From ancient Egypt to the dermatologic office: An overview of skin substitutes and modern‐day applications in dermatologic surgery

Abstract Skin grafting (specifically xenografting) dates back to as early as 1500 before Christ (BC) in the Ebers papyrus, an Egyptian medical papyrus. In 1503, the use of human skin allograft was described in the manuscript of Branca of Sicily, and among the Hindu Tilemaker Caste approximately 2500–3000 years ago, surgeons repaired defects secondary to nose amputations of those who committed adultery and thievery. Over the years, many advancements in skin grafts/substitutes and their applications have propelled the field to focus on better graft survival, contracture prevention, cosmesis, and quality of life. We provide a general overview of skin substitutes (SS) with a particular focus on placental SS and their current applications in dermatologic surgery.

grafts such as xenografts and allografts. Xenografts are derived from animals, with porcine and bovine being the most commonly used.
They are successful in treating exposed bone, tendons, and cartilage by creating dermal regeneration and restoration while still maintaining the integrity and mobility of the existing area. Allografts are sourced from humans and can be further divided into dermal, epidermal, and composite allografts.
Alternatively, SS can be classified based on durability (temporary/permanent) ( Table 2) and type (synthetic/biological). Recently, there has been a push toward establishing a universal classification system inspired by factorial design, whereby an algorithm is used to search for a SS with consideration of multiple factors: (1) cellularity (acellular or cellular), (2) layering (single layer or bilayer), (3) targeted area of skin to be replaced (dermal, epidermal or both), (4) materials used (synthetic, biological or both), and (5) permanence (temporary or permanent). 4

| Synthetic SS
Synthetic SS (SSS) are comprised of stable biodegradable immunocompatible polymers that provide three-dimensional structural support and an environment conducive to tissue regeneration.
Ideally, they should last for at least 3 weeks to allow for neovascularization, fibroblast, and epithelial cells formation followed by natural biodegradation. 2 SSS have an advantage of precision/ control and enhanced effect depending on additive growth factors and matrix components with the additional benefit of reduced risk for disease transmission. 2 However, they may not be as useful when trying to produce a biologically compatible material as they typically lack basement membranes, and thus do not resemble native skin. Table 3 outlines some of the currently available SSS in the market.

| Biological SS
Biological SS (BSS) have a more intact extracellular matrix (ECM) structure and a basement membrane, which allows for a more natural dermis and re-epithelialization. They have the advantage of being relatively less expensive and more abundant in supply than synthetic substitutes. However, due to its natural components, there may be issues with revascularization in comparison to synthetic substitutes.
The most common BSS used are porcine skin xenograft, skin allograft, and amnion 2 ( Table 4). Xenografts are used to temporarily cover wounds and will not revascularize. Allografts are cadaveric skin grafts that are used to prepare a wound bed for autografting and have an initial revascularization period. Autografts are taken from the patient and have the advantage of permanent skin healing through antigenic compatibility. CEAs are prepared from isolated keratinocytes from a full-thickness skin biopsy and then incorporated and expanded into a neoepidermis. Dermal substitutes are obtained from cadaveric allografts and are comprised of a matrix of glycosaminoglycans and collagen. 5 More recently, multilayered substitutes have garnered some attention. They are typically prepared from a dermal-epidermal junction biopsy, in which a suspension composed of autologous keratinocytes, fibroblasts, and melanocytes is sprayed onto a wound.
The silicone sheet, which is composed of collagen and glycosaminoglycans, serves as an epidermis that encourages neovascularization T A B L E 1 Kumar's three category system

| PLACENTAL SS IN DERMATOLOGY
The placenta is a specialized organ that serves as a materno-fetal interface enabling the transfer of nutrients, gases, hormones, and cytokines, including insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor-2, vascular endothelial growth factor, and transforming growth factorβ. 8 The placenta is composed of three layers; the innermost amniotic layer surrounds the embryo/fetus and consists of a single-celled epithelial layer firmly fixed to a deeper collagen containing mesodermal layer, the middle allantois layer is rich in blood supply, and the outermost chorion which comes into contact with the endometrium and consists of trophoblastic and mesenchymal tissue. 9 Placental tissue effectively supports wound healing through a rich ECMcontaining proteins (collagens I, III, IV, VI, proteoglycans, glycoproteins), growth factors, cytokines, and viable endogenous cells and mesenchymal stem cells that help facilitate the wound-healing process. 10,11 Further, these various components impact cell differentiation, hormone/protein production, and basement membrane remodeling. 10 Such properties are beneficial for the treatment of complex, chronic, nonhealing burns, ulcers, and wounds.
The amnion is the dominant membrane used in placental skin substitutes (PSS) due to ease of separation and purification compared to the chorion. 12 Further, the amnion has antibacterial, antiinflammatory, and antiscarring properties. 13   tissue can support rapid tissue repair and affects all phases of wound healing and tissue remodeling. Additionally, there is potential for achieving great cosmesis, which is not only determined by timely wound debridement and treatment but also due to no risk of PSS rejection and its unique antifibrotic and anti-inflammatory properties.
The major limitations of placental tissue use include costly treatments, ethical concerns regarding repurposing human tissue, patient preference and lack of clinical trials and randomized control studies with sufficient data demonstrating its effectiveness.
Although there has not yet been a "perfect" SS developed, the current array of available SS has greatly broadened the arena for dermatologists aiming to heal substantial wounds. Having a background knowledge of what they are, how they were derived, their applications in medicine, and their flaws can allow for the most effective and productive use of SS in dermatology.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article.

TRANSPARENCY STATEMENT
The lead author Alison Tran affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.