A primary cell-based fluidic co-culture model to investigate drug transport across the human placenta

Abstract

Although women often need to take medication during pregnancy, reliable human-based models mimicking the maternal-fetal interface and allowing predictions on drug transport across the human placenta are scarce. In this study, we developed a novel microfluidic Transwell®-based co-culture model consisting exclusively of primary cells (trophoblasts/endothelial cells) for assessing maternal-fetal drug transfer. We aimed to 1) investigate the effects of fluidic flow on drug transfer patterns, 2) evaluate barrier integrity and different transfer processes (diffusion, active transport) across the combined trophoblast/endothelial monolayers, and 3) determine the expression and functional activity of main placental drug efflux transporters (ABCB1 and ABCG2). After applying different flow rates (50/150 µL/min), our system maintained cellular integrity and barrier function while enhancing syncytialization markers such as hCG. Our model effectively mimics key features of the placental microenvironment, including polarized expression and functional activity of both efflux transporters. Using fluorescent substrates and specific inhibitors (ABCB1: Rhodamine 123/Cyclosporin A; ABCG2: Bodipy-FL-Prazosin/Ko123), we confirmed that both transporters are not only expressed in the primary co-cultures, but also actively restrict the passage of compounds in the mother-to-fetus direction. Importantly, our system also captured passive diffusion dynamics of reference compounds (antipyrine/caffeine), with transport rates increasing under higher flow, mirroring in vivo behavior. While our model does not yet replicate the full complexity of the placenta, our findings provide strong evidence that dynamic flow systems can recapitulate key placental transport phenomena and offer a valuable in vitro model to study human-based transplacental transport processes.

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ORCID for Bram Sengers: orcid.org/0000-0001-5859-6984

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