Restoring LV Function Post-MI Using Fibrin-Gel Based Engineered Myocardium

描述（由申请人提供）：心血管疾病可导致心肌梗死（Ml）和随后的心力衰竭。目前有许多旨在预防或治疗心肌梗死后心力衰竭的疗法。只有心脏移植替代梗死心肌来恢复心脏功能，但供体心脏缺乏，心血管疾病的发病率持续上升。一种新的创新选择是使用体外制造的“心脏贴片”在体内植入。本文提出的研究旨在解决与此类心脏贴片的功能和最终使用有关的3个关键问题：1)细胞成分对收缩力和构建机械稳定性的影响，2)仿生培养环境对组织形态和功能的影响，以及3)体外仿生工程心肌等效物在心肌梗死后恢复左心室功能的功效。这项工作的总体假设是，在体外仿生培养条件下，心肌工程修复心肌梗死后左心室功能比基于细胞治疗的修复方法更好。明尼苏达大学的独特环境使我能够解决这个假设，因为世界著名的利勒黑心脏研究所和心脏修复中心都位于附近，并且一直是我们实验室过去合作者的家。这个机会使我能够用组织工程方法以及健康和疾病中的心脏解剖学和生理学来增强我在组织力学方面已经相当可观的背景。我的职业规划包括在指导阶段获得细胞和组织培养技术、生物反应器开发、手术技术和心肌梗死大鼠模型的生理评估方面的相当多的专业知识。然后，我将利用这些技术直接比较体外心肌组织工程与当前基于细胞治疗的心脏修复方法在心肌梗死后独立期恢复左心室功能的功效。考虑到心脏病发病率的持续上升，这项研究尤其重要。这项研究的结果可能有助于阐明对体外工程制造功能性心肌至关重要的设计参数，从而使“心脏贴片”的目标更接近现实。相关性（见说明书）：本研究计划的相关性涉及心力衰竭期间心脏功能修复的高潜力方法的研究。考虑到心脏病发病率的持续上升，这项研究尤其重要。提出的研究旨在阐明在实验室工程心脏组织的创建和培养中的关键设计参数，并找到提高该组织在恢复受伤心脏功能方面的功效的方法。

DESCRIPTION (provided by applicant): Cardiovascular disease can lead to myocardial infarction (Ml) and subsequent heart failure. There are currently a number of therapies aimed at preventing or treating heart failure post-Mi. Only heart transplantation replaces infarcted myocardium to restore heart function, but there is a paucity of donor hearts and the incidence of cardiovascular disease continues to rise. A new and innovative option is the use of "heart patches" created in vitro for implantation in vivo. The research proposed here aims to address 3 critical issues pertaining to the function and eventual use of such heart patches - 1) the effect of cellular composition on the contraction force and construct mechanical stability, 2) the effect of a biomimetic culture environment on tissue morphology and function, and 3) the efficacy of myocardial equivalents biomimetically-engineered in vitro in restoring left ventricular function post-Mi. The overall hypothesis of this work is that myocardium engineered in vitro in biomimetic culture conditions restores post-Mi left ventricular function better than cell therapy-based methods of repair. The environment at the University of Minnesota uniquely positions me to address this hypothesis, as the world-renowned Lillehei Heart Institute and the Center for Cardiac Repair are both located nearby and have been home to past collaborators with our lab. This opportunity affords me the ability to augment my already considerable background in tissue mechanics with tissue engineering methods as well as cardiac anatomy and physiology in health and disease. My career plan includes gaining considerable expertise in cell and tissue culture techniques, bioreactor development, as well as surgical techniques and physiological evaluation in a rat model of MI during the mentored phase. I will then leverage these skills to directly compare the efficacy of myocardial tissue engineered in vitro with current cell-therapy based methods of cardiac repair in restoring function to the left ventricle post-Mi during the independent phase. This research is especially critical considering the continuing rise in incidence of heart disease. The results of this research may help elucidate design parameters that are critical to the creation of functional myocardium engineered in vitro and thus advance the goal of the "heart patch" closer to reality. RELEVANCE (See instructions): The relevance of this research proposal regards the study of a high potential method for functional repair of the heart during heart failure. This research is especially critical considering the continuing rise in incidence of heart disease. The proposed research aims to elucidate critical design parameters in the creation and culture of heart tissue engineered in the lab and to find way to improve this tissue's efficacy in restoring functionality to the injured heart.