The Skin I Live In Subtitle

[Autumn Pitz]

Properwound care starts with patient and wound assessment. Medical comorbidities (diabetes, kidney disease, coronary artery disease, peripheral artery disease, and other conditions) must be addressed. Wound related conditions such as infection, or vascular problems are also addressed.1

A large number of dressings are available to treat chronic wounds. Wound dressings include nonadherent dressings that allow wound exudate to pass through into a secondary dressing while helping to maintain a moist wound environment, hydrocolloid dressings that absorb exudate and maintain a moist wound environment, foam dressings also absorb exudate and maintain a moist wound environment, alginate dressings made from natural polysaccharides derived from brown seaweed form a gel on contact with exudate, hydrofiber dressings made of sodium carboxymethylcellulose fibers absorb large amounts of exudate while forming a gel, and hydrogel sheets that provide moisture to dry wounds.2

A standard of care regimen featuring weekly to monthly wound assessments, infection control, debridement, and dressings that maintain a moist wound environment has been recommended by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine.3 Despite standard care and moisture retaining wound dressings, many chronic wounds do not heal. For diabetic foot ulcers, failure to show more than 50% wound area reduction in 4 weeks, indicates the need for adjunctive wound therapy.3 Adjunctive therapy may include negative pressure therapy, hyperbaric oxygen therapy, or biologics such as bioengineered cellular therapies, extracellular matrix products, and amniotic membrane products.

The skin substitutes included in the earlier evidence report are a broad collection of various combinations of cellular and acellular components, both human and animal derived, intended to stimulate the host to regenerate lost tissue and replace the wound with functional skin.2 Cellular therapies, also called bioengineered cellular therapies provide skin cells (fibroblasts, keratinocytes or both) to create a source of growth factors, cytokines, and enzymes that promote tissue regeneration.4 Natural and synthetic material, such as collagen and polyglactin, respectively, may be used to create the extracellular matrix for tissue ingrowth. Acellular products provide an extracellular matrix devoid of cells and composed of a collagen substrate or other material into which cells can migrate and initiate tissue regeneration. Beyond being merely a scaffold, the extracellular matrix may also have an active role in stimulating tissue growth.1 The broad category of skin substitutes may have the potential to stimulate chronic wound healing and reduce the medical burden these wounds create.

This Technical Brief will describe the various products commercially available in the United States that may be considered skin substitutes, examine systems used to classify skin substitutes, identify and assess randomized controlled trials evaluating skin substitutes published since the 2012 AHRQ report Skin Substitutes for Treating Chronic Wounds, and suggest the best practices that should be part of any future studies evaluating skin substitutes.

The KIs will have expertise in one or more of the following areas: chronic wound care including wound assessment technologies, wound care research, tissue engineering, dermatology, and reconstructive surgery. We will ask for KI input to refine the systematic literature search, identify grey literature resources, provide information about ongoing research, discuss evidence limitations, and recommend approaches to help fill these evidence gaps. KI input will be helpful for informing Guiding Questions 3, 4, and 6. Table 1 presents potential questions that we will ask the KIs.

ECRI will follow the draft grey literature protocol developed by the EPC Librarian Working Group. This includes review organizations, clinical trial registries, regulatory agencies, and Google. Secondary sources such as Epistemonikos, TRIP and the Cochrane Library will also be included in the search. Since the scope of this project includes evaluating classification of skin substitutes as well as evidence, ECRI's searches will include the classifications used by the U.S. FDA, Health Canada, and other controlled vocabularies used to index biomedical literature. Date limits and platforms for these sources are listed in Table 2. For this technical brief, grey literature will be most helpful for addressing Guiding Questions 1, 2, 5, and 6.

Searches will be limited to randomized controlled trials, systematic reviews, and meta-analyses published since 2012, the publications date of the evidence report "Skin Substitutes for Treating Chronic Wounds."2 Literature searches will be updated during the Peer Review process, before finalization of the review. Literature searches may also be expanded to include additional study designs (e.g., prospective non-randomized comparison studies) if preliminary searches identify insufficient evidence (

Table 4 displays our proposed strategy in Embase.com syntax. We will translate the strategies for the Wiley, EBSCO, and PubMed platforms. Since searching is an iterative process, there may be differences between this initial proposed strategy and that included in the final version of this report.

'acellular dermal matrix'/exp OR 'artificial skin'/exp OR 'biological dressing'/exp OR 'engineered cartilage graft'/exp OR 'engineered skin autograft'/exp OR 'tissue engineering'/exp OR 'tissue scaffold'/exp

S6 AND ([english]/lim AND [humans]/lim AND [2012-2018]/py) NOT (abstract:nc OR annual:nc OR book/de OR 'case report'/de OR conference:nc OR 'conference abstract':it OR 'conference paper'/de OR 'conference paper':it OR 'conference proceeding':pt OR 'conference review':it OR congress:nc OR editorial/de OR editorial:it OR erratum/de OR letter:it OR note/de OR note:it OR meeting:nc OR sessions:nc OR 'short survey'/de OR symposium:nc)

Literature screening will be performed using the database Distiller SR (Evidence Partners, Ottawa, Canada). Literature search results will initially be screened for relevancy. Relevant abstracts will then be screened by a single reviewer based on eligibility criteria listed in Table 5. Studies that appear to fit the scope of the brief will be retrieved in full and screened again. Studies will be included if they address a guiding question; present data on patients with chronic wounds being treated with a skin substitute commercially available in the U.S.; and administer similar standard of care to all individuals enrolled in the study. Questions regarding inclusion will be resolved by the principal investigator. This process will be repeated if additional evidence is identified in updated literature searches.

Systematic review of randomized controlled trials (RCTs) or individual RCTs. If Study quality assessment for systematic reviews will be based on the author's risk-of-bias assessment. Study quality assessment for individual studies will be conducted in duplicate using risk-of-bias criteria based on Viswanathan et al. 20185 and emphasizing criteria important to chronic wound care management.

For Guiding Questions 1 and 2, we will categorize skin substitutes by FDA regulatory classifications identified in the grey literature, by classification systems identified in the literature, and by systems suggested by clinical experts among the Key Informants. We will extract information on product descriptions to determine distinguishing features of these products. Results from the screening of clinical evidence from the published literature will inform Guiding Questions 3, 4 and 6. Information on patient characteristics, wound treatments, and outcomes assessed will be stratified by wound types. A summary sentence for each included investigation will be provided. Ongoing clinical trials sourced from the grey literature and KI input on best practices will help inform Guiding Question 5 and 6.

A list of FDA-regulated skin substitutes and ongoing trials as well as data abstracted from clinical studies will be presented in evidence tables. Distinguishing features of skin substitute classifications and a summary of published evidence will be displayed graphically in an evidence map.

1. What skin substitutes currently used to treat chronic wounds are being regulated by the U.S. Food and Drug Administration (FDA) under the following pathways: PMA, 510(k), PHS 361[21 CFR 1270 and 1271]?

FDA requested that we remove any reference to FDA regulatory procedures that may pertain to skin substitutes. The fact that a skin substitute is commercially available is not a reflection of its legal status.

For Guiding Questions 1 and 2, we will categorize skin substitutes by FDA regulatory classifications identified in the grey literature, by classification systems identified in the literature, and by systems suggested by clinical experts among the Key Informants.

Commercially available skin substitute products regulated by the FDA (Premarket Approval, 510(k) marketing clearance, and Human cells, tissues, and cellular and tissue-based products).

Non FDA-regulated skin substitutes

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