A microphysiological model of the human placental barrier

Abstract

During human pregnancy, the fetal circulation is separated from maternal blood in the placenta by two cell layers – the fetal capillary endothelium and placental trophoblast. This placental barrier plays an essential role in fetal development and health by tightly regulating the exchange of endogenous and exogenous materials between the mother and the fetus. Here we present a microengineered device that provides a novel platform to mimic the structural and functional complexity of this specialized tissue in vitro. Our model is created in a multilayered microfluidic system that enables co-culture of human trophoblast cells and human fetal endothelial cells in a physiologically relevant spatial arrangement to replicate the characteristic architecture of the human placental barrier. We have engineered this co-culture model to induce progressive fusion of trophoblast cells and to form a syncytialized epithelium that resembles the syncytiotrophoblast in vivo. Our system also allows the cultured trophoblasts to form dense microvilli under dynamic flow conditions and to reconstitute expression and physiological localization of membrane transport proteins, such as glucose transporters (GLUTs), critical to the barrier function of the placenta. To provide a proof-of-principle for using this microdevice to recapitulate native function of the placental barrier, we demonstrated physiological transport of glucose across the microengineered maternal-fetal interface. Importantly, the rate of maternal-to-fetal glucose transfer in this system closely approximated that measured in ex vivo perfused human placentas. Our “placenta-on-a-chip” platform represents an important advance in the development of new technologies to model and study the physiological complexity of the human placenta for a wide variety of applications.

Native extracellular matrix-derived semipermeable, optically transparent, and inexpensive membrane inserts for microfluidic cell culture

“…Microchannels used in our study were fabricated using conventional soft lithography (4, 5). In brief, a prepolymer of poly(dimethylsiloxane) (PDMS) (Sylgard, Dow Corning) was mixed with curing agent at 10:1 (w/w) and degassed in a desiccator to remove air bubbles.…”

“…By enabling new capabilities to present cultured cells with physiologically relevant structural, biochemical, and biomechanical cues, organ-on-a-chip models make it possible to mimic the native phenotype of various tissue types and their integrative behaviors that give rise to complex organ-level functions. Over the last decade, considerable success has been achieved in demonstrating the feasibility of leveraging this biomimetic microengineering strategy to model the functional units of various organs for basic and translational research (4–7). …”

“…In this configuration, the membranes provide a physical barrier to cell migration and enable the compartmentalization of different cell populations while permitting their exchange of soluble signaling molecules through the pores, recapitulating the role of the basement membrane in vivo (8, 9). This approach has been used extensively in microengineered cell culture models to reconstitute various types of tissue-tissue interfaces and to study their physiological functions in a range of contexts including immune responses (7), biomolecular transport (4), gas and fluid exchange (10), drug delivery (5), and nanoparticle absorption (11). …”

Programming microphysiological systems for children’s health protection

“…A microfluidics device that mimics the structural and functional complexity of the placenta was engineered to reflect the dynamic flow conditions of maternal-fetal exchange, and to reconstitute expression and physiological localization of membrane transport proteins such as glucose transporters, at the maternal-fetal interface. 35 The 'placenta-on-a-chip' platform closely approximated glucose exchange similar to an ex vivo model, and could potentially be incorporated into integrated toxicity assessments of human pregnancy with regard to the complexity of maternal-fetal exchange across multiple tissue layers.…”

3D Miniaturization of Human Organs for Drug Discovery

“…Blundell et al leveraged microfluidic and microfabrication technologies to develop a microengineered biomimetic model that replicates the architecture and function of the placenta. [79] The "Placenta-on-a-Chip" microdevice was generated using a set of soft elastomer-based microfabrication techniques, i.e., soft lithography. This microsystem consisted of two PDMS microfluidic channels separated by a thin ECM membrane.…”