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: 10645005
• 负责人: christopher Kane breuer
• 金额: $ 30.68万
• 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/10645005
• 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; Functional Regeneration; Geometry; Goals; Grant; Growth; Heart Ventricle; Image; 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; 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; Vasodilation; 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; pharmacologic; pre-clinical; preclinical study; pressure; prevent; repaired; respiratory; response; scaffold; sex; sheep model; standard of care; ultrasound; vascular tissue engineering; vasoconstriction

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.

项目摘要 组织工程提供了一种策略，用于开发改进的假体生物材料以用于先天性 心脏手术。我们作品的主要前提是组织工程可用于再生 自体新维修，以修复或替换先天性畸形的心血管组织 组织工程结构的性能要比修复生物材料更好。我们开发了一个由组织设计的 血管移植（TEVG）专门用于先天性心脏手术，目前正在进行临床试验 评估其作为Fontan操作中血管移植物的Fontan操作中的安全性 将下腔静脉（IVC）连接到肺动脉。这项研究的广泛，长期目标是 将该技术转换为诊所，用于先天性心脏病儿童。为了获得FDA 批准，我们必须证明TEVG在相关的临床前动物模型中的功效。目标的目标 建议是评估TEVG的晚期疗效与PTFE移植物（当前的临床标准） 护理）使用我们以前开发和验证的卵线IVC血管介入移植模型 这个目的。为此，我们提出了三个具体目标：在第一个目标中，我们将评估生理 在9 - 10年内植入的TEVG的特性，包括合规性和 除增长能力外，血管反应性。我们将使用血管内超声（IVU）和侵入性压力 监视以测量和比较TEVG和本地IVC的符合年龄和性别匹配的绵羊的依从性 在各种加载条件下。接下来，我们还将使用IVU和侵入性压力监测。 药理测试以评估和比较TEVG和天然IVC对各种的响应 生理相关剂量的药理试剂。最后，我们将衡量大小的变化和 使用串行3D血管造影对TEVG的几何形状排除动脉症扩张并确定功能 在我们的研究中，TEVG对动物的​​自然寿命的增长能力。在我们的第二个目标中，我们将使用 计算机断层扫描以评估和比较TEVG和PTFE之间的异位钙化程度 植入卵巢模型中的移植物。在第三个目标中，我们将评估和比较血液动力学性能 使用4D MRI和侵入性血液动力学监测植入卵子模型中的PTFE移植物的TEVG。 然后，我们将使用多巴丁胺应力测试在休息和模拟应力期间评估移植物的性能 使用4D流量和侵入性血液动力学数据来分析流量无序的程度和 在不同血液动力学状态下的心脏和呼吸周期内移植物内的相关能量损失 使用计算流体动力学。具有增长能力的提高TEVG的发展具有 改善先天性心脏病的儿童的预后潜力。