Skin Substitute Grafts/Cellular and/or Tissue-Based Products for the Treatment of Diabetic Foot Ulcers and Venous Leg Ulcers

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for skin substitute graft/CTPs for the treatment of diabetic foot ulcers and venous leg ulcers. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations, and rules for Medicare payment for skin substitute graft/CTPs for the treatment of diabetic foot ulcers and venous leg ulcers and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
  ~ Chapter 15, Section 50.4.1 Approved Use of Drug
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
  ~ Chapter 17, Section 40 Discarded Drugs and Biologicals
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
  ~ Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD
• CMS IOM Publication 100-03, National Coverage Determinations Manual, Chapter 1, Sections 270.3, 270.4 & 270.5

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment may be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Code of Federal Regulations (CFR) References:

• CFR, Title 21, Volume 8, Chapter 1, Subchapter L, Part 1271.10 Human cells, tissues, and cellular and tissue-based products

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

This LCD addresses the medically reasonable and necessary threshold for coverage of skin replacement surgery for application of skin substitute graft, also referred to as cellular and/or tissue-based products (CTPs) for diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs). The use of skin substitute grafts/CTPs when providing scaffolding for skin growth to treat wounds that fall outside the scope of the LCD may be considered on claim-by-claim basis.

Application of skin substitute graft for ulcer care indications other than for DFU or VLU are not addressed by this LCD. Use of skin substitute graft or CTPs must meet the medically reasonable and necessary threshold for coverage and these devices must be used in accordance with their intended use as approved/regulated by the United States (U.S.) Food and Drug Administration (FDA).

For the purpose of this policy and consistent with the AMA’s CPT codebook, skin substitute grafts/CTPs include non-autologous human skin grafts, non-human skin substitute grafts, and biological products that form a sheet scaffolding for skin growth. Also, for the purposes of this policy, wound coverings or wound dressings, which are utilized to provide a physical barrier to protect the ulcer (wound) surface, prevent infection, and allow healing underneath, and are typically removed as the ulcer or chronic wound heals are NOT included in the definition of skin substitute grafts/CTPs. Wound coverings and dressings are NOT anchored or applied surgically to ulcers to form scaffolding for skin growth and are therefore NOT skin substitute grafts/CTPs.

Generally, depending on the purpose of the product and how it functions, skin substitute graft or CTPs are regulated by the FDA premarket approval (PMA) process, FDA 510(k) premarket notification process, or the FDA regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps). It has been noted that there are instances in which certain products might have an ulcer healing indication but may not necessarily meet the definition of skin substitute graft or CTPs. Therefore, FDA classification and indication alone does not determine if a product meets the definition of skin substitute graft and/or meets the medically reasonable and necessary threshold for coverage.

Amniotic/chorionic-based products are HCT/Ps as defined in 21 CFR 1271.3(d) and must meet criteria in 21 CFR 1271 and 361 of the Public Health Service Act (PHS Act). The HCT/Ps not regulated under 361 are regulated as drugs as defined under section 201(g) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. In order to lawfully market a drug that is also a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after a showing of safety and efficacy for the product's intended use.^1-4

Standard treatment of lower extremity ulcers (e.g., DFUs and/or VLUs) may include mechanical offloading, infection control, mechanical compression, limb elevation, debridement of necrotic tissue, management of systemic disease and medications, nutrition assessment, tissue perfusion and oxygenation, and counseling on the risk of continued tobacco use. In addition, maintenance of a moist ulcer environment through appropriate dressings facilitates development of healthy granulation tissue and epithelialization and thus may potentiate complete healing at a ulcer site. Dressings are an integral part of ulcer management by not only maintaining a moist environment but by stopping contamination and absorbing exudate.^3,5-9

Despite advancements in various synthetic occlusive dressings some ulcers fail to heal. The development of skin substitute graft or CTPs has been employed as an adjunct to established ulcer care methods intended to increase the chances of healing.^10,11

Chronic DFUs and VLUs may be unresponsive to initial therapy or persist despite additional care. A DFU or VLU that has failed to response to standard of care treatment after 30 (thirty) days may be considered chronic and the application of a skin substitute graft or CTP may be considered medically reasonable and necessary for certain patients.^10-13

Patients receiving skin replacement surgery with a skin substitute graft or CTP should be under the care of a physician/non-physician practitioner (NPP) for the treatment of their systemic disease process (e.g., diabetes mellitus, chronic venous insufficiency, and/or peripheral vascular disease). It is imperative that their systemic disease be monitored/treated in order to ensure adequate healing of the ulcer.^6,13

It is the expectation that a specific skin substitute graft or CTP will be used for the episode of skin replacement surgery (defined as 12 weeks from the first application of a skin substitute graft or CTP) assuming its use is not in conflict with the FDA assessments (e.g., indications, contraindications, how supplied and directions for use, etc.) and/or the American Association of Tissue Banks (AATB) approved use and assuming there is one related ulcer. Repeat application of a skin substitute graft within the 12-week episode of skin replacement surgery may be appropriate based on ulcer re-assessment and must be supported in the medical record documentation for that encounter. Additional applications of a skin substitute product beyond the 12- week episode of skin replacement surgery is not expected if the ulcer has responded to the skin replacement surgery with epithelialization and other progression. This LCD does not endorse particular products for separate payment. The medical record documentation must support the medical necessity for skin replacement surgery and that the product is being used within its approved FDA indications as an ulcer treatment and not as a wound covering.

Covered Indications

All of the following criteria must be met for the application of a skin substitute graft/CTP for lower extremity DFU or VLU to be considered medically reasonable and necessary:

If the patient meets all of the criteria as outlined in this LCD, application of a skin substitute graft or CTP for lower extremity DFU or VLU is considered medically reasonable and necessary for the following:

1. The presence of a chronic, non-infected DFU, or chronic, non-infected VLU having failed to respond to documented standard of care treatment (outlined below) for a minimum of 30 days with documented compliance to prescribed treatment.⁵
2. Has Failure to respond to documented standard of care treatment is defined as an ulcer that has increased in size or depth, or no change in baseline size or depth, or no sign of improvement or indication that improvement is likely (such as granulation, epithelialization, or progress towards closing). Documentation of response requires measurements of the initial ulcer, measurements at the completion of at least 30 days of standard of care treatment, and measurements immediately prior to placement of the skin substitute graft or CTP for a DFU. For VLUs, standard of care measures must continue for no less than 30 days and include on-going compression therapy. ^5,7,11
3. Standard of care treatment includes, but are not limited to ^4-7,9,12,14:

• • Comprehensive patient assessment (history, exam, Ankle-Brachial Index [ABI]) and diagnostic tests as indicated) and implemented treatment plan.

• • For patients with a DFU - assessment of Type 1 vs. Type 2 diabetes and management history with attention to certain comorbidities (e.g., vascular disease, neuropathy, osteomyelitis), review of current blood glucose levels/hemoglobin A1c (HbA1c), diet and nutritional status, activity level, physical exam that includes assessment of skin and ulcer, ABI, and check of off-loading device or assessment of appropriate footwear.¹³

• • For patients with a VLU - assessment of clinical history (prior ulcers, thrombosis risks), physical exam (edema, skin changes), ABI, diagnostic testing to verify superficial or deep venous reflux, perforator incompetence, and chronic (or acute) venous thrombosis.

4. An implemented treatment plan demonstrating all of the following:

• Debridement as appropriate.
• Some form of offloading for DFUs and some form of compression for VLUs.
• Infection control.
• Management of exudate - maintenance of a moist environment (moist saline gauze, other classic dressings, bioactive dressing, etc.).
• Documentation of smoking history, and that the patient has received counseling on the effect of smoking on surgical outcomes and treatment for smoking cessation (if applicable) as well as outcome of counselling (if applicable).

5. Skin substitute graft/CTPs utilized per their intended use as approved/regulated by the FDA.
6. The patient is under the care of a qualified physician/NPP for the treatment of the systemic disease process(es) etiologic for the condition (e.g., venous insufficiency, diabetes, neuropathy).^6,13

Limitations

The following are considered not medically reasonable and necessary^6-7,10,12-13:

1. Greater than four applications of a skin substitute graft or CTP within the episode of skin replacement surgery (defined as 12 weeks from the first application of a skin substitute graft or CTP). Product change within the episode of skin replacement surgery is allowed but in situations where more than one specific product is used, it is expected that the number of applications or treatments will still not exceed four.
   
   • The expectation is treatment will consist of the fewest repeat applications and amount of product to heal the ulcer. It is not expected that every ulcer, in every patient will require the maximum number of applications.

2. Application of a skin substitute graft product beyond 12-weeks per episode of care.
3. Repeat applications of skin substitute graft/CTPs when a previous application was unsuccessful. Unsuccessful treatment is defined as 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).
4. Application of skin substitute graft/CTPs in patients with inadequate control of underlying conditions or exacerbating factors, or other contraindications (e.g., uncontrolled diabetes, active infection, active Charcot arthropathy of the ulcer extremity, active vasculitis).
5. Use of surgical preparation services (for example, debridement), in conjunction with routine, simple and/or repeat skin replacement surgery with a skin substitute graft or CTP.
6. Excessive wastage (discarded amount).
   • The skin substitute graft or CTP must be used in an efficient manner utilizing the most appropriate size product available at the time of treatment. It is expected that where multiple sizes of a specific product are available, the size that best fits the ulcer with the least amount of wastage will be utilized.
7. All liquid or gel skin substitute products or CTPs for ulcer care.¹⁶

Note: Refer to the CFR, Title 21, Volume 8, Chapter 1, Subchapter L, Part 1271.10 for Human-derived products regulated as human cells, tissues, or cellular or tissue-based product (HCT/P).

Provider Qualifications

Services provided within the LCD coverage indications will be considered medically reasonable and necessary when all aspects of care are within the scope of practice of the provider’s professional licensure; and when all procedures are performed by appropriately trained providers in the appropriate setting.

Notice: Services performed for any given diagnosis must meet all the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

Definitions

Autografts/tissue cultured autografts: Include the harvest or application of an autologous skin graft.

Chronic Wound: A chronic wound may be defined as one that is physiologically impaired due to a disruption of the wound healing cycle as a result of impaired angiogenesis, innervation, or cellular migration, among other reasons for 30 days or longer.¹⁷

Cellular and/or Tissue Based Products (CTPs) grafts (also called skin substitutes graft*): : Include non-autologous human cellular and/or tissue products (e.g., dermal or epidermal, cellular and acellular, homograft or allograft), non-human cellular and/or tissue products (i.e., xenograft), and biological products (synthetic or xenogeneic) that form a sheet scaffolding for skin growth when applied in a sheet over an open wound or ulcer to augment closure or skin growth.^13,18

Wound dressing: applications applied to wounds as a selective barrier to clean, cover and protect wounds from the surrounding environment to promote optimal environment for wound healing.

*There is a lack of clarity in the definition of skin substitute. For the purpose of this policy, skin substitute graft will align with the AMA CPT codebook¹⁸ description “non-human skin substitute grafts and biological products that for a sheet scaffolding for skin growth”. This surface is not intended to be removed, but grows into place or serves as surface for new skin to grow in.

A literature search was conducted using the following key words: Non-healing ulcer; chronic; diabetic foot; foot ulcer; venous leg ulcer; guidelines; ulcer healing; skin substitutes; dermal skin substitute; human skin allograft; randomized trial; standard of care; venous leg ulcer; skin grafts; ulcer dressing; human derived products; animal derived products; FDA regulations. The literature search was filtered to locate articles within 5-10 years, full- text articles, clinical trials, and systematic reviews. In general, improved health outcomes of interest include patient quality of life and function.

