Policy title: Application of Bio-Engineered Skin and Soft Tissue Substitutes

Policy number: MA 1.158

Effective date 7/1/2026

Policy

Breast reconstructive surgery using allogeneic acellular dermal matrix products may be considered medically necessary:

• When there is insufficient tissue expander or implant coverage by the pectoralis major muscle and additional coverage is required;
• When there is viable but compromised or thin postmastectomy skin flaps that are at risk of dehiscence or necrosis; or
• The inframammary fold and lateral mammary folds have been undermined during mastectomy and reestablishment of these landmarks is needed.

Treatment of dystrophic epidermolysis bullosa using the following tissue-engineered skin substitutes may be considered medically necessary:

• For the treatment of mitten-hand deformity when standard wound therapy has failed and when provided in accordance with the humanitarian device exemption [HDE] specifications of the U.S. Food and Drug Administration [FDA].

Treatment of second- and third-degree burns using the following tissue-engineered skin substitutes may be considered medically necessary:

• Epicel^® (for the treatment of deep dermal or full-thickness burns comprising a total body surface area ≥30% when provided in accordance with the HDE specifications of the FDA).

For guidance on lower extremity ulcers, please refer the latest version of Medicare Local Coverage Determination (LCD).

All other uses reviewed herein of the bioengineered skin and soft tissue substitutes listed above are considered investigational as there is insufficient evidence to support a conclusion concerning the general health outcomes or benefits associated with this procedure.

Policy Guidelines

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).

Wound healing is impaired by the systemic use of tobacco. Therefore, ideally patients who have smoked will have ceased smoking or have refrained from systemic tobacco intake for at least 4 weeks during conservative wound care and prior to planned bioengineered skin replacement therapy.

This medical policy applies to Medicare Advantage plans offered by Capital Blue Cross and its subsidiaries.

Cross-references:
MA 1.167 Products of Bio-Engineered Skin and Soft Tissue Substitutes
MA 1.159 Amniotic Membrane and Amniotic Fluid
MA 4.028 Wound and Burn Care and Specialized Treatment Centers

Description/Background

Skin and Soft Tissue Substitutes

Bioengineered skin and soft tissue substitutes may be either acellular or cellular. Acellular products (e.g., dermis with cellular material removed) contain a matrix or scaffold composed of materials such as collagen, hyaluronic acid, and fibronectin. Acellular dermal matrix (ADM) products can differ in a number of ways, including as species source (human, bovine, porcine), tissue source (e.g., dermis, pericardium, intestinal mucosa), additives (e.g., antibiotics, surfactants), hydration (wet, freeze-dried), and required preparation (multiple rinses, rehydration).

Cellular products contain living cells such as fibroblasts and keratinocytes within a matrix. The cells contained within the matrix may be autologous, allogeneic, or derived from other species (e.g., bovine, porcine). Skin substitutes may also be composed of dermal cells, epidermal cells, or a combination of dermal and epidermal cells, and may provide growth factors to stimulate healing. Bioengineered skin substitutes can be used as either temporary or permanent wound coverings.

Applications

There are a large number of potential applications for artificial skin and soft tissue products. One large category is nonhealing wounds, which potentially encompass diabetic neuropathic ulcers, vascular insufficiency ulcers, and pressure ulcers. A substantial minority of such wounds do not heal adequately with standard wound care, leading to prolonged morbidity and increased risk of mortality. For example, nonhealing lower-extremity wounds represent an ongoing risk for infection, sepsis, limb amputation, and death. Bioengineered skin and soft tissue substitutes have the potential to improve rates of healing and reduce secondary complications.

Other situations in which bioengineered skin products might substitute for living skin grafts include certain postsurgical states (e.g., breast reconstruction) in which skin coverage is inadequate for the procedure performed, or for surgical wounds in patients with compromised ability to heal. Second- and third-degree burns are another indication in which artificial skin products may substitute for auto- or allografts. Certain primary dermatologic conditions that involve large areas of skin breakdown (e.g., bullous diseases) may also be conditions in which artificial skin products can be considered as substitutes for skin grafts. ADM products are also being evaluated in the repair of other soft tissues including rotator cuff repair, following oral and facial surgery, hernias, and other conditions.

