Female Reproductive Tract Organ-on-Chips: Modeling Barrier Function and Drug Transport

Female reproductive tract (FRT) disorders such as maternal conditions and gynecological cancers represent a significant global health burden. However, women's health, and particularly locally acting therapies targeting the FRT, has historically been underprioritized in drug development and translational research. Developing safe and effective therapies requires a clear understanding of drug transport across FRT barriers. Conventional in vitro culture systems and animal studies fail to recapitulate the physiological complexity of the human FRT, including stratified mucosal architecture, functional mucus barriers, microbiome interactions, as well as dynamic hormonal regulation. Recently, organ-on-chip (OoC) microfluidic platforms, integrating human cells with precisely controlled perfusion, have emerged as advanced in vitro systems capable of recreating dynamic physiological microenvironments. This review summarizes the major anatomical and physiological barriers of the FRT, including the vagina, cervix, endometrium, and placenta, and discusses critical design considerations for the development of FRT-on-chip models. We highlight the advanced OoC developed to study infection, drug permeation, hormonal responses, and maternal-fetal interface dynamics. Finally, future perspectives are outlined, including the integration of immune components, vascularization strategies, and multi-organ systems to better simulate inter-organ communication. Collectively, these advances underscore the potential of FRT-on-chip models as predictive platforms for preclinical drug screening, toxicity evaluation, and personalized medicine.