Development of an Improved Vascular Graft for Use in Congenital Heart Surgery

 描述(申请人提供)：尽管在先天性心脏病的外科和医学管理方面取得了重大进展，但先天性心脏畸形仍然是导致新生儿死亡的主要原因。大多数严重的先天性心脏病需要手术治疗。使用现有假体引起的并发症 血管移植物、补片或替换心脏瓣膜等形式的材料是先天性心脏病手术后发病率和死亡率的主要来源。目前可用的假体材料，如聚四氟乙烯(PTFE)，是血栓栓塞症的重要来源，由于新生内膜增生而耐用性差，容易感染，而且可能最重要的是缺乏生长能力，这导致随着儿童生长超过他们的假体需要额外的手术。开发更好的具有生长潜力的生物材料可以显著改善需要接受先天性心脏手术的儿童的结局，因为它减少了与移植相关的并发症，并使早期确定的手术修复成为可能，而不会有连续再次手术的风险。组织工程为这一重大问题提供了一种创新的解决方案。利用组织工程方法，生物假体可以从个人自身的细胞中制造出来，创造出具有极好的生物相容性和生长、修复和重塑能力的活材料。我们之前创造了第一个专门为儿童设计的组织工程血管移植物(TEVG)，在那里它的生长潜力可以发挥出最大的优势。随后，我们进行了第一次临床试验，评估了TEVG在先天性心脏病手术中的应用。在这项研究中，我们证实了TEVG的生长能力，但也证明了狭窄是移植物相关的主要并发症和阻碍该技术广泛临床应用的关键障碍。我们的目标是优化我们的TEVG的设计。使用TEVG作为专门为先天性心脏手术开发的生物假体模型，我们将调查导致狭窄的基本机制，这是当前TEVG的主要限制，然后将我们的发现应用于改进的血管移植物的设计。在这一应用中，我们将重点讨论转化生长因子-β(转化生长因子-β)的作用，我们先前已经证明，转化生长因子-DNA在小鼠TEVG狭窄的形成中起关键作用。我们将探索这种细胞因子在渗透宿主巨噬细胞(目标1)，然后对形成狭窄病变的血管细胞(目标2)的作用，应用小鼠遗传学的力量来剖析这些过程。最后，由于在小鼠身上的发现并不总是有效地转化到临床上，我们将在FDA要求的绵羊模型和人源化小鼠模型(AIM 3)中验证我们的发现。这项工作的成功完成将促进这项前景光明的技术的进一步开发和转化 将长凳移至床边，用于修复先天性心脏畸形，并克服阻碍其广泛使用的关键障碍。它还将为创造更复杂的组织工程心血管结构(如带瓣管道)打开大门并提供一条途径，从而进一步提高我们治疗甚至治愈最严重形式的先天性心脏病的能力。

 DESCRIPTION (provided by applicant): Despite significant advances in the surgical and medical management of congenital heart disease, congenital cardiac anomalies remain a leading cause of death in the newborn period. Most severe forms of congenital heart disease require surgical intervention. Complications arising from the use of currently available prosthetic materials in the form of vascular grafts, patches, or replacement heart valves are a leading source of morbidity and mortality after congenital heart surgery. Currently available prosthetic materials such as polytetraflouroethylene (PTFE) are a significant source of thromboembolism, have poor durability due to neointimal hyperplasia, are susceptible to infection, and perhaps most importantly lack growth capacity, which results in the need for additional operations as children outgrow their prosthetics. The development of better biomaterials with growth potential could substantially improve the outcomes of children requiring congenital heart surgery by reducing the number of graft-related complications and enabling earlier definitive surgical repair without the risk of serial re-operation. Tissue engineering offers an innovative solution to this significant problem. Using tissue engineering methods, bioprosthetics can be made from an individual's own cells creating a living material with excellent biocompatibility and the ability t grow, repair, and remodel. We previously created the first tissue engineered vascular graft (TEVG) specifically designed for use in children, where its growth potential could be used to its greatest advantage. We subsequently performed the first clinical trial evaluating the use of the TEVG in congenital heart surgery. In this study we confirmed the growth capacity of the TEVG but also demonstrated that stenosis was the primary graft-related complication and the critical barrier preventing the widespread clinical adaptation of this technology. Our goal is to optimize the design of our TEVG. Using the TEVG as a model for bioprosthetics specifically developed for use in congenital heart surgery, we will investigate the fundamental mechanisms that lead to stenosis, the principal limitation of current TEVGs, and then apply our discoveries to the design of an improved vascular graft. In this application, we will focus on the role of transforming growth factor-β (TGF-β), which we have previously demonstrated is critical for the formation of TEVG stenosis in mouse models. We will explore the role of this cytokine both upon infiltrating host macrophages (aim 1) and then upon vascular cells that form the stenotic lesions (aim 2), applying the power of mouse genetics to dissect these processes. Finally, because findings in mice do not always effectively translate into the clinic, we will validate our findings in both a FDA-required ovine model and in a humanized mouse model (aim 3). Successful completion of this work will facilitate the further development and translation of this promising technology from the bench to the bedside for use in the repair of congenital cardiac anomalies and overcome a critical barrier preventing its widespread use. It would also open the door and provide a pathway for creating more complex tissue-engineered cardiovascular structures such as valved- conduits, which could further improve our abilities to treat and even cure the most severe forms of congenital heart disease.