Development of a Microstructurally Inspired and Compliance Matched Tissue Enginee

描述（由申请人提供）：心脏病是美国女性和男性的主要死亡原因。心脏病最常见的形式之一是冠状动脉疾病（CAD）。仅在2006年，CAD就造成425，245人死亡，176，138例患者植入冠状动脉旁路移植术[1]。对替代血管替代物的需求是必要的，因为自体血管（例如，乳房动脉、隐静脉）由于先前的使用或心血管疾病而经常不可用。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中，几个研究小组取得了重大进展，但尚未开发出机械和生物功能的TEVG [22-26]。该提议的总体工作假设是，由SMC嵌入的胶原蛋白/纤维蛋白和交联的人弹性蛋白原的交替层组成的TEVG将产生可以与天然猪冠状动脉的顺应性匹配的血管替代物。本研究提案的主要目标是制造由非合成聚合物组成的TEVG，其以模仿天然血管结构的方式排列，并且与天然猪冠状动脉相匹配。将通过完成以下具体目标来实现这一目标。具体目标1a：作为培养时间的函数，确定待用于最终优化TEVG的各个层的生物力学特性和负荷依赖性细胞外基质（ECM）微观结构组织。具体目标1b：定量外源性TGF β 2的添加如何影响pASMC包埋的胶原/纤维蛋白构建体的生物力学性质和负载依赖性ECM微观结构组织。具体目标2a：使用计算优化程序来确定交替的弹性蛋白原和pASMC嵌入层的最佳数量和厚度，其导致TEVG的顺应性与猪冠状动脉的顺应性相匹配。最后，我们的最后一个目标（具体目标2b）是确定使用优化参数（来自SA 2a）制造的TEVG是否符合要求，并具有与猪冠状动脉相似的微结构。成功完成所提出的目标将产生完全由非合成材料构造的TEVG，其灵感来自天然动脉微结构，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，如何开发结构的顺应性和细胞外基质组织耦合，因为他们在文化中发展。!

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. !