Engineering Skin Microphysiological Systems for Transdermal Drug Screening based on Strategic Model Selection and Quantitative Prediction Roadmaps

As transdermal drug delivery systems (TDDS) gain increasing importance, the need for screening platforms that accurately recapitulate human skin physiology has become essential. Conventional static evaluation methods, such as Franz diffusion cells, remain limited in their ability to recapitulate in vivo dynamic transport, metabolism, and clearance processes. This review examines the technical significance and emerging applicability of skin microphysiological systems (MPS) as next-generation platforms for transdermal drug screening. We first outline the multilayered structure of the skin, principal permeation pathways, and key physiological determinants governing transdermal absorption, while critically assessing the limitations of conventional ex vivo and in vitro methods. We then systematically present the design principles, evaluation metrics, and representative applications of diverse skin MPS, classified by vascularization and flow conditions. Through this analysis, we highlight how skin MPS improve the accuracy of permeability assessment and enable more physiologically relevant evaluation of drug efficacy and toxicity. Importantly, we emphasize that the primary value of skin MPS lies not in maximal complexity, but in the strategic selection of model architecture tailored to specific research objectives. Finally, we discuss future directions toward quantitative prediction, including integration of skin MPS data with physiologically based pharmacokinetic (PBPK) models via in vitro – in vivo extrapolation (IVIVE), alongside key challenges related to structural fidelity, standardization, and regulatory translation.