Regulatory Status

The FDA does not refer to any product or class of products as “skin substitutes.” However, products commonly described as “skin substitutes” are regulated by FDA under one of the four categories described below depending on the origin and composition of the product.

Human Cells, Tissues, and Cellular and Tissue-Based Products - Cells and tissues taken from human donors and transplanted to a recipient are regulated under PHS 361 [21 CFR 1270 & 1271]. This regulation describes the rules concerning the use of 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). The Center for Biologics Evaluation and Research is responsible for regulating biological and related products including blood, vaccines, allergens, tissues, and cellular and gene therapies. Establishments producing HCT/Ps must register with FDA and list their HCT/Ps. HCT/Ps establishments are not required to demonstrate the safety or effectiveness of their products and FDA does not evaluate the safety or effectiveness of these products.

Premarket Approval - Premarket approval (PMA) by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Before Class III devices can be marketed, they must have an approved PMA application. Therefore, wound care products regulated under the PMA process will require evidence that they promote wound healing before they are approved for marketing.

510(k) Submissions - According to FDA documents a 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent (SE), to a legally marketed device [21 CFR 807.92(a)(3)] that is not subject to PMA. Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalence claims. Unlike PMA, 510(k) confers reasonable assurance of safety and effectiveness via demonstration of substantial equivalence to a legally marketed device that does not require premarket approval. Therefore, wound care products regulated under the 510(k) process will not typically require clinical evidence to establish effectiveness in wound healing, as compared with products regulated under the PMA process in which substantial clinical evidence is always required.

Humanitarian Device Exemption (HDE) - An HDE is similar in both form and content to a premarket approval (PMA) application but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market. Humanitarian Device Exemption approval is based on evidence of probable benefit in a disease population occurring at a frequency of less than 4,000 patients per year in the United States.

Human Amniotic Membrane (HAM)

HAM consists of two conjoined layers, the amnion, and chorion, and forms the innermost lining of the amniotic sac or placenta. When prepared for use as an allograft, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated. Many products available using amnion, chorion, amniotic fluid, and umbilical cord are being studied for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions. The products are formulated either as patches, which can be applied as wound covers, or as suspensions or particulates, or connective tissue extractions, which can be injected or applied topically.

Fresh amniotic membrane contains collagen, fibronectin, and hyaluronic acid, along with a combination of growth factors, cytokines, and anti-inflammatory proteins such as interleukin-1 receptor antagonist. There is evidence that the tissue has anti-inflammatory, anti-fibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause a substantial immune response. It is believed these properties are retained in cryopreserved HAM and HAM products, resulting in a readily available tissue with regenerative potential. In support, one HAM product has been shown to elute growth factors into saline and stimulate the migration of mesenchymal stem cells, both in vitro and in vivo.

Use of a HAM graft, which is fixated by sutures, is an established treatment for disorders of the corneal surface, including neurotrophic keratitis, corneal ulcers, and melts, following pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Amniotic membrane products that are inserted like a contact lens have more recently been investigated for the treatment of corneal and ocular surface disorders. Amniotic membrane patches are also being evaluated for the treatment of various other conditions, including skin wounds, burns, leg ulcers, and prevention of tissue adhesion in surgical procedures. Additional indications studied in preclinical models include tendonitis, tendon repair, and nerve repair. The availability of HAM opens the possibility of regenerative medicine for an array of conditions.

Amniotic Fluid

Amniotic fluid surrounds the fetus during pregnancy and provides protection and nourishment. In the second half of gestation, most of the fluid is a result of micturition and secretion from the respiratory tract and gastrointestinal tract of the fetus, along with urea. The fluid contains proteins, carbohydrates, peptides, fats, amino acids, enzymes, hormones, pigments, and fetal cells. Use of human and bovine amniotic fluid for orthopedic conditions was first reported in 1927. Amniotic fluid has been compared with synovial fluid, containing hyaluronan, lubricant, cholesterol, and cytokines. Injection of amniotic fluid or amniotic fluid-derived cells is currently being evaluated for the treatment of osteoarthritis and plantar fasciitis.

