![]() Both reconstructed human epidermis (RHEm) and full-thickness skin models (FTSm) have been used for many applications including basic, pharmacological and cosmetic research. These models can be assembled into complex structures to simulate more physiologically relevant conditions. Recently, 3D cell culturing techniques have improved the relevance of the available models and demonstrated the synergistic effects that different cell types have on each other. The combinatory effect of the high prevalence of skin diseases, R&D decline and restrictions on animal testing pressured the development of physiologically relevant skin models that could replace conventional, inefficient approaches. In 2013, a full marketing ban was put in place for all human health effects tested in animals, including repeated-dose toxicity, reproductive toxicity and toxicokinetics, irrespective of the availability of alternative non-animal tests. The European Centre for the Validation of Alternative Methods (ECVAM) was established in 2010 as a reference laboratory for researching and validating alternative methods, following 3R principles. Since 2009, the European Commission has been approving regulations on cosmetics, establishing a testing and marketing ban: a prohibition against testing finished cosmetic products or ingredients on animals and commercializing any cosmetic product or ingredient that has been tested on animals within the European Union. The cosmetic industry has been greatly affected by the restrictions imposed on animal testing. Ethical guidelines dictate that, where possible, animal experimentation should be replaced, reduced, or refined (3R principle). ![]() įrom an ethical perspective, the replacement of animal models satisfies a growing societal concern regarding animal experimentation. ![]() These flaws in the conventional testing methods result in a lack of correlation between the input (drug candidates) and output (approved drugs), contributing to the R&D decline. Moreover, animal models suffer from low throughput and interspecies variability. However, mouse skin is structurally and functionally different from human skin it is thinner, contains more hair follicles, includes fewer keratinocyte layers, presents decreased barrier function and greater absorption. During the development of pharmaceutical skin-targeted formulations, mouse models are often mandatory for in vivo translational research. On the other hand, in vivo animal models offer information on systemic effects but cannot replicate human skin anatomy and physiology. The lack of a 3D physiological tissue environment greatly minimizes the models’ physiological relevance and applicability. While these models offer a rapid, reproducible system to study drug responses, they are not good predictors of the complex interactions seen in vivo. Most commonly, in vitro cell culture relies on two-dimensional (2D) cell culture systems, typically monolayers of epidermal keratinocytes and/or dermal fibroblasts. Finally, this review highlights the current challenges that need to be overcome for the clinical translation of SoC devices.Ĭonventional preclinical drug testing relies on in vitro cell cultures and animal models. ![]() Recent advancements in SoC devices are here presented, and their main achievements and drawbacks are compared and discussed. Technical (e.g., SoC fabrication and sensor integration) and biological (e.g., cell sourcing and scaffold materials) aspects are discussed. In this Review, the major challenges and key prerequisites for the creation of physiologically relevant SoC devices for drug testing are considered. Moreover, integrating sensors on the SoC device allows real-time, non-destructive monitoring of skin function and the effect of topically and systemically applied drugs. Importantly, contrary to conventional cell culture techniques, SoC devices can perfuse the skin tissue, either by the inclusion of perfusable lumens or by the use of microfluidic channels acting as engineered vasculature. These devices allow the simulation of key mechanical, functional and structural features of the human skin, better mimicking the native microenvironment. One of the most promising approaches is the use of in vitro microfluidic systems to generate advanced skin models, commonly known as skin-on-a-chip (SoC) devices. The increased demand for physiologically relevant in vitro human skin models for testing pharmaceutical drugs has led to significant advancements in skin engineering.
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