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: 10670735
• 负责人: Arum Han
• 金额: $ 41.26万
• 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/10670735
• 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 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; Morbidity - disease rate; 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 Factors; Risk Reduction; Source; Structure; Teratogens; Term Birth; Testing; Tissue Microarray; Tissue Model; Tissues; 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; immune cell infiltrate; 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.

摘要 自发性早产(PTB)影响了大约11%的新生儿，是导致 新生儿死亡率和病死率。目前对肺结核的干预措施是为了阻止产妇子宫 宫缩以推迟分娩，但效果有限。感染和宿主炎症反应是 易患肺结核的主要因素。胎儿-母体界面(FMI)的炎症，特别是在绒毛膜- 蜕膜界面，在应对各种危险因素时会损害免疫耐受性，从而维持 妊娠，放大炎症反应，并触发肺结核的通路。临床前试验中的多种药物 已经证明，它们可以减少炎症，延缓肺结核。然而，在测试毒品运输方面的挑战， 代谢变化和致畸作用阻碍了肺结核药物的开发。不幸的是，目前的体外细胞 培养模型和动物模型有几个局限性，只关注胎盘转运。 毒品。为了克服这些限制，我们已经成功地开发了几种组织芯片模型 FMI使用原代人类细胞，并已证明它们可以概括功能和反应 FMI的健康和疾病状态。然而，我们的组织芯片模型缺乏高通量筛选 (HTS)功能。该方案将在96个井中开发高通量3D生物打印FMI组织芯片 格式，可用于大型药库的HTS，同时保持了FMI组织的关键优势 芯片在模拟子宫内的结构和功能。我们将特别关注绒毛膜-蜕膜的界面， 受两个最新发现的推动：1)药物通过绒毛-蜕膜界面(FMI)有效地转运 就像在胎盘中看到的那样，以前人们认为大多数转运都是通过 胎盘和2)普伐他汀(这里测试的药物)通过这个FMI转运的疗效要高得多 而不是通过胎盘来减少炎症。在UH2阶段，健康和疾病(感染和 炎症驱动的肺结核)组织芯片模型将与NCATS的内部调查人员一起开发， 结合我们在PTB、FMI细胞、组织芯片开发、细胞/ECM生物打印和高通量方面的专业知识 药物筛查。在UH3阶段，我们将利用组织芯片筛选多达1000种药物化合物 NCATS，然后使用我们的先进(但较低)对选定的最感兴趣的药物进行进一步分析 吞吐量)最适合机制研究的FMI组织芯片型号。我们的组织芯片模型有望 实现对候选治疗药物的快速测试，以更快地将实验药物带入临床试验。