Developing trimester-specific placenta organ-on-chips to model healthy and oxidative stress and inflammation-associated pathologies

Placental dysfunctions arising from oxidative stress (OS) and inflammation are major pathophysiological contributors to adverse pregnancy outcomes (APOs; ~11% of all pregnancies). Risk-induced OS and inflammation compromise various placental homeostatic functions, leading to APOs. The majority of APOs lead to either indicated or spontaneous preterm birth, as delivery is the only option to reduce the risk of feto-maternal mortalities and morbidities. Currently, no successful interventions are available for reducing the risk of APOs. The lack of therapeutic strategies preventing APOs is partly due to the lack of models that accurately recreate human placenta pathology and the in utero environment of the human fetal (placental)-maternal (F-M) barriers. The placenta exhibits distinct cellularity in each of the pregnancy trimesters, which are under different O2 environments. Current models (e.g., explant, 2D and transwell cultures, placental perfusion, and animals) have several limitations as they do not address the complex and dynamic interplay between placental and maternal cells, which has hindered understanding of placental physiology during normal pregnancies and pathologies in APOs. To overcome these current limitations, we will develop a novel Placental (fetal)-decidual (Maternal) interface (PMi) 5-chamber organ-on-chip (PMi-OOC) designed to mimic PMi structure and function representing each of the three pregnancy trimesters, with specific O2 environments. New knowledge gained from this study will be crucial in elucidating placental biology/pathology. Using three aims, we advance our current placenta OOC and test the hypothesis that OS and inflammation-associated placental hologies compromise PMi homeostasis, leading to APOs.