Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft

顺应性匹配的生物聚合物血管移植物的临床前评估

• 批准号: 10540762
• 负责人: Jonathan Pieter Vande Geest
• 金额: $ 63.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540762
• 关键词: Acute; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Aorta; Autologous; Bilateral; Biopolymers; Blood Vessels; Bypass; Cd68; Cells; Cessation of life; Characteristics; Clinical; Clinical Treatment; Collagen; Computer Simulation; Coronary Artery Bypass; Coronary heart disease; Deposition; Development; Diameter; Disease; Elements; Endothelium; Environment; Exhibits; Extracellular Matrix; Failure; Gelatin; Heart Diseases; Hyperplasia; Implant; In Vitro; Individual; Infiltration; Legal patent; Macrophage; Maintenance; Mechanics; Modeling; Myosin Heavy Chains; Organ Transplantation; Performance; Phenotype; Play; Process; Production; Rattus; Reporting; Research; Research Project Grants; Role; Saphenous Vein; Sheep; Site; Smooth Muscle Myocytes; Sprague-Dawley Rats; Testing; Thrombosis; Tissue Engineering; Transforming Growth Factor Beta 2; Tropoelastin; United States; Vascular Diseases; Vascular Graft; Vascular Smooth Muscle; Woman; Work; calponin; computerized tools; controlled release; cost efficient; design; graft failure; hemodynamics; implantation; improved; in vivo; in vivo Model; mechanical properties; men; novel; pre-clinical; pre-clinical assessment; preimplantation; recruit; response; thrombogenesis; translational potential; vascular tissue engineering

Project Summary There are approximately 250,000 coronary artery bypass graft (CABG) procedures performed annually to treat coronary heart disease (CHD) with graft failure rates reported to be as high as 42.8%. A major cause of graft failure in CABG has been attributed to graft compliance mismatch leading to subsequent intimal hyperplasia and graft thrombosis. The development of a compliance matched functional small diameter vascular graft will therefore significantly improve the treatment of those with CHD. Tissue engineering has shown promise in achieving some but not all of the required characteristics for a functional tissue engineered vascular graft (TEVG). A particularly challenging aspect in the development of a functional TEVG is the design of a fully biodegradable biopolymer graft that can be tuned to a desired compliance pre-implantation and subsequently maintain its compliance as it degrades and remodels in-vivo. As such there is a critical need to develop a compliance matched TEVG that remains compliance matched throughout the host remodeling process while also maintaining a functional endothelium. To meet this need we will develop and functionally assess a tropoelastin layered and endothelialized TEVG that is and remains compliance matched. We will utilize computational simulation to optimize the compliance of a biodegradable gelatin/tropoelastin layered TEVG that elutes TGFb2 in a controlled manner to promote early cell infiltration and late matrix deposition in our graft, thus stabilizing its compliance as our graft degrades. The overall working hypothesis of our research is that the intravital (in-vitro and in-vivo) compliance of our graft can be maintained by temporally controlling TGFb2 elution from a computationally optimized TEVG. We will test this hypothesis by completing the following Specific Aims. Aim 1 of our research project will assess if compliance and TGFb2 elution can maintain the compliance of our TEVG in-vivo using a rat aortic interpositional implantation model. Aim 2 of our proposed work will assess the function of our TEVG in a preclinical large animal (sheep carotid) implantation model. The proposed studies will establish a novel pre- and post-implantation compliance controlled fully biodegradable biopolymer TEVG with excellent patency, anti-thrombogenicity, vasoreactivity, and functional performance.

项目摘要 每年进行大约250，000例冠状动脉旁路移植术（CABG），以治疗 冠状动脉心脏病（CHD）移植失败率高达42.8%。贪污的主要原因 冠状动脉旁路移植术的失败归因于移植物顺应性不匹配，导致随后的内膜增生 和移植物血栓形成。顺应性匹配的功能性小直径血管移植物的开发将 从而显著改善冠心病患者的治疗。组织工程学已经显示出在 实现功能性组织工程血管移植物的一些但不是全部所需特征 （TEVG）.在功能性TEVG的开发中，一个特别具有挑战性的方面是设计一个完整的 可生物降解的生物聚合物移植物，其可在植入前和随后调节至所需的顺应性， 在体内降解和重塑时保持其顺应性。因此，迫切需要制定一项 在整个主机改造过程中保持合规性匹配的TEVG， 还维持功能性内皮。为了满足这一需求，我们将开发和功能评估 弹性蛋白原分层和内皮化的TEVG是并保持顺应性匹配。我们将利用 计算模拟以优化可生物降解的明胶/原弹性蛋白分层的TEVG的顺应性， 以受控的方式洗脱TGF β 2以促进我们移植物中的早期细胞浸润和晚期基质沉积， 从而在移植物降解时稳定其顺应性。我们研究的总体工作假设是， 我们的移植物的活体内（体外和体内）顺应性可以通过暂时控制TGF β 2来维持 从计算优化的TEVG洗脱。我们将通过完成以下操作来检验此假设 具体目标。我们研究项目的目标1将评估依从性和TGF β 2洗脱是否可以维持 使用大鼠主动脉间置植入模型的体内TEVG的顺应性。我们的目标2 工作将评估我们的TEVG在临床前大型动物（绵羊颈动脉）植入模型中的功能。的 拟议的研究将建立一种新的植入前和植入后的依从性控制完全可生物降解 生物聚合物TEVG具有优异的通畅性、抗血栓形成性、血管反应性和功能性能。