Introduction

Diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) that have failed to respond to standard of care treatment after 30 days or four weeks may be considered chronic and the application of a skin substitute graft or cellular and/or tissue-based product (CTP) may be considered medically reasonable and necessary for certain patients.^10,12,13 Chronic wounds such as DFUs and VLUs impact patient quality of life due to impaired mobility, pain, and substantial morbidity.^{10 12 13}

Evidence-Based Guidelines for Standard of Care

Evidence-based guidelines indicate that standard of care (SOC) treatment of lower extremity ulcers (e.g., [DFUs] and/or [VLUs]) may include mechanical offloading, infection control, mechanical compression, limb elevation, debridement of necrotic tissue, management of systemic disease and medications, nutrition assessment, tissue perfusion and oxygenation, education regarding care of the foot, callus, and nail and fitting of shoes, and counseling on the risk of continued tobacco use. In addition, maintenance of a moist ulcer environment through appropriate dressings facilitates development of healthy granulation tissue and epithelialization and thus may potentiate complete healing at an ulcer site. Dressings are an integral part of ulcer management by not only maintaining a moist environment but by stopping contamination and absorbing exudate.^4-7,9,14

A comprehensive assessment of patients and their ulcers will also facilitate appropriate care by identifying and correcting systemic causes of impaired healing. The presence of a severe illness or systemic disease and drug treatments such as immunosuppressive drugs and systemic steroids may inhibit ulcer healing by changes in immune functioning, metabolism, inflammation, nutrition, and tissue perfusion. Therefore, this information in conjunction with a detailed history of the ulcer itself is essential.^6,13

A vascular evaluation is also vital for all chronic ulcers. Palpation of pulses may be problematic in cases of medial arterial calcification. An ankle-brachial index (ABI) should be taken for patients with a questionable pulse deficit although the ABI levels may be falsely elevated with medial arterial calcification. The patient is considered to have impaired arterial perfusion when the ABI is below 0.9. To supplement ankle-brachial studies, toe blood pressure readings, pulse volume recordings, transcutaneous oxygen measurements (TCOMs), and skin perfusion pressure measurements have been suggested as acceptable benchmarks for the prediction of ulcer healing.¹³

Venous ulcers require a series of diagnostic testing to verify superficial or deep venous reflux, perforator incompetence, and chronic (or acute) venous thrombosis. In this regard, venous duplex ultrasound is recommended and if the venous duplex ultrasound does not provide definitive diagnostic information, a venous plethysmography is recommended. Patients with mixed arterial and venous disease require a combination of arterial and venous noninvasive testing. The use of a Class 3 (most supportive) high-compression method is strongly recommended in the treatment of venous ulcers. High strength compression may be applied using techniques such as multilayered elastic compression, inelastic compression, Unna boot, compression stockings, and others. The extent of compression should be modified for patients with mixed venous/arterial disease.^7,13

The clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum recommend that patients with VLUs have the ulcer classified using the Clinical class, Etiology, Anatomy, and Pathophysiology (CEAP) classification (confirmed by duplex scan). The Venous Clinical Severity Score (VCSS) is recommended to assess changes in response to therapy. Specific classification of venous disease is essential for standardization of venous disease severity and evaluation of treatment efficiency.⁹

The Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine has recommended a SOC treatment schedule for DFUs that includes weekly to monthly ulcer evaluations of ulcer size and healing progress, infection control, debridement of all devitalized tissue and surrounding callus material, dressings that maintain a moist ulcer environment, control of exudate, and avoiding maceration of adjacent intact skin. Adequate glycemic control of hemoglobin A1c is also recommended to reduce the incidence of DFUs and infections and periodic assessments of appropriate footwear and/or off-loading device.^5,9

Regulation of Skin Substitute Grafts/CTPs

Despite standard of care and advancements in various moisture retaining synthetic occlusive dressings, many chronic ulcers fail to heal. After standard of care fails to heal an ulcer, skin substitute grafts or CTPs have been employed as an ulcer management method to increase the chances of healing.^{10 19} Skin substitute grafts or CTPs can be organized into the following groups: 1) Human-derived products regulated as human cells, tissues, and cellular and tissue- based products (HCT/Ps); 2) Human and human/animal-derived products regulated through premarket approval (PMA) by the U.S. Food and Drug Administration (FDA); 3) Animal-derived products regulated under the 510(k) process; and 4) Synthetic products regulated under the 510(k) process.^1,2,5

Human tissue can be obtained from human donors, processed, and used in exactly the same role in the recipient, such as a dermal replacement to be placed in a ulcer as a skin substitute graft or CTP (regulated as HCT/Ps). These products may be regulated under the Biologics License Application (BLA) (under the Public Health Service Act [PHS Act]) or PMA (under the Federal Food, Drug, and Cosmetic Act [FEDCA]), depending on their composition and primary mode of action. Amniotic/chorionic-based products are HCT/Ps as defined in 21 CFR 1271.3(d) and must meet criteria in 21 CFR 1271 and 361 of the PHS Act. The HCT/Ps not regulated under 361 are regulated as drugs as defined under section 201(g) of the FEDCA [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. In order to legally market a drug that is also a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after a showing of safety and efficacy for the products intended use.³

Evidence-Based Guidelines for Skin Substitute

Skin substitute grafts or CTPs are a heterogeneous group of biological and/or synthetic elements that allow the temporary or permanent occlusion of ulcers. Dermal substitutes may vary from skin xenografts or allografts to a combination of autologous keratinocytes over the dermal matrix, but all have a mutual goal to attain resemblance with an individual’s skin to the greatest extent possible.⁹ Skin substitute grafts or CTPs are recommended as an advanced therapy in addition to the established SOC treatment protocols for ulcer care to increase the chances of healing. In this regard, evidence-based guidelines recommend ulcer bed preparation prior to the application of any biologically active dressing which includes complete removal of slough, debris and/or necrotic tissue.¹⁵ Skin substitute grafts are recommended in conjunction with SOC treatment for DFUs that have failed to demonstrate more than 50% ulcer area reduction after a minimum of 30 days of standard therapy.⁵ For VLUs, if substantial ulcer improvement is not demonstrated after a minimum of 30 days of standard therapy, skin substitute grafts or CTPs are recommended in addition to compression therapy.⁷

Technology Assessment

The Agency for Healthcare Research and Quality (AHRQ) provided an evidenced-based technical brief for skin substitute grafts for treating chronic ulcers.¹⁶ This technical brief was developed to describe assorted products that may be considered skin substitute graft in the U.S., which are utilized for the treatment of chronic ulcers. In addition, systems utilized to classify skin substitute grafts were assessed, randomized controlled trials (RCTs) involving skin substitute grafts were reviewed, and recommendations were made regarding best practices for future studies. A systematic search of the published literature since 2012 was conducted for systematic reviews/meta-analyses, RCTs, and prospective non-randomized comparative studies studying commercially available skin substitute grafts for individuals with DFUs, VLUs, pressure ulcers, and arterial leg ulcers.

Seventy-six skin substitute grafts were identified and categorized using the Davison-Kotler classification system, a method structured according to cellularity, layering, replaced region, material used, and permanence. Of these, 68 (89%) were categorized as acellular dermal substitutes, largely replacements from human placental membranes and animal tissue sources. Acellular dermal substitutes prepared from natural biological materials are the most common commercially available skin substitute graft product for treating or managing chronic ulcers. Cellularity is a significant difference among skin substitute graft as the presence of cells raises the rejection risk and production complexity. This category includes decellularized donated human dermis (14 products recognized), human placental membranes (28 products recognized), and animal tissue (21 products recognized). Less products are prepared from synthetic materials (two products recognized) or a blend of natural and synthetic materials (two products recognized). A limited number of skin substitute products are acellular replacements for both the epidermis and dermis (one product recognized). Only eight products were recognized that contain cells and would be classified in the cellular grouping.

Three systematic reviews and 22 RCTs studied the utilization of 16 distinct skin substitutes, comprising acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes in DFUs, pressure ulcers, and VLUs. Twenty-one ongoing studies (all RCTs) assessed an additional nine skin substitute grafts with comparable classifications. It was noted that studies seldom reported clinical outcomes, such as amputation, ulcer recurrence at least two weeks after treatment ended, or patient-related outcomes, such as return to function, pain, exudate, and odor. This review found that more studies are needed to assess the effectiveness of most skin substitutes and studies need to be better designed and include clinically relevant outcomes.

Of the 22 included RCTs, 16 studies contrasted a skin substitute with SOC. The SOC for each ulcer type involved sharp debridement, glucose control, compression bandages for VLUs, pressure redistribution support surfaces for pressure ulcers, infection control, offloading, and daily dressing changes with a moisture-retentive dressing, such as an alginate or hydrocolloid type dressing. Though 85% of the studies examining acellular dermal substitutes portrayed the experimental intervention as favorable over SOC for ulcer healing and quicker time to heal, inadequate data is available to determine whether ulcer recurrence or other sequela are less frequent with acellular dermal substitutes. Only three studies contrasted cellular dermal substitutes with SOC. Clinical evidence for cellular dermal substitutes may be limited by the lack of robust, well-controlled clinical trials.

Of the six head-to-head comparative studies, results from five studies did not show substantial differences between skin substitute grafts in outcomes measured at the latest follow-up (>12 weeks). One study concluding at 12 weeks described a substantial difference in ulcer healing favoring an acellular dermal skin substitute over a cellular epidermal and dermal skin substitute. Another study compared two acellular dermal substitutes and seemed to have deliberately underpowered one arm of the study as statistical significance was not sought or expected for this study arm. Of the two studies reporting on recurrence, one study described comparable recurrence, while the other study reported no recurrence at 26 weeks. The current evidence base, as portrayed by the authors for the literature reviewed, may be inadequate to determine whether one skin substitute graft product is superior to another.

Industry sponsored most of the studies reviewed; 20 of the 22 RCTs in this review, which presents concerns regarding bias for these studies. This AHRQ technical brief also noted that a skin substitute’s commercial availability is not a reflection of its legal status. Manufacturers self-determine whether their human cells, tissues, or cellular or tissue-based product (HCT/P) may be marketed without FDA preapproval and frequently misunderstand or mischaracterize the conditions they must meet for the product to be regulated solely for communicable disease risk. The Code of Federal Regulations (CFR) was referenced; 21 CFR 1271.10(a). Also, the ‘FDA Announces Comprehensive Regenerative Medicine Policy Framework was referenced.¹⁶

Systemic Review and Meta-Analysis

Santema et al²⁰ provided a systematic review and meta-analysis to assess the efficiency of skin substitute grafts utilized for the treatment of DFUs regarding ulcer healing and limb salvage. Using the Cochrane Collaboration methodology, 17 clinical trials were identified, which included a total of 1,655 randomized study participants with diabetic foot ulceration. The number of study participants per clinical trial ranged from 23 to 314. Fourteen studies included chronic or difficult to heal ulcers that were present for a minimum of 2, 4, or 6 weeks.

Skin substitute grafts were contrasted with SOC in 13 trials. The results collectively demonstrated that SOC treatment, together with skin substitute, enhance the chances of attaining complete ulcer closure in contrast to SOC alone after 6 to 16 weeks (risk ratio [RR] 1.55, 95% confidence interval [CI] 1.30 to 1.85, low quality of evidence). Apligraf/Graftskin, Epifix, and Hyalograft 3D were the only individual products that demonstrated a statistically substantial beneficial effect on complete ulcer closure (i.e., full epithelialization without any evidence of drainage or bleeding). Four clinical trials contrasted two different types of skin substitute, although no product demonstrated a greater effect over another. Sixteen of the trials evaluated the efficacy of a bioengineered skin substitute. Only one trial evaluated the efficacy of a non-bioengineered skin graft.

The total occurrence of lower limb amputations was only reported for two trials and the results for these two trials collectively produced a substantially lower amputation rate for individuals treated with skin substitute grafts (RR 0.43, 95% CI 0.23 to 0.81), though the absolute risk difference (RD) was small (-0.06, 95% CI -0.10 to -0.01, very low quality of evidence). Of the included studies, 16 reported on adverse events (AEs) in different ways, although there were no reports of a substantial difference in the incidence of AEs between the intervention and the control group. Additionally, support of long-term effectiveness is lacking, and cost-effectiveness is unclear. Noted limitations included a variable risk of bias among the studies, the lack of blinding (i.e., study participants and investigators knew which patients were receiving the experimental therapy and which patients were receiving the standard therapy), and 15 of the studies conveyed industry involvement; the majority of which did not indicate if the industry applied any limitations regarding data analysis or publication.²⁰

Jones et al²¹ provided a fourth update for a systematic literature review to evaluate the effect of skin substitute grafts for the treatment of VLUs. Using the Cochrane Collaboration methodology, one new trial was identified, generating a total of 17 RCTs, which included a total of 1,034 study participants. The studies comprised participants of any age, in any care setting, and with VLU. Given the process for diagnosis of venous ulceration differed between studies, a standard definition was not applied. The trials also involved study participants with arterial, mixed, neuropathic, and diabetic ulcers provided that the outcomes for patients with venous ulcers were conveyed separately. To be included in the review, trials also had to report at least one of the primary outcomes (i.e., objective measures of healing, such as relative or absolute rate of change in ulcer area, time for complete healing, or proportion of ulcers healed within the trial period).

Eleven studies contrasted a graft with SOC. Two of these studies (102 patients) contrasted an autograft with a dressing, three studies (80 patients) contrasted a frozen allograft with a dressing, and two studies (45 patients) contrasted a fresh allograft with a dressing. Two studies (345 patients) contrasted a tissue-engineered skin (bilayer artificial skin) with a dressing. In two studies (97 patients) a single-layer dermal replacement was contrasted with SOC.

Six studies contrasted alternative skin grafting techniques. The first study (92 patients) contrasted an autograft with a frozen allograft, a second study (51 patients) contrasted a pinch graft (autograft) with a porcine dermis (xenograft), the third study (110 patients) contrasted growth-arrested human keratinocytes and fibroblasts with a placebo, the fourth study (10 patients) contrasted an autograft delivered on porcine pads with an autograft delivered on porcine gelatin microbeads, the fifth study (92 patients) contrasted a meshed graft with a cultured keratinocyte autograft, and the sixth study (50 patients) contrasted a frozen keratinocyte allograft with a lyophilized (freeze-dried) keratinocyte allograft.

Overall, the results show that substantially more ulcers healed when treated with bilayer artificial skin than with dressings. There was inadequate evidence from the other trials to establish whether other types of skin grafting improved the healing of venous ulcers. The authors concluded that bilayer artificial skin, used together with compression bandaging, improves venous ulcer healing contrasted with a simple dressing plus compression.

