A Synergystic In Vitro-In Silico Model of the Placental Barrier for Predicting Fetal Exposure and 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 chemicals' negative health effects in humans and address key limitations
of current in vitro barrier test systems.
