A Study Evaluating the Safety and Efficacy of Second-Generation Tissue Engineered Vascular Grafts (TEVG2)

项目总结 我们开发了一种专门用于先天性心脏的组织工程血管移植物(TEVG) 做手术。TEVG是通过将自体骨髓来源的单个核细胞种植到 可生物降解管状支架。一旦被植入，支架就会降解，TEVG会转化为 在结构和功能上与天然血管相似的新生血管。第一次FDA的结果- 经批准的评估TEVG在儿童中使用的临床试验表明，TEVG是第一个- 可生长的血管导管使其特别适合用于复杂先天性心脏病的外科修复 然而，心脏缺陷；这项研究的结果也表明，狭窄的发生率太高， 推荐常规使用这项前景看好的技术。我们随后开发了一种改进的，第二种- 生成TEVG，结合了两种合理设计的抑制TEVG形成的策略 除了较新的不那么严格的措施外，还采取了组装TEVG的狭窄和工艺改进措施 进行TEVG血管成形术的标准。在此，我们提出了下一步的开发和翻译 TEVG：一项单一机构、前瞻性、单臂、探索性-验证性临床试验，旨在 对24名患者进行为期两年的第二代TEVG的安全性和有效性评估。在这 研究，我们将评估第二代TEVG的短期(2年)安全性和有效性 心外管道在改良Fontan手术治疗单室心脏畸形中的应用 我们将使用超声心动图和核磁共振对所有移植受者进行为期两年的连续监测。我们 假设第二代TEVG的临界狭窄发生率将显著降低 与我们先前FDA批准的先导性研究中的原始TEVG结果进行比较。此外，我们假设 随着时间的推移，TEVG将增长并转变为高度兼容的电容容器。我们将评估 Fontan循环中移植物顺应性对跨TEVG的流动、湍流和功率损失的影响。 具有生长能力的人造血管移植物的开发将使 早期明确的重建外科手术，减少对额外手术的需求 到体细胞过度生长(儿童生长超过植入物的过程)，从而改善预后 患有先天性心脏病的患者。

PROJECT SUMMARY We developed a tissue engineered vascular graft (TEVG) designed specifically for use in congenital heart surgery. The TEVG is made by seeding autologous bone marrow-derived mononuclear cells onto a biodegradable tubular scaffold. Once implanted the scaffold degrades and the TEVG transforms into a neovessel that resembles a native blood vessel both in structure and function. Results of the first FDA- approved clinical trial evaluating the use of the TEVG in children demonstrated that the TEVG is the first man- made vascular conduit that grows making it uniquely suited for use in the surgical repair of complex congenital heart defects, however; results of this study also demonstrated that incidence of stenosis was too high to recommend routine use of this promising technology. We subsequently developed an improved, second- generation TEVG that incorporates both rationally designed strategies for inhibiting the formation of TEVG stenosis and process improvement measures for assembling the TEVG, in addition to newer less stringent criteria for performing TEVG angioplasty. Herein we propose the next step in the development and translation of the TEVG: a single-institution, prospective, single-armed, exploratory-confirmatory clinical trial designed to evaluate the safety and efficacy of the second-generation TEVG in 24 patients over a 2-year period. In this study, we will evaluate the short-term (2 year) safety and efficacy of a second-generation TEVG for use as an extracardiac conduit in children with single ventricle cardiac anomalies undergoing modified Fontan surgery. We will serially monitor all graft recipients over a 2-year time course using echocardiography and MRI. We hypothesize that the second-generation TEVG will have a significantly lower incidence of critical stenosis compared to the results of original TEVG in our previous FDA-approved pilot study. In addition, we hypothesize that the TEVG will grow and transform over time into a highly compliant capacitance vessel. We will evaluate the effect of graft compliance on flow, turbulence, and power loss across the TEVG in the Fontan circulation. The development of a man-made vascular graft with growth capacity would enable the performance of definitive reconstructive surgical procedures at an early age and mitigate the need for additional surgeries due to somatic overgrowth (the process by which a child outgrows their implant), thereby improving outcomes in patients with congenital heart disease.