Mechanisms of Vascular Neotissue Formation in Tissue Engineered Vascular Grafts

 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，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，也许最重要的是缺乏生长能力，这导致随着儿童生长超过假体的年龄，需要进行额外的手术。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。组织工程为这个棘手的问题提供了一个潜在的解决方案。 使用组织工程方法，生物假体可以从个人自身的细胞中制造出来，创造出具有良好生物兼容性和生长、修复和重塑能力的活材料。这项应用的目标是优化用于先天性心脏手术的改良血管移植物的设计。利用组织工程血管移植物(TEVG)作为专门用于先天性心脏手术的生物假体模型，我们将根据血管新生组织形成的机制合理地设计一种改进的TEVG。我们的工作将集中在宿主来源的巨噬细胞在血管新生组织形成中的作用，我们之前已经证明，这对新生血管的形成和长期移植物功能的主要决定因素至关重要。我们将使用小鼠模型来研究巨噬细胞在TEVG狭窄形成中所起作用的细胞和分子机制，然后根据我们的发现，合理地设计优化新组织形成、新生血管功能和TEVG性能的策略。最后，我们将使用人性化的小鼠模型来验证这些策略。这项工作将补充我们正在进行的评估TEVG在先天性心脏手术中的使用的临床研究，并促进这一有前途的技术的开发和从工作台到床边的转换。

 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 polytetrafluoroethylene 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 risk of serial re-operation. Tissue engineering offers a potential solution to this vexing 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 to grow, repair, and remodel. The goal of this application is to optimize the design of an improved vascular graft for use in congenital heart surgery. Using the tissue engineered vascular graft (TEVG) as a model for bioprosthetics specifically developed for use in congenital heart surgery, we will rationally design an improved TEVG based on the mechanisms underlying vascular neotissue formation. We will focus our work on the role of host-derived macrophages on vascular neotissue formation, which we have previously demonstrated are critical to neovessel formation and the primary determinants of long-term graft function. We will use murine models to investigate the cellular and molecular mechanisms underlying the role of macrophages in the formation of TEVG stenosis, and then, based on our discoveries, rationally design strategies for optimizing neotissue formation, neovessel function, and TEVG performance. Finally we will validate these strategies using a humanized mouse model. This work will complement our ongoing clinical studies evaluating the use of TEVG in congenital heart surgery and facilitate the development and translation of this promising technology from the bench to the bedside.