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
