amniotext Patch, AmnioWrap2, Amniply, Artacent Cord, Axolotl Ambient, Axolotl Cryo, Axolotl DualGraft, Axolotl Graft, BellaCell HD, BioNextPATCH, BioWound, BioWound Plus, BioWound XPlus, carePATCH, Cellesta Cord, Cogenex Amniotic Membrane, Cogenex Flowable Amnion, CoreText, Corplex, Corplex P, Cryo-Cord, Derm-Maxx, DermACELL AWM, DermACELL AWM Porous, Dermacyte, Fluid Flow, Fluid GF, Kerasorb, Membrane Graft, Membrane Wrap, Novafix, Novafix DL, NuDyn, Procenta, ProgenaMatrix, ProText, REGUaRD, Stravix, Stravix PL, SureDerm Acellular Dermal Matrix, SurFactor, SurgiCORD, SurgiGRAFT-DUAL, SurGraft, Therion, WoundFix, WoundFix Plus, WoundFix XPlus Membrane, XCellerate

Revisions From 11.08.20w:

10/01/2020

This policy has been identified for the HCPCS code update, effective 10/01/2020.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4249, Q4250, Q4254, Q4255

Revisions From 11.08.20v:

07/01/2020

This policy has been identified for the HCPCS code update, effective 07/01/2020.

The following HCPCS codes have been added to this policy as Medically Necessary: C1849, Q4227, Q4228, Q4229, Q4230, Q4231, Q4232, Q4233, Q4234, Q4235, Q4236, Q4237, Q4238, Q4239, Q4244, Q4245, Q4246, Q4247, Q4248

The following HCPCS narrative has been revised in this policy: Q4176

Revisions From 11.08.20u:

10/01/2019

This policy has been identified for the HCPCS code update, effective 10/01/2019.

The following HCPCS codes have been added to this policy as Medically Necessary: Q4205, Q4206, Q4208, Q4209, Q4210, Q4211, Q4214, Q4215, Q4216, Q4217, Q4218, Q4219, Q4220, Q4221, Q4222

The following HCPCS narratives have been revised in this policy: Q4122, Q4165, Q4184

Revisions From 11.08.20t:

07/29/2019

NOTABLE REVISIONS TO THE POLICY

Policy

CHRONIC NON-HEALING WOUNDS

The following criteria has been revised:

FROM: The wound is clean and free of necrotic debris or exudate

TO: The wound is clean and free of infection, necrotic debris, or exudate, and without evidence of underlying osteomyelitis

COVERAGE LIMITATIONS

The following criteria have been added to the policy:

It is expected that a specific skin substitute will be used for each documented wound, and in compliance with FDA assessments and guidelines for the specific skin substitute.
Treatment of any chronic wound will typically last no more than 12 weeks.
Greater than 10 applications for the treatment of a single wound within a 12-week period of time is considered not medically necessary.
Simultaneous use of more than one skin substitute for the treatment of a single wound within a 12-week period of time is considered not medically necessary. A change in skin substitute within the 12-week treatment period is covered, as long as the 10 application limit per wound is not exceeded.

Billing Requirements

The following skin substitutes were added to the list of skin substitutes in which application codes are not to be reported: Artacent AC Powder, Cellesta Flowable Amnion, FlowerFlo (FlowerAmnioFlow), Keroxx Flowable Wound Matrix, Restorgin AFT.

The following skin substitutes were removed from the list of skin substitutes in which application codes are not to be reported because these products have been discontinued: Amniogen-A, Amniogen-C, AmnioPro Flow, BioRenew Flow.

Policy Guidelines

The definition of a non-healing wound (i.e., "a failed response") has been revised.

Revisions to Attachment A

The following skin substitutes were added to Attachment A of this policy:

Amnio Wound, AmnioArmor, AmnioExCel Plus, Artacent AC, Artacent AC Powder, Cellesta Amniotic Membrane, Cellesta Flowable Amnion, Coll-e-derm, FlowerDerm, FlowerFlo (FlowerAmnioFlow), FlowerPatch (FlowerAmnioPatch), Geistlich Derma-Gide, Genesis Amniotic Membrane, GrafixPL Core, GrafixPL Prime, Kerecis Omega3 Wound, Keroxx Flowable Wound Matrix, Matrion, NeoPatch, Neox Cord RT, Novachor, PalinGen ProMatrX ACF, PuraPly Antimicrobial XT Wound Matrix, Restorgin AFT, Restorgin Amnion Patch, Revita, SkinTE, surgiGRAFT, XWRAP.

The following skin substitutes were removed from Attachment A because these products have been discontinued:

Amniogen-45, Amniogen-200, Amniogen-A, Amniogen-C, AmnioPro, AmnioPro Flow, BioRenew, BioRenew Flow.

Revisions From 11.08.20s:

01/01/2019

The following HCPCS codes have been added to the policy as medically necessary: Q4183, Q4184, Q4185, Q4186, Q4187, Q4188, Q4189, Q4190, Q4191, Q4192, Q4193, Q4194, Q4195, Q4196, Q4197, Q4198, Q4200, Q4201, Q4202, Q4203, Q4204

The following HCPCS codes have been added to the policy as experimental/investigational: A6460, A6461

The following code was deleted: Q4131, Q4172

Revisions From 11.08.20r:

01/01/2018

This policy has been identified for the HCPCS code update effective 01/01/2018.