Amniotic membrane and amniotic fluid are also being investigated as sources of pluripotent stem cells. Pluripotent stem cells can be cultured and are capable of differentiation toward any cell type. The use of stem cells in orthopedic applications is addressed in evidence review MP 2.080.

Regulatory Status

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. In 2017, the FDA published clarification of what is considered minimal manipulation and homologous use for human cells, tissues, and cellular and tissue-based products (HCT/Ps).

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

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 (STSG) includes the entire epidermis and a portion of the dermis. A full thickness skin graft (FTSG) includes all layers of the skin. Although autografts are the optimal choice for full thickness wound coverage, areas for skin harvesting may be limited, particularly in cases of large burns or venous stasis ulceration. Harvesting procedures are painful, disfiguring and require additional wound care.

Allografts which use skin from another human (e.g., 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 replaced by an autograft or the ingrowth of the patient’s own skin.

Bioengineered skin / cultured epidermal autografts (CEA) are autografts derived from the patient’s own skin cells grown or cultured from very small amounts of skin or hair follicle. Production time is prolonged. One such product is grown on a layer of irradiated mouse cells, bestowing some elements of a xenograft. Widespread usage has not been available due to limited availability or access to the technology.

Bioengineered Skin Substitutes or Cellular and Tissue Based Products (CTPs), referred to as Skin Substitutes by CMS, the Current Procedural Terminology (CPT) and the Healthcare Common Procedure Coding Manuals, have been developed in an attempt to circumvent problems inherent with autografts, allografts and xenografts. These constitute biologic covers for refractory wounds with full thickness skin loss secondary to 3rd 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 biologic skin substitutes or CTPs varies by company and product but generally involves the creation of immunologically inert biological products containing protein, hormones or enzymes seeded into a matrix which 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. Sufficient data is 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 are bioengineered from human skin components and human tissue which 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, though some have been approved for the treatment of full-thickness skin and soft tissue loss. Most are biodegradable and disappear after 3-4 weeks 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 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 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.

Rational

Summary of Evidence

Breast Reconstruction

For individuals who are undergoing breast reconstruction who receive allogeneic acellular dermal matrix (ADM) products, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life (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 patient decision making about reconstruction options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Tendon Repair

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 patients 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.

Surgical Repair of Hernias or Parastomal Reinforcement

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.

Diabetic Lower-Extremity Ulcers

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. Randomized controlled trials 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, and TheraSkin over the standard of care (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 ADM products other than AlloPatch, Apligraf, Dermagraft, Integra, mVASC, or TheraSkin, 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 patients who only required a single application of the ADM. Studies are needed to further define those populations 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. An RCT of Omega3 Wound (Kerecis) has been published and 2 larger RCTs are registered and reported as completed but have not been published. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Lower-Extremity Ulcers due to Venous Insufficiency

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. Randomized controlled trials 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 any more effective than controls for the primary or secondary endpoints in the entire population and was only slightly more effective than controls (an 8% to 15% increase in healing) in subgroups of patients 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.

Deep Dermal Burns

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 U.S. Food and Drug Administration approval under a humanitarian device exemption for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30% or more. Comparative studies have demonstrated improved outcomes for biosynthetic skin substitute Integra Dermal Regeneration Template for the treatment of burns. 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 another 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.

Dystrophic Epidermolysis Bullosa

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 patients 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., 5 patients). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Definitions

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 (STSG) includes the entire epidermis and a portion of the dermis. A full thickness skin graft (FTSG) includes all layers of the skin. Although autografts are the optimal choice for full thickness wound coverage, areas for skin harvesting may be limited, particularly in cases of large burns or venous stasis ulceration. Harvesting procedures are painful, disfiguring and require additional wound care.

Allografts which use skin from another human (e.g., 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 replaced by an autograft or the ingrowth of the patient’s own skin.

Bioengineered skin / cultured epidermal autografts (CEA) are autografts derived from the patient’s own skin cells grown or cultured from very small amounts of skin or hair follicle. Production time is prolonged. One such product is grown on a layer of irradiated mouse cells, bestowing some elements of a xenograft. Widespread usage has not been available due to limited availability or access to the technology.