It was noted that the overall quality of the studies reviewed was poor, thus affecting the risk of inherent bias. Many of the studies did not convey inclusion criteria, insufficient information was provided regarding randomization techniques, and withdrawals and AEs were inadequately reported. Deficient data regarding withdrawals and the inclination to perform per-protocol analyses rather than intention-to-treat (ITT) analyses signify that the outcomes in the original study documentation may be biased.²¹

Clinical Trials for Skin Substitute Grafts or CTPs for Diabetic Foot Ulcers

Barbul et al²² conducted a retrospective, matched-cohort study to establish the efficacy of a cryopreserved human bioactive split-thickness skin allograft (BSA) (i.e., TheraSkin®) plus SOC when contrasted to SOC alone for the treatment of diabetic ulcers. Data was obtained from electronic medical records (EMRs) of an initial pool of 650,309 diabetic ulcers for patients treated at 470 outpatient ulcer care centers in the U.S. from January 1, 2012 to October 25, 2018.

Primary inclusion criteria included: 1) Adults ≥ 18 years of age; 2) DFU, Wagner grade 1-4 present for ≥ 30 days for individuals diagnosed with Type 1 or Type 2 diabetes; 3) Ulcer sited on foot, leg, or toe; and 4) Wound area ≥ 1 cm² and ≤ 50 cm². Primary exclusion criteria included: 1) Ulcers treated at skilled nursing facilities; 2) Ulcers treated with advanced biological products other than BSA; 3) Individuals in the control cohort who received any cellular and/or tissue-based products; and 4) Individuals who showed ≥ 50% closure of their ulcers four weeks before the study treatment period.

Following elimination of ineligible patients and those missing important information (i.e., ulcer characteristics) and/or lack of treatment documentation, data included a total of 778 patients who were treated with the BSA (treatment cohort) (mean age 65.67) and these study participants were paired with 778 patients (mean age 62.95) drawn from a pool of 126,864 patients treated with SOC alone (control cohort), by utilizing propensity matching to create almost identical cohorts. Complications and comorbidities for both groups included Alzheimer’s disease, coronary artery disease, cellulitis, chronic obstructive pulmonary disease, congestive heart failure, end stage renal disease, immunosuppressive conditions, morbid obesity, peripheral vascular disease (arterial and venous), smoking status, and venous insufficiency. Although the disparity in body mass index (BMI) improved with propensity matching, a noteworthy difference remained between groups with those in the BSA cohort having a substantially higher mean BMI than those in the control cohort (p < 0.002).

Both cohorts received SOC treatment involving debridement, offloading, and application of any kind of nonbiologic ulcer dressings, such as hydrogels, saline-moistened gauze, and antimicrobial dressings. Study participants who received a BSA may have utilized any or all of the same dressings.

Amputation rates and recurrence at 3 months, 6 months, and 1 year after ulcer closure were analyzed. Diabetic ulcers were 59% more likely to close in the treatment cohort contrasted to the control cohort (p=0.0045). The healing rates with the BSA were greater than with SOC across multiple subsets, but the most substantial improvement was noted in the worst ulcers that had a duration of 90-179 days prior to treatment (p=0.0073), exposed deep structures (p=0.036), and/or Wagner Grade 4 ulcers (p=0.04). Additionally, the reduction in recurrence was substantial at 3 months, 6 months, and 1 year, with and without initially exposed deep structures (p < 0.05). The amputation rate in the treatment cohort was 41.7% less than that of the control cohort at 20 weeks (0.9% vs. 1.5%, respectively). This study showed that diabetic ulcers treated with a cryopreserved bioactive split-thickness skin allograft were more likely to heal and stay closed contrasted to ulcers treated with SOC alone.²²

Cazzell et al²² performed a prospective, randomized, controlled, open-label trial with a primary objective to contrast the healing rates of a human decellularized acellular dermal matrix (D-ADM) for chronic DFUs with a SOC arm and an active comparator, human acellular dermal matrix (ADM) arm for the treatment of DFUs. Secondary objectives studied differences in time to ulcer closure, economic burden, quality of life questionnaires and product utilization between D-ADM, SOC, and a second active comparator human ADM.

Inclusion criteria included, but was not limited to: 1) Enrolled study participants must have the capability to comply with offloading and dressing change requirements; 2) The ulcer of focus must have been open and receiving SOC for 30 days with an area ≥ to 1 cm² and < than 25 cm²; 3) Patient must be between 21 and 80 years of age, have a single DFU of focus with a Wagner Ulcer Classification Grade of 1 or 2, and no infection present; and 4) Patients must have had acceptable circulation to the affected area, specified as having at least one of the following criteria within the past 60 days: TCOM at the dorsum of the foot ≥ 30 mmHg, ABI ranging from 0.8 - 1.2, or at least biphasic Doppler arterial waveforms at the dorsalis pedis and posterior tibial arteries.

Exclusion criteria included, but was not limited to: 1) Patient had ulcer treatments including biomedical or topical growth factors within 30 days prior to screening; 2) Patient had circulating HbA1c > 12% within 90 days of the screening visit, serum creatinine concentrations of 3.0 mg/dL or > within 30 days before screening; 3) The presence of peripheral vascular disease, active infection or untreated malignancy, Charcot’s disease, or necrosis, purulence, or sinus tracts unable to be removed by debridement; 4) Patient had a revascularization procedure aimed at improving blood flow in the target limb, or received a living skin equivalent within 4 weeks before screening; and 5) Patient has a sensitivity to lincomycin, gentamicin, polymyxin B, vancomycin, polysorbate 20, N-lauroyl sarcosinate, benzonase, or glycerol.

Patients with a diagnosis of diabetes mellitus on a stable treatment regimen (no modifications in treatment for 30 days prior to screening) who visited the clinic for care of a chronic lower extremity ulcer and met the above inclusion criteria and none of the exclusion criteria were asked to join the study. In this regard, the study enrolled 168 DFU patients in 13 centers across nine states in the U.S. Patients were randomized into one of three treatment arms; D-ADM (DermACELL®), SOC ulcer management, or GJ-ADM (GraftJacketTM) at a ratio of 2:2:1. The authors of this study indicated that the active comparator arm for GJ-ADM was not intended to compare the difference between the ADMs as several articles have reported the safety and efficiency of GJ-ADM; this arm was added to the study to determine a baseline ADM healing rate.

Numbered envelopes holding the treatment designation were arranged by an outside contract research organization and the study investigators were blinded to the randomization codes matching each envelope. After a patient successfully passed screening to be in the study, the investigator would open the envelope to ascertain which randomized arm the patient was assigned to. The ADM is visible upon application; therefore, it would have been impossible to continue blinding the investigator once treatment was applied. Therefore, as a secondary examination to avoid bias, a clinician, blinded to the treatment arm assessed the ulcer images for confirmation of healing condition.

Initially, the ulcer beds were debrided with a sharp blade, scissors or Versajet system to remove necrotic tissue for study participants in all three treatment groups. Wound size was recorded using an imaging system pre-and post- debridement as well as before dressing applications. The ulcer areas were calculated by the imaging system and utilized for subsequent analysis of the ulcer areas.

Patients in the D-ADM arm and the GJ-ADM arm had the appropriate ADM dressing applied and covered with a nonadherent dressing. A second ADM was applied between two weeks (at a minimum) and 12 weeks (at the latest) after the first D-ADM application. Patients could have a maximum of two ADM applications, which included the first application at baseline. Wounds in the conventional care arm were provided with ulcer therapy involving alginates, foams, or hydrogels. The treating provider then selected either a moist or dry gauze to be placed over the ulcer. In all three treatment arms, the dressing covered the ulcer for a minimum of 5 days, but no more than 9 days, (7 days ± 2 days) until the next visit and dressings were only changed by the study team. Also, during following weekly visits, debridement was used to remove necrotic tissue, as needed. In addition, off-loading utilizing a removable cast walker, diabetic shoe, surgical shoe, walker cast, or a total contact cast was essential for all treatment arms unless the investigator considered it to be inappropriate, such as situations involving a wheelchair bound patient or if the ulcer was located on the dorsal surface of the foot. Though either removable or nonremovable offloading techniques were permitted, 95% of all patients used some type of removable method; 68% of patients used removable boots and 16% of patients used removable boots and 16% of patients used surgical shoes.

Wounds were assessed on a weekly basis until ulcer closure was noted or the patient completed 24 weekly follow- up visits. Wound closure was defined as 100% re-epithelialization of the ulcer without drainage. A second visit was scheduled two weeks after the initial ulcer closure was noted to verify complete ulcer closure. Additionally, all healed ulcers were followed at 4, 8, and 12 weeks after confirmation of complete ulcer closure to determine if the ulcer remained healed.

A total of 168 patients were included in this study: 71 patients in the D-ADM arm, 69 patients in the SOC arm, and 28 patients in the GJ-ADM arm. Patients that withdrew from the study prematurely because of severe adverse events (SAEs), which affected the ability to follow the ulcer of focus, offloading non-compliance, or ≥ 25% missed visits involved 18 patients in the D-ADM arm, 13 patients in the SOC arm, and 5 patients in the GJ-ADM arm. To this end, 53 patients remained in the D-ADM arm and 40 of these patients received one application, 56 patients remained in the SOC arm, and 23 patients remained in the GJ-ADM arm and 16 of these patients received only one application. The percentage of overall early withdrawals and the percentage of SAEs were comparable between the three treatment groups based on relative population size (p ≥ 0.05).

Baseline ulcer features, including ulcer size, were comparable between the three ITT arms. The average age for patients in the D-ADM arm was 59.1, 56.9 in the SOC arm, and 58.5 in the GJ-ADM arm. The mean HbA1c at screening was 8.51% in the D-ADM arm, 8.38% in the SOC arm, and 7.63% in the GJ-ADM arm. Patients diagnosed with Type 2 diabetes involved 93.5% of the enrolled population, with 90.1% randomized to D-ADM, 97.1% randomized to SOC, and 92.9% randomized to GJ-ADM. The treatments prescribed for diabetes control were evenly dispersed across study arms, thus eliminating the potential confounding effect of insulin levels on cell responses and healing. Also, it was noted that almost half of the study participants (41.1%) were current or past smokers and 58.9% had never smoked. Additionally, the majority of patients in all three arms of the study had ulcers classified as Wagner class 2 (ulcers that extend into tendon or capsule); D-ADM arm (83.1%), SOC arm (79.7%), and GJ-ADM arm (82.1%).

Patients were followed for 24 weeks for all three treatment arms. Results for the per protocol population showed that a single application of D-ADM showed a substantially greater ulcer healing probability in comparison to SOC across all three endpoints at Week 12 (65.0% vs. 41.1%; HR = 1.969; 95% CI = 1.1–3.5; p=0.0123), Week 16 (82.5% vs. 48.1%; HR = 2.397; 95% CI = 1.4–4.1; p=0.0003), and Week 24 (89.7% vs. 67.3%; HR = 2.107; 95% CI = 1.3–3.5; p=0.0008). Patients in the D-ADM arm who received all applications also demonstrated a substantially greater ulcer healing probability over SOC during follow-up visits at Week 16 (67.9% vs. 48.1%; HR = 1.716; 95% CI=1.04–2.831; p=0.0283) and Week 24 (83.7% vs. 67.3%; HR = 1.546; 95% CI = 0.9821–2.435; p=0.0489). The patients in the D-ADM arm who received only one application exhibited ulcer healing in an average of 9 weeks, whereas patients in the conventional arm showed ulcer healing in an average of 16.5 weeks (p=0.0020). No substantial differences were observed between patients in the GJ-ADM arm and patients in the SOC arm or between patients in the D-ADM and GJ-ADM arms.

The SF-36 v2.0 (Optum, Inc.) was utilized to acquire the perception of general health in eight areas for each study participant. The average, overall SF-36 scores at the end of the study were 425 for D-ADM, 430 for SOC, and 404 for GJ-ADM. There were no substantial differences perceived between treatment arms for the overall total score or in any of the eight areas. Also, a limitation noted for this study indicates that the manufacturer of the D-ADM (DermACELL®) sponsored this trial.²³

Driver et al²⁴ conducted The Foot Ulcer New Dermal Replacement Study (FOUNDER) to assess the safety and effectiveness of the Integra Dermal Regeneration Template (IDRT) (i.e., Omnigraft® Dermal Regeneration Matrix) for the treatment of nonhealing DFUs. The study was a multicenter, randomized, controlled, parallel group clinical trial performed under an Investigational Device Exemption. This study was designed based on guidelines from the FDA for creating products to treat chronic cutaneous ulcers. The FOUNDER study involved 32 clinical sites and 307 patients that were randomized into two parallel groups. 

The primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetes with a HbA1c ≤ 12%; 2) Patients ≥ 18 years of age; 3) Presence of a full-thickness neuropathic ulcer positioned distal to the malleolus; 4) The ulcer of focus must have been in existence for greater than 30 days with the ulcer area between 1 and 12 cm² post-debridement; and 5) Satisfactory vascular perfusion as defined by ABI ≥ 0.65 and ≤ 1.2 or toe pressure > 50 mmHg or transcutaneous oxygen pressure (TcPO2) > 40 mmHg or doppler ultrasound consistent with sufficient blood flow to the affected extremity.

The primary exclusion criteria were active infection involving osteomyelitis, exposed capsule, tendon, or bone, and reduction of ulcer ≥ 30% during the screening interval. The trial was separated into three phases: screening/run-in, randomization/treatment, and follow-up. Patients entered the screening/run-in phase after providing written consent and underwent a series of screening evaluations and a 14-day run-in period in which patients received SOC treatment on the ulcer of focus to establish eligibility for the study. The following procedures were performed during the run-in period for the ulcer of focus: 1) Infection and exudate evaluation; 2) Sharp debridement; 3) Measurement of the deepest aspect (post-debridement); 4) Photograph (pre- and post-debridement); 5) Tracing for planimetric evaluation (post-debridement); 6) SOC that involved sharp debridement followed by application of a moist ulcer therapy consisting of 0.9% sodium chloride gel and a secondary dressing involving a nonadherent foam dressing, an outer gauze wrap, and an offloading/protective device (i.e., Active Offloading Walker [boot and/or shoe]); and 7) Patients were instructed on the SOC treatment for daily dressing changes.

