Oral Mucosa‐on‐a‐Chip for Modeling Chemotherapy‐Induced Mucositis and Evaluating Drug Efficacy

ABSTRACT Oral mucositis, a common complication in chemotherapy patients, causes severe pain and ulceration, yet effective treatment options remain limited. However, the development of new therapies is hindered by the significant limitations of conventional preclinical models, including low physiological relevance, ethical concerns, and high costs. Organ‐on‐a‐chip (OoC) technology has emerged as a promising alternative by replicating human tissue microenvironments with enhanced physiological relevance. In this study, a three‐channel oral mucosa (OM)‐on‐a‐chip was developed, recapitulating the oral epithelium (EP), lamina propria (LP), and capillary (CP) regions. This chip features a CP channel designed as an independent structure separated from the other regions, enabling simulation of in vivo vascular drug delivery. In addition, incorporation of a spheroid outgrowth model enhances physiological relevance while significantly reducing fabrication time. To validate its potential as an alternative to animal testing, chemotherapy‐induced mucositis was modeled by 5‐fluorouracil (5‐FU) treatment and compared with an established animal model. Furthermore, keratinocyte growth factor (KGF) administration demonstrated the capability of the chip to reproduce both vascular and topical drug delivery responses. Taken together, OM‐on‐a‐chip provides a practical platform for modeling oral mucositis and evaluating therapeutic efficacy, showing strong potential for drug screening and translation.