Bioengineered Skin Substitutes or Cellular and Tissue Based Products (CTPs), referred to as Skin Substitutes by CMS, the Current Procedural Terminology (CPT) and the Healthcare Common Procedure Coding Manuals, have been developed in an attempt to circumvent problems inherent with autografts, allografts and xenografts. These constitute biologic covers for refractory wounds with full thickness skin loss secondary to 3rd 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 biologic skin substitutes or CTPs varies by company and product but generally involves the creation of immunologically inert biological products containing protein, hormones or enzymes seeded into a matrix which 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. Sufficient data is 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 are bioengineered from human skin components and human tissue which 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, though some have been approved for the treatment of full-thickness skin and soft tissue loss. Most are biodegradable and disappear after 3-4 weeks 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 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 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.

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding Information

Note: This list of codes is not exhaustive and may change from time to time as permitted by law or applicable clinical guidelines. The inclusion of a code in this section is not a guarantee of coverage or payment. In addition, not all covered services are eligible for separate reimbursement.

Covered when medically necessary, associated procedures:

Covered when medically necessary for breast reconstructive surgery using allogeneic acellular dermal matrix products:

Covered when medically necessary for treatment of dystrophic epidermolysis bullosa:

Covered when medically necessary for treatment of second- and third-degree burns:

Investigational:

