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.
