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

描述(申请人提供)：心血管疾病可导致心肌梗死(毫升)和随后的心力衰竭。目前有许多旨在预防或治疗小米后心力衰竭的疗法。目前仅有心脏移植替代梗死心肌恢复心功能，但供心稀缺，心血管疾病发病率持续上升。一个新的和创新的选择是使用在体外创造的用于体内植入的“心脏贴片”。这项研究旨在解决与这种心脏补片的功能和最终使用有关的3个关键问题-1)细胞组成对收缩压力和构造机械稳定性的影响，2)仿生培养环境对组织形态和功能的影响，3)体外仿生工程心肌等价物在恢复小鼠心脏损伤后左心功能方面的效果。这项工作的总体假设是，在仿生培养条件下体外培养的心肌比基于细胞治疗的修复方法更好地恢复了Mi后的左心功能。明尼苏达大学的环境使我能够独一无二地回答这一假设，因为世界著名的利莱黑心脏研究所和心脏修复中心都位于附近，也是我们实验室过去的合作者的所在地。这个机会让我有能力通过组织工程方法以及健康和疾病方面的心脏解剖学和生理学来充实我在组织力学方面已经相当丰富的背景。我的职业规划包括在指导阶段获得相当多的细胞和组织培养技术、生物反应器开发以及外科技术和MI大鼠模型的生理评估方面的专业知识。然后，我将利用这些技能来直接比较体外培养的心肌组织工程和目前基于细胞疗法的心脏修复方法在恢复Mi后独立阶段左心室功能方面的效果。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创造体外工程功能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(参见说明)：这项研究建议的相关性在于研究一种在心力衰竭期间对心脏进行功能性修复的高潜力方法。考虑到心脏病发病率的持续上升，这项研究尤其重要。这项拟议的研究旨在阐明在实验室中构建和培养心脏组织的关键设计参数，并找到提高该组织在恢复受损心脏功能方面的有效性的方法。

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.