A microfluidic skin-on-a-chip enabling in situ construction of full-thickness human skin for modeling inflammatory disease

Abstract

Physiologically relevant in vitro skin models are crucial tools for investigating disease-related responses, evaluating drug efficacy, and enhancing the translational value of dermatological research. While skin-on-a-chip technologies enable dynamic culture and enhanced microenvironmental control, most existing platforms are constrained by incomplete tissue architecture, discontinuous fabrication workflows, and limited experimental accessibility, factors that collectively undermine reproducibility and downstream analysis. Herein, we present a vertically stacked dual-chamber microfluidic platform with a detachable assembly, enabling stable long-term perfusion and intact tissue retrieval for standard histological and molecular analyses. Modulating dermal construction parameters during early formation under continuous perfusion effectively suppressed collagen contraction, yielding a uniform, mechanically stable dermal interface supporting reproducible epidermal seeding, stratification, and air–liquid interface (ALI)-induced maturation. Using primary human dermal fibroblasts and epidermal keratinocytes, the platform supports in situ formation of a hierarchically organized full-thickness skin model with appropriate epidermal stratification and differentiation marker expression under sustained dynamic culture. As a proof-of-concept application, a Th2 cytokine-driven inflammatory skin phenotype was established on-chip, recapitulating key molecular features of barrier impairment and inflammation. Pharmacological intervention induced quantifiable, reversible molecular responses, demonstrating the platform’s ability to distinguish inflammatory and treatment states in a dynamically maintained skin microenvironment. Collectively, this work presents a practical microfluidic strategy for process-integrated skin tissue construction, offering an experimentally accessible framework for inflammatory skin modeling and drug evaluation in organ-on-a-chip systems.