Abstract

Advanced human tissue equivalents are an emerging drug discovery tool that aims at minimizing costly candidate attrition in later stages of preclinical and clinical development. 3-D cellular tissue models amenable to screening in 96-well plate format and drug monitoring in real time provide more accurate compound screening in a physiologically relevant context, not achievable in traditional two dimensional, single cell type-based assays. Currently, equivalents that represent the healthy or pathological physiology of human tissues including skin, vasculature, lung, prostate, and various malignant tumors are used for rapid activity screening, toxicity profiling, and pharmacokinetic characterization of compound libraries. Human skin equivalents with intact stratum corneum reconstructed in vitro from matrix-embedded dermal fibroblasts and epidermal primary keratinocytes closely resemble the complex architecture and functional complexity of skin. Using human skin equivalents, delivery of novel topical agents for photoprotection has been studied, and toxicity and activity profiling of skin care products and FDA-approved drugs including sunscreens has been performed. Importantly, human skin equivalents are better predictors of drug activity than available animal models as mouse and guinea pig skin do not reflect the architecture of human skin in terms of physico-optical properties such as light reflectance and scattering, epidermal thickness, cellularity, and biochemical composition. Recently, cellular composition of advanced commercial skin reconstructs has been further optimized by incorporation of melanogenic melanocytes and immunomodulatory dendritic (Langerhans) cells in order to assess drug modulation of cutaneous pigmentation, inflammation, photo-immunosuppression, and photo-carcinogenesis. Continuous progress in skin equivalent engineering will ensure the expanding role of skin equivalents in disease model-based assays for rapid identification and development of novel cutaneous therapeutics.