Other patient evaluations conducted during the run-in period included: A medical history; medication usage; therapies; physical examination; and neuropathic, laboratory, and vascular perfusion assessments. Once the patients completed the screening/run-in phase, patients were then assessed to determine continued satisfaction of eligibility criteria. The ulcer of focus was then debrided using sharp debridement prior to the first treatment. Also, a planimetric evaluation was performed (blindly by a central laboratory).

Patients with study ulcers that had healed < 30% in the run-in period were randomized using a software algorithm at a central location in mixed blocks of 2 and 4 in a 1:1 ratio to the active or control treatment. Randomization was stratified by study location and ulcer size (≤ 3 cm2 versus > 3 cm2). Treatment started on the day of randomization as assigned and the treatment phase continued until the patient had 100% ulcer closure or for up to 16 weeks. The SOC was the control treatment and the IDRT was the active treatment. The SOC treatments were just as described in the screening/run-in phase and daily dressing changes were done either by the patient in the control group or by a trained caregiver.

For the active treatment group, fenestrating and meshing of the IDRT was acceptable to allow for drainage and in the presence of exudating ulcers or hematomas. The IDRT was placed on the debrided ulcer, trimmed to size, and secured with sutures or staples, and covered with a secondary dressing. When the collagen layer was replaced by new tissue, typically in 14 to 21 days after application, the silicone layer of the IDRT was removed. Re-applications of the IDRT were done as deemed necessary by the investigator. The site personnel performed the secondary dressing changes for the active treatment group on a weekly basis.

Wounds were assessed on a weekly basis during the treatment phase or until ulcer closure was noted. A visit was scheduled one week after the initial ulcer closure was noted to verify complete ulcer closure. An additional visit was then scheduled for confirmation of wound closure. Following completion of the treatment phase, all patients were followed every four weeks during the 12-week follow-up phase.

Complete closure of the ulcer of focus during the treatment phase (16 weeks) (defined as 100% re-epithelialization of the ulcer surface with no discernable exudate and without drainage or dressing needs), was substantially greater in the active group (51%; 79/154) in contrast to the control group (32%; 49/153, p=0.001). Comparable results were observed when ulcer closure was evaluated by computerized planimetry: 50% (77/154) in the active group and 31% (48/153) in the control group (p=0.001). The probabilities of complete ulcer closure established at the end of the treatment phase were 2.2 times higher (95% CI = 1.4, 3.5; p=0.001) for the active group contrasted with the control group. Assessment using planimetric data to evaluate ulcer closure was consistent with an odds ratio of 2.2 (95% CI = 1.3, 3.5; p=0.001). When complete ulcer closure was evaluated at 12 weeks, the results were substantially different between the two groups (45% active [70/154] vs. 20% control [31/153]; p < 0.001). The probabilities of complete ulcer closure at 12 weeks were 3.3 times higher (95% CI = 2.0, 5.4; p < 0.001) for the active group contrasted with the control group. The average number of applications per individual, including the initial application, for the active group was 1 (range 1–15).

The degree of decrease in ulcersize was 7.2% per week for the active group vs. 4.8% per week for the control group (p=0.012). At the end of the follow-up phase, ulcer recurrence was experienced by 19% of the active treatment group and by 26% of the control treatment group (p=0.32). Quality of life data demonstrated substantial improvements in physical functioning (p=0.047) and bodily pain (p=0.033) for the active group contrasted with the control group.

Most AEs in both groups were mild. Severe AEs were incurred by 15.6% of patients in the active group and by 26.8% in the control group (p=0.016). Moderate AEs were incurred by 31.8% of patients in the active group and by 42.5% of patients in the control group (p=0.053). The AEs possibly linked to study treatment were comparable in both treatment groups (7/154 [4.5%] in the active group vs. 8/153 [5.2%] in the control group). Also, a limitation noted for this study is the manufacturer of the IDRT used in the active treatment group sponsored this trial.²⁴

Lavery et al²⁵ performed a prospective, multi-center, randomized, single-blinded study to contrast the effectiveness of a human viable ulcer matrix (hVWM) (i.e., Grafix®) to standard ulcer care in treating chronic DFUs from May 2012 to April 2013. The primary outcome was the percentage of patients with complete ulcer closure by 12 weeks. Complete ulcer closure was defined as 100% re-epithelialization with no ulcer drainage. Secondary outcomes encompassed the time to ulcer closure, AEs, and ulcer closure in a crossover phase. 

Primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetic patients 18-80 years of age; 2) Diabetic ulcer present for 4 to 52 weeks; and 3) Diabetic ulcer positioned below the malleoli on the plantar or dorsal surface of the foot and ulcer 1 to 15 cm2 in size. Primary exclusion criteria included: 1) HbA1c above 12%; 2) Indication of active infection, including osteomyelitis or cellulitis; 3) Insufficient circulation to the affected foot defined by an ABI < 0.70 or > 1.30, or toe brachial index ≤ 0.50 or Doppler study with insufficient arterial pulsation; 4) Exposed muscle, tendon, bone, or joint capsule; and 5) Decrease of ulcer area by ≥ 30% during the screening period.

After a 1-week screening period, patients were randomized to the active treatment arm (i.e., hVWM) or control treatment arm (i.e., standard ulcer care) in a 1:1 ratio. Patients in the active treatment group received an application of hVWM once a week (± 3 days) for up to 84 days (blinded treatment phase). Patients in the control group received SOC ulcer therapy once a week (± 3 days) for up to 84 days and ulcers were cleaned and surgically debrided to remove all non-viable soft tissue from the ulcer by scalpel, tissue nippers and/or curettes at each weekly visit.

Ulcers in both groups received SOC that involved surgical debridement, off-loading and non-adherent dressings and either saline moistened gauze or an absorbent foam dressing for moderately draining ulcers. Also, an outer dressing was applied. In addition, walking boots were provided for patients with ulcers on the sole of the foot and post-op shoes were provided for patients with ulcers on the dorsum of the foot or at the ankle.

Patients were evaluated weekly at the clinical site. Patients who attained complete ulcer closure then continued to be assessed during the follow-up phase, twice during the first month and then monthly for two additional visits.

Patients in the control group whose ulcers were not closed by the end of the blinded treatment phase were able to receive the hVWM in the open-label treatment phase, in which the hVWM was applied weekly for up to 84 days.

During screening, 139 patients were assessed. A total of 42 patients failed screening and of these, 6 were excluded due to a decrease of their ulcer areas by ≥ 30% during the screening period. A total of 97 patients were randomized: 50 to the active treatment arm and 47 to the control arm.

The percentage of patients who attained complete ulcer closure was substantially higher in the active treatment group (62%) compared with the control group (21%, P=0.0001). The average time for healing was 42 days in the active treatment arm contrasted with 69.5 days in the control arm (P=0.019). There were less AEs in the active arm (44% versus 66%, P=0.031) and less ulcer-related infections (18% versus 36.2%, P=0.044). Among the study participants that healed, ulcers remained closed in 82.1% of patients (23 of 28 patients) in the active group versus 70% (7 of 10 patients) in the control group (P=0.419). The authors concluded that treatment with the hVWM substantially improved DFU healing contrasted with SOC therapy. Also, a limitation noted for this study is the manufacturer of the hVWM used in the active treatment group sponsored this trial.²⁵

Sanders et al²⁶ performed a prospective, multi-center, randomized, controlled trial to contrast an in vitro-engineered, human fibroblast-derived dermal skin substitute (HFDS) (i.e., Dermagraft®) to a biologically active cryopreserved human skin allograft (HSA) (i.e., TheraSkin®) in the treatment of DFUs. The primary objectives were to establish the relative number of DFUs healed (100% epithelization without drainage) and the number of grafts needed by week 12. Secondary objectives involved the percentage of DFUs healed at weeks 16 and 20, time to heal during the study and ulcer size progression.²⁶

Primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetic patients > 18 years of age; 2) HbA1C < 12%; 3) Full-thickness foot ulcer existing > 30 days; 4) Ulcer > 1 cm² and < 10 cm² in size with at least 2 cm between study ulcer and other ulcers; and 5) ABI > 0.65, toe pressure > 50 mmHG, and TcPO2 > 20 mmHG. Primary exclusion criteria included: 1) Wound infection or gangrene of the foot; 2) Patient has received oral or parenteral corticosteroids, immune-suppressive or cytotoxic drugs within the last 12 months; and 3) Treatment with growth factors or bioengineered skin substitute graft within the past 30 days.

A total of 23 patients participated in the study at two hospital-based ulcer care centers in three phases. During the first phase, screening was performed, and eligible patients were randomly assigned to the HFDS treatment group (12 patients) (mean age 57) or the HSA treatment group (11 patients) (mean age 60) using a series of sealed envelopes employing a block randomization technique that described the treatment to be applied. During the second phase (one week later), the treatment phase started and continued for 12 weeks. All ulcers (both groups) were debrided to remove nonviable tissue and callous from the ulcer surface and adjacent ulcer perimeter and then cleansed with saline. Afterwards, the initial application of the biologically active product was applied as randomly assigned and all ulcers were then covered with a non-adherent dressing and were offloaded with 1/2 inch felt as part of an aperture type of device. All patients were then given a healing sandal developed from a surgical shoe or a fixed ankle boot.

Patients in the HSA group received a product application every other week and patients in the HFDS group were treated every week with ulcers prepared as described above prior to application of the product. Since both products have a distinctive appearance, it was not possible to conceal the type of product used during ulcer assessments. Wounds were photographed at each visit and the margins of the ulcers were traced along the inner edge of the margins. At week 12, patients with an unhealed ulcer continued into the third phase (follow-up) for treatment and assessment for up to eight more weeks. After the week 12 visit, no additional biologically active products were used in either treatment group. In this phase, ulcers were treated with saline-moistened gauze and debridement as needed. Patients with ulcers verified to be healed were scheduled for a confirmatory visit. Patients with incomplete ulcer closure continued to be evaluated through week 20; subsequent treatment was then provided outside the scope of the study.

There were no substantial differences discerned between patient demographics and ulcer attributes at baseline in the two treatment groups. At week 12, seven (63.6%) ulcers in the HSA treatment group versus four (33.3%) in the HFDS treatment group were healed (P=0.0498). At the end of week 20, 90.91% of ulcers in the HSA group versus 66.67% of ulcers in the HFDS group were healed (P=0.4282). Among the subset of ulcers that healed during the first 12 weeks of treatment, a mean of 4.36 (range 2-7) HSA grafts were applied versus 8.92 (range 6­12) in the HFDS subset group (P < 0.0001, SE 0.77584). Time to healing in the HSA group was substantially less (8.9 weeks) than in the HFDS group (12.5 weeks) (log-rank test, P=0.0323). The results of this study showed that, after 12 weeks of care, DFUs treated with HSA are probably twice as likely to heal as DFUs managed with HFDS with about half the number of grafts required. Limitations noted for this study are the small sample size and the manufacturer of the HSA product used in one of the active treatment groups sponsored this trial.²⁶

Zelen et al²⁷ performed a prospective, randomized, controlled, multicenter study to evaluate the healing rates, safety, and cost using an open-structure human reticular acellular dermis matrix (HR-ADM) (i.e., AlloPatch® PliableTM) plus SOC to facilitate ulcer closure in DFUs compared to treatment with SOC alone. The trial was conducted from December 2014 to November 2015 at five outpatient ulcer care centers in Virginia and Ohio.

Primary inclusion criteria included: 1) Patients with Type 1 or Type 2 diabetes with a non-healing neuropathic foot ulcer that failed a minimum of 4 weeks of documented conservative care; 2) Adequate renal function as shown by a serum creatinine level < 3.0 mg/dl; and 3) Sufficient circulation to the affected extremity within the past 60 days as evidenced by TCOM with result ≥ 30 mmHg, ABI with result of ≥ 0.7 and ≤ 1.2 or Doppler arterial waveforms, which were triphasic or biphasic at the ankle of the affected leg.

All eligible patients meeting inclusion and exclusion criteria were treated with SOC alone, which included surgical debridement, for a 2-week screening period and patients whose index ulcer had not healed greater than 20% at 2 weeks were then considered eligible for the study. A total of 40 study participants were eligible for enrollment in the study and were randomized to HR-ADM plus SOC (n = 20) (HR-ADM applications weekly) or SOC alone (n = 20) (daily dressing changes). There were no significant group differences regarding patient and ulcer attributes, with the exception of the average ulcer area, which was larger in the HR-ADM group (4.7 cm2) contrasted with the SOC group (2.7 cm2).

