ABSTRACT 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 pathologies compromise PMi homeostasis, leading to APOs. Specific Aims are: SA 1: Engineer all three trimester-specific “healthy, physiological state” PMi-OOCs with or without the addition of maternal decidua immune cells. SA2: Develop a trimester-specific disease state model to study the effects of OS and inflammation. This model will be validated with the use of antioxidant N-Acetyl-L-Cysteine or anti-inflammatory interleukin-10 to mitigate the effect of OS or inflammation. This research will develop trimester-specific placenta OOC models that can be utilized to study healthy, and disease states of pregnancy as well as conduct various preclinical trials.

NARRATIVE Scientists encounter numerous limitations of studying the human placenta using animal models or cell/tissue cultures from samples obtained from term delivery, which has reduced our understanding of placental functions in normal pregnancy as well as in placental disease-associated adverse pregnancy outcomes (APOs). To overcome these limitations and to better study placental functions, we will develop both normal and disease- state Placenta-Maternal interface organ-on-chip (PMi-OOC) models representing the distinctly different three trimesters of pregnancy. Using these in-vivo-like in vitro models, we will recreate oxidative stress and inflammation-associated placental pathologies that compromise PMi homeostasis, leading to APOs.