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 testing a wide range of MPS for their utility in drug safety evaluation to QUALIFY these MPS for their specific contexts of use and seek regulatory approval for their use as drug development tools. Collectively, this Center addresses a clear need by translating five pregnancy and women's health MPS into drug development tools for repurposing or testing newly developed drugs that can be used during pregnancy.

OVERALL CENTER PROJECT NARRATIVE To improve clinical translational research in a highly vulnerable population (pregnant women and fetuses), we will use our five distinct humanized feto-maternal interface organs on a chip (Microphysiologic systems [MPS]) that uses cells from pregnancy to test its utility in preclinical drug trials. We will test the repurposing of 4 FDA- approved drugs during pregnancy by testing their kinetics, metabolism, and toxicity at the feto-maternal interface. Further, these devices and cells will undergo a qualification process to determine their translational properties by closely engaging with the pharmaceutical industry end-users and submitting the data to the FDA.