A 3D microfluidic model for preclinical drug permeation studies: Advancing validation of skin-on-chip technology

Recent progress in 3D cell culture and microfluidic technology has accelerated the development of organ-on-chip (OoC) models for preclinical applications. Yet, the lack of standardized, cost-effective platforms that accurately mimic human tissue physiology remains a significant challenge, particularly for drug permeability testing. This study presents a single-compartment skin-on-chip (SoC) model involving 3D co-culture of human dermal fibroblasts and keratinocytes. The microfluidic chip, designed using Autodesk Fusion 360® and fabricated via soft lithography, supported dynamic perfusion culture for 11 days. A static replica was developed for TEER-based barrier assessment. Morphological characterization was performed using advanced imaging techniques, while barrier integrity was evaluated through TEER and permeability of 4 kDa FITC-dextran. Rheological analysis provided insights into the biomechanical properties of skin co-culture. To assess functional relevance and establish a protocol for OoC validation, drug transport studies were conducted using model drugs (caffeine, hydrocortisone, salicylic acid, clotrimazole) with varying polarities. Results confirmed good barrier formation, consistent drug permeability, and mechanical robustness. Unlike previous reports with other SoC devices, this manuscript offers a more extensive approach for high-resolution structural analysis, rheological characterization, and sensitive drug quantification, paving a way for the development of a more standardized and predictive OoC models for dermocosmetic, pharmaceutical, toxicological, wound healing, disease modelling and drug delivery research.