Approximately 10.5% of all pregnancies end in preterm around the world. Spontaneous preterm birth (PTB) and preterm birth due to preeclampsia (PE) contribute to both maternal and neonatal mortality and morbidity. Current interventions for both these conditions are unsuccessful, and PTB and PE drug development has been hindered by inability of drugs to cross the feto-maternal (F-M) barriers to treat both the mother and her fetus and lack of proper ways of testing drug absorption, metabolism and cytotoxicity. Pathologically, PTB and a large subset of PE have inflammation as a major mechanism driving preterm labor or contributing to placental vascular pathology, respectively. Statins, competitive inhibitors of HMG-CoA reductase, have been shown to reduce the expression of pro-inflammatory mediators. They have been successfully tested to reduce inflammation and oxidative stress in both PTB and PE in vitro and animal models. Before these drugs can advance to clinical trials, their efficacy and mechanism of action on the F-M and understanding their perfusion kinetics across the F-M barriers are needed. However, current drug testing models have many limitations: 1) the mouse F-M interface does not structurally mimic human, and chorionic trophoblast is obscure in the mouse; 2) non-human primates models are cost prohibitive; 3) placental perfusions studies are restricted to the placental-decidual interface, and thus drugs? passage through the other interface is not tested, confounding data and disrupting clinical trials. Besides, there are two distinct F-M interfaces: 1) between placenta and decidua basalis and 2) between fetal membranes and decidua parietalis. Drugs and/or other metabolites must pass through the two interfaces which are structurally and functionally very different. Therefore, simultaneous testing of both F-M interfaces is necessary. To address these limitations, we will use F-M interface organ-on- chips (OOCs) using cells from human tissues that can closely mimic the structure and functions of both F-M interfaces. In this OOC model, we will test statins? (rosuvastatin and pravastatin) properties and efficacy in reducing inflammation.
Aim 1 will test properties of drugs in two independent OOC models (placenta-decidua and fetal membrane- decidua interfaces).
Aim 2 will recreate an inflammatory model of interfaces and test drugs? efficacy.
Aim 3 will integrate the two interfaces into one OOC device and test statins? properties and efficacies. OOC models generated can test the effect of candidate therapeutic molecules to more rapidly bring experimental drugs (modeled using statins here) to streamline preclinical evaluation and minimize costs of clinical trials.
Testing drugs during pregnancy is challenging as the drugs? efficacy and toxic effects on the fetus are difficult to determine using current strategies. In this study, we will use an already developed maternal-fetal interface tissue (passage route of materials as well as drugs from the mother to the fetus) on a microchip (organ on a chip) using cells from human pregnancies and test the properties (such as toxicity and effectiveness) of statins in reducing inflammation that can lead to preterm birth. Development of such a tool to test drug properties can eliminate use of animal models for such studies, rapidly bring experimental drugs to use, and minimize costs of clinical trials.
