Novel Biometric Tissue Architecture as a Cell Delivery Vehicle for Cardiac Regene

描述（由申请人提供）：该项目的目标是创建一个植入式心脏贴片，其功能是在心肌梗死（通常称为“心脏病发作”）后替代受损组织。修复心脏的再生医学策略尤其受到无法重建心脏结构的阻碍。具体来说，细胞必须正确排列才能传播心脏的电信号。排列不当的细胞可导致心律失常。此外，移植细胞需要一个允许的环境（适当的细胞基质、可溶性信号和支持细胞）来整合到宿主组织中。我们提出的计划是使用自然发生的基质和工程来产生排列的细胞用于植入。该项目的三个主要目标如下：(1)表征三种候选生物材料单独和组合的内在物理特性，支持细胞活力和组织重塑。这些矩阵将单独探索并组合成层进行优化；1.1)维持大量存活的心肌细胞和内皮细胞，1.2)具有强度和刚度的机械性能，适合手工操作和植入，1.3)允许细胞重塑和血管形成的材料。(2)为所提出的三维贴片开发最佳的结构设计，为每个凝胶提供适当的孔隙度，以实现高细胞密度的播种和不同材料层的集成。拓扑通道的结合允许心肌细胞和内皮细胞对齐。材料中通道的顺序图案将使用激光蚀刻和/或薄层印刷来完成。成功的设计将允许最大限度地提供细胞组合（播种密度）和各种细胞基质层的集成。由于营养梯度随着细胞密度的增加和离营养源距离的增加而减弱，因此也将评估细胞活力。结构分析将用扫描电子显微镜（SEM）和共聚焦显微镜完成。分析适当的电排列的心肌细胞将分析使用染料交换和电传导研究。(3)比较直接注射细胞的3- d支架递送模式，以及心肌生成和血管生成联合修复策略（心脏贴片中的心脏和内皮细胞）的心肌生成和血管生成策略（心脏贴片中的心脏和内皮细胞）的修复策略。临床前大型动物（猪）心肌梗死模型将与加州大学戴维斯分校的Ronald Li博士合作使用。结果将集中于评估细胞活力和保留，血管形成，壁变薄和心脏功能表现。

DESCRIPTION (provided by applicant): This project's objective is to create an implantable cardiac patch which functions to replace damaged tissue after a myocardial infarction, commonly referred to as a "heart attack". Regenerative medicine strategies for repair of the heart are hampered particularly by the inability to recreate the cardiac architecture. Specifically, cells must be properly aligned in order to propagate the electrical signals of the heart. Misaligned cells can lead to arrhythmias. Furthermore, implanted cells need a permissive environment (proper cell matrix, soluble signals, and supporting cells) for integration into the host tissue. Our proposed plan is to use natural occurring matrices and engineering to produce aligned cells for the purpose of implantation. The three primary aims of this project are as follows: (1) Characterize three candidate biomaterials alone and in combination for inherent physical properties that support cell viability and tissue remodeling. These matrices will be explored individually and combined into layers for optimization of; 1.1) maintenance of high populations of viable cardiomyocytes and endothelial cells, 1.2) mechanical properties that possess strength and stiffness for manual manipulation and implantation, and 1.3) materials that allow for cellular remodeling and vessel formation. (2) To develop an optimal architectural design for the proposed 3-D patch which incorporates appropriate porosity for each gel working towards seeding at high cell densities and integration of layers of different materials. The incorporation of topological channels allows alignment of cardiomyocytes and endothelial cells. Sequenced patterning of channels in materials will be accomplished using laser etching and/or thin layer printing. Successful designs will allow for maximum delivery of cell combinations (seeding density) and integration of various cell-matrix layers. Because nutritional gradients wane with both increased cell density and increased distance from a nutrient source, cell viability will also be assessed. The analysis of architecture will be done with scanning electron microscopy (SEM), and confocal microscopy. Analysis of proper electrical alignment of the cardiomyocytes will be analyzed using dye exchange and electrical conduction studies. (3) To compare 3-D scaffolding modes of delivery with direct injection of cells, and a myogeneic strategy of repair (cardiac cells only in the cardiac patch) with a combined myogenic and angiogenic strategy (cardiac and endothelial cells in the cardiac patch). A pre-clinical large animal (swine) myocardial infarction model will be used in collaboration with Dr. Ronald Li, UC, Davis. Outcomes will focus on the evaluation of cell viability and retention, blood vessel formation, wall thinning, and functional performance of the heart. PUBLIC HEALTH RELEVANCE: Over 8 million Americans live with damaged heart tissue, due to the inability of the adult hearts to produce new cardiomyocytes after damage, and could benefit from innovations in regenerative medicine. Successful replacement of scar tissue in the heart with cardiac cells leads to proper cardiac function and alleviates physical strain that is a precursor to heart failure and death. This proposal will focus on the development of a patch as a cell delivery vehicle for these cardiac cells, providing an environment which is nourishing and time permissive for integration into the heart.