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（MI）和随后的心力衰竭。目前有许多旨在预防或治疗MI后心力衰竭的疗法。只有心脏移植才能替代梗死心肌恢复心脏功能，但供体心脏缺乏，心血管疾病的发病率持续上升。一个新的和创新的选择是使用体外产生的“心脏贴片”用于体内植入。本文提出的研究旨在解决与这种心脏补片的功能和最终用途有关的3个关键问题- 1）细胞组成对收缩力和结构机械稳定性的影响，2）仿生培养环境对组织形态和功能的影响，以及3）体外仿生工程化心肌等同物在Mi后恢复左心室功能的功效。这项工作的总体假设是，在仿生培养条件下体外工程化的心肌比基于细胞治疗的修复方法更好地恢复Mi后左心室功能。明尼苏达大学的环境使我能够解决这个假设，因为世界著名的Lillehei心脏研究所和心脏修复中心都位于附近，并且是我们实验室过去合作者的所在地。这个机会使我有能力增加我已经相当大的背景，在组织力学与组织工程方法，以及心脏解剖学和生理学的健康和疾病。我的职业计划包括在指导阶段获得细胞和组织培养技术、生物反应器开发以及MI大鼠模型的手术技术和生理评估方面的大量专业知识。然后，我将利用这些技能直接比较体外心肌组织工程与目前基于细胞治疗的心脏修复方法在独立阶段恢复MI后左心室功能的功效。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设计参数，这对体外工程化功能心肌的创建至关重要，从而使“心脏补丁”的目标更接近现实。相关性（参见说明）：本研究提案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。拟议的研究旨在阐明在实验室中创建和培养心脏组织工程的关键设计参数，并找到提高这种组织在恢复受损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.