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: 10650713
• 负责人: Jianping Fu
• 金额: $ 17.85万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10650713
• 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; Epithelium; Etiology; Experimental Models; Extracellular Matrix; Extravasation; Fibroblasts; Goals; Human; Image; Immune response; Inflammation; Inflammatory Response; Intervention; Invaded; Investigation; Knowledge; 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; Technology; Testing; Time; Tissue membrane; Tissues; United States National Institutes of Health; adverse outcome; amnion; amniotic cavity; cytokine; experimental study; fetal; high throughput screening; human pluripotent stem cell; human tissue; implantation; innovation; innovative technologies; intraamniotic infection; manufacture; 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.

项目概要 羊膜内感染又称绒毛膜羊膜炎，是早产的主要病因。 胎膜破裂（pPROM），导致早产。尽管其普遍存在且后果严重， 由于缺乏可处理的人类治疗方法，羊膜内感染的病理学尚未完全了解。 相关型号。尽管早产动物模型已成功开发用于测试 尽管羊膜内感染的医疗干预措施仍然不适合动态定量研究 宫腔内细菌与羊膜的相互作用。早产人类羊膜样本的稀缺， 特别是从妊娠早期/中期阶段开始，也阻止这些人体组织作为实验模型 研究羊膜内感染及其与胎膜早破的功能联系。总而言之，迫切需要 定量、易处理、与人类相关的羊膜模型，用于增进对 羊膜内感染。 NIH R21 项目的主要目标是专门解决这一重大技术需求，方法是 开发与人类相关的羊膜模型，可以忠实地再现羊膜之间的相互作用 细菌和羊膜组织，同时允许高分辨率、定量实验 研究细菌侵入羊膜腔的机制。在我们的初步研究中，我们有 出人意料地发现了人类多能干细胞（hPSC）的羊膜分化能力， 成功开发了基于 hPSC 的合成微流控胚胎发生平台，其中关键 可以概括早期人类植入后发育过程中的发育里程碑 以高度可控和可扩展的方式连续进行。重要的是，我们还观察到敏感 hPSC 来源的羊膜细胞对细菌感染的炎症反应。因此，在本研究中我们提出 利用 hPSC 的羊膜分化潜力，结合创新的微流体技术， 开发出首个人类羊膜器官芯片系统。我们将进一步应用这一易于处理的 定量研究细菌侵入羊膜腔动态的实验系统 阐明炎症诱导的羊膜重塑与体内羊膜重塑之间的功能联系 羊膜细菌贩运。这项拟议研究的成功完成将带来创新 用于可控、可重复和可扩展的人类羊膜制造的技术和方法 膜组织，为研究相关妊娠并发症提供了一个易于处理的实验系统， 包括羊膜内感染。人羊膜器官的再现性和可扩展性 芯片系统将使其成为一个有前景的筛选平台，用于探索人类之间复杂的相互作用 羊膜、细菌病原体、药物和有毒物质。