A high throughput 3D bioprinted human placenta as a novel predictive platform to study drug safety and pathological conditions during pregnancy

Authors

• WE Thompson
• R Tredinnick
• DM Goldsmith
• K Kevorkian
• T Nelson
• PF Brennan

Abstract

During pregnancy, fetal exposure to xenobiotics, such as medications or infective agents, can lead to adverse gestational complications and long-term health consequences. Unfortunately, due to the limited ability to monitor the human maternofetal interface and the lack of physiologically relevant in vitro models, the underlying mechanisms behind gestational pathology and the downstream effects in placenta and fetus remains poorly understood. Therefore, we developed a novel biomimetic in vitro 3D human placenta (hPB) model at different stages of pregnancy in a high throughput format using 3D bioprinting technology, to study placenta physiology, pathology, and pharmacology. Primary trophoblasts and vasculature-derived cells were resuspended in ECM-like solutions and bioprinted on a 96-well transwell plate, recreating the placental villi. Bioprinted constructs were then exposed to Forskolin treatment at different oxygen pressure conditions for 6 days to enable tissue differentiation and recreation of progressive stages of development. The anatomical resemblance to human placenta was confirmed by immunostaining assays. High levels of syncytialization markers and CK7 indicated the formation of a bilayer trophoblastic barrier, whereas the expression of CD31 and Vimentin indicated the development of subjacent vascularized stroma. The functionality of hPB was validated by transepithelial electrical resistance and paracellular transport measurements, including nutrients and non-permeable metabolites. Other function like hormone production was also demonstrated by ELISA assays. This new platform will provide a powerful tool for understanding the relationships between prenatal exposure to xenobiotics and developmental outcomes, and will ultimately serve as the foundation for establishing global public health guidelines to prevent pregnancy complications.

Scientific Focus Area: Biomedical Engineering and Biophysics

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