# Decellularized Scaffolds for Skin Repair and Regeneration
###### Abstract  
The skin is the largest organ in the body, fulfilling a variety of functions and acting as a barrier for internal organs against external insults. As for extensive or irreversible damage, skin autografts are often considered the gold standard, however inherent limitations highlight the need for alternative strategies. Engineering of human-compatible tissues is an interdisciplinary and active field of research, leading to the production of scaffolds and skin substitutes to guide repair and regeneration. However, faithful reproduction of extracellular matrix (ECM) architecture and bioactive content capable of cell-instructive and cell-responsive properties remains challenging. ECM is a heterogeneous, connective network composed of collagens, glycoproteins, proteoglycans, and small molecules. It is highly coordinated to provide the physical scaffolding, mechanical stability, and biochemical cues necessary for tissue morphogenesis and homeostasis. Decellularization processes have made it possible to isolate the ECM in its native and three-dimensional form from a cell-populated tissue for use in skin regeneration. In this review, we present recent knowledge about these decellularized biomaterials with the potential to be used as dermal or skin substitutes in clinical applications. We detail tissue sources and clinical indications with success rates and report the most effective decellularization methods compatible with clinical use. skin repair; wound healing; decellularization; scaffolds; skin tissue engineering; skin alternate; biomaterial; skin regeneration +
Footnote †: journal: Medical  
layer, constituting the lower part of the dermis, has a denser and thicker ECM network with fewer nerve fibers and capillaries. In this sublayer, collagen fibers are aggregated into thick bundles that are largely aligned parallel to the skin surface [6; 7]. Beneath the reticular dermis is the adipose tissue, which provides insulation from heat and cold and performs endocrine functions involved in food intake, glucose homeostasis, lipid metabolism, inflammation, and angiogenesis. Recent findings henceforth discriminate the dermal white adipose tissue, which consists of intradermal pre-adipocyte and adipocyte populations, from the subcutaneous white adipose tissue [8]. Damage or loss of integrity of the skin caused by wounds may impair the functions of the skin to varying extents. Wounds can be caused by mechanical trauma, surgical procedures, reduced blood circulation, burns, or aging. Most skin wounds can heal naturally through dynamic and interactive processes, which involve soluble factors, blood elements, ECM components, and cells [9]. However, in cases of extensive or irreversible damage, surgical strategies are often needed to provide immediate skin coverage using skin substitutes or scaffolds to guide repair and regeneration. This scenario is typical for chronic wounds that do not proceed through the normal phases of wound healing for multifactorial reasons [10]. A chronic wound may enter a persistent inflammatory state and perpetual non-healing state characterized by chronicity and frequent relapses. A number of pathophysiological factors can cause a failure of normal wound healing, including inflammation, infection, malnutrition, age, diabetes, tissue maceration, pressure necrosis, and renal impairment [11; 12; 13]. The restoration of dermis requires three-dimensional (3D) scaffolds to provide elasticity and strength to the epidermal graft and to feed the keratinocytes in the epidermal layer. Thus, one crucial factor in skin tissue engineering is the construction of a tissue scaffold that serves as a template to guide restructuring of cells and subsequent host infiltration of the graft. In the case of important tissue injury or disease, tissue autografts are often considered the gold standard, but inherent limitations including donor site morbidity, low availability, and troubling failure rates highlight the need for alternative strategies [14; 15].