The primary outcome of this study focused on a comparison of ulcer healing at 6 weeks using HR-ADM plus SOC versus SOC alone. Wounds were considered as healed if there was complete (100%) re-epithelization with no drainage and no need for a dressing. Secondary outcomes involved comparing healing at 12 weeks, time to heal at 6 and 12 weeks, graft count, wastage, and assessment of product cost to closure. An ITT method was utilized for all analyses. At 6 weeks, 65% (13/20) of the HR-ADM-treated ulcers had healed contrasted with 5% (1/20) of the ulcers treated with SOC alone (P=0.00028). The decrease in the ulcer area size between the groups changed significantly over time, with an average time to heal within 6 weeks of 28 days (95% CI: 22–35 days) for the HR-ADM group contrasted with 41 days (95% CI: 40–43 days) for the SOC group. After adjusting for area of ulcer at randomization, the hazard ratio (HR) for HR-ADM contrasted with SOC was 168 (95% CI: 10–2704), P=0.00036. Ten study participants from the SOC group (50%) and one patient from the HR-ADM group (5%) discontinued the study at 6 weeks per protocol as their ulcer failed to decrease in area by at least 50%.

At 12 weeks, 80% (16/20) of the HR-ADM-treated ulcers had healed contrasted with 20% (4/20) of the ulcers treated with SOC alone (P=0.00036). The average time to heal within 12 weeks was 40 days (95% CI: 27–52 days) for the HR-ADM group contrasted with 77 days (95% CI: 70–84 days) for the SOC group (P=0.00014).

The average number of HR-ADM grafts used to achieve closure per ulcer was 4.7 (SD=3.3). The average percentage of wastage (healed ulcers only) was 51.7% (SD: 10.7; n = 16). There was no occurrence of increased AEs or SAEs between groups, or any AEs related to the graft. This study concluded that the use of HR-ADM plus SOC is more effective in the treatment of DFUs than with SOC alone. This study was limited by the patients unblinded to treatment allocation and the study was also funded by the manufacturer of the HR-ADM graft.²⁷

Clinical Trials for Skin Substitute graft CTPs for Venous Leg Ulcers

Cazzell²³ conducted a multicenter, randomized, controlled, open-label trial designed to evaluate the safety and efficacy of human decellularized acellular dermal matrices (D-ADM) contrasted with SOC management in patients with chronic VLUs. This exploratory pilot study included eight implanting surgeons from seven medical centers in five states that enrolled patients with VLUs. The study participants were randomly assigned to the D-ADM (i.e., Dermacell AWM®) treatment arm or a SOC treatment arm in a 2:1 ratio. Numbered envelopes holding the treatment designation were arranged by an outside contract research organization and the study investigators were blinded to the randomization codes matching each envelope. After a patient successfully passed screening to be in the study, the investigator would open the envelope to ascertain which randomized arm the patient was assigned to. The D-ADM is visible upon application; therefore, it would have been impossible to continue blinding the investigator once treatment was applied. Therefore, as a secondary examination to avoid bias, a blinded, independent adjudicator also assessed the healing condition of all ulcers.

Primary inclusion criteria included: 1) Adults ≥ 21 and ≤ 80 years of age; 2) Presence of a single target VLU with a CEAP ulcer classification Grade 6; 3) Duration of the target VLU ≥ 60 days; 4) Absence of infection; 5) VLU area ≥ 1 cm² and < 25 cm², depth ≤ 9 mm; and 6) Able to comply with offloading and dressing change stipulations.

Primary exclusion criteria included: 1) HbA1c < 12% within 90 days of screening visit; 2) Serum creatinine ≥ 3.0 mg/dL within 30 days of screening; 3) Application of biomedical, topical growth factors or living skin equivalents to the target VLU within 30 days of screening; 4) Recent revascularization procedure to increase blood flow in the target limb; 5) Sensitivity to possible D-ADM processing reagents (e.g., gentamicin, polymyxin B, vancomycin, N-lauroyl sarcosinate, Benzonase, glycerol); and 6) Manifestation of severe peripheral vascular disease, active infection, untreated malignancy, active Charcot’s disease, necrosis, purulence, or sinus tracts in the ulcer unable to be removed by debridement.

Eighteen patients were included in the D-ADM arm (mean age 64.6) and 10 patients in the control arm (mean age 61.8). Initially, all ulcers for both groups were debrided to remove necrotic tissue utilizing a sharp blade, scissors, or Versajet system. Wound size was recorded using an imaging system pre-and post-debridement as well as before dressing application. Patients in the treatment arm had the D-ADM applied and covered with a nonadherent dressing. A second D-ADM was applied between two weeks (at a minimum) and 12 weeks (at the latest) after the first D-ADM application. Patients could have a maximum of two D-ADM applications, which included the first application at baseline.

Wounds in the SOC arm were provided with ulcer therapy involving alginates, foams, or hydrogels. The treating provider then selected either a moist or dry gauze to be placed over the ulcer and left in place for 7 ± 2 days, which was only to be removed during weekly visits. During the weekly visits, debridement was used to remove necrotic tissue, as needed. Compression therapy was used in the treatment and control arms. Wounds were assessed on a weekly basis until ulcer closure was noted or the patient completed 24 weekly follow-up visits. Wound closure was defined as 100% re-epithelialization of the ulcer without drainage. A second visit was scheduled two weeks after the initial ulcer closure was noted to verify complete ulcer closure. Additionally, all healed ulcers were followed at 4, 8, and 12 weeks after confirmation of complete ulcer closure to determine if the ulcer remained healed.

The primary outcome of the study contrasted the full ulcer closure rates between the two groups. The second outcome of the study involved contrasting the decrease in ulcer size over time, time to ulcer closure, and treatment-related AEs. Twenty-eight patients completed at least 12 weeks of follow-up; 18 patients in the D-ADM arm and 10 in the SOC arm. Of the 18 patients receiving the D-ADM, nine (50%) received a second application during the study. At 24 weeks, patients in the D-ADM arm demonstrated a strong trend of reduction in the ulcer area, with a mean reduction of 59.6%, in comparison to the SOC arm, with a mean reduction of 8.1%. Also, the ulcer areas in the SOC arm increased more than 100% in size for one-third (3/9) of the patients. Furthermore, healed ulcers in the D-ADM arm stayed closed at a significantly greater rate after initial confirmation of complete ulcer closure than healed ulcers in the control arm. Limitations noted for this study included a small patient population with an unbalanced proportion between the 2 groups (2:1) that ensured a low probability of achieving statistical significance, the lack of blinding for the study investigators, and the study was funded by the manufacturer of the D-ADM graft.

Harding et al²⁸ conducted an open label, prospective, multicenter, randomized controlled study that assessed the human fibroblast-derived dermal substitute (HFDS) (i.e., Dermagraft®) in addition to four-layer compression therapy contrasted with compression therapy alone in the treatment of VLUs. The primary outcome variable was the proportion of patients with completely healed study ulcers by 12 weeks. Complete healing was characterized by having a closed ulcer (with full epithelization and no exudate or scab) for two consecutive weekly visits.

Primary inclusion criteria included: 1) Individuals ≥ 18 years of age referred to participating facilities/clinics in the United Kingdom (UK), Canada or the U.S.; 2) Presence of a VLU between the knee and ankle existing for at least 2 months and ≤ 5 years prior to screening; 3) Size of VLU 3-25 cm² without exposure of muscle, tendon or bone; 4) Presence of a clean, granulating base with negligible adherent slough, suitable for a skin graft; and 5) ABI of 0.8 to 1.2 and reflux of > 0.5 seconds in saphenous, calf perforator or popliteal veins as confirmed by duplex ultrasonography.

Primary exclusion criteria included: 1) Individuals with ulcers caused by a medical condition other than venous insufficiency; 2) Presence of sinus tracts in ulcer; 3) Signs of a ulcer infection (purulence and/or odor), cellulitis and/or verified osteomyelitis; 4) Morbid obesity; 5) Skin disease near study ulcer; 6) Malignant disease within the past 5 years; and 7) Severe peripheral vascular disease or renal disease, congestive heart failure, cell anemia, thalassemia or uncontrolled diabetes. Also, individuals who had received immune suppressants, systemic corticosteroids, cytotoxic chemotherapy, or topical steroids for more than 2 weeks and within one month of initial screening or who had a history of radiation at the ulcer site were not eligible to participate in the study. In addition, patients who had received an investigational drug within 30 days of randomization or had been previously treated with an HFDS and/or other tissue-engineered materials were also excluded from the study.

All patients received a SOC dressing treatment during the screening period; each ulcer was covered with a layer of non-adherent dressing followed by a four-layer compression bandage. During the 2-week screening period, ulcers were evaluated weekly to establish absence of necrotic tissue and infection and the presence of a vascular bed. Ulcers that decreased in size (cm²) by < 50% while under compression therapy during the 2-week screening period for the trial were eligible for randomization into the study.

Of the 573 patients screened, 207 failed screening (36%). The primary causes for screening failure were study ulcers decreasing in size by more than 50% during screening, study ulcers less than 3 cm2 at randomization and patients without indication of venous reflux. The remaining 366 patients were randomized to receive treatment at a total of 25 centers: 19 in the UK, 1 in Canada and 5 in the U.S. The ITT population (patients who received treatment at baseline and had a follow-up visit post-baseline) included 186 patients in the HFDS group and 180 patients in the control group with a mean age of 68.5 years. Patients were randomized to receive an application of HFDS plus the four-layer compression bandage therapy (active) or the four-layer compression bandage therapy alone (control). Patients randomized to the active treatment group received the HFDS applied to the ulcer at weeks 0, 1, 4 and 8.

A total of 10% (19 of 186) of patients in the HFDS group discontinued the trial early contrasted with 23% (41 of 180) of patients in the control group. The causes for early discontinuation were AEs (3% in the HFDS group versus 6% in the control group), patient’s own request (2% versus 9%), patient lost to follow-up (2% versus 3%) and ‘other’ (4% from each group).

Sixty-four (34%) of 186 patients in the HFDS group demonstrated healing by week 12 contrasted with 56 (31%) of 180 patients in the control group (P=0.235). For ulcers ≤ 12 months duration, 49 (52%) of 94 patients in the HFDS group contrasted with 36 (37%) of 97 patients in the control group healed at 12 weeks (P=0.029). For ulcers ≤ 10 cm², complete healing at week 12 was shown in 55 (47%) of 117 patients in the HFDS group contrasted with 47 (39%) of 120 patients in the control group (P=0.223). The most common AEs were ulcer infection, cellulitis, and skin ulcer. The occurrence of AEs was not significantly different between the treatment and control groups. Statistical significance was not achieved for the primary outcome of patients with VLUs completely healed by 12 weeks. Also, a limitation noted for this study is the manufacturer of the HFDS used in the control group helped sponsor this trial.²⁸

Literature submitted during the comment period

A 2021 report from Armstrong and colleagues presented a retrospective analysis from the Medicare Limited Data set (2015-2018) comparing DFU treatment with advanced treatments defined as cellular and acellular dermal substitutes, compared to no advanced treatments. Out of 9,738,760 patients identified with a diagnosis of diabetes, 909,813 had a LEDU. In propensity-matched Group 1, AT patients had fewer minor amputations (p = 0.0367), major amputations (p < 0.0001), ED visits (p < 0.0001), and readmissions (p < 0.0001) contrasted with NAT patients (12,676 episodes per cohort). In propensity-matched Group 2, AT FPFU patients had fewer minor amputations (p = 0.002) contrasted to patients with AT not FPFU (1,131 episodes per cohort). Patients who received AT with skin substitute grafts had 3.7 applications on average, with a standard deviation of 3.6 (propensity-matched Group 1). ²⁹

Tettelbach et al.³⁰ performed a prospective, multi-center, RCT to confirm the effectiveness of a dehydrated human amnion/chorion membrane allograft (dHACM) (i.e., EpiFix) in the treatment of chronic lower extremity ulcers in diabetic patients. Study adjudicators who assessed photographic images for confirmation of healing at completion of the study were blinded as to group assignment.

Inclusion criteria: Patient with Type 1 or Type 2 diabetes; Age 18 or older with an ulcer located below the level of the ankle; ulcer size > 1 cm² and < 25 cm²; ulcer duration of > four weeks unresponsive to SOC; no clinical signs of infection; HbA1c < 12%; serum creatinine < 3.0 mg/dl; adequate circulation of target extremity as demonstrated by dorsum TcPO2 > 30 mmHg, ABI 0.7 - 1.2 or triphasic or biphasic Doppler arterial waveforms at the ankle of target leg.

For patients in the dHACM group, a wound size-appropriate allograft was applied to the debrided wound bed and then hydrated with several drops of sterile saline, as needed. The wound was then dressed with a non-adherent silicone dressing and an absorbent non-adhesive hydropolymer secondary dressing and wrapped with gauze. Patients in the dHACM group received weekly applications. Undo Tettelbach et al.[31] performed a multi-center, prospective, randomized, parallel study to compare dehydrated human umbilical cord (i.e., EpiCord) with SOC to treat chronic DFUs. Inclusion criteria included: Patient with Type 1 or Type 2 diabetes; Age 18 or older with an ulcer located below the level of the ankle; ulcer size post debridement 1 - 15 cm²; ulcer duration of > 30 days; no clinical signs of infection; HbA1c < 12%; and adequate circulation of target extremity.

Patients randomized to the EpiCord group received applications weekly, post-debridement on the wound bed and hydrated with sterile normal saline as needed, followed by a non-adherent silicone dressing and a non-adhesive absorbent hydropolymer secondary dressing, and wrapped with an outer layer of gauze.

