A Preclinical Study Evaluating and Comparing the Efficacy of Tissue Engineered Vascular Grafts to Polytetrafluoroethylene Grafts

评估和比较组织工程血管移植物与聚四氟乙烯移植物功效的临床前研究

• 批准号: 10420151
• 负责人: christopher Kane breuer
• 金额: $ 33.51万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420151
• 关键词: 3-Dimensional; 4D MRI; Acetylcholine; Adolescent; Affect; Age; Angiography; Animal Model; Animals; Autologous; Biocompatible Materials; Blood Vessel Prosthesis; Blood Vessels; Blood flow; Cardiac; Cardiac Surgery procedures; Cardiovascular system; Caring; Cause of Death; Characteristics; Child; Cine Magnetic Resonance Imaging; Clinic; Clinical; Clinical Trials; Common Ventricle; Congenital Abnormality; Congenital Heart Defects; Coupled; Data; Development; Devices; Disease; Dobutamine; Dose; Electric Capacitance; Fontan Procedure; Geometry; Goals; Grant; Growth; Heart Ventricle; Implant; Inferior vena cava structure; Investigation; Liquid substance; Live Birth; Longevity; Measures; Medical; Modeling; Monitor; Morbidity - disease rate; Natural regeneration; Newborn Infant; Nitroglycerin; Norepinephrine; Operative Surgical Procedures; Orphan; Performance; Pharmacology; Physiological; Polytetrafluoroethylene; Postoperative Complications; Procedures; Property; Prosthesis; Public Health; Pulmonary artery structure; Reagent; Regulatory Pathway; Resistance; Rest; Risk; Safety; Sheep; Source; Stress; Stress Tests; Technology; Testing; Time; Tissue Engineering; Tissues; Translating; Vascular Graft; Ventricular Function; Work; X-Ray Computed Tomography; calcification; cohort; comparative efficacy; congenital heart disorder; design; disability; heart valve replacement; hemodynamics; implantation; improved; improved outcome; in vivo; morphometry; mortality; operation; pre-clinical; preclinical study; pressure; prevent; reconstruction; repaired; respiratory; response; scaffold; sex; sheep model; standard of care; ultrasound; vascular tissue engineering

PROJECT SUMMARY Tissue engineering provides a strategy for developing improved prosthetic biomaterials for use in congenital heart surgery. The overriding premise of our work is that tissue engineering can be used to regenerate autologous neotissue to repair or replace cardiovascular tissues that are congenitally malformed and that the tissue engineered constructs will perform better than prosthetic biomaterials. We developed a tissue engineered vascular graft (TEVG) specifically for use in congenital heart surgery and are currently performing a clinical trial evaluating its safety as an extracardiac conduit in the Fontan operation in which a vascular graft is used to connect the inferior vena cava (IVC) to the pulmonary artery. The broad, long term objective of this study is to translate this technology to the clinic for use in children with congenital heart disease. In order to obtain FDA approval, we must demonstrate the efficacy of the TEVG in a relevant preclinical animal model. The goal of this proposal is to evaluate the late term efficacy of TEVGs compared to PTFE grafts (the current clinical standard of care) using the ovine IVC vascular interposition graft model which we previously developed and validated for this purpose. To this end we propose three specific aims: In the first aim we will evaluate the physiological properties of the TEVG implanted in the ovine model between 9-10 years including compliance and vasoreactivity in addition to growth capacity. We will use intravascular ultrasound (IVUS) and invasive pressure monitoring to measure and compare the compliance of the TEVG and native IVC in age- and sex-matched sheep at various loading conditions. Next we will also use the IVUS and invasive pressure monitoring coupled with pharmacological testing to evaluate and compare the response of the TEVG and the native IVC to various pharmacological reagents at physiologically relevant doses. Finally, we will measure the change in size and geometry of the TEVG using serial 3D angiography to rule out aneurismal dilation and determine the functional growth capacity of the TEVG over the natural life span of the animals in our study. In our second aim we will use computed tomography to evaluate and compare the degree of ectopic calcification between TEVGs and PTFE grafts implanted in the ovine model. In the third aim we will evaluate and compare the hemodynamic performance of TEVGs to PTFE grafts implanted in the ovine model using 4D MRI and invasive hemodynamic monitoring. We will evaluate graft performance both at rest and during simulated stress using dobutamine stress testing then use the 4D flow and invasive hemodynamic pressure data to analyze the degree of disordered flow and associated energy loss within the grafts over cardiac and respiratory cycles at different hemodynamic states using computational fluid dynamics. The development of an improved TEVG with growth capacity has the potential to improve outcomes for children born with congenital heart disease.

项目概要 组织工程为开发用于先天性疾病的改进的假体生物材料提供了策略 心脏手术。我们工作的首要前提是组织工程可用于再生 自体新生组织修复或替代先天畸形的心血管组织 组织工程结构将比假体生物材料表现更好。我们开发了一种组织工程 专门用于先天性心脏手术的血管移植物（TEVG），目前正在进行临床试验 评估其在 Fontan 手术中作为心外导管的安全性，其中使用血管移植物 将下腔静脉 (IVC) 连接到肺动脉。这项研究的广泛、长期目标是 将这项技术转化为临床，用于治疗患有先天性心脏病的儿童。为了获得FDA 如果获得批准，我们必须在相关的临床前动物模型中证明 TEVG 的有效性。此举的目标 建议是评估 TEVG 与 PTFE 移植物相比的近期疗效（当前的临床标准 护理）使用我们之前开发和验证的绵羊 IVC 血管介入移植模型 这个目的。为此，我们提出三个具体目标： 在第一个目标中，我们将评估生理学 TEVG 植入绵羊模型中 9-10 年的特性，包括顺应性和 除了生长能力之外，还包括血管反应性。我们将使用血管内超声 (IVUS) 和有创压力 监测以测量和比较年龄和性别匹配的绵羊 TEVG 和本地 IVC 的依从性 在各种负载条件下。接下来我们还将使用 IVUS 和有创压力监测以及 药理学测试，以评估和比较 TEVG 和天然 IVC 对各种药物的反应 生理相关剂量的药理学试剂。最后，我们将测量尺寸的变化 使用连续 3D 血管造影检查 TEVG 的几何形状，以排除动脉瘤扩张并确定功能 我们研究中动物自然寿命期间 TEVG 的生长能力。在我们的第二个目标中，我们将使用 计算机断层扫描评估和比较 TEVG 和 PTFE 之间的异位钙化程度 将移植物植入绵羊模型中。在第三个目标中，我们将评估和比较血流动力学性能 使用 4D MRI 和侵入性血流动力学监测将 TEVG 移植到植入绵羊模型中的 PTFE 移植物。 我们将使用多巴酚丁胺压力测试评估静止状态和模拟压力期间的移植物性能 利用4D血流和有创血流动力学压力数据分析血流紊乱程度 在不同血流动力学状态下心脏和呼吸周期内移植物内相关的能量损失 使用计算流体动力学。具有生长能力的改进型 TEVG 的开发具有 改善患有先天性心脏病的儿童的结局的潜力。