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

基本信息

批准号：
10366911
负责人：
Jonathan Pieter Vande Geest
金额：
$ 65.86万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10366911
关键词：
Acute Adult Animal Model Animals Anti-Inflammatory Agents Autologous Bilateral Biopolymers Blood Vessels Bypass Caliber Cells Cessation of life Characteristics Clinical Clinical Treatment Collagen Computer Simulation Coronary Artery Bypass Coronary heart disease Deposition Development Disease Elements Endothelium Environment Exhibits Extracellular Matrix Failure Gelatin Heart Diseases Hyperplasia Implant In Vitro Individual Infiltration 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 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 macrophage mechanical properties men novel pre-clinical pre-clinical assessment preimplantation recruit response thrombogenesis translational potential vascular tissue engineering

项目摘要

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.

项目概要每年约有 250,000 例冠状动脉旁路移植术 (CABG) 手术用于治疗据报道，冠心病（CHD）移植失败率高达 42.8%。移植的一个主要原因 CABG 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。顺应性匹配的功能性小直径血管移植物的开发将因此显着改善了冠心病患者的治疗。组织工程在以下方面显示出前景实现功能性组织工程血管移植物的部分但不是全部所需特性（TEVG）。功能性 TEVG 开发中一个特别具有挑战性的方面是设计一个完全可生物降解的生物聚合物移植物，可在植入前和随后调整至所需的顺应性当其在体内降解和重塑时保持其顺应性。因此，迫切需要开发一个合规性匹配 TEVG 在整个主机改造过程中保持合规性匹配，同时还维持功能性内皮细胞。为了满足这一需求，我们将开发并进行功能评估原弹性蛋白分层和内皮化 TEVG 具有并保持顺应性匹配。我们将利用计算模拟优化可生物降解明胶/原弹性蛋白分层 TEVG 的顺应性以受控方式洗脱 TGFb2，以促进移植物中的早期细胞浸润和晚期基质沉积，从而在我们的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（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任务来检验这个假设具体目标。我们研究项目的目标 1 将评估合规性和 TGFb2 洗脱是否可以维持使用大鼠主动脉介入植入模型来验证我们的 TEVG 体内依从性。我们提出的目标 2 这项工作将评估我们的 TEVG 在临床前大型动物（绵羊颈动脉）植入模型中的功能。这拟议的研究将建立一种新型的植入前和植入后顺应性控制的完全可生物降解的方法生物聚合物 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。