Development of a Microstructurally Inspired and Compliance Matched Tissue Enginee

描述(申请人提供)：心脏病是美国女性和男性的主要死因。最常见的心脏病之一是冠状动脉疾病(CAD)。仅在2006年，冠心病就导致425,245人死亡，176,138例患者植入了冠状动脉搭桥术[1]。由于自体血管(例如，乳动脉、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品。因此，为CABG手术提供功能性组织工程血管移植物(TEVG)将大大改善患者的护理。尽管几个研究小组在过去几十年中取得了重大进展，但机械和生物功能的TEVG尚未开发出来[22-26]。这项建议的总体工作假设是，由SMC包埋的胶原/纤维蛋白和交联人原弹性蛋白交替层组成的TEVG将产生一种可以与天然猪冠状动脉相匹配的血管替代品。这项研究计划的主要目标是制造一种由非合成聚合物组成的TEVG，这种聚合物以模仿天然血管结构的方式排列，并符合天然猪冠状动脉的顺应性。这一目标将通过完成以下具体目标来实现。具体目标1a：作为培养时间的函数，确定用于最终优化的TEVG的各层的生物力学特性和负荷依赖的细胞外基质(ECM)的微结构组织。具体目标1b：量化外源性转化生长因子2的添加如何影响PASMC包埋的胶原/纤维蛋白结构的生物力学性能和负荷依赖的ECM微结构组织。具体目标2a：使用计算优化程序确定交替的原弹性蛋白和PASMC包埋层的最佳数量和厚度，从而产生与猪冠状动脉相匹配的TEVG。最后，我们的最后一个目标(特定目标2b)将确定使用优化的参数(来自SA2a)制造的TEVGs是否顺应性匹配，并且具有与猪冠状动脉相似的微结构。成功完成拟议的目标将导致TEVG完全由非合成材料构建，灵感来自于天然动脉的微结构，并显示出功能性冠状动脉的顺应性。我们拟议的研究还将产生新的实验信息，即当发育中的结构在文化中发育时，顺应性和细胞外基质组织是如何耦合的。好了！

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. !