A total of 155 patients were treated and included in the ITT analysis; 101 in the EpiCord group and 54 in the SOC group. Healing rate at 12 weeks was 70% (71/101) for the EpiCord group and 48% (26/54) in the SOC group (P = 0.0089). The average number of EpiCord allografts applied was seven (range 2-12). A limitation of the study is the manufacturer of EpiCord sponsored the study.

The intention to treat analysis on 134 subjects who completed the study protocol showed FDUs treated with Epicord were more likely to heal within 12 weeks than those receiving alginate dressings with 71 of 101 (70%) verses 26 to 54(48%) achieving healing, respectively=0.0089). Limitations of the study include risk of bias (funding by manufacture), and lack of blinding. Strengths of this study were control group (alginate), and larger sample size.³¹

Zelen et al.³² performed a prospective, randomized, controlled, parallel group, multi-center comparative effectiveness study using dehydrated human amnion/chorion membrane allograft (dHACM) (i.e., EpiFix), a bioengineered skin substitute graft (donated human neonatal male foreskin tissue) (i.e., Apligraf), or SOC in the treatment of chronic lower extremity diabetic ulcers. Study adjudicators who assessed photographic images for confirmation of healing at completion of the study were blinded as to group assignment.

Inclusion criteria: Patient with Type 1 or Type 2 diabetes; Age 18 or older with an ulcer located below the level of the ankle; ulcer size > 1 cm² and < 25 cm²; ulcer duration of > four weeks unresponsive to SOC; no clinical signs of infection; HbA1c < 12%; serum creatinine < 3.0 mg/dl; adequate circulation of target extremity as demonstrated by dorsum TcPO2 > 30 mmHg, ABI 0.7 - 1.2 or triphasic or biphasic Doppler arterial waveforms at the ankle of target leg.

Patients in the Epifix or Apligraf groups had weekly applications applied. A total of 60 patients were enrolled in the treatment phase, 20 were randomized in the EpiFix group, 20 in the Apligraf group, and 20 in the SOC group. At six weeks, healing rates were at 95% (19/20) for the EpiFix group, 45% (9/20) for the Apligraf group, and 35% (7/20) for the SOC group. The average number of grafts applied ranged from 2 – 15 for EpiFix and an average of 6.2 for Apligraf. Limitations of this study included a shorter time period than other studies to compare treatment groups (e.g., 6 weeks versus 12 weeks) and the study was sponsored by the manufacturer of Epifix.

A 2016 prospective, randomized, controlled, parallel group, multi-center clinical trial with 104 participants and directly compared dHACM (EpiFix®) to standard wound care (SWC) and bioengineered skin substitute (Apligraf®) concluding that dHACM was superior in achieving complete wound closure within 4–6 weeks. The proportion of wounds achieving complete closure within the 12-week study period were 73% (24/33), 97% (31/32), and 51% (18/35) for Apligraf, EpiFix and SWC, respectively (adjusted P = 0⋅00019). Mean time-to-heal was 47.9 days (95% CI: 38.2–57.7) with Apligraf, 23.6 days (95% CI: 17.0–30.2) with EpiFix group and 57.4 days (95%CI: 48.2–66.6) with the SWC alone group (adjusted P = 3.2x 10.7). Median number of grafts used per healed wound were six (range 1–13) for the Apligraf and 2.5 (range 1–12) for EpiFix groups. The study was limited by small sample size, lack of blinding and potential risk of bias as funding source was not disclosed.³²

Serena et al.³³ conducted a multi-center, RTC using one or two applications of dehydrated human amnion/chorion membrane (dHACM) (i.e., EpiFix) allografts and multi-layer compression therapy (MLCT) versus MLCT alone to assess effectiveness for treatment of VLUs. The principal study outcome was the percentage of patients achieving 40% wound closure at four weeks.

Inclusion criteria included: Age 18 or older; Presence of a VLU extending through the full thickness of the skin but not down to muscle, tendon, or bone; VLU present for at least a month; VLU is a minimum of 2 cm² and a maximum of 20 cm²; VLU has been treated with compression therapy for at least 14 days; and ulcer has a clean, granulating base with minimal adherent slough.

A total of 84 patients participated in the study; 26 in the one dHACM application group, 27 in the two dHACM application group, and 31 in the MLCT only group. At four weeks, 62% (16/26) of the one application dHACM group, 63% (17/27) of the two application dHACM group, and 32% (10/31) of the MLCT only group demonstrated more than 40% wound closure (p=0.005). A limitation of the study is the manufacturer of EpiCord sponsored the study.³³

Bianchi et al.³⁴ performed a multi-center, randomized, controlled, open-label study assessing the effectiveness of weekly applications of dehydrated human amnion/chorion membrane (dHACM) (i.e., EpiFix) allografts as an adjunct to SOC including multilayer compression therapy (MLCT) (n=52) versus SOC and MLCT (n=57) in the treatment of VLUs for 16 weeks. Inclusion criteria included patients over the age of 18 with a full-thickness VLU of at least 30 days duration and with an ABI of > 0.75.

A total of 109 patients participated in the study and were included for analysis; 52 patients in the EpiFix group and 57 in the SOC group. Patients in the EpiFix group received 12 weekly applications of the EpiFix allograft in addition to standard moist wound dressings and MLCT.

At 12 weeks, 31/52 (60%) of patients in the EpiFix group achieved complete healing in comparison to 20/57 (35%) of the patients in the SOC group (P = 0.0128). At 16 weeks, complete healing was demonstrated in 37/52 (71%) of patients in the EpiFix group and 25/57 (44%) in the SOC group (P = 0.00625). Average percentage decrease in wound area within 12 weeks was 66% for the patients in the EpiFix group and 40% for the patients in the SOC group. At 16 weeks, the average VLU area was decreased by 72% in the EpiFix group contrasted to 39% in the SOC group. A limitation of the study is the manufacturer of the dHACM sponsored the study.³⁴

2017 RCT evaluating dehydrated human amnion chorion membrane (EpiFix) for the treatment of venous leg ulcers randomly assigned 52 subjects to receive EpiFix and 57 dressings and compression alone. The authors reported that the EpiFix group showed significant time to improved healing 60% vs 35% at 12 weeks p=0.0128. Limitations in the study included the lack of blinding and risk of bias (funded by manufacture).³⁴

Snyder et al.³⁵ performed a prospective, randomized, multi-center, open label, parallel group study for assessment of a dehydrated amniotic membrane allograft (DAMA) (i.e., Amnioexcel) with SOC (n=15) in comparison to SOC alone (n=14) for chronic DFUs for six weeks. The DAMA with SOC group had wound debrided, DAMA applied, covered with non-adherent dressings, lightly secured, and wrapped with a compression dressing. Patients in the DAMA with SOC group had a total of 4.3 + 1.7 allografts applied.

Inclusion criteria included adults with type 1 or type 2 diabetes mellitus with one or more ulcers with a Wagner classification of grade one or superficial two measuring between 1 cm² and 25 cm² in area, presenting for more than one month with no signs of infection/osteomyelitis; ABI > 0.7; HbA1c < 12%; and serum creatinine < 3.0 mg/dL.

Results showed that 33% of patients in the DAMA with SOC group achieved complete wound closure at or before week six, compared with 0% of the SOC alone group (ITT population, P = 0.017). The per protocol population showed 45.5% of patients in the DAMA with SOC group achieved complete wound closure, while 0% of SOC-alone patients achieved complete closure (P = 0.0083).

Frequency of application in the treatment group was 4.3 ± 1.7 and left to individual provider. Limitations of this study included four early withdrawals leaving only 25 patients in the final cohort, small sample size, lack of blinding, lack of control group, and risk of bias as the study was sponsored by the manufacturer of the allograft. The authors call for the need for additional studies.³⁵

Glat et al.³⁶ conducted a RCT to contrast a dehydrated human amnion and chorion allograft (dHACA) (i.e., AmnioBand) with SOC and a tissue-engineered skin substitute graft (TESS) (i.e., Apligraf) with SOC in the treatment of DFUs.

Inclusion criteria: Patient with Type 1 or Type 2 diabetes; Age 18 or older with an ulcer located below the malleoli of the ankle; ulcer size > 1 and < 25 cm²; ulcer duration between four weeks and one year; no clinical signs of infection; HbA1c < 12% within past 90 days unless under care of a diabetologist; serum creatinine < 3.0 mg/dl; adequate circulation of target extremity as demonstrated by one of the following within the past 90 days: dorsum TCOM or SPP > 30 mmHg, ABI 0.7 - 1.2 in conjunction with Doppler arterial waveforms (triphasic or biphasic) at the ankle of target leg.

The average time to heal within six weeks for the dHACA group (n=30) was 24 days (95% CI, 18.9–29.2) versus 39 days (95% CI, 36.4–41.9) for the TESS group (n=30); the average time to heal at 12 weeks was 32 days (95% CI, 22.3–41.0) for the dHACA group versus 63 days (95% CI, 54.1–72.6) for the TESS group. The healing rate at 12 weeks was 90% (27/30) for the dHACA group versus 40% (12/30) for the TESS group. A limitation noted for this study is the manufacturer of the allograft sponsored this trial.³⁶

Serena et al.[37] performed an open-label, multicenter randomized controlled study comparing two application treatments of dehydrated human amniotic and chorion allograft (dHACA) (i.e., AmnioBand) with SOC versus SOC alone for the treatment of 60 patients with VLUs. Patients were randomized into one of three study groups; SOC alone (control), weekly dHACA with SOC or biweekly dHACA with SOC (20 patients per group).

Inclusion criteria included: Age 18 or older; ABI > 0.75 or SPP > 30 mmHg or TCOM > 30 mmHg; Presence of a VLU extending through the full thickness of the skin but not down to muscle, tendon, or bone; VLU present for at least a month; VLU is a minimum of 2 cm² and a maximum of 20 cm²; VLU has been treated with compression therapy for at least 14 days; and ulcer has a clean, granulating base with minimal adherent slough.

At 12 weeks, healing rates were 30/40 (75%) in the two dHACA groups and 6/20 (30%) in the SOC group; p= 0.001. Treatment with dHACA stayed substantial after adjustment for wound area (p= 0.002), with an odds ratio of 8.7 (95% CI: 2.2-33.6). Only six VLUs (30%) healed in the SOC group contrasted to 15 (75%) in the weekly dHACA group (p= 0.02) and 15 (75%) in the biweekly dHACA group (p= 0.02). There were no substantial differences in the proportion of wounds with percent area reduction (PAR) ≥40% at four weeks among all groups. All analyses used the ITT approach. A limitation noted for this study is the manufacturer of the allograft sponsored this trial.³⁷

Manning et al.³⁸performed an open-label, prospective pilot study to evaluate a bioresorbable polymeric matrix infused with ionic and metallic silver (i.e., Microlyte) as a primary wound contact dressing in the treatment of 32 patients (average age of 62 years) with a total of 35 hard-to-heal wounds along with SOC (one patient had three DFUs and another patient had two venous stasis ulcers). The wounds encompassed venous stasis ulcers, DFUs, postoperative surgical wounds, burn wounds, and chronic, non-pressure lower extremity ulcers unresponsive to standard protocols of care. Of the 35 chronic wounds, the majority consisted of venous stasis ulcers (54%) (19/35), followed by DFUs (23%; 8/35). The mean wound surface area at the start of the study was 6.7 cm² (range 0.1 cm² – 33 cm²); the average wound surface area was 2.1 cm². These wounds were considered as nonhealing for an average of 39 weeks (range, 3-137 weeks) and suspected to have persistent microbial colonization that had not responded to standard antimicrobial products and/or antibiotics.

The micrometer-thick bioresorbable matrix conforms closely to the underlying wound bed to exert localized and sustained antimicrobial action of noncytotoxic levels of silver. The matrix was applied to the wounds once every three days to provide a scaffold for uniform loading of silver nanoparticles and a template for cells migration and then covered with a secondary dressing. Any residual matrix still in the wound was not removed due to the bioresorbable nature of the matrix. Three patients were lost to follow-up after initial application. At three weeks, 72% of wounds (22/32) had a mean wound area reduction of 66%. Of the 16 venous stasis ulcers, 11 improved by an average healing rate of 60%, and six of eight DFUs improved by an average wound area reduction of 79%. At the three-week assessment, the burn wound, and postoperative wounds had average wound area reduction of 38% and 58%, respectively.

By 12 weeks, 91% of wounds (29/32) either healed completely (i.e., fully re-epithelialized) or improved substantially with an average wound area reduction of 73%. The venous stasis ulcers and DFUs had an average wound area reduction greater than 75%, with visual signs of healthy granulation tissue formation and re-epithelialization. Limitations of this study included a small sample size, and the same clinical investigator performed all assessments during the study.³⁸

DiDomenico et al.³⁹ conducted a prospective, RCT to compare a dehydrated human amnion and chorion allograft (dHACA) (i.e., AmnioBand) used with SOC to SOC alone in the treatment of DFUs for up to 12 weeks.

Inclusion criteria included: Patient with Type 1 or Type 2 diabetes; Age 18 or older with an ulcer located below the malleoli of the ankle; ulcer size > 1 cm²; ulcer present for at least four weeks with documented failure of prior treatment; no signs of infection; HbA1c < 12% at randomization; serum creatinine < 3.0 mg/dL; adequate circulation of target extremity as demonstrated by one of the following within the past 60 days: dorsum TCOM > 30 mmHg, ABI > 0.7 and < 1.2 or Doppler arterial waveforms (triphasic or biphasic) at the ankle of target leg. Forty patients participated in the study; 20 patients in the dHACA group and 20 patients in the SOC group. The dHACA was applied weekly during the study period until healing occurred (complete epithelialization without drainage), the patient was withdrawn, or the study was completed.

