Improving Tissue Engineered Vascular Graft Performance via Computational Modeling

项目总结 我们团队的第一项人体研究表明，我们基于聚合物的组织工程化血管移植物 (TEVGs)为患有先天性心脏病的儿童提供了一种令人兴奋的新治疗选择。在……里面 特别是，这些移植物来自可生物降解的管状支架的自然进化 细胞移植到由天然细胞和细胞外基质组成的新生细胞代表了第一个真正生长的移植物 潜力“，可以消除与躯体过度生长相关的问题，患者通过这个过程 长出了他们的嫁接。然而，这些TEVGs的广泛临床适应性用于治疗儿童 先天性心脏病因“狭窄”发生率高而延缓，尽管血管成形术可以 用来安全地处理这种并发症。然而，我们小组最近的发现表明，观察到的 被解释为狭窄的TEVG早期狭窄实际上可能会自然和简单地解决 是其正常自然历史的一部分，因此不需要或甚至不建议进行血管成形术。有一个 迫切需要更好地了解新星形成的自然历史。 为此，我们开发了一种大型动物(绵羊)模型，在该模型中植入了TEVGs表型人类 移植物，也就是说，有些会发生狭窄，而另一些则不会。我们认为：(I)该动物模型可以提供 纵向数据(体内几何和血流动力学、体外生物力学和细胞生物学和组织学) 这是建立TEVG开发的新计算模型所需的，以及(Ii)这样的计算模型 模型可以提供对TEVG发展自然历史的独特洞察，以及预测 能够对潜在的介入治疗(血管成形术)做出更明智的决策 在TEVG开发期间。为此，我们提出的“流体-固体-生长”模型将整合经过验证的 受试者特定的流固相互作用以及血管生长和重塑的三维模拟 量化TEVG在体内发展的自然历史，包括潜在的狭窄和治疗的需要 不管有没有血管成形术。该模型将使用活体绵羊数据进行通知和验证，其预测 在预期的模型指导下的血管成形术过程中验证了能力。由此产生的计算框架 将实现第一个三维的、特定于对象的流体-固体-生长血管模拟，这将 改进TEVGs在先天性手术中的使用和未来设计，并在预测中具有广泛的实用价值 由免疫或机械生物学驱动的各种心血管应用中的疾病进展 机械装置。这项工作将通过汇集三个互补小组的专业知识来完成， 具有先前成就的跟踪记录，以促进具有以下优点的有前景的技术的使用 有可能对先天心脏畸形患者的健康产生重大影响。

PROJECT SUMMARY First-in-human studies by our group demonstrated that our polymer-based tissue engineered vascular grafts (TEVGs) represent an exciting new treatment option for children afflicted with congenital heart disease. In particular, the natural evolution of these grafts from a biodegradable tubular scaffold seeded with autologous cells to a neovessel consisting of native cells and extracellular matrix represents the first graft with true “growth potential”, which could eliminate problems associated with somatic overgrowth, the process by which patients outgrow their graft. Nevertheless, widespread clinical adaptation of these TEVGs to treat children with congenital heart disease has been slowed by a high incidence of “stenosis” even though angioplasty can be used to safely manage this complication. Recent findings from our group suggest, however, that the observed early narrowing of the TEVG that has been interpreted as stenosis may actually resolve naturally and simply be a part of its normal natural history, thus rendering angioplasty not needed or even ill advised. There is a pressing need to understand better the natural history of neovessel formation. Toward this end, we developed a large animal (sheep) model wherein implanted TEVGs phenocopy human grafts, that is, some develop a narrowing while others do not. We submit that (i) this animal model can provide longitudinal data (in vivo geometric & hemodynamic, in vitro biomechanical, and cell biological & histological) that are needed to build a novel computational model of TEVG development and (ii) such a computational model can provide unique insight into the natural history of TEVG development as well as a predictive capability that will enable better informed decisions regarding potential interventional treatment (angioplasty) during TEVG development. To this end, our proposed “fluid-solid-growth” model will integrate validated subject-specific fluid-solid interaction and vascular growth and remodeling simulations in three dimensions to quantify the natural history of TEVG development in vivo, including potential narrowing and the need to treat with angioplasty or not. The model will be informed and validated using in vivo sheep data, and its predictive capability verified in prospective model-guided angioplasty procedures. The resulting computational framework will enable the first three-dimensional, subject-specific fluid-solid-growth vascular simulations, which will improve the use and future design of TEVGs for congenital surgery as well as have broad utility for predicting disease progression in diverse cardiovascular applications that are driven by immuno- or mechano-biological mechanisms. This work will be accomplished by bringing together expertise from three complementary groups, having a track record of prior accomplishments, to advance the use of a promising technology that has the potential to impact significantly the well being of those afflicted with congenital cardiac anomalies.