References

1. Snyder DL, Sullivan N, Margolis DJ, Schoelles K. Skin substitutes for treating chronic wounds. Technology Assessment Program Project ID No. WNDT0818. (Prepared by the ECRI Institute–Penn Medicine Evidence-based Practice Center under Contract No. HHSA 290-2015-00005-I) Rockville, MD: Agency for Healthcare Research and Quality. February 2020. Available at: https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/skin-substitute_0.pdf. Accessed March 25, 2025.
2. U.S. Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. December 2017. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulatory-considerations-human-cells-tissues-and-cellular-and-tissue-based-products-minimal. Accessed March 23, 2025.
3. U.S. Food and Drug Administration. Executive Summary Breast Implant Special Topics. March 2019. https://wayback.archive-it.org/7993/20201226003814/https://www.fda.gov/media/122956/download. Accessed March 24, 2025.
4. U.S. Food & Drug Administration. Acellular Dermal Matrix (ADM) Products Used in Implant-Based Breast Reconstruction Differ in Complication Rates: FDA Safety Communication. March 2021. https://www.fda.gov/news-events/fda-brief/fda-warns-about-differing-complication-rates-acellular-dermal-matrix-type-surgical-mesh. Accessed March 25, 2025.
5. Davila AA, Seth AK, Wang E, et al. Human Acellular Dermis versus Submuscular Tissue Expander Breast Reconstruction: A Multivariate Analysis of Short-Term Complications. Arch Plast Surg. Jan 2013; 40(1): 19-27. PMID 23362476
6. Ng TP, Loo BYK, Yong N, et al. Review: Implant-Based Breast Reconstruction After Mastectomy for Breast Cancer: A Meta-analysis of Randomized Controlled Trials and Prospective Studies Comparing Use of Acellular Dermal Matrix (ADM) Versus Without ADM. Ann Surg Oncol. May 2024; 31(5): 3366-3376. PMID 38285304
7. Lee KT, Mun GH. Updated Evidence of Acellular Dermal Matrix Use for Implant-Based Breast Reconstruction: A Meta-analysis. Ann Surg Oncol. Feb 2016; 23(2): 600-10. PMID 26438439
8. McCarthy CM, Lee CN, Halvorson EG, et al. The use of acellular dermal matrices in two-stage expander/implant reconstruction: a multicenter, blinded, randomized controlled trial. Plast Reconstr Surg. Nov 2012; 130(5 Suppl 2): 57S-66S. PMID 23096987
9. Hinchcliff KM, Orbay H, Buse S BK, et al. Comparison of two cadaveric acellular dermal matrices for immediate breast reconstruction: A prospective randomized trial. J Plast Reconstr Aesthet Surg. May 2017; 70(5): 568-576. PMID 28341592
10. Mendenhall SD, Anderson LA, Ying J, et al. The BREASTrial Stage II: ADM Breast Reconstruction Outcomes from Definitive Reconstruction to 3 Months Postoperative. Plast Reconstr Surg Glob Open. Jan 2017; 5(1): e1209. PMID 28203509
11. Mendenhall SD, Moss WD, Graham EM, et al. The BREASTrial Stage III: Acellular Dermal Matrix Breast Reconstruction Outcomes from 3 Months to 2 Years Postoperatively. Plast Reconstr Surg. Jan 01 2023; 151(1): 17-24. PMID 36194057
12. Davison SP, Harbour S, Fassihi E. Comparison of Different Acellular Dermal Matrix in Breast Reconstruction: A Skin-to-Skin Study. Aesthet Surg J. Jul 15 2024; 44(8): 829-837. PMID 38377366
13. Keane AM, Chiang SN, Tao Y, et al. Cortiva versus AlloDerm in Prepectoral and Partial Submuscular Implant-Based Breast Reconstruction: A Randomized Clinical Trial. Plast Reconstr Surg. Oct 01 2024; 154(4S): 13S-26S. PMID 38085977
14. Dikmans RE, Negenborn VL, Bouman MB, et al. Two-stage implant-based breast reconstruction compared with immediate one-stage implant-based breast reconstruction augmented with acellular dermal matrix: an open-label, phase 4, multicentre, randomised, controlled trial. Lancet Oncol. Feb 2017; 18(2): 251-258. PMID 28012977
15. Barber FA, Burns JP, Deutsch A, et al. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. Jan 2012; 28(1): 8-15. PMID 21978432
16. Rashid MS, Smith RDJ, Nagra N, et al. Rotator cuff repair with biological graft augmentation causes adverse tissue outcomes. Acta Orthop. Dec 2020; 91(6): 782-788. PMID 32691656
17. Bellows CF, Smith A, Malsbury J, et al. Repair of incisional hernias with biological prosthesis: a systematic review of current evidence. Am J Surg. Jan 2013; 205(1): 85-101. PMID 22867726
18. Espinosa-de-los-Monteros A, de la Torre JI, Marrero I, et al. Utilization of human cadaveric acellular dermis for abdominal hernia reconstruction. Ann Plast Surg. Mar 2007; 58(3): 264-7. PMID 17471129
