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Principal Investigator: Arum Han
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $234,053
Funding agency: National Center for Advancing Translational Sciences
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.
Terms: <3-D><3-Dimensional><3D><Adverse drug effect><Adverse effects><Affect><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptosis><Apoptosis Pathway><Assay><Bioassay><Biological Assay><Birth><Body Tissues><Carrier Proteins><Cell Body><Cell Culture Techniques><Cell model><Cell-Extracellular Matrix><Cells><Cells Placenta-Tissue><Cellular model><Chorion><Clinical><Clinical Trials><Collaborations><Conduct Clinical Trials><Decidua Basalis><Decidual Cell><Development><Disease><Disorder><Drug Compounding><Drug Modelings><Drug Preparation><Drug Screening><Drug Transport><Drug toxicity><Drug usage><Drugs><ECM><Eptastatin><Extracellular Matrix><Fetal Membranes><Fetus><Fullterm Birth><Gatekeeping><Gel><Gender><Gestation><High Throughput Assay><Human><Immune Tolerance><Immune infiltrates><Immunoassay><Immunologic Tolerance><In Vitro><Infection><Infiltration><Inflammation><Inflammatory Response><Intervention><Intervention Strategies><Investigators><Kinetics><Libraries><Lytotoxicity><Manuals><Maternal Mortality><Maternal placenta><Medication><Membrane><Metabolic><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mothers><Murine><Mus><Myometrial Contraction><NCATS><National Center for Advancing Translational Sciences><Necrosis><Necrotic><Neonatal Mortality><Normal Placentoma><Outcome><Parturition><Pathologic><Pathway interactions><Patients><Perfusion><Persons><Pharmaceutical Preparations><Phase><Placenta><Placenta Embryonic Tissue><Placentome><Pravastatin><Predisposing Factor><Pregnancy><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Programmed Cell Death><Race><Races><Reporting><Research Personnel><Researchers><Risk Factors><Risk Reduction><Source><Structure><Teratogenic><Teratogenicity><Teratogens><Term Birth><Testing><Tissue Arrays><Tissue Chip><Tissue Microarray><Tissue Model><Tissues><Transport Protein Gene><Transport Proteins><Transporter Protein><Uncertainty><Uterine Contraction><Uterus><bio-printing><bioprinting><cell culture><cell cultures><cell immortalization><cost><cytotoxicity><death among neonates><death among newborns><death in neonates><death in newborn><decidua parietalis><design><designing><developmental><disease model><disorder model><doubt><drug detection><drug development><drug efficacy><drug metabolism><drug testing><drug use><drug-related adverse effects><drug/agent><efficacy testing><expectant mother><expecting mother><fetal><fetus membrane><full-term birth><fullterm newborn><gatekeeper><high throughput screening><high-throughput drug screening><hydrogel scaffold><immune cell infiltrate><immune system tolerance><immune unresponsiveness><immunological paralysis><in utero><in vitro Model><interest><interventional strategy><maternal death><membrane structure><model of animal><mortality among neonates><mortality among newborns><mortality in neonates><mortality in newborns><neonatal death><neonatal demise><neonatal morbidity><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><newborn death><newborn morbidity><newborn mortality><next generation therapeutics><non-human primate><nonhuman primate><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pre-clinical trial><preclinical trial><pregnant mothers><premature childbirth><premature delivery><preterm delivery><racial><racial background><racial origin><rapid testing><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><response><risk-reducing><screening><screenings><success><successful intervention><term newborn><therapeutic candidate><three dimensional><trafficking><trophoblast><womb>