3-D biofabricated feto-maternal interface tissue model to determine drug efficacy during pregnancy to reduce the risk of preterm birth

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ABSTRACT Spontaneous preterm birth (PTB) affects approximately 11% of all births and is a significant contributor to neonatal mortalities and morbidities. Current interventions in PTB are designed to stop maternal uterine contractions to delay delivery but have limited success. Infection and host inflammatory responses are the major factors predisposing to PTB. Inflammation of the feto-maternal interface (FMi), specifically at the chorio- decidual interface, in response to various risk factors can compromise immune tolerance that maintains pregnancy, amplify inflammatory response, and trigger pathways of PTB. Multiple drugs in preclinical trials have shown that they can reduce inflammation and delay PTB. However, challenges in testing drug transport, metabolic changes, and teratogenicity have hindered PTB drug development. Unfortunately, current in vitro cell culture models and animal models have several limitations, and focus is given only to placental transport of drugs. To overcome these limitations, we have been successfully developing several tissue chip models of the FMi using primary human cells and have demonstrated that they can recapitulate the functions and responses of healthy and disease states of the FMis. However, our tissue chip models lack high-throughput screening (HTS) capabilities. This proposal will develop a high-throughput 3D bioprinted FMi tissue chip in a 96-well format, which can be used for HTS of large drug libraries, while keeping the key advantages of FMi tissue chips in mimicking in utero structure and functions. We will specifically focus on the chorio-decidua interface, motivated by two recent findings: 1) drug transport efficiently occurs through the chorio-decidual interface (FMi) like that seen in placenta, where previously it was thought that most transport occurs exclusively through placenta and 2) efficacy of Pravastatin (drug tested here) transported through this FMi is substantially higher than through placenta in reducing inflammation. In the UH2 phase, the healthy and disease (infection and inflammation-driven PTB) tissue chip model will be developed together with NCATS' intramural investigators, combining our expertise of PTB, FMi cells, tissue chip development, cell/ECM bioprinting, and high-throughput drug screening. In the UH3 phase, we will utilize the tissue chip to screen up to 1,000 drug compounds at NCATS, followed by further analysis of selected drugs of highest interest using our advanced (but lower throughput) FMi tissue chip model that is best suited for mechanistic studies. Our tissue chip model is expected to enable rapid testing of candidate therapeutics to bring epxperimental drugs more quickly to clinical trials.