19. Gupta A, Zahriya K, Mullens PL, et al. Ventral herniorrhaphy: experience with two different biosynthetic mesh materials, Surgisis and Alloderm. Hernia. Oct 2006; 10(5): 419-25. PMID 16924395
20. Bocchicchio GV, De Castro GP, Bocchicchio KM, et al. Comparison study of acellular dermal matrices in complicated hernia surgery. J Am Coll Surg. Oct 2013; 217(4): 606-13. PMID 23973102
21. Roth JS, Zachem A, Plymale MA, et al. Complex Ventral Hernia Repair with Acellular Dermal Matrices: Clinical and Quality of Life Outcomes. Am Surg. Feb 01 2017; 83(2): 141-147. PMID 28228200
22. Bellows CF, Shaddock P, Helton WS, et al. Early report of a randomized comparative clinical trial of Strattice™ reconstructive tissue matrix to lightweight synthetic mesh in the repair of inguinal hernias. Hernia. Apr 2014; 18(2): 221-30. PMID 23543334
23. Fleshman JW, Beck DE, Hyman N, et al. A prospective, multicenter, randomized, controlled study of non-cross-linked porcine acellular dermal matrix fascial sublay for parastomal reinforcement in patients undergoing surgery for permanent abdominal wall ostomies. Dis Colon Rectum. May 2014; 57(5): 623-31. PMID 24819103
24. Kalaiselvan R, Carlson GL, Hayes S, et al. Recurrent intestinal fistulation after porcine acellular dermal matrix reinforcement in enteric fistula takedown and simultaneous abdominal wall reconstruction. Hernia. Jun 2020; 24(3): 537-543. PMID 31811593
25. Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. Feb 11 2016; (2): CD011255. PMID 26866804
26. Veves A, Falanga V, Armstrong DG, et al. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. Feb 2001; 24(2): 290-5. PMID 11213881
27. Marston WA, Hanft J, Norwood P, et al. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. Jun 2003; 26(6): 1701-5. PMID 12766097
28. Frykberg RG, Marston WA, Cardinal M. The incidence of lower-extremity amputation and bone resection in diabetic foot ulcer patients treated with a human fibroblast-derived dermal substitute. Adv Skin Wound Care. Apr 2015; 28(4): 17-20. PMID 25407883
29. Zelen CM, Orgill DP, Serena TE, et al. A prospective, randomized, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allograft human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J. Apr 2017; 14(2): 307-315. PMID 27073000
30. Zelen CM, Orgill DP, Serena TE, et al. An aseptically processed, acellular, reticular, allogeneic human dermis improves healing in diabetic foot ulcers: A prospective, randomized, controlled, multicenter follow-up trial. Int Wound J. Oct 2018; 15(5): 731-739. PMID 29682897
31. Driver VR, Lavery LA, Reyzelman AM, et al. A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Repair Regen. 2015; 23(6): 891-900. PMID 26297933
32. Campitiello F, Mancone M, Della Corte A, et al. To evaluate the efficacy of an acellular Flowable matrix in comparison with a wet dressing for the treatment of patients with diabetic foot ulcers: a randomized clinical trial. Updates Surg. Dec 2017; 69(4): 523-529. PMID 28497218
33. Gould LJ, Orgill DP, Armstrong DG, et al. Improved healing of chronic diabetic foot wounds in a prospective randomised controlled multi-centre clinical trial with a microvascular tissue allograft. Int Wound J. May 2022; 19(4): 811-825. PMID 34469077
34. Armstrong DG, Galindo RD, Orgill DP, et al. Multi-centre prospective randomised controlled clinical trial to evaluate a bioactive split thickness skin allograft as standard of care in the treatment of diabetic foot ulcers. Int Wound J. May 2022; 19(4): 932-944. PMID 35080127
35. Sanders L, Landsman AS, Landsman A, et al. A prospective, multicenter, randomized, controlled clinical trial comparing a bioengineered skin substitute to a human skin allograft. Ostomy Wound Manage. Sep 2014; 60(9): 26-38. PMID 25211605
36. DiDomenico L, Landsman AR, Emch KJ, et al. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds. Jul 2011; 23(7): 184-9. PMID 25879172
37. Brigido SA, Boc SF, Lopez RC. Effective management of major lower extremity wounds using an acellular regenerative tissue matrix: a pilot study. Orthopaedics. Jan 2004; 27(1 Suppl): s145-9. PMID 14763548
38. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. Jun 2009; 6(3): 196-208. PMID 19368581
39. Reyzelman AM, Bazarov I. Human acellular dermal wound matrix for treatment of DFU: literature review and analysis. J Wound Care. Mar 2015; 24(3): 128;129-34. PMID 25764957
40. Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: a prospective 16-week pilot study. Int Wound J. Sep 2006; 3(3): 181-7. PMID 16984575
41. Winters J, Cazzell S, Pham H, et al. Healing Rates in a Multicenter Assessment of a Sterile, Room Temperature, Acellular Dermal Matrix Versus Conventional Care Wound Management and an Active Comparator in the Treatment of Full-Thickness Diabetic Foot Ulcers. Eplasty. 2016; 16: e10. PMID 26933467
42. Cazzell S, Vayser D, Pham H, et al. A randomized clinical trial of a human acellular dermal matrix demonstrated superior healing rates for chronic diabetic foot ulcers over conventional care and an active acellular dermal matrix comparator. Wound Repair Regen. May 2017; 25(3): 483-497. PMID 28544150
43. Frykberg RG, Cazzell SM, Arroyo-Rivera J, et al. Evaluation of tissue engineering products for the management of neuropathic diabetic foot ulcers: an interim analysis. J Wound Care. Jul 2016; 25 Suppl 7: S18-25. PMID 27410467
44. Lantis JC, Snyder R, Reyzelman AM, et al. Fetal bovine acellular dermal matrix for the closure of diabetic foot ulcers: a prospective randomized controlled trial. J Wound Care. Jul 01 2021; 30(Sup7): S18-S27. PMID 34256588
45. Niezgoda JA, Van Gils CC, Frykberg RG, et al. Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care. Jun 2005; 18(5 Pt 2): 258-66. PMID 15942317
46. Uccioli L, Giurato L, RotoIo V, et al. Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up. Int J Low Extrem Wounds. Jun 2011; 10(2): 80-5. PMID 21693443
47. Lullove EJ, Liden B, Winters C, et al. A Multicenter, Blinded, Randomized Controlled Clinical Trial Evaluating the Effect of Omega-3-Rich Fish Skin in the Treatment of Chronic, Nonresponsive Diabetic Foot Ulcers. Wounds. Jul 2021; 33(7): 169-177. PMID 33872197
48. Lullove EJ, Liden B, McEneaney P, et al. Evaluating the effect of omega-3-rich fish skin in the treatment of chronic, nonresponsive diabetic foot ulcers: penultimate analysis of a multicenter, prospective, randomized controlled trial. Wounds. Apr 2022; 34(4): E34-E36. PMID 35797557
49. Lantis JC, Lullove EJ, Liden B, et al. Final efficacy and cost analysis of a fish skin graft vs standard of care in the management of chronic diabetic foot ulcers: a prospective, multicenter, randomized controlled clinical trial. Wounds. Apr 2023; 35(4): 71-79. PMID 37023475
50. O’Meara S, Cullum N, Nelson AE, et al. Compression for venous leg ulcers. Cochrane Database Syst Rev. Nov 14 2012; 11(11): CD000265. PMID 23152202
51. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol. Mar 1998; 134(3): 293-300. PMID 9521027
52. Mosch WEN, Haraway GD, Dalsing M, et al. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg. May 2005; 41(5): 837-43. PMID 15886669
53. Romanelli M, Dini V, Bertone M, et al. OASIS wound matrix versus Hyaloskin in the treatment of difficult-to-heal wounds of mixed arterial/venous aetiology. Int Wound J. Mar 2007; 4(1): 3-7. PMID 17245543
54. Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound dressing in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology. Adv Skin Wound Care. Jan 2010; 23(1): 34-8. PMID 20101114
55. Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int Wound J. Apr 2013; 10(2): 132-7. PMID 23506344
56. Cazzell S. A Randomized Controlled Trial Comparing a Human Acellular Dermal Matrix Versus Conventional Care for the Treatment of Venous Leg Ulcers. Wounds. Mar 2019; 31(3): 68-74. PMID 30720443
57. Carsin H, Ainaud P, Le Bever H, et al. Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five year single-center experience with 30 patients. Burns. Jun 2000; 26(4): 379-87. PMID 10751706
58. Lagus H, Sarlomo-Rikala M, Böbling T, et al. Prospective study on burns treated with Integra^®, a cellulose sponge and split thickness skin graft: comparative clinical and histological study—randomized controlled trial. Burns. Dec 2013; 39(8): 1577-87. PMID 23880091
59. Branski LK, Herndon DN, Pereira C, et al. Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial. Crit Care Med. Nov 2007; 35(11): 2615-23. PMID 17828040
60. Heimbach DM, Warden GD, Luterman A, et al. Multicenter postapproval clinical trial of Integra dermal regeneration template for burn care. J Burn Care Rehabil. 2003; 24(1): 42-8. PMID 12543990
61. Hicks KE, Huynh MN, Jeschke M, et al. Dermal regenerative matrix use in burn patients: A systematic review. J Plast Reconstr Aesthet Surg. Nov 2019; 72(11): 1741-1751. PMID 31492583
