Engineering Vascularized Cardiac Muscle

工程血管化心肌

• 批准号: 7282481
• 负责人: Gordana Vunjak-Novakovic
• 金额: $ 33.78万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282481
• 关键词: Acute myocardial infarction; Adhesions; Adult; Area; Bioreactors; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Survival; Cell Transplants; Cells; Cellular biology; Cicatrix; Coagulants; Coculture Techniques; Collaborations; Condition; Congenital Abnormality; Congestive Heart Failure; Contracts; Coupled; Culture Media; Elastomers; Electric Stimulation; Endothelial Cells; Engineering; Experimental Models; Fibroblasts; Generations; Heart Diseases; Histocompatibility Testing; In Vitro; Infarction; Investigation; Laboratories; Left ventricular structure; Modeling; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Neonatal; Nutrient; Outcome; Patients; Perfusion; Phenotype; Physiological; Rate; Rattus; Research; Resources; Structure; Testing; Thick; Tissue Engineering; Tissues; Universities; Vascular Endothelial Cell; Vascularization; Wound Healing; angiogenesis; clinically relevant; data modeling; density; design; implantation; in vivo; injured; migration; molecular scale; mortality; muscle engineering; repaired; response; scaffold; vascular tissue engineering; vasculogenesis

DESCRIPTION (provided by applicant): Our current inability to vascularize and perfuse thick cell masses has hindered efforts to engineer many types of functional tissues including, most critically, cardiac muscle. To serve as a graft for myocardial repair, an engineered cardiac construct must be thick and compact, contain physiologic density of differentiated cells, and contract synchronously in response to electrical stimulation. In addition, the graft must have a capability to integrate with the host vasculature in order to maintain the viability and function of transplanted cells. We propose to engineer functional vascularized myocardium by integrating and advancing our ongoing efforts in the areas of cardiac tissue engineering (MIT) and vascular tissue engineering (Duke). We hypothesize that the cultivation of cardiac myocytes and endothelial cells on specialized scaffolds (highly porous, biodegradable, elastic, with an array of channels) in a bioreactor with medium perfusion and electrical stimulation will promote functional assembly of synchronously contractile engineered muscle. We further hypothesize that vascularization in vitro will enhance the graft capacity for survival, integration and function in vivo. In order to test these hypotheses, which have been derived from two lines of our previous investigations, we propose studies with the following Specific Aims: (1) High density culture of cardiac myocytes on channeled scaffolds with medium perfusion and electrical stimulation, (2) Tissue engineering of a vascularized network, and (3) Tissue engineering and functional characterization of a vascularized cardiac muscle. The effects of perfusion and electrical stimulation on the progression of endothelial cell and myocyte assembly into a synchronously contractile myocardium will be studied in vitro and in vivo (implantation onto a left ventricle in an adult rat model of infarction). Tissue structure and function will be characterized at various hierarchical scales (molecular, structural, functional) and the obtained experimental and modeling data will be used to tailor the conditions and duration of cultivation and engineer implantable grafts. As such, the current proposal is a blueprint for the generation of vascularized cardiac muscle suitable for implantation into injured myocardium.

描述（由申请人提供）： 我们目前无法使厚细胞团血管化和灌注，这阻碍了工程设计许多类型的功能组织的努力，其中最关键的是心肌。为了作为心肌修复的移植物，工程化的心脏构造必须厚且紧凑，包含分化细胞的生理密度，并且响应于电刺激而同步收缩。此外，移植物必须具有与宿主脉管系统整合的能力，以维持移植细胞的活力和功能。我们建议通过整合和推进我们在心脏组织工程（MIT）和血管组织工程（杜克）领域的持续努力来工程化功能性血管化心肌。我们假设，培养心肌细胞和内皮细胞的专用支架（高度多孔，可生物降解，弹性，与一系列的通道）在一个生物反应器中与介质灌注和电刺激，将促进同步收缩工程肌肉的功能组装。我们进一步假设，体外血管化将提高移植物的生存能力，整合和功能在体内。为了验证这些假设，这已经从我们以前的两条线的调查，我们提出了以下具体目标的研究：（1）高密度培养心肌细胞的通道支架与介质灌注和电刺激，（2）组织工程的血管化网络，和（3）组织工程和功能表征的血管化心肌。将在体外和体内研究灌注和电刺激对内皮细胞和肌细胞组装成同步收缩心肌进展的影响（植入成年大鼠梗死模型的左心室）。组织结构和功能将在各种层次尺度（分子，结构，功能）进行表征，获得的实验和建模数据将用于定制培养和工程植入移植物的条件和持续时间。因此，目前的建议是一个蓝图的血管化心肌适合植入到受伤的心肌的产生。