Drug-induced skin toxicity: gaps in preclinical testing cascade as opportunities for complex in vitro models and assays

Skin is the largest organ of the body and serves as the principle barrier to the environment. Composed of multiple cell types arranged in stratified layers with highly specialized appendages, it serves sensory and immune surveillance roles in addition to its primary mechanical function. Several complex in vitro models of skin (i.e. microphysiological systems (MPS) including but not limited to 3D tissues, organ-on-a-chip, organoids), have been developed and assays validated for regulatory purposes. As such, skin is arguably the most advanced organ with respect to model development and adoption across industries including chemical, cosmetic, and to a somewhat lesser extent, pharmaceutical. Early adoption of complex skin models and associated assays for assessment of irritation and corrosion spurred research into other areas such as sensitization, absorption, phototoxicity, and genotoxicity. Despite such considerable advancements, opportunities remain for immune capabilities, inclusion of appendages such as hair follicles, fluidics, and innervation, among others. Herein, we provide an overview of current complex skin model capabilities and limitations within the drug development scheme, and recommendations for future model development and assay qualification and/or validation with the intent to facilitate wider adoption of use within the pharmaceutical industry.