The following HCPCS codes have been added to this policy: Q4176, Q4177, Q4178, Q4179, Q4180, Q4181

Transcyte has been removed from the list of medically necessary skin substitutes that are to be reported using NOC code Q4100 and is replaced by HCPCS code Q4182.

The following HCPCS narratives have been revised in this policy: Q4132, Q4133, Q4148, Q4156, Q4158, Q4162, Q4163

Revisions From 11.08.20q:

12/01/2017

POLICY SECTION

Chronic Non-Healing Wounds

Criteria was revised in the policy section regarding Chronic Non-Healing Wounds.
Language defining chronic wounds and non-healing wounds was moved from the policy section to the Guidelines section.

Deep Second-Degree (Partial-Thickness) Burns and Third-Degree (Full-Thickness) Burns

Integra Omnigraft Dermal Regeneration Matrix was added as Medically Necessary for burn wounds when medical necessity criteria in the policy are met.
Language was removed from the policy section regarding all other uses of the IntegraDermal Regeneration Template.

Experimental/Investigational

The following Experimental/Investigational language was removed:

The following skin substitutes, which are represented by a specific HCPCS code, are considered experimental/investigational for all wound-care uses and, therefore, are not covered because the safety and/or effectiveness of these products cannot be established by review of the available published peer-reviewed literature; this list may not be all inclusive:

and replaced with:

Skin substitutes that are FDA approved to treat conditions other than burns and chronic, non-healing wounds are considered experimental/investigational for the treatment of burns and chronic, non-healing wounds and, therefore, are not covered because the safety and/or effectiveness of these products cannot be established by review of the available published peer-reviewed literature.

AlloPatch HD and Matrix HD were removed from the list of Experimental/Investigational skin substitutes because they are considered Medically Necessary.
Alloderm, Allowrap Dry/Allowrap DS, Arthroflex, BioDFence DryFlex, Cymetra, FlexHD Acellular Dermal Matrix, Repriza, Strattice Tissue Matrix, and XCM Biologic Tissue Matrix were removed from the list of Experimental/Investigational skin substitutes because they are used to treat conditions other than burns and chronic, non-healing wounds, which is out of scope for this policy.

Billing Requirements

Under billing requirements, the following skin substitutes were added to the list of skin substitutes in which application codes are not to be reported: AmnioBand Particulate, Amniogen-A, Amniogen-C, AmnioPro Flow, BioRenew Flow, BioSkin Flow, Interfyl, MatriStem MicroMatrix, PalinGen Flow, PalinGen SportFlow, ProMatrX ACF, and WoundEx Flow.

GUIDELINES SECTION

Language defining standard wound therapy was added to the Guidelines section.

Benefit Applications

Under Benefit Applications, AlloPatch HD and Matrix HD were removed from the Experimental/Investigational statement because they are considered Medically Necessary.
Under Benefit Applications, Alloderm, Allowrap Dry/Allowrap DS, Arthroflex, BioDFence DryFlex, Cymetra, FlexHD Acellular Dermal Matrix, Repriza, Strattice Tissue Matrix, and XCM Biologic Tissue Matrix were removed from the Experimental/Investigational statement because they are used to treat conditions other than burns and chronic, non-healing wounds, which is out of scope for this policy.

CODING

The following statement was added to ICD-10 Diagnosis Codes: Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.
The following HCPCS codes were removed from this policy: Q4112, Q4116, Q4125, Q4130, Q4138, Q4142, Q4143, Q4150
HCPCS code Q4128 was moved from Experimental/Investigational to Medically Necessary in the coding table.

REVISIONS TO ATTACHMENT A

The following skin substitutes were added to Attachment A:
AlloPatch HD, AmnioBand Particulate, Amniogen-45, Amniogen-200, Amniogen-A, Amniogen-C, AmnioPro, AmnioPro Flow, Architect Px Extracellular Collagen Matrix, Architect Fx Extracellular Collagen Matrix, Artacent Wound, Bio-ConneKt Wound Matrix, BioRenew, BioRenew Flow, BioSkin, BioSkin Flow, Cygnus, Cytal Wound Matrix, EpiCord, Helicoll, Integra Dermal Regeneration Template (DRT), Integra Omnigraft Dermal Regeneration Matrix, Interfyl, Keramatrix, Matrix HD, Miroderm, PalinGen Flow, PalinGen SportFlow, PalinGen Membrane, PalinGen XPlus Membrane, Plurivest, ProMatrX ACF, TruSkin, WoundEx, WoundEx Flow
The following skin substitutes were removed from Attachment A:
MatriStem Burn Matrix (now know as Cytal Wound Matrix), MatriStem Wound Matrix (now know as Cytal Wound Matrix), Unite Biomatrix (product is no longer available)

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

10/1/2026

Version Issued Date:

10/1/2026

Version Reissued Date:

Commercial

Medical Policy

Notification

Policy

Guidelines

Description

References

Coding

CPT Procedure Code Number(s)

ICD - 10 Procedure Code Number(s)

ICD - 10 Diagnosis Code Number(s)

HCPCS Level II Code Number(s)

Revenue Code Number(s)

MPMiscCodesNarrativesPub​

Coding and Billing Requirements

Cross Reference

Policy History

MPMiscCodesNarrativesPub