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

3D 生物制造胎儿-母体界面组织模型，用于确定妊娠期间的药物疗效，以降低早产风险

• 批准号: 10438407
• 负责人: Arum Han
• 金额: $ 42.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438407
• 关键词: 3-Dimensional; Adverse drug effect; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Apoptosis; Biological Assay; Birth; Carrier Proteins; Cell Culture Techniques; Cell model; Cells; Chorion; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Decidua; Decidua Basalis; Decidual Cell; Development; Disease; Disease model; Drug Compounding; Drug Modelings; Drug Screening; Drug Transport; Drug toxicity; Drug usage; Extracellular Matrix; Fetal Membranes; Fetus; Gatekeeping; Gel; Gender; Human; Immune Tolerance; Immunoassay; In Vitro; Infection; Infiltration; Inflammation; Inflammatory Response; Intervention; Kinetics; Libraries; Manuals; Maternal Mortality; Membrane; Metabolic; Microscopy; Modeling; Mothers; Mus; National Center for Advancing Translational Sciences; Necrosis; Neonatal Mortality; Outcome; Pathologic; Pathway interactions; Patients; Perfusion; Persons; Pharmaceutical Preparations; Phase; Placenta; Pravastatin; Predisposing Factor; Pregnancy; Pregnant Women; Premature Birth; Race; Reporting; Research Personnel; Risk; Risk Factors; Source; Structure; Teratogens; Term Birth; Testing; Tissue Microarray; Tissue Model; Tissues; Tumor-infiltrating immune cells; Uncertainty; Uterine Contraction; Uterus; bioprinting; cell immortalization; cost; cytotoxicity; decidua parietalis; design; drug development; drug efficacy; drug metabolism; drug testing; efficacy testing; fetal; high throughput screening; high-throughput drug screening; hydrogel scaffold; in utero; in vitro Model; interest; neonatal morbidity; nonhuman primate; novel therapeutics; preclinical trial; rapid testing; response; screening; success; successful intervention; therapeutic candidate; trafficking; trophoblast

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.

抽象的 自发早产（PTB）影响了所有分娩的11％，这是重要的贡献者 新生儿死亡率和病态。 PTB中目前的干预措施旨在阻止母体子​​宫 延迟交货但成功有限的收缩。感染和宿主炎症反应是 偏爱PTB的主要因素。 Feto母亲界面（FMI）的炎症，特别是在合唱处 对各种危险因素的响应，判决界面可能会损害维持的免疫耐受性 怀孕，扩增炎症反应和触发PTB的途径。临床前试验中的多种药物 已经表明它们可以减少炎症并延迟PTB。但是，测试药物运输方面的挑战， 代谢变化和致畸性阻碍了PTB药物的发展。不幸的是，当前的体外细胞 培养模型和动物模型有几个局限性，仅将重点放在胎盘运输 毒品。为了克服这些局限性，我们已经成功地开发了几个组织芯片模型 FMI使用原代人细胞，并证明它们可以概括功能和响应 FMI的健康和疾病状态。但是，我们的组织芯片模型缺乏高通量筛选 （HTS）功能。该提案将在96孔中开发高通量3D生物打印FMI组织芯片 格式，可用于大型药物库的HT，同时保持FMI组织的关键优势 模仿子宫结构和功能的芯片。我们将专门关注合唱 - decidua界面， 由两个最近的发现激励：1）有效地通过合唱界面（FMI）进行药物运输有效发生 就像在胎盘中看到的那样，以前有人认为大多数运输都是仅通过 胎盘和2）通过该FMI运输的pravastatin的功效（在此测试）较高 比通过胎盘减少炎症。在UH2阶段，健康和疾病（感染和 炎症驱动的PTB）组织芯片模型将与NCAT的壁内研究者一起开发 结合我们的PTB，FMI细胞，组织芯片开发，细胞/ECM生物打印和高通量的专业知识 药物筛查。在UH3阶段，我们将使用组织芯片筛选多达1,000种药物化合物 NCAT，然后使用我们的晚期对选定的最高兴趣药物进行进一步分析（但较低 吞吐量）FMI组织芯片模型，最适合机械研究。我们的组织芯片模型是可以的 为了使候选治疗剂的快速测试能够将癫痫病毒更快地带入临床试验。