A Translational Center for Microphysiological Systems-Based Drug Development Tools for Pregnancy and Women's Health Overall Program Description: Human pregnancy and parturition are fascinating and biologically complex phenomena. Two independent physiological systems, namely the fetus and the mother, co-exist for a defined period of time to maintain pregnancy, aid fetal growth and development.1 This co-existence ends with parturition, a unique synchronized process that terminates all homeostatic states of pregnant uterine tissues2-6. Unfortunately, an unacceptable and growing number of pregnancies do not end at term with a delivery of a fully developed fetus. Approximately 25-30% of the 3.5 million births per year in the United States alone occur in the context of a range of placenta-, fetal membrane-, decidua/myometrium-, and/or cervix (maternal)-mediated adverse pregnancy outcomes such as preterm birth, preeclampsia, small-for-gestational-age birth, gestational diabetes, and others.7-10 Globally, preterm labor and delivery (birth at <37 weeks of gestation) accounts for 15 million births and 1 million neonatal deaths per year. 11-14 Survivors of adverse pregnancy outcomes face lifelong challenges, and mothers who deliver preterm often face medical complications.15-17 Therefore, reducing the risk of adverse pregnancy outcomes is a global need;13,18 however, pregnant women are excluded from most clinical trials.19-23 Instead, “women who may become pregnant” are a population of interest in drug development. Indeed, unique physiological characteristics of the mother-fetus co-existence during pregnancy are difficult to study. Challenges in conducting research and/or drug development in pregnancy include (i) recruitment hurdles due to paucity of data needed to convince the clinicians, subjects, and regulators on the utility of a drug in pregnancy, (ii) lack of suitable preclinical models (in vitro or animal models) to address both pharmacokinetics and pharmacodynamics, and (iii) absence of informative biomarkers to assess the feto-placental response to therapeutics. These limitations lead to systematic exclusion of pregnant women from medical interventions and therapeutics research.20,24 Recent advances in our group’s efforts to create a suite of five pregnancy and women's health-focused human microphysiological systems (MPS) that model 'healthy' and 'disease' states of intrauterine tissues25-32 present a unique opportunity to translate them into drug development tools. These MPS use cell lines created from both human placenta and lower and upper uterine tissues (feto-maternal membrane), to faithfully recreate the mother-fetus interface in pregnancy, parturition, and in adverse pregnancy outcomes. Collectively, these MPS and cells form a RESOURCE for drug development that will be tested for its suitability under several drug development contexts of use with a range of small molecules and a biological agent. We will also use our years of experience test...