A Guide to Tissue-Engineered Skin Substitutes

January 2018 | Volume 17 | Issue 1 | Original Article | 57 | Copyright © 2018

Penelope J. Kallis BS BA,a Adam J. Friedman MD,b and Hadar Lev-Tov MD MASa

aDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL bDepartment of Dermatology, George Washington School of Medicine and Health Sciences, Washington, DC

Abstract

Wounds that exhibit delayed healing have a tremendous impact on health care expenditures and place patients at serious risk for severe complications including death. The healing of a chronic wound requires the restoration of multiple factors that normally work in concert to repair the damaged skin barrier. Skin substitutes have shown great promise for use as adjunctive therapies for refractory wounds by providing cells, soluble mediators, and extracellular matrix materials needed to stimulate healing. There are a growing variety of skin substitutes available on the market with many indications, and appropriate selection can impact healing outcomes. Skin substitutes can be broadly divided into cellular and acellular devices, yet within these categories, each product has its own unique composition and mechanism for promoting healing. Here we summarize the characteristics and indications of cellular and acellular matrices commonly used in wound care with the most evidence supported by randomized control trials and prospective studies. This review aims to provide dermatologists and other wound care clinicians with a helpful guide on how to approach skin substitutes, from preparing the wound bed for application, to making the proper selection for patients’ individual wounds.

J Drugs Dermatol. 2018;17(1):57-64.

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INTRODUCTION

In recent years chronic wounds have assumed epidemic proportions, significantly affecting patients’ quality of life, adding an enormous burden to healthcare systems and in some cases resulting in mortality rates similar to common types of cancer.1-4 Decubitus ulcers, venous leg ulcers, neuropathic ulcers and ulcers resulting from peripheral arterial disease are the most common types of ulcers.5 Despite the magnitude of the problem, years of investigation and significant resources invested in research, the exact pathophysiology of these wounds is not clear. Wound healing is a complex process, involving interactions between various cell types, cytokines, growth factors, proteases, and extracellular matrix (ECM) materials.6 The healing process takes place in a series of four overlapping phases: hemostasis, inflammation, proliferation, and remodeling with scar formation.7 Chronic wounds occur when a wound fails to progress normally through each these four phases. In fact, chronic wounds have been found to exhibit elevated levels of pro-inflammatory cytokines, high protease activity, and diminished growth factor activity at the molecular level when compared to acute wounds, stalling in the first phase and creating a hostile wound environment that is not conducive to healing.6 Tissue-engineered skin substitutes are a promising option for the treatment of chronic wounds that fail to heal with standard wound care (SWC) alone.8 This article outlines the characteristics and indications for some commonly used, well-studied, and commercially available skin substitutes to help expand the dermatologist’s armamentarium of therapies for nonhealing wounds (Figure 1).How Skin Substitutes Support HealingSkin substitutes are thought to provide matrix materials, cells, and other key healing elements that may be missing in chronic wounds, without the requirement of a donor site.9 They can be derived from biological sources, manufactured synthetically, or a combination of the two.10 Tissue-engineered skin is not meant to persist as permanent wound coverage but is instead biodegradable and replaced by the recipient’s own tissue.11,12Skin substitutes reviewed here can be broadly categorized into those containing cells and those without cells.12 Acellular matrices are made of materials similar to host ECM and function as scaffolds, allowing the patient’s own fibroblasts and endothelial cells to migrate in, repopulate, and synthesize a new connective tissue matrix to replace it.13,14 Compared to cellular matrices, acellular ones are typically easier to produce, less expensive and easier to store. Cellular matrices contain viable cells seeded onto the matrix material. The cells secrete cytokines and growth factors necessary to promote fibrovascular ingrowth and epithelialization.15,16 The source of cells in these products tends to be derived from human neonatal foreskin, due to their decreased immunogenicity and increased responsiveness to mitogens compared to adult cells.11,15 The amniotic membrane has also been utilized as cellular matrix source. It is comprised of a single layer of epithelial cells, with properties similar to stem cells, a thick basement membrane, which acts as the scaffolding material, and an avascular stroma. Amniotic membranes additionally are believed to have anti-inflammatory, anti-microbial, anti-fibrotic, and anti-scarring effects.17 Regardless of the product, the exact mechanism by which each skin substitute produces its positive effects on chronic wounds is not clear. Some emerging evidence suggests that at least in venous leg ulcers, skin substitutes revert the wound bed into an acute wound environment to promote healing.18

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