At 6 weeks, 70% (14/20) of the DFUs in the dHACA group achieved healing compared to 15% (3/20) of the DFUs in the SOC group. At 12 weeks, 85% (17/20) of the DFUs in the dHACA group healed compared with 25% (5/20) in the SOC group (average time to heal of 36 and 70 days, respectively). At 12 weeks, the average number of grafts used per healed wound for the dHACA group was 3.8 (average 3.0). All analyses used the ITT approach. A limitation noted for this study is the manufacturer of the allograft sponsored this trial.³⁹

DiDomenico et al.⁴⁰ performed a prospective, randomized, multi-center trial to compare a dehydrated human amnion and chorion allograft (dHACA) (i.e., AmnioBand) used with SOC to SOC alone in the treatment of DFUs for up to 12 weeks.

Inclusion criteria included: patient with Type 1 or Type 2 diabetes; age 18 or older with an ulcer located below the malleoli of the ankle; ulcer size > 1 cm²; ulcer present for at least 4 weeks with documented failure of prior treatment; no signs of infection; HbA1c < 12% at randomization; serum creatinine < 3.0 mg/dL; adequate circulation of target extremity as demonstrated by one of the following within the past 60 days: dorsum TCOM > 30 mmHg, ABI > 0.7 and < 1.2 in conjunction with Doppler arterial waveforms (triphasic or biphasic) at the ankle of target leg. Eighty patients participated in the study; 40 patients in the dHACA group and 40 patients in the SOC group. The dHACA was applied weekly during the study period until healing occurred (complete epithelialization without drainage), the patient was withdrawn, or the study was completed.

At six weeks, 68% (27/40) of the DFUs in the dHACA group achieved healing contrasted to 20% (8/40) of the DFUs in the SOC group (P = 1.9 × 10⁻⁵) At 12 weeks, 85% (34/40) of the DFUs in the dHACA group achieved healing compared with 33% (13/40) of the DFUs in the SOC group. The average time to heal within 12 weeks was substantially quicker for the dHACA group contrasted with the SOC group, 37 days versus 67 days in the SOC group (P = .000006). The average number of grafts used per healed wound during the same time period was 4.0. All analyses used the ITT approach. A limitation noted for this study is the manufacturer of the allograft sponsored this trial.⁴⁰

Raspovic et al.⁴¹ conducted a retrospective study utilized a healthcare database to evaluate the proportion of diabetic foot ulcers that achieved complete closure with cryopreserved placental membranes (vCPM) (Grafix PRIME and Grafix CORE, Osiris Therapeutics, Inc., Columbia, MD) as compared to standard wound care by 12 weeks and the number of wound related infections and amputations. They reported closure in 59.4% of 350 wounds with the median treatment duration of 42 days and a median of 4 applications (95%CI 4-5) of vCPM with 3% rate of infection and 2% amputation. Smaller wounds were quicker to heal. There was no comparison to wounds that did not have vCPM applied. Limitations of the study include the retrospective nature, lack of standardized treatment practices, no comparator group, risk of incomplete records and variabilities in evaluations.⁴¹

Fryberg et al.⁴² conducted a prospective, multicentered, open labeled single arm clinical trial evaluated the use of vCPM (GrafixCORE®, Osiris Therapeutics, Inc, Columbia, MD, USA) in 31 complex DFUs with exposed deep structures. The wounds were cleaned and debrided weekly with weekly application of vCHPM and protective foam dressings applied. Fifty-nine percent achieved complete wound closure by 16 weeks. This study was limited by a lack of comparison to standard wound care, no disclosure of funding sources so potential risk of bias and high dropout rate given the small number of patient enrolled.

Sledge et al.⁴³ performed an observational study, funded by product manufacture, included 26 patients with DFU (4.65±4.89cm²) with failure to heal by >50% after two to four weeks of standard of care and randomized to a larger clinical trial that had been discontinued for logistic reasons. Patients were randomized to weekly or biweekly applications of dual layer amniotic membrane National Institute for Clinical Excellence Guidelines (Tides Medical, US) plus standard of care for 12 weeks. 17/26 (65%) complete closure. The small sample size precluded meaningful comparison between the weekly and biweekly applications. Limitations of the study include risk of bias, observational design, lack of control group, variability in length of standard of care treatment, small sample size, and unable to determine if healing was impacted by the product, frequency of product or other factors.

Skin Substitute Grafts

In order to qualify as skin substitute graft the product must be:

1. Non-autologous human skin OR
2. Non-human skin substitute grafts (“ie, xenograft”), AND
3. Form a sheet scaffolding for skin growth

The graft is intended to remain on the recipient and grow in place or have the recipient’s cells grow into the implanted graft material. Products that require regular replacement (i.e., weekly) do not meet this definition.

Societal Input

National Institute for Health and Care Excellence (NICE) Diabetic foot problems: prevention and management

The clinical guideline on diabetic foot problems considers dermal or skin substitute grafts as an advanced to standard care when treating diabetic foot ulcers only when healing has not progressed and on the advice of the multidisciplinary foot care service. 

International Working Group on the Diabetic Foot (IWGDF)¹¹

IWGDF recommends the consideration of placental-derived products as an adjunctive treatment to the best standard of care when standard care alone has failed to reduce the size of the ulcer. (GRADE Strength of recommendation: Weak; Quality of evidence: Low). This was based on a number of studies, including those of moderate bias, suggesting that placenta-derived products may have a beneficial effect on ulcer healing, but the authors also state that these findings need to be confirmed in large, randomized trials. They state there is insufficient evidence to support superiority of any particular products.

For use of topically applied treatments, the IWGDF recommends against the use of bioengineered skin products in comparison to standard of care.

For both of these recommendations, the IWGDF considered the available evidence to be of low quality, and their recommendation was weak (i.e., based on the quality of evidence, balance between benefits and harms, patient values and preferences, and cost or resource utilization).

Wound Healing Society (WHS)^7-8

The WHS has published updated evidence-based guidelines on the treatment of diabetic ulcers. Regarding the use of skin substitute, the WSH concluded that level I evidence suggests that cellular and acellular skin equivalents improve the healing of diabetes-related foot ulcers. In these guidelines Level I required at least two RCT supporting the intervention of the guidelines. The quality of evidence was not assessed.

• ‘In 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 ulcer 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’.⁸

Society for Vascular Surgery/American Podiatric Medical Association/Society for Vascular Medicine (SVS/APMA/SVM)

The SVS/APMA/SVM published a joint evidence-based guideline using Grades of Recommendation Assessment, Development, and Evaluation system for the management of patients with diabetes, including treatment of diabetes related chronic foot ulcers ⁶. 

• These organizations recommendations for diabetic foot ulcers that fail to demonstrate improvement (> 50% ulcer area reduction) after a minimum of 4 weeks of standard ulcer therapy, adjunctive ulcer therapy options include negative pressure therapy, biologics (platelet-derived growth factor, living cellular therapy, extracellular matrix products, amniotic membrane products) and hyperbaric oxygen therapy. 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 (Grade 1B).
• Consideration of living cellular therapy using a bilayer keratinocyte/fibroblast construct or a fibroblast-seeded matrix for treatment of diabetic foot ulcers when the individual is recalcitrant to standard therapy (Grade 2B).
• Consideration of the use of extracellular matrix products employing acellular human dermis or porcine small intestinal submucosal tissue as an adjunctive therapy for diabetic foot ulcers when the individual is recalcitrant to standard therapy (Grade 2C).

Chronic DFUs and VLUs may be unresponsive to initial therapy or persist despite additional care. A DFU or VLU that has failed to respond to standard of care treatment after 30 days may be considered chronic and the application of a skin substitute graft or CTP may be considered medically reasonable and necessary for certain patients. Chronic DFUs and VLUs affect patient quality of life due to impaired mobility, pain, and substantial morbidity. 

Standard treatment of lower extremity chronic ulcers include, but is not limited to, mechanical offloading, infection control, mechanical compression, limb elevation, debridement of necrotic tissue, management of systemic disease and medications, nutrition assessment, tissue perfusion and oxygenation, appropriate dressings, education regarding the care of the foot, callus, and nail and fitting of shoes, and counseling on the risk of continued tobacco use. Nonhealing lower extremity ulcers should also have a vascular evaluation, including, but not limited to, documentation of ulcer location, size, depth, drainage, and tissue type; palpation of pedal pulses; and measurement of the ankle-brachial index.

In the absence of underlying disease or non-adherence to prescribed basic treatment, skin substitute graft/CTPs are recommended in accordance with evidence-based guidelines for the following: 1) DFUs that have failed to demonstrate more than 50% ulcer area reduction after a minimum of 30 days of standard of care ulcer treatment, and 2) VLUs if substantial ulcer improvement is not demonstrated after a minimum of 30 days of standard therapy.

An extensive variety of ulcer care products are available for providers to select from when treating chronic ulcers. Many of these products may simulate or substitute for some aspect of the skin’s structure and function to promote healing and ulcer closure. The materials used to create these products may be derived from human or animal tissue and may undergo extensive or minimal processing to generate the finished product. The degree of processing and the source of the material used in the product also governs which regulatory pathway may be required before the product may be marketed.

The regulation of tissue-engineered products in the U.S. occurs by one of several pathways established by the FDA, including a BLA, a 510(k) (Class I and Class II devices), PMA (Class III devices), or HCT/Ps (human cells, tissues, and cellular and tissue-based products) designation. Key differentiators among these regulatory classifications include the amount and type of data required to support a filing.

FDA has a tiered, risk-based approach to the regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). If all of the criteria in 21 CFR 1271.10(a) are met, and the exceptions in 21 CFR 1271.15 do not apply, then the HCT/P is regulated solely under section 361 of the Public Health Service Act (PHS Act) and the regulations in part 1271 (“361 HCT/P”), and FDA’s premarket review and approval are not required. If an HCT/P does not meet the criteria in 21 CFR 1271.10(a), and the exceptions in 21 CFR 1271.15 do not apply, the HCT/P is regulated as a drug, device, and/or biological product under the FFDCA and/or section 351 of the PHS Act, and FDA’s premarket review and approval are required.

Establishments that manufacture 361 HCT/Ps must register and list in FDA’s electronic Human Cell and Tissue Establishment Registration System (eHCTERS). Manufacturers self-designate their products as 361 HCT/Ps in the FDA’s eHCTERS system. Notably, pursuant to 21 CFR 1271.27(b), FDA acceptance of an establishment registration and HCT/P listing does not constitute an FDA determination that an establishment is in compliance with applicable rules and regulations or that the HCT/P is licensed or approved by FDA. The availability of a HCPCS code for a particular human cell, tissue, or cellular or tissue-based product (HCT/P) does not mean that that product is appropriately regulated solely under section 361 of the PHS Act and the FDA regulations in 21 CFR part 1271 (86 FR 42018).

Amniotic/chorionic-based products that are HCT/Ps as defined in 21 CFR 1271.3(d) must meet criteria in 21 CFR 1271 and 361 of the PHS Act. Manufacturers of HCT/Ps should consult with the FDA Tissue Reference Group (TRG) or obtain a determination through a Request for Designation (RFD) on whether their HCT/Ps are appropriately regulated solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271 (85 FR 86058). The HCT/Ps that are drugs are defined under section 201(g) of the FFDCA [21 U.S.C. 321(g)] and biological products are defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. To lawfully market a drug that is also a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after a showing of safety and efficacy for the product's intended use. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug (IND) application in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312].

The HCT/Ps which are more than minimally manipulated, or are intended for non-homologous use, may be subject to additional regulation as medical devices under the FFDCA, 21 U.S.C. section 301 et seq. (see 21 CFR section 1271.20). A manufacturer/distributor of HCT/Ps must register with the FDA as a "tissue establishment" and follow certain guidelines for designation of a product as an HCT/P (21 CFR sections 1271.10; 1271.21-22). The FDA imposes labeling requirements for HCT/Ps (refer to 21 CFR section 1271.370). The HCT/P labeling must include, inter alia, "instructions for use when related to the prevention of the introduction, transmission, or spread of communicable diseases," and "other warnings, where appropriate" (21 CFR section 1271.370(c)(3)-(4)).

The FDA acceptance of an establishment registration and HCT/P listing does not constitute a determination that an establishment is in compliance with applicable rules and regulations or that the HCT/P is licensed or approved by the FDA (21 CFR 1271.27(b)). To establish compliance with the FDA requires a letter from the FDA indicating that the HCT/P has met regulatory compliance under section 361 of the Public Health Service Act and/or the FFDCA.

Studies are lacking for many skin substitute grafts/CTPs which are essential to evaluate effectiveness and the impact that the product has on health outcomes. Available studies do not have a high level of evidence or even non-randomized prospective studies evaluating their effectiveness. The quality of current research for these products is moderate to low with high probability of publication bias and study limitations. Evidence is needed to show that the product(s) improve health outcomes or provide benefits relative to established alternatives or standard of care. Many of the current studies are noted to be funded by industry, which presents concerns regarding bias for these studies. The evidence to support skin substitute grafts is also challenged by the lack of high-quality studies, standard practices, huge variability in products and lack of consistency in care across providers. Additional investigation is clearly needed to understand the role of these products on a broader scale. This is best summarized by the AHRQ technology assessment of 22 RCTs revealing significant challenges within this literature, inadequate data, and a lack of robust, well controlled studies. In head-to-head comparative studies, 5/6 did not show a substantial difference between skin substitutes and outcomes measured up to 12 weeks follow-up. Most studies published since that time are low quality, lack comparative groups and at risk of bias with industry sponsorship. In areas where there is a paucity of evidence a service is considered investigational or experimental. 

