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 每年大约有25万例冠状动脉旁路移植(CABG)手术用于治疗 冠状动脉疾病(CHD)移植物失败率高达42.8%。贪污的一个主要原因 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 以及移植物血栓形成。顺应性匹配的功能性小直径血管移植物的开发将 因此，显著提高了CHD患者的治疗水平。组织工程学在以下领域显示出希望 获得功能性组织工程血管移植物所需的部分但不是全部特征 (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，可在植入前和随后调整到所需的顺应性 在体内降解和重塑时保持其顺应性。因此，迫切需要开发一种 合规性与TEVG匹配，在整个主机重建过程中保持合规性匹配，同时 也维持着有功能的内皮细胞。为了满足这一需求，我们将制定并从功能上评估 原弹性蛋白分层和内皮化的TEVG是并保持顺应性匹配的。我们将利用 优化可生物降解明胶/原弹性蛋白层状TEVG顺应性的计算模拟 以受控的方式洗脱TGFb2以促进移植物中早期细胞渗透和晚期基质沉积， 从而在我们的移植物退化时稳定其顺应性。我们研究的总体工作假设是 我们的移植物体内(体外和体内)顺应性可以通过暂时控制TGFb2来维持。 从计算优化的TEVG中洗脱。我们将通过完成以下操作来验证这一假设 明确的目标。我们研究项目的目标1将评估依从性和TGFb2洗脱是否可以维持 我们的TEVG在体内使用大鼠主动脉间置植入模型的依从性。我们建议的目标2 我们的工作将评估我们的TEVG在临床前大动物(绵羊颈动脉)植入模型中的功能。这个 拟议的研究将建立一种新的植入前后依从性受控的完全生物降解 生物聚合物TEVG具有优异的透明性、抗凝血性、血管反应性和功能性能。