3D microfluidics-assisted modeling of glucose transport in placental malaria

Abstract

The human placenta is a critical organ, mediating the exchange of nutrients, oxygen, and waste products between fetus and mother. Placental malaria (PM) resulted from Plasmodium falciparum infections causes up to 200 thousand newborn deaths annually, mainly due to low birth weight, as well as 10 thousand mother deaths. In this work, a placenta-on-a-chip model is developed to mimic the nutrient exchange between the fetus and mother under the influence of PM. In this model, trophoblasts cells (facing infected or uninfected blood simulating maternal blood and termed “trophoblast side”) and human umbilical vein endothelial cells (facing uninfected blood simulating fetal blood and termed “endothelial” side) are cultured on the opposite sides of an extracellular matrix gel in a compartmental microfluidic system, forming a physiological barrier between the co-flow tubular structure to mimic a simplified maternal–fetal interface in placental villi. The influences of infected erythrocytes (IEs) sequestration through cytoadhesion to chondroitin sulfate A (CSA) expressed on the surface of trophoblast cells, a critical feature of PM, on glucose transfer efficiency across the placental barrier was studied. To create glucose gradients across the barrier, uninfected erythrocyte or IE suspension with a higher glucose concentration was introduced into the “trophoblast side” and a culture medium with lower glucose concentration was introduced into the “endothelial side”. The glucose levels in the endothelial channel in response to CSA-adherent erythrocytes infected with CS2 line of parasites in trophoblast channel under flow conditions was monitored. Uninfected erythrocytes served as a negative control. The results demonstrated that CSA-binding IEs added resistance to the simulated placental barrier for glucose perfusion and decreased the glucose transfer across this barrier. The results of this study can be used for better understanding of PM pathology and development of models useful in studying potential treatment of PM.

Endocrine-disrupting compounds and their impact on human placental function: evidence from placenta organ-on-chip studies

“…10), in close agreement with other microphysiological models of the placenta. 23,25–34 One group of chips was fixed with paraformaldehyde to arrest any physiological activity within the cells, including glucose transporters while maintaining structural integrity; 94 this setup was used as a positive control for this experiment. Placental glucose transport post-fixation with paraformaldehyde resulted in the highest percentage of glucose crossing from the setups (25.64 ± 1.09%), did not vary significantly compared to BPA (17.43 ± 10.31%), BPS (38.21 ± 10.27%), PBDEs (35.02 ± 41.11%), or CSE (27.80 ± 10.68%).…”

“…10), in close agreement with other microphysiological models of the placenta. 23,[25][26][27][28][29][30][31][32][33][34] One group of chips was fixed with paraformaldehyde to arrest any physiological activity within the cells, including glucose transporters while maintaining structural integrity; 94 this setup was used as a positive control for this experiment. Placental glucose transport post-fixation with paraformaldehyde resulted in the highest percentage In summary, we demonstrated that overall placental glucose transport was unaffected regardless of exposure, suggesting that low levels of inflammation induced by these compounds did not significantly impact glucose transport at concentrations even higher than those reported in adverse pregnancy outcomes.…”

“…The latest advancements in the placenta OOC model have been recently summarized by Elzinga et al 22 The most widely described models include two-cell chips, which have trophoblasts and endothelial cell compartments. [23][24][25][26][27][28][29][30][31][32] Single-cell chips have also been developed, in which only trophoblast cells are maintained, 33,34 while a three-chamber chip has also been developed from the Menon Laboratory, which includes cytotrophoblasts, syncytiotrophoblasts, and endothelial cells. 21 The main thrust of the study is to provide a new model that incorporates multiple cells representative of the placental architecture while preserving necessary intercellular connections through microchannels.…”

“…The latest advancements in the placenta OOC model have been recently summarized by Elzinga et al 22 The most widely described models include two-cell chips, which have trophoblasts and endothelial cell compartments. 23–32 Single-cell chips have also been developed, in which only trophoblast cells are maintained, 33,34 while a three-chamber chip has also been developed from the Menon Laboratory, which includes cytotrophoblasts, syncytiotrophoblasts, and endothelial cells. 21…”

Modeling the Progression of Placental Transport from Early‐ to Late‐Stage Pregnancy by Tuning Trophoblast Differentiation and Vascularization

“…[3] Human-based in vitro placental models have recently been developed with the goal of modeling placental barrier function. [4][5][6][7] Placenta-on-chip cultures have been designed with trophoblast and endothelial cells cultured on opposites sides of either a semipermeable membrane or hydrogel, [8] whose compartmentalized culture allows for simple molecular transport studies. The cultures are subjected to perfusion on each side: trophoblast channel perfusion to model maternal blood flow and endothelial channel perfusion to mimic fetal blood flow.…”