Tissue Chip Models for Cardiovascular Development and Disease

项目摘要 准确模拟器官水平结构和功能的人体组织芯片是 功能齐全的人体微生理系统（MPS），以重建复杂的系统级交互， 各种器官和组织。人类MPS具有巨大的潜力，可以彻底改变基础和转化研究 并提供与人类直接相关的药物测试和疾病建模平台。心脏组织 芯片特别重要，因为它们不仅可以用于模拟心血管疾病， 代表用于药物发现的任何MPS平台的基本组成部分，如药物诱导的心脏毒性 （心律失常风险）是FDA批准的药物的制药撤回的主要原因。发展 由于缺乏合适的人体模型，人体心肌的生理学相关模型是具有挑战性的。 细胞类型和培养系统。干细胞研究的最新突破导致人类诱导 多能干细胞衍生的心肌细胞（hiPS-CM），但这些细胞在表型上是不成熟的，并且与 在电生理功能、钙处理、代谢方面， 收缩功能心脏是一个动态器官，负责维持体循环和平台 为了培养工程组织，需要重建与生理或生理学相关的压力-体积变化， 病理生理心脏（泵）功能。为了解决当前心脏组织芯片平台的缺点， 我们开发了一种仿生心脏组织模型（BCTM）， 与心室腔相关的压力-容积变化。使用BCTM，我们生成了新的数据 这证明了我们有能力：（1）重建与胚胎心脏相关的压力-容积变化 发育以实现hiPS-CM的早期成熟和（2）重建病理性组织重塑 与压力和容量超负荷有关。建立一种功能强大的心脏组织芯片模型 它既可以独立地作为心血管发育和疾病的模型， 在药物发现和测试的MPS中，我们假设：“建立生理相关的 人体心脏组织芯片模型，可以复制体内类似的结构重建和功能 在心脏发育、正常功能和疾病过程中看到的适应需要培养 在与这些条件中的每一个相关的压力-体积变化下的工程化心脏组织”。 为了验证这一假设，我们提出了三个独立的目标，重点是hiPS的分化和成熟， CM作为先天性心脏病模型，基于器械的方法可减轻病理性心脏组织 重塑和评估发育和疾病中的心肌细胞生物钟。成功完成 该项目的研究将验证BCTM作为心血管疾病人类心室的相关模型 建模以及与MPS平台的潜在集成。

PROJECT SUMMARY Human Tissue Chips that accurately mimic organ-level structure and function are essential building blocks for fully functional Human Microphysiological Systems (MPS) to recreate complex system-level interactions between various organs and tissues. Human MPS have great potential to revolutionize basic and translational research and provide platforms for drug testing and disease modeling with direct relevance to humans. Cardiac Tissue Chips are of particular importance as they can not only be used to model cardiovascular disease but also represent an essential component of any MPS platform used for drug discovery as drug induced cardiotoxicity (arrhythmia risk) is a major reason for pharmaceutical withdrawal of FDA approved drugs. Development of physiologically relevant models of the human myocardium is challenging due to the lack of appropriate human cell types and culture systems. Recent breakthroughs in stem cell research have resulted in human induced pluripotent stem cell derived cardiomyocytes (hiPS-CM) but these cells are immature in phenotype and differ from human adult cardiomyocytes in terms of electrophysiological function, calcium handling, metabolism, and contractile function. The heart is a dynamic organ responsible for maintaining systemic circulation and platforms to culture engineered tissue need to recreate pressure-volume changes associated with physiological or pathophysiological heart (pump) function. To address shortcomings with current Cardiac Tissue Chip platforms, we developed a biomimetic cardiac tissue model (BCTM) that can subject engineered 3D cardiac tissue to pressure-volume changes associated with the ventricular chamber. Using the BCTM, we generated new data that demonstrates our ability to: (1) recreate pressure-volume changes associated with embryonic heart development to accomplish early maturation of hiPS-CMs and (2) recreate pathological tissue remodeling associated with pressure and volume overload. To establish the BCTM as a powerful Cardiac Tissue Chip Model that can either be used independently as a model of cardiovascular development and disease, or integrated within MPS for drug discovery and testing, we hypothesize: “Establishment of physiologically relevant Human Cardiac Tissue Chip Models that can replicate in vivo –like structural remodeling and functional adaptation as seen during heart development, normal function, and disease requires culture of engineered cardiac tissue under pressure-volume changes associated with each of these conditions”. To test this hypothesis, we propose three independent aims that focus on differentiation and maturation of hiPS- CMs as a model of congenital heart disease, device-based approach to mitigate pathological cardiac tissue remodeling and evaluate the cardiomyocyte circadian clock in development and disease. Successful completion of this project will validate the BCTM as a relevant model of the human ventricle for cardiovascular disease modeling and for potential integration with MPS platforms.