Despite the paucity of quality studies, the moderate to low quality of current research, and the likelihood of bias, limited coverage has been provided to increase the chances of improved health outcomes of interest which include patient quality of life and function. Coverage will be provided for products which meet the necessary FDA regulatory requirements as of publication, and that act as a skin substitute graft/CTP providing scaffolding for skin growth, and are intended to remain on the recipient, and allow the recipient’s skin to grow into the implanted graft material. Products that require regular replacement (e.g., weekly) which do not act as a skin substitute graft/CTP are non-covered. These products act as coverings/dressings, are part of standard wound care, and do not provide active ulcer treatment by providing scaffolding and stimulating cell growth. In conclusion, there is no separate payment for the application of wound coverings or wound dressings, which are utilized to provide a physical barrier to protect the ulcer (wound) surface, prevent infection, and allow healing underneath, and are typically removed as the ulcer or chronic wound heals. Wound coverings (e.g. not anchored or applied surgically to ulcers to form scaffolding for skin growth) and are therefore not skin substitute grafts/CTPs.

In Armstrong et al propensity-matched Group 1 received AT with skin substitute grafts had 3.7 applications on average, with a standard deviation of 3.6. Based on this data, greater than four applications of a skin substitute graft or

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CTP within the episode of skin replacement surgery (defined as 12 weeks from the first application of a skin substitute graft or CTP) will not be considered medically reasonable and necessary. Product change within the episode of skin replacement surgery is allowed but in situations where more than one specific product is used, it is expected that the number of applications or treatments will still not exceed four.

Each skin substitute graft or CTP has specific designated approved usage. New products will be considered for coverage if meeting the regulatory requirements and criteria. Satisfactory evidence of FDA regulatory requirements include:

1) A copy of the FDA’s letter to the drug’s manufacturer approving the new drug application (NDA),

2) A listing of the drug or biological in the FDA’s “Approved Drug Products” or “FDA Drug and Device Product Approvals”

3) A copy of the manufacturer’s package insert approved by the FDA as part of the labeling of the drug, containing its recommended uses and dosage, as well as possible adverse reactions and recommended precautions in using it

4) A TRG letter from the FDA

5) Information from the FDA’s Website. For skin substitute graft or CTPs classified as HCT/Ps, a letter from the FDA indicating that the HCT/P has met regulatory guidance is acceptable evidence of the FDA regulatory compliance for HCT/Ps regulated under section 361 of the Public Health Service Act and/or the Federal Food, Drug, and Cosmetic Act.

It is recommended that the manufacturer of the particular skin substitute graft or CTP obtain the appropriate evidence of FDA regulatory compliance (at least one of the items listed above that indicates the skin substitute graft/CTP provides scaffolding for skin growth, and is intended to remain on the recipient, and allows the recipient’s skin to grow into the implanted graft material) and send it to the MAC along with any available peer reviewed evidence-based literature to support the medically reasonable and necessary criteria for the product(s). Once this information has been received by the MAC, the product will be considered for coverage.

Please refer to the related Local Coverage Article: Billing and Coding: Skin Substitute Graft for the Treatment of Diabetic Foot Ulcers and Venous Leg Ulcers (A56696) for documentation requirements, utilization parameters and all coding information as applicable.

This bibliography presents those sources that were obtained during the development of this policy. The Contractor is not responsible for the continuing viability of Website addresses listed below.

1. Snyder D, Sullivan N, Margolis D, Schoelles K. Skin substitutes for treating chronic wounds [Internet]. 2020
2. Frykberg R, Banks J. Challenges in the Treatment of Chronic Wounds. J Advances in wound care 2015; 4(9). https://www.liebertpub.com/doi/pdf/10.1089/wound.2015.0635?download=true.
3. Administration. USFaD. Premarket Notification 510(k). Secondary Premarket Notification 510(k). March 2020. https://www.fda.gov/medical-devices/premarket-submissions-selecting-and-preparing-correct-submission/premarket-notification-510k.
4. Marston W, Tang J, Kirsner RS, Ennis W. Wound Healing Society 2015 update on guidelines for venous ulcers. Wound Repair Regen 2016;24(1):136-44 doi: 10.1111/wrr.12394[published Online First: Epub Date]|.
5. https://www.fda.gov/news-events/press-announcements/fda-announces USFaDA. FDA announces comprehensive regenerative medicine policy framework. . Secondary FDA announces comprehensive regenerative medicine policy framework. 2017 Nov 15. https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework.
6. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63(2 Suppl):3S-21S doi: 10.1016/j.jvs.2015.10.003[published Online First: Epub Date]|.
7. Lavery LA, Davis KE, Berriman SJ, et al. WHS guidelines update: diabetic foot ulcer treatment guidelines. 2016;24(1):112-26
8. Marston W, Tang J, Kirsner RS, Ennis W. Wound Healing Society 2015 update on guidelines for venous ulcers. J Wound repair 2016;24(1):136-44
9. O'Donnell TF, Jr., Passman MA, Marston WA, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg 2014;60(2 Suppl):3S-59S doi: 10.1016/j.jvs.2014.04.049[published Online First: Epub Date]|.
10. Bueno J, Demirci F, Baser KHC. Antimicrobial Strategies in Novel Drug Delivery Systems: Applications in the Treatment of Skin and Soft Tissue Infections. The Microbiology of Skin, Soft Tissue, Bone and Joint Infections: Elsevier, 2017:271-86.
11. Rayman G, Vas P, Dhatariya K, Driver V, Hartemann A, Londahl M. IWGDF Guideline on interventions to enhance healing of foot ulcers in persons with diabetes. Secondary IWGDF Guideline on interventions to enhance healing of foot ulcers in persons with diabetes 2019. https://iwgdfguidelines.org/wp-content/uploads/2021/03/06-Wound-Healing-Guideline.pdf.
12. NICE. Chronic wounds: advanced wound dressings and antimicrobial dressings. Secondary Chronic wounds: advanced wound dressings and antimicrobial dressings 2016. https://www.nice.org.uk/advice/esmpb2/chapter/Key-points-from-the-evidence.
13. Pourmoussa A, Gardner DJ, Johnson MB, Wong AK. An update and review of cell-based wound dressings and their integration into clinical practice. Ann Transl Med 2016;4(23):457 doi: 10.21037/atm.2016.12.44[published Online First: Epub Date]|.
14. Administration. UFaD. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue- Based Products: Minimal Manipulation and Homologous Use-Guidance for Industry and Food and Drug Administration Staff. . Secondary Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue- Based Products: Minimal Manipulation and Homologous Use-Guidance for Industry and Food and Drug Administration Staff. July 2020. https://www.fda.gov/media/109176/download.
15. Schaper NC vNJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA; IWGDF Editorial Board. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020 36:Suppl 1:e3266. doi: doi:10.1002/dmrr.3266[published Online First: Epub Date]|.
16. (AHRQ). AfHRaQ. Evidence-based Practice Center Technical Brief Protocol. Project Title: Skin substitute graft for Treating Chronic Wounds. Secondary Evidence-based Practice Center Technical Brief Protocol. Project Title: Skin substitute graft for Treating Chronic Wounds 2018 (rev 2019). https://effectivehealthcare.ahrq.gov/products/skin-substitutes/protocol.
17. Evans K, Kim PJ. Overview of treatment of chronic wounds. Secondary Overview of treatment of chronic wounds 7/13/22. www.uptodate.com.
18. Panel CE. cpt 2023 In: Association AM, ed., 2023.
19. Game F, Gray K, Davis D, et al. The effectiveness of a new dried human amnion derived membrane in addition to standard care in treating diabetic foot ulcers: A patient and assessor blind, randomised controlled pilot study. International Wound Journal 2021;18(5):692-700
20. Santema TB, Poyck PP, Ubbink DT. Systematic review and meta-analysis of skin substitutes in the treatment of diabetic foot ulcers: Highlights of a Cochrane systematic review. Wound Repair Regen 2016;24(4):737-44 doi: 10.1111/wrr.12434[published Online First: Epub Date]|.
21. Jones JE NE, Al-Hity A. Skin grafting for venous leg ulcers. . Cochrane Database of Systematic Reviews 2013,;Art. No.: CD001737(1) doi: 10.1002/14651858.CD001737[published Online First: Epub Date]|.
22. Barbul A GG, Gordon H, Bakewell K, Carter MJ. Matched-cohort study comparing bioactive human split-thickness skin allograft plus standard of care to standard of care alone in the treatment of diabetic ulcers: A retrospective analysis across 470 institutions. . Wound Repair Regen 2020 28(1):81-89 doi: 10.1111/wrr.12767.[published Online First: Epub Date]|.
23. Cazzell S VD, 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 2017 25(3):483-97 doi: 10.1111/wrr.12551[published Online First: Epub Date]|.
24. Driver VR LL, Reyzelman AM, et al. . A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Repair Regen. 2015 23(6):891-900 doi: 0.1111/wrr.12357[published Online First: Epub Date]|.
25. Lavery LA FJ, Shebetka KA, et al. Grafix Diabetic Foot Ulcer Study Group. The efficacy and safety of Grafix®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. . Int Wound J. 2014 5:554-60 doi: 10.1111/iwj.12329[published Online First: Epub Date]|.
26. 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 management 2014;60(9):26-38
27. Zelen CM OD, Serena T, et al. I. . A prospective, randomised, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allogenic human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J 2017;14(2):307-15 doi: 10.1111/iwj.12600[published Online First: Epub Date]|.
28. Harding K SM, Cardinal M. . A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. . Int Wound J 2013;10(2):132-7 doi: 10.1111/iwj.12053[published Online First: Epub Date]|.
29. Armstrong DG, Tettelbach WH, Chang TJ, et al. Observed Impact of Skin Substitutes in Lower Extremity Diabetic Ulcers: A Retrospective Analysis of a Medicare Limited Database (2015-2018). 2021
30. Tettelbach W, Cazzell S, Reyzelman AM, Sigal F, Caporusso JM, Agnew PS. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: a prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics. International wound journal 2019;16(1):19-29
31. Tettelbach W, Cazzell S, Sigal F, et al. A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. International wound journal 2019;16(1):122-30
32. Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. International wound journal 2016;13(2):272-82
33. Serena TE CM, Le LT, Sabo MJ, DiMarco DT; EpiFix VLU Study Group. A multicenter, 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;22:668-93 doi: 10.1111/wrr.12227[published Online First: Epub Date]|.
34. Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix®) allograft for the treatment of venous leg ulcers. International wound journal 2018;15(1):114-22
35. Snyder RJ, Shimozaki K, Tallis A, et al. A Prospective, Randomized, Multicenter, Controlled Evaluation of the Use of Dehydrated Amniotic Membrane Allograft Compared to Standard of Care for the Closure of Chronic Diabetic Foot Ulcer. Wounds: a compendium of clinical research and practice 2016;28(3):70-77
36. Glat P OD, Galiano R, et al. . Placental Membrane Provides Improved Healing Efficacy and Lower Cost Versus a Tissue-Engineered Human Skin in the Treatment of Diabetic Foot Ulcerations. . Plast Reconstr Surg Glob Open 2019;7(8):e2371. doi: 10.1097/GOX.0000000000002371[published Online First: Epub Date]|.
37. Serena TE, Orgill DP, Armstrong DG, et al. A Multicenter Randomized Controlled Clinical Trial Evaluating Two Application Regimens of Dehydrated Human Amniotic Membrane and Standard of Care vs Standard of Care Alone in the Treatment of Venous Leg Ulcers. Plastic and Reconstructive Surgery 2022
38. Manning SW HD, Shillinglaw WR, et al. . Efficacy of a Bioresorbable Matrix in Healing Complex Chronic Wounds: An Open-Label Prospective Pilot Study. Wounds. 2020;;32(11):309-18
39. DiDomenico LA, Orgill DP, Galiano RD, et al. Aseptically processed placental membrane improves healing of diabetic foot ulcerations: prospective, randomized clinical trial. Plastic and Reconstructive Surgery Global Open 2016;4(10)
40. DiDomenico LA, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: a prospective, randomised, multi-centre clinical trial in 80 patients. International wound journal 2018;15(6):950-57
41. Raspovic KM, Wukich DK, Naiman DQ, et al. Effectiveness of viable cryopreserved placental membranes for management of diabetic foot ulcers in a real world setting. Wound Repair and Regeneration 2018;26(2):213-20
42. Frykberg RG, Gibbons GW, Walters JL, Wukich DK, Milstein FC. A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane. International wound journal 2017;14(3):569-77
43. Sledge I, Maislin D, Bernarducci D, Snyder R, Serena TE. Use of a dual-layer amniotic membrane in the treatment of diabetic foot ulcers: an observational study. Journal of Wound Care 2020;29(Sup9):S8-S12
44.  NICE. Diabetic foot problems: Prevention and management (NICE Guideline NG19). 2019