text: Human skin is the first line of defense against many pathogens and can itself be subject to a variety of diseases and issues, such as cancers and inflammation. As such, skin-on-a-chip (SoC) applications include testing of topical pharmaceuticals and cosmetics, studying the pathology of skin diseases and inflammation, and "creating noninvasive automated cellular assays" to test for the presence of antigens or antibodies that could denote the presence of a pathogen. Despite the wide variety of potential applications, relatively little research has gone into developing a skin-on-a-chip compared to many other organ-on-a-chips, such as lungs and kidneys. Issues such as detachment of the collagen scaffolding from microchannels, incomplete cellular differentiation, and predominant use of poly(dimethysiloxane) (PDMS) for device fabrication, which has been shown to leach chemicals into biological samples and cannot be mass-produced stymie standardization of a platform. One additional difficulty is the variability of cell-culture scaffolding, or the base substance in which to culture cells, that is used in skin-on-chip devices. In the human body, this substance is known as the extracellular matrix.
  The extracellular matrix (ECM) is composed primarily of collagen, and various collagen-based scaffolding has been tested in SoC models. Collagen tends to detach from the microfluidic backbone during culturing due to the contraction of fibroblasts. One study attempted to address this problem by comparing the qualities of collagen scaffolding from three different animal sources: pig skin, rat tail, and duck feet. Other studies also faced detachment issues due to contraction, which can problematic considering that the process of full skin differentiation can take up to several weeks. Contraction issues have been avoided by replacing collagen scaffolding with a fibrin-based dermal matrix, which did not contract. Greater differentiation and formation of cell layers was also reported in microfluidic culture when compared to traditional static culture, agreeing with earlier findings of improved cell-cell and cell-matrix interactions due to dynamic perfusion, or increased permeation through interstitial spaces due to the pressure from continuous media flow. This improved differentiation and growth is thought to be in part a product of shear stress created by the pressure gradient along a microchannel due to fluid flow, which may also improve nutrient supply to cells not directly adjacent to the medium. In static cultures, used in traditional skin equivalents, cells receive nutrients in the medium only through diffusion, whereas dynamic perfusion can improve nutrient flow through interstitial spaces, or gaps between cells. This perfusion has also been demonstrated to improve tight junction formation of the stratum corneum, the tough outer layer of the epidermis, which is the main barrier to penetration of the surface layer of the skin.
  Dynamic perfusion may also improve cell viability, demonstrated by placing a commercial skin equivalent in a microfluidic platform that extended the expected lifespan by several weeks. This early study also demonstrated the importance of hair follicles in skin equivalent models. Hair follicles are the primary route into the subcutaneous layer for topical creams and other substances applied to the surface of the skin, a feature that more recent studies have often not accounted for.
  One study developed a SoC consisting of three layers, the epidermis, dermis, and endothelial layer, separated by porous membranes, to study edema, swelling due to extracellular fluid accumulation, a common response to infection or injury and an essential step for cellular repair. It was demonstrated that pre-application of Dex, a steroidal cream with anti-inflammatory properties, reduced this swelling in the SoC.