Session: 07-04-01: Biomaterials and Tissue: Modelling, Fabrication and Characterization

Paper Number: 198448

Placenta-on-a-Chip: An in Vitro Platform for Evaluating Maternal-Fetal Pharmaceutical Transport 

The human placenta is a highly specialized organ that functions as the primary interface between the maternal and fetal circulations, regulating the exchange of nutrients, gases, metabolites, hormones, and xenobiotics while protecting the developing fetus through a selective physiological barrier. Experimental investigation of placental transport and drug disposition remains challenging because of the limited availability of viable human placental tissue, ethical constraints associated with pregnancy research, and the inability of conventional two-dimensional cell culture and animal models to accurately recapitulate human placental physiology. To address these limitations, we developed a biomimetic placenta-on-a-chip that reproduces key structural, functional, and physiological characteristics of the human placental barrier under dynamic flow conditions.

The microfluidic platform consists of a coculture of trophoblast-like BeWo cells in the maternal compartment and human umbilical vein endothelial cells (HUVECs) in the fetal compartment, separated by an extracellular matrix-coated semipermeable membrane that mimics the maternal–fetal interface. Continuous perfusion in both microchannels recreates physiologically relevant fluid shear stress and maternal and fetal blood circulation. Dynamic flow promoted robust cell proliferation and the formation of continuous epithelial and endothelial monolayers with well-defined adherens junctions, as confirmed by E-cadherin and VE-cadherin expression, demonstrating the structural integrity of the engineered placental barrier. Importantly, fluid shear stress served as a critical mechanical cue that induced trophoblast differentiation and the formation of elongated microvilli on the maternal surface without requiring chemical stimulants such as forskolin or cAMP. These findings highlight the essential role of biomechanical stimuli in regulating placental structure and function and demonstrate the ability of the microfluidic environment to reproduce physiological features that are difficult to achieve under conventional static culture conditions.

The barrier function of the engineered placenta was validated using fluorescein–dextran permeability assays. Compared with acellular control devices, the coculture placental model significantly restricted the transport of macromolecules across the membrane, demonstrating the establishment of a selective and functional placental barrier. The dense microvilli network formed under dynamic flow further enhanced the physiological relevance of the model by recreating the specialized apical architecture responsible for maternal–fetal exchange in vivo.

To demonstrate the utility of the platform for evaluating maternal-fetal drug transport, the opioid antagonist naltrexone and its primary active metabolite, 6β-naltrexol, were administered to the maternal channel. Quantitative analysis revealed that the coculture placental model substantially limited drug transfer, with fetal concentrations reaching only approximately 2.5% and 2.2% of the initial maternal concentrations for naltrexone and 6β-naltrexol, respectively. In contrast, acellular control devices exhibited significantly higher transport, with fetal concentrations of approximately 10.5% and 10.3%, demonstrating the critical contribution of the cellular placental barrier to regulating drug permeability. In addition, gene expression analyses of trophoblast and endothelial cells following drug exposure revealed distinct cellular responses associated with direct maternal exposure and secondary fetal exposure after transplacental transport, providing further insight into the biological effects of pharmaceutical agents on placental tissues.

Collectively, these results demonstrate that the proposed placenta-on-a-chip successfully reproduces key structural, mechanical, and transport functions of the human placental barrier, including trophoblast differentiation, epithelial and endothelial barrier formation, microvilli development, selective molecular permeability, and physiologically relevant drug transport. This microphysiological system represents a robust and physiologically relevant in vitro platform for studying placental biology, maternal–fetal transport, and pregnancy-related diseases, while providing a powerful alternative to conventional cell culture and animal models for drug screening, toxicity assessment, and the evaluation of fetal exposure to therapeutic agents. The platform also establishes a foundation for future personalized and patient-specific placental models capable of improving the safety and efficacy of medications used during pregnancy.

Presenting Author: Nicole Hashemi University of Missouri

Presenting Author Biography: Nicole Hashemi is a MizzouForward Professor in the Department of Mechanical and Aerospace Engineering at the University of Missouri in Columbia. Hashemi’s research interests include microfluidics and materials. Hashemi is a Fellow of the American Society of Mechanical Engineers, a Fellow of the American Institute for Medical and Biological Engineering, a Fellow of the Royal Society of Chemistry, and a Senior Member of the National Academy of Inventors. She has been recognized by both the National Academy of Engineering’s U.S. Frontiers of Engineering and the National Academy of Sciences’ Kavli Frontiers of Science.

Authors:

Nicole Hashemi University of Missouri