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

项目总结 组织工程学为开发用于先天性心脏病的改良假体生物材料提供了一种策略 心脏手术。我们工作的最重要的前提是组织工程可以用来再生 修复或替换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得更好。我们开发了一种组织工程学 血管移植物(TEVG)专门用于先天性心脏手术，目前正在进行临床试验 评价其在Fontan手术中作为心外管道的安全性 将下腔静脉(IVC)连接到肺动脉。这项研究的广泛、长期目标是 将这项技术转化为临床，用于患有先天性心脏病的儿童。为了获得FDA 为了获得批准，我们必须在相关的临床前动物模型中证明TEVG的有效性。这样做的目的是 建议评估TEVGs与PTFE移植物(目前的临床标准)的远期疗效 使用我们先前开发并验证的绵羊下腔静脉血管间置移植模型 这就是目的。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年期间植入绵羊模型的TEVG的特性，包括顺应性和 血管反应性和生长能力。我们将使用血管内超声(IVUS)和有创压力 监测和比较年龄和性别匹配的绵羊TEVG和自然下腔静脉的依从性 在各种加载条件下。接下来，我们还将使用血管内超声和有创压力监测相结合 药理学测试，以评估和比较TEVG和天然下腔静脉对不同 生理剂量的药理试剂。最后，我们将测量大小和 应用连续3D血管造影术确定TEVG的几何形状以排除动脉瘤扩张并确定功能性 在我们研究的动物的自然寿命内，TEVG的生长能力。在第二个目标中，我们将使用 CT评估和比较TEVGs和PTFE的异位钙化程度 在绵羊模型中植入移植物。在第三个目标中，我们将评估和比较血流动力学性能 应用4DMRI和有创血流动力学监测，对植入绵羊模型的TEVGs与PTFE移植物进行对比研究。 我们将使用多巴酚丁胺负荷测试评估移植物在静息和模拟应激过程中的性能。 利用4D血流和有创血流动力学数据分析血流紊乱程度和 不同血流动力学状态下心脏和呼吸周期移植物内的相关能量损失 使用计算流体力学。改进的具有增长能力的TEVG的开发具有 有可能改善先天心脏病儿童的预后。

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.