Skin Substitutes for Treating Chronic Wounds Advances

At the request of the Centers for Medicare and Medicaid Services (CMS), the ECRI Institute-Penn Medicine Evidence-Based Practice Center (ECRI-Penn EPC), under contract to the Agency for Healthcare Research and Quality (AHRQ), conducted research on skin substitutes. Systematic reviews are developed by the EPC (AHRQ sponsored) to assist public and private organizations to improve US health care quality. The findings from the EPC evidence are expected to provide appropriate information to inform individual health care plans, US health care system, purchasers, and health care providers.¹

In this technical brief, various products are outlined, systems used to classify skin substitutes are examined, the clinical literature evaluating skin substitutes published after the 2012 AHRQ report Skin Substitutes for Treating Chronic Wounds was identified and assessed, and best practices to consider for future studies were suggested.¹

Defining “Skin Substitutes”

The researchers’ definition of a “skin substitute” encompassed what the products should accomplish in a way that may enhance wound healing potential beyond the SOC. For their review, the researchers considered skin substitutes to be a “heterogeneous group of biological and/or synthetic elements that enable temporary or permanent occlusion of wounds” with a common objective of achieving the greatest possible similarity with the patient’s skin and “have functional and structural characteristics that closely match those of autologous skin.”¹

Conducting the Review

To conduct their review, the investigators searched EMBASE, MEDLINE, PubMed, and CINAHL databases for systematic reviews/meta-analyses, randomized controlled trials (RCTs), and prospective nonrandomized comparative studies examining commercially available skin substitutes in individuals with diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers (PUs), and arterial leg ulcers.

The researchers extracted data on clinical outcomes, such as complete wound healing, rate of healing, and wound recurrence. They compared study eligibility criteria and outcomes measured between included studies and ongoing clinical trials registered in ClinicalTrials.gov to identify trends.

In addition to a systematic search of the published literature and grey literature since 2012, the researchers also received scientific packets from manufacturers during AHRQ’s call for Supplemental Evidence and Data for Systematic Reviews from March 25, 2019, to April 29, 2019.

Experts in the study and treatment of chronic wound healing were also interviewed to help identify classification systems to categorize the skin substitutes, guide study eligibility criteria, describe limitations in the current field, and recommend best practices for designing future studies.

Results of the Review

The researchers identified 76 commercially available skin substitutes and categorized them based on the Davison-Kotler classification system, which emphasizes cellularity as the primary discriminator. Of those 76 skin substitutes, 68 products (89.5%) were categorized as acellular dermal substitutes, mostly replacements from human placental membranes and animal tissue sources.

Using the modified Davison-Kotler classification system, studies will have examined acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes. Ongoing studies continue the trend of examining acellular dermal substitutes, mostly replacements from human placental membranes. Registries specific to wound care may provide additional effectiveness and harm data on the use of skin substitutes for DFUs, VLUs, and PUs.

The studies identified through the literature search and SEADS submissions resulted in a total of 245 studies. After screening, only 22 RCTs met the required study design characteristics. Findings showed that in the 22 RCTs, 16 (21.1%) of the 76 distinct skin substitutes were examined. Of the 22 RCTs, 9 RCTs (40.9%) met the primary endpoints and were considered low risk of bias. In the 9 RCTs remaining, 6 distinct skin substitutes were examined; of those, 1 skin substitute (dehydrated human amnion/chorion membrane) was examined in 4 RCTs (44.4%).

The SOC in these studies for each wound type included sharp debridement, glucose control, compression bandages for VLUs, pressure redistribution support surfaces for PUs, infection control, offloading, and daily dressing changes with a moisture-retentive dressing, such as an alginate or hydrocolloid.

While 85% of studies examining acellular dermal substitutes described the experimental intervention as favorable over the SOC for wound healing and shorter time to heal, insufficient data were available to determine whether wound recurrence or other sequela are less frequent with acellular dermal substitutes.

Only 3 studies compared cellular dermal substitutes with the SOC. The researchers said clinical evidence for cellular dermal substitutes may be limited by the lack of robust, well-controlled clinical trials of these products in this category.

In addressing evidence gaps, the researchers noted most studies examined treatment options for DFUs. More studies are needed on the treatment options for VLUs, PUs, and other chronic wounds to determine whether skin substitutes should be considered as an appropriate therapy for these wounds.

Although manufacturers argue that their respective skin substitute product (of the 76 commercially available) enhances wound healing outcomes, it is important to remember that all processing methods differ between manufacturers. However, this argument cannot be substantiated without robust, high-quality studies. The researchers agreed RCTs comparing different types of product categories—as well as studies within categories—are needed.

Conclusions

Based on the results of their review, the researchers found the evidence currently available in the published literature may not be sufficient enough to support the superiority of one skin substitute over another.  

The researchers noted the clearest implications of the technical brief are the lack of studies examining the effectiveness of most skin substitute products and the need for better-designed and better-reported studies providing more clinically relevant data. Studies rarely reported clinical outcomes such as amputation, wound recurrence at least 2 weeks after treatment ended, or patient- or wound-related outcomes, such as return to function, pain, exudate, and odor.

Experts had noted comparisons across studies may be enhanced by standardizing approaches for inclusion criteria (such as wound size, wound duration pre-enrollment, and wound severity) by the following: using a 2- to 4-week run-in period before study enrollment and a 12-week study period, reporting wound recurrence up to 6 months as well as wounds healed during the study, and blinding wound assessment.

Expanding inclusion criteria to include patients more representative of clinical practice and of poorer health than typical patients included in RCTs was suggested by the experts. This expansion to include real-world patient representation would allow a subanalysis of sex, race, ethnicity, age, and comorbidities that may help direct specific product use for different wound conditions.

They also suggested that failure to heal after 6 weeks of treatment with a skin substitute product may be an appropriate criterion for discontinuing the use of a skin substitute and switching to another advanced therapy option. Experts suggested that 40% to 50% wound closure in 4 weeks was a good predictor of complete wound closure.

— Carol Brzozowski

Reference

1. Snyder DL, Sullivan N, Margolis D, Schoelles K. Skin Substitutes for Treating Chronic Wounds. Rockville, MD: Agency for Healthcare Research and Quality (US); February 2020. https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id109TA.pdf