62. Gonzalez SR, Wolter KG, Yuen JC. Infectious Complications Associated with the Use of Integra: A Systematic Review of the Literature. Plast Reconstr Surg Glob Open. Jul 2020; 8(7): e2869. PMID 32802634
63. Luze H, Nischwitz SP, Smolle C, et al. The Use of Acellular Fish Skin Grafts in Burn Wound Management-A Systematic Review. Medicina (Kaunas). Jul 09 2022; 58(7). PMID 35888631
64. Holmes JH, Molnar JA, Shupp JW, et al. Demonstration of the safety and effectiveness of the RECELL^® System combined with split-thickness meshed autografts for the reduction of donor skin to treat mixed-depth burn injuries. Burns. Jun 2019; 45(4): 772-782. PMID 30578048
65. Holmes IV JH, Molnar JA, Carter JE, et al. A Comparative Study of the ReCell^® Device and Autologous Split-Thickness Meshed Skin Graft in the Treatment of Acute Burn Injuries. J Burn Care Res. Aug 17 2018; 39(5): 694-702. PMID 29800234
66. Fivenson DP, Scherschun L, Cohen LV. Apligraf in the treatment of severe mitten deformity associated with recessive dystrophic epidermolysis bullosa. Plast Reconstr Surg. Aug 2003; 112(2): 584-8. PMID 12900618
67. Baldursson BT, Kjartansson H, Konráðsdóttir F, et al. Healing rate and autoimmune safety of full-thickness wounds treated with fish skin acellular dermal matrix versus porcine small-intestine submucosa: a noninferiority study. Int J Low Extrem Wounds. Mar 2015; 14(1): 37-43. PMID 25759413
68. Still J, Glat P, Silverstein P, et al. The use of a collagen sponge/living cell composite material to treat donor sites in burn patients. Burns. Dec 2003; 29(8): 837-41. PMID 14636761
69. Brown-Etris M, Milne CT, Hodde JP. An extracellular matrix graft (Oasis^® wound matrix) for treating full-thickness pressure ulcers: a randomized clinical trial. J Tissue Viability. Feb 2019; 28(1): 21-26. PMID 30509850
70. Gurtner GC, Garcia AD, Bakewell K, et al. A retrospective matched-cohort study of 3994 lower extremity wounds of multiple etiologies across 644 institutions comparing a bioactive human skin allograft, TheraSkin, plus standard of care, to standard of care alone. Int Wound J. Feb 2020; 17(1): 55-64. PMID 31729833
71. Thomson SE, Ng NY, Riehle MO, et al. Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb. Cochrane Database Syst Rev. Dec 07 2022; 12(12): CD012574. PMID 36477774
72. Lazic T, Falanga V. Bioengineered skin constructs and their use in wound healing. Plast Reconstr Surg. Jan 2011; 127 Suppl 1: 75S-90S. PMID 21200276
73. Saffle JR. Closure of the excised burn wound: temporary skin substitutes. Clin Plast Surg. Oct 2009; 36(4): 627-41. PMID 19793557
74. National Institute for Health and Care Excellence (NICE). Diabetic Foot Problems: Prevention and Management [NG19]. 2023.
75. Peirce SC, Carolan-Rees G. ReCell^® Spray-On Skin System for Treating Skin Loss, Scarring and Depigmentation after Burn Injury: A NICE Medical Technology Guidance. Appl Health Econ Health Policy. Apr 2019; 17(2): 131-141. PMID 30635844
76. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Porcine Skin and Gradient Pressure Dressings (270.5). n.d.
77. Centers for Medicare & Medicaid Services (CMS). Fact Sheet. CMS finalizes Medicare Hospital Outpatient Prospective Payment System and Ambulatory Surgical Center Payment System changes for 2019. https://www.cms.gov/newsroom/fact-sheets/cms-finalizes-medicare-hospital-outpatient-prospective-payment-system-and-ambulatory-surgical-center. Accessed March 25, 2025.
78. Centers for Medicare & Medicaid Services. 2022. Fact Sheet. Calendar Year (CY) 2023 Medicare Physician Fee Schedule Final Rule.

Policy History

• MA 1.158
  • 03/09/2026 New policy. Full adoption (in conjunction with MA 1.167).
  • 06/05/2026 Administrative update. Added codes 1044T-1049T. Effective 07/01/2026.

Plans issued by Capital Blue Cross and it’s subsidiaries are independent licensees of the Blue Cross Blue Shield Association. Communications issued by Capital Blue Cross in its capacity as administrator of programs and provider relations for all companies.

Health care benefit programs issued or administered by Capital Blue Cross and/or its subsidiaries, Capital Advantage Insurance Company^®, Capital Advantage Assurance Company^® and Keystone Health Plan^® Central. Independent licensees of the Blue Cross BlueShield Association. Communications issued by Capital Blue Cross in its capacity as administrator of programs and provider relations for all companies.