ASynergysticInVitro-InSilicoModelofthePlacentalBarrierforPredictingFetalExposureand Toxicity of Xenobiotic Compounds

Project Summary/Abstract: The placenta is one of the least understood organs of the human body. Acting as a barrier between mother and fetus, the placenta mediates transport of oxygen, nutrients, fetal waste products and other compounds present in maternal circulation. Full term placental explants are currently the most widely used models for assessing transport and barrier function. Unfortunately, these models are dependent upon the availability of fresh placentas. There is a critical need for standardized tools that quantitatively assess placental barrier transport to enable prediction of maternal and fetal pharmacokinetics (PK) and placental and fetal toxicity. We seek to develop a platform that meets both aspects of this need by implementing a synergistic in vitro-in silico approach. We will develop a microfluidic device that accurately represents the complex physiology of the placental barrier. The device will contain i) maternal and fetal vascular channels which will be lined with placentally-sourced endothelial cells and ii) a trophoblast chamber representing the placental membrane that separates maternal and fetal blood supplies. The device geometry and flow rate will be physiologically-based to ensure relevance. A native placenta-derived extra cellular matrix will be used to better mimic the in vivo environment. The placental barrier device will be evaluated for viability, sustainability and functionality as compared to placental explant data from literature. The microfluidic model will eventually be expanded to include a fetal cell compartment for evaluating specific fetal toxicities (i.e. neural, hepatic, cardiac). In parallel, we will develop maternal and fetal physiologically-based (PB) PK models which will be connected through a high-resolution placenta model using in-house developed and software, CoBi tools. The combined PBPK-Placenta model will enable prediction of maternal and fetal PK. Data obtained from in vitro experiments will be used to characterize drug transport at the level of the whole placenta. As a precursor, we will develop a first-principles based model of the placental barrier device to evaluate the predictive capability of the transport model and then scale up to the level of the whole placenta. The computational model will account for diffusive and active transport. The development of this platform will aide in the prediction of chemicalsandapos; negative health effects in humans and address key limitations of current in vitro barrier test systems.Project Narrative: This project addresses the critical need for a standardized platform which improves understanding of the placental barrier and enables prediction of transplacental drug transport. This study combines modeling approaches to create a whole picture of maternal and fetal exposure to drugs taken by a pregnant woman. These studies will aide in the safe and effective treatment of the medical needs of pregnant women, enabling the provision of guidelines for prescription of medications and open up the possibility of therapeutically treating fetuses by maternal administration.