3D in vitro Human Stem Cell-derived Cardiovascular Tissue Model and Microfluidic Platform for Targeted Preclinical Drug Screening

项目摘要： 心血管疾病（CVD）很难研究和药物干预治疗 由于需要个性化的药物治疗方案， 样品，以及与体外培养原代心肌细胞用于临床前 药检体内动物研究目前用于筛选新的CVD治疗剂，但不适用于任何治疗剂。 由于相关的高成本和先进的技术技能水平而效率低下。结合人类 诱导多能干细胞（hiPSC）衍生的心血管细胞进入相关的微流体 器械提供了一个受控的、可重现的和患者特异性（靶向）的研究平台， 体外CVD进展的复杂过程沿着细胞对生化反应的反应， 和微环境的生物物理变化。当前体外心血管组织模型 整合了来自不同来源的细胞，但尚未证明整合了 具有由内皮细胞组成的毛细血管样网络的心肌细胞。此外，委员会认为， 与这些模型一起使用的微流体装置主要依赖于外部泵来移动流体 通过系统。 我的长期目标是开发一种患者特异性心血管组织模型， 微流控培养平台：1）评估药物的作用 体外人体心肌暴露和2）进行实时基础研究 心肌病的心肌细胞-内皮细胞-细胞外基质相互作用，心房 纤维性颤动和动脉粥样硬化。核心假设是，结合hiPSC衍生的3D 具有逆流微流体装置的心血管组织将产生患者特异性， 生理学相关的模型，有助于功能性人心肌的体外研究。的 这项工作的主要影响是开发了一种有针对性的单一来源的心血管组织， 该模型将通过反映人类对药物的反应， 治疗和帮助减少昂贵的动物模型的使用。这项工作也有助于 扩大临床前药物测试研究的遗传多样性， 代表了普通民众。

PROJECT ABSTRACT: Cardiovascular Diseases (CVDs) are difficult to study and treat with pharmacological interventions due to the need for personalized medicine regimens, limited availability of human myocardium samples, and the difficulty associated with culturing primary cardiomyocytes in vitro for preclinical drug testing. In vivo animal studies are currently used to screen novel CVD therapeutics but are inefficient due to the associated high cost and advanced technical skill level. Incorporating human induced pluripotent stem cell (hiPSC) derived cardiovascular cells into relevant microfluidic devices provides a controlled, reproducible, and patient-specific (targeted) platform to study in vitro the complex process of CVD progression along with the cellular response to biochemical and biophysical changes in their microenvironments. Current in vitro cardiovascular tissue models incorporate cells from different sources and have not yet demonstrated a functional integration of cardiomyocytes with capillary-like networks composed of endothelial cells. Furthermore, microfluidic devices used with these models predominantly rely on external pumps to move fluid through the system. My long-term goals are to develop a patient-specific cardiovascular tissue model and autonomous-flow microfluidic culture platform to: 1) assess the effects of pharmaceutical drug exposure on human myocardium in vitro and 2) conduct fundamental studies of real-time cardiomyocyte-endothelial cell-extracellular matrix interaction for cardiomyopathy, atrial fibrillation, and atherosclerosis. The central hypothesis is that combining hiPSC derived 3D cardiovascular tissue with an autonomous-flow microfluidic device will create a patient-specific, physiologically relevant model that facilitates in vitro study of functional human myocardium. The primary impact of this work is development of a targeted, single source cardiovascular tissue model that will contribute to more effective drug discovery by reflecting human response to therapeutics and help reduce the use of costly animal models. This work also contributes to expanding the genetic diversity in preclinical drug testing studies so results are more representative of the general population.