A synergistic in vitro-in silico model of the placental barrier for predicting fetal exposure and toxicity of xenobiotic compounds

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. In Phase I, we developed and demonstrated a physiologically relevant, microfluidic model of the placental barrier, comprising the maternal vasculature, placenta and fetal vasculature. Immortalized cytotrophoblasts were differentiated in the device into syncytiotrophoblasts, as verified by extensive characterization. Barrier function in the model was demonstrated by showing size-dependent permeability of compounds across the device. In parallel, we developed and validated an in vitro model of the microfluidic device, as a first step toward development of a physiologically- based, high-resolution model of transplacental species transport. In Phase II, we will continue to develop and integrate our in vitro and in silico components of this tool kit. We will extend the microfluidic model to comprise primary cells (trophoblasts and endothelial cells) and determine morphological, genetic and phenotypic differences between it and the Phase I cell line-based model. Further, we will test transplacental transport for a panel of compounds including xenobiotics, endogenous molecules, lipids, antibodies and toxins, for thorough evaluation of barrier function and replication of species transport in vivo. In parallel, we will develop a physiologically-based (PB), high-resolution model of the placenta to support mechanistic modeling of transplacental species transport. This model will be integrated with maternal and fetal PBPK models to 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 using the integrated toolkit. The computational model will account for passive 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. A multidisciplinary team with expertise in microfluidic cell-based assays and placental biology has been assembled for the successful completion of the proposed project. By providing a more realistic representation of the placental barrier both in vitro and in silico, the toolkit promises to establish a new paradigm for assessment of the placenta as a barrier.