Transport of Maternally Administered Pharmaceutical Agents Across the Placental Barrier In Vitro

Abstract

To understand the transport of pharmaceutical agents and their effects on developing fetus, we have created a placental microsystem that mimics structural phenotypes and physiological characteristic of a placental barrier. We have shown the formation of a continuous network of epithelial adherens junctions and endothelial cell–cell junctions confirming the integrity of the placental barrier. More importantly, the formation of elongated microvilli under dynamic flow condition is demonstrated. Fluid shear stress acts as a mechanical cue triggering the microvilli formation. Pharmaceutical agents were administered to the maternal channel, and the concentration of pharmaceutical agents in fetal channel for coculture and control models were evaluated. In fetal channel, the coculture model exhibited about 2.5 and 2.2% of the maternal initial concentration for naltrexone and 6β-naltrexol, respectively. In acellular model, fetal channel showed about 10.5 and 10.3% of the maternal initial concentration for naltrexone and 6β-naltrexol, respectively. Gene expressions of epithelial cells after direct administration of naltrexone and 6β-naltrexol to the maternal channel and endothelial cells after exposure due to transport through placental barrier are also reported.

Roadmap on biomaterials for women’s health

“…The significance of the placental barrier during pregnancy has been investigated for decades, but the newly emerged techniques have enabled new in-vitro technology that accurately mimics the anatomical structure and physiological function of the placenta and the barrier. Multiple placenta-on-a-chip [99,108,116] platforms have appeared from the imitation of both placental barrier anatomy and physiology and deepens the understanding of this vital organ system. With the advent of more advanced placenta-on-a-chip models of the placental barrier, such models are expected to substantially change how research and development are done in this field.…”

“…Moreover, it has been reported that due to the size of cell culture chambers and channels, the shear stress developed is significantly lower than the shear stress developed in fetal capillaries [108]. In addition, further studies are required to assess the effect of shear stress on the formation of syncytiotrophoblasts since It is possible for trophoblasts to detect flow shear stress via mechanotransduction; blood flow shear stress rates through invading uterine spirals range from 1 to 10 dyn cm −2 ; however, the shear stress lowers to less than 0.1 dyn cm −2 in the intervillous area, according to studies [116]. The cells subjected to shear stress after differentiation into trophoblast-like cells showed proof of the formation of syncytium compared to those not subjected to shear stress when trophectoderm-like cells from human naive induced pluripotent stem cells were placed under a shear stress of 10 dyn cm −2 .…”

“…The cells subjected to shear stress after differentiation into trophoblast-like cells showed proof of the formation of syncytium compared to those not subjected to shear stress when trophectoderm-like cells from human naive induced pluripotent stem cells were placed under a shear stress of 10 dyn cm −2 . Consequently, shear stress has been found to be essential for the syncytialization of trophoblasts [116]. Additionally, multiple cell lines of the human placenta should be used to better mimic the physiology and anatomy of the human placenta developed for placenta-on-a-chip studies [108].…”

“…Developing a working model for conducting drug intake studies is vital for a better assessment of the influences of drugs on the maternal-fetal barriers. Moreover, including genetic studies to assess the placental expression of genes could help researchers in examining their models to achieve a model which is closer to the actual in-vivo studies [116]. Creating truly representative placenta models that accurately mimic the human placenta's significant changes during different pregnancy stages remains a challenge.…”

Inkject Printed Graphene Microelectrodes for Real-Time Impedance Spectroscopy of Neural Cells in Organ-on-a-Chip

“…To construct the microfluidic chip, a SU-8 mold was created using soft lithography, allowing for the fabrication of the top and bottom layers with channels. The chip comprises a top and bottom layer with a porous PETE membrane (2x10 mm) sandwiched between them [13][14][15]. Graphene electrodes were printed on top of the membrane prior to assembly.…”