Amnion membrane organ-on-chip for modeling intra-amniotic infection

用于模拟羊膜内感染的羊膜器官芯片

• 批准号: 10372321
• 负责人: Jianping Fu
• 金额: $ 21.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372321
• 关键词: 37 weeks gestation; Address; Adhesions; Animal Model; Apical; Automobile Driving; Bacteria; Bacterial Infections; Biological Models; Birth; Cells; Characteristics; Clinical; Clinical Research; Collagen Type IV; Complex; Development; Diagnosis; Discipline of obstetrics; Disease; Early Diagnosis; Early Intervention; Embryonic Development; Epithelial; Etiology; Experimental Models; Extracellular Matrix; Extravasation; Goals; Human; Image; Immune response; Inflammation; Inflammatory Response; Intervention; Investigation; Knowledge; Lead; Link; Medical; Membrane; Mesenchymal; Methodology; Microfluidics; Modeling; Molecular Target; Morbidity - disease rate; Pathologic; Pathology; Perinatal; Pharmaceutical Preparations; Poison; Pregnancy; Pregnancy Complications; Premature Birth; Prevalence; Prevention; Process; Reproducibility; Research; Resolution; Risk Factors; Role; Sampling; Screening procedure; Study models; Surface; System; Testing; Time; Tissue membrane; Tissues; United States National Institutes of Health; adverse outcome; amnion; amniotic cavity; base; cytokine; experimental study; fetal; high throughput screening; human pluripotent stem cell; human tissue; implantation; innovation; innovative technologies; intraamniotic infection; membrane model; molecular marker; monolayer; mortality; neonatal outcome; organ on a chip; pathogenic bacteria; prenatal; preterm premature rupture of membranes; prevent; public health relevance; screening; tool; trafficking

Project Summary Intra-amniotic infection, also referred to as chorioamnionitis, is a major etiological factor of preterm premature rupture of the membranes (pPROM), leading to preterm birth. Despite its prevalence and grave consequences, the pathology of intra-amniotic infection has yet to be completely understood due to a lack of tractable human- relevant models. Even though animal models of preterm birth have been successfully developed for testing medical interventions of intra-amniotic infection, they remain suboptimal for quantitative studies of dynamic bacterium-amnion interactions in the intrauterine cavity. The scarcity of preterm human amnion samples, especially from early/mid-gestation stages, also prevents these human tissues as experimental models for studying intra-amniotic infection and its functional link to pPROM. Altogether, there is a critical need for quantitative, tractable, human-relevant amnion membrane models for advancing fundamental understanding of intra-amniotic infection. The primary goal of this NIH R21 project is to specifically address this significant technological need, by developing a human-relevant amnion membrane model that can faithfully recapitulate the interaction between bacteria and amnion membrane tissues, and at the same time, allow high-resolution, quantitative experiments to study mechanisms underlying bacterial invasion of the amniotic cavity. In our preliminary study, we have unexpectedly discovered the amniogenic differentiation potency of human pluripotent stem cells (hPSCs) and successfully developed an hPSC-based, synthetic microfluidic embryogenesis platform in which key developmental landmarks during early human post-implantation development can be recapitulated successively in a highly controllable and scalable fashion. Importantly, we also observed sensitive inflammatory response of hPSC-derived amniotic cells to bacterial infection. Thus, in this research we propose to leverage the amnion differentiation potential of hPSCs, in conjunction with innovative microfluidics, to develop the first-of-its-kind human amnion membrane organ-on-chip system. We will further apply this tractable experimental system to quantitatively study the dynamics of bacterial invasion of the amniotic cavity and to elucidate the functional connection between inflammation-induced amniotic membrane remodeling and intra- amniotic bacterial trafficking. Successful accomplishment of this proposed research will lead to innovative technologies and methodologies for controllable, reproducible, and scalable manufacturing of human amnion membrane tissues, offering a tractable experimental system for studying related pregnancy complications, including intra-amniotic infection. The reproducibility and scalability of the human amnion membrane organ-on- chip system will make it a promising screening platform to explore complex interactions between the human amnion membrane, bacterial pathogens, drugs and toxic substances.

项目摘要 洋内部感染，也称为绒毛膜炎，是早产的主要病因。 膜破裂（PPROM），导致早产。尽管盛行和严重后果，但 由于缺乏可进行的人类 - 相关模型。即使已经成功开发了早产的动物模型 对养护内感染的医疗干预措施，它们仍然是最佳的，用于定量研究动态 宫内腔中的细菌 - 肿瘤相互作用。早产的人类羊膜样本的稀缺， 特别是从早期/中期阶段开始，也可以防止这些人体组织作为实验模型 研究肿瘤内感染及其与PPROM的功能联系。总共有关键的需求 定量，可拖动，与人相关的羊膜膜模型，用于促进对 内部感染。 该NIH R21项目的主要目标是通过 开发一个与人相关的羊膜膜模型，该模型可以忠实地概括 细菌和羊膜膜组织，同时允许高分辨率，定量实验 研究羊水腔细菌侵袭的基础机制。在我们的初步研究中，我们有 出乎意料地发现了人多能干细胞（HPSC）和 成功地开发了基于HPSC的合成微流体胚胎发生平台，其中关键 可以概括人类早期植入后发展期间的发展地标 以高度可控制和可扩展的方式依次。重要的是，我们还观察到敏感 HPSC衍生的羊膜细胞对细菌感染的炎症反应。因此，在这项研究中，我们建议 为了利用HPSC的羊膜分化潜力，并与创新的微流体相结合 开发首先的人羊膜膜器官片系统。我们将进一步应用此处理 定量研究细菌浸润的动力学的实验系统 阐明炎症引起的羊膜重塑和内部的功能连接 羊膜细菌贩运。这项拟议研究的成功完成将导致创新 人类羊膜的可控，可再现和可扩展制造的技术和方法 膜组织，提供可进行的可进行的实验系统，用于研究相关的妊娠并发症， 包括肿瘤内感染。人羊膜膜器官的可重复性和可伸缩性 芯片系统将使它成为探索人之间复杂互动的有希望的筛选平台 羊膜膜，细菌病原体，药物和有毒物质。