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

摘要 自发性早产（PTB）影响约11%的所有出生，是一个重要的贡献者， 新生儿死亡率和发病率。目前对PTB的干预旨在阻止产妇子宫内膜异位症的发生。 宫缩以延迟分娩，但成功有限。感染和宿主炎症反应是 诱发肺结核的主要因素。胎儿-母体界面（FMi）的炎症，特别是在绒毛膜- 蜕膜界面，在应对各种风险因素可能会损害免疫耐受，维持 妊娠，放大炎症反应，并触发PTB途径。临床前试验中的多种药物 已经证明它们可以减轻炎症并延缓PTB。然而，测试药物运输的挑战， 代谢变化和致畸性阻碍了PTB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，并且仅关注胎盘转运， 毒品为了克服这些局限性，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，并已证明它们可以重现功能和反应， 健康和疾病的状态。然而，我们的组织芯片模型缺乏高通量筛选 (HTS)能力的该提案将在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HTS，同时保持FMi组织的关键优势 模拟子宫内结构和功能的芯片。我们将特别关注绒毛膜-蜕膜界面， 最近的两个发现激发了药物转运：1）药物通过绒毛膜-蜕膜界面（FMi）有效转运 就像在胎盘中看到的那样，以前认为大多数转运仅通过 胎盘和2）普伐他汀（此处测试的药物）通过该FMi转运的功效显著更高 而不是通过胎盘来减少炎症。在UH 2阶段，健康和疾病（感染和 炎症驱动的PTB）组织芯片模型将与NCATS的内部研究人员一起开发， 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， 药物筛选在UH 3阶段，我们将利用组织芯片筛选多达1,000种药物化合物， NCATS，然后使用我们先进的（但较低的） 通量）最适合于机理研究的FMi组织芯片模型。我们的组织芯片模型 以使候选治疗剂的快速测试成为可能，从而使实验药物更快地进入临床试验。

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.