Development of a Microstructurally Inspired and Compliance Matched Tissue Enginee

描述（由申请人提供）：心脏病是美国男女死亡的主要原因。冠状动脉疾病（CAD）是最常见的心脏病之一。仅在2006年，冠心病就导致425,245人死亡，176,138人接受了冠状动脉搭桥手术。由于自体血管（如乳腺动脉、隐静脉）通常由于先前使用或心血管疾病而无法使用，因此需要替代血管替代物。因此，为CABG手术提供功能性组织工程血管移植物（TEVG）将大大改善患者护理。尽管在过去的几十年里，几个研究小组取得了重大进展，但尚未开发出具有机械和生物学功能的TEVG[22-26]。该建议的总体工作假设是，由SMC嵌入的胶原/纤维蛋白和交联的人类tropoelastin交替层组成的TEVG将产生与天然猪冠状动脉顺应性匹配的血管替代品。本研究计划的主要目标是制造一种TEVG，该TEVG由非合成聚合物组成，以模仿天然血管结构的方式排列，并与天然猪冠状动脉相匹配。这一目标将通过完成以下具体目标来实现。具体目标1a：确定作为培养时间的函数，用于最终优化的TEVG的各个层的生物力学特性和负载依赖的细胞外基质（ECM）微观结构组织。具体目标1b：量化外源性TGF¿2的添加如何影响pASMC嵌入胶原/纤维蛋白构建物的生物力学特性和负荷依赖的ECM微结构组织。具体目标2a：使用计算优化程序确定交替的tropoelastin和pASMC嵌入层的最佳数量和厚度，从而产生与猪冠状动脉的依从性相匹配的TEVG。最后，我们的最后一个目标（Specific aim 2b）将是确定使用优化参数（来自SA2a）制造的tevg是否符合要求，并且具有与猪冠状动脉相似的微观结构。成功完成所提出的目标将导致TEVG完全由非合成材料构建，灵感来自天然动脉微观结构，并显示功能性冠状动脉的顺应性。我们提出的研究还将产生新的实验信息，研究发育中的构建体的顺应性和细胞外基质组织在培养过程中是如何耦合的。！

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both women and men in the United States. One of the most common forms of heart disease is coronary artery disease (CAD). In 2006 alone, CAD killed 425,245 people, and 176,138 coronary artery bypass grafts were implanted in patients [1]. The need for an alternative vascular substitute is warranted as autologous vessels (e.g., mammary artery, saphenous vein) are oftentimes unavailable due to prior use or cardiovascular disease. Providing a functional tissue engineered vascular graft (TEVG) for CABG surgeries would therefore result in drastic improvements in patient care. Despite significant progress by several research groups in the last few decades, a mechanically and biologically functional TEVG has yet to be developed [22-26]. The overall working hypothesis of this proposal is that a TEVG composed of alternating layers of SMC embedded collagen/fibrin and cross-linked human tropoelastin will result in a vascular substitute that can be compliance-matched to that of a native porcine coronary artery. The primary goal of this research proposal is to fabricate a TEVG that is composed of non-synthetic polymers arranged in a fashion that mimics native vessel architecture and that is compliance matched to a native porcine coronary artery. This goal will be met by completing the following specific aims. Specific Aim 1a: Determine, as a function of time in culture, the biomechanical properties and load dependent extracellular matrix (ECM) microstructural organization of the individual layers to be used in the final optimized TEVG. Specific Aim 1b: Quantify how the addition of exogenous TGF¿2 affects the biomechanical properties and load dependent ECM microstructural organization of the pASMC embedded collagen/fibrin constructs. Specific Aim 2a: Use a computational optimization procedure to identify the optimum number and thickness of alternating tropoelastin and pASMC embedded layers that result in a TEVG whose compliance matches that of porcine coronary artery. Finally, our last aim (Specific Aim 2b) will be to determine if TEVGs fabricated using the optimized parameters (from SA2a) are compliance matched and have similar microstructure to a porcine coronary artery. Successful completion of the proposed aims will result in a TEVG that is constructed entirely from non- synthetic materials, is inspired by native arterial microstructure, and displays the compliance of a functional coronary artery. Our proposed research will also generate novel experimental information on how the compliance and extracellular matrix organization of developing constructs are coupled as they develop in culture. !