Improving Tissue Engineered Vascular Graft Performance via Computational Modeling

通过计算建模提高组织工程血管移植物的性能

• 批准号: 10082302
• 负责人: Jay D. Humphrey
• 金额: $ 88.23万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-04-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082302
• 关键词: 3-Dimensional; Affect; Angioplasty; Animal Model; Animals; Autologous; Biological; Biomechanics; Blood Circulation; Blood Vessels; Cardiac Surgery procedures; Cardiovascular system; Cause of Death; Cells; Child; Clinical; Clinical Trials; Collaborations; Common Ventricle; Complex; Complication; Computer Models; Congenital Abnormality; Congenital Heart Defects; Data; Development; Disease Progression; Evolution; Extracellular Matrix; Future; Geometry; Goals; Growth; Guidelines; Heart Abnormalities; Histologic; Human; Implant; In Vitro; Incidence; Inferior vena cava structure; Intervention; Joints; Liquid substance; Live Birth; Mediating; Medical; Modeling; Morbidity - disease rate; Mus; Natural History; Newborn Infant; Operative Surgical Procedures; Outcome; Patients; Performance; Personal Satisfaction; Phenocopy; Polymers; Positioning Attribute; Procedures; Process; Property; Public Health; Publications; Randomized; Reconstructive Surgical Procedures; Repeat Surgery; Resolution; Safety; Sheep; Solid; Stenosis; Structure; Technology; Tissue Model; Tubular formation; Validation; Vascular Graft; Work; animal data; base; biodegradable polymer; clinical decision-making; computer framework; congenital heart disorder; design; disability; first-in-human; heart valve replacement; hemodynamics; high risk population; improved; improved outcome; in vivo; in vivo Model; in vivo imaging; insight; man; model development; mortality; novel; palliate; pediatric patients; prospective; scaffold; serial imaging; sheep model; simulation; vascular tissue engineering

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.

项目摘要 我们小组的首次人体研究表明，我们的聚合物组织工程血管移植物 （TEVG）代表了一种令人兴奋的新的治疗选择患有先天性心脏病的儿童。在 特别是，这些移植物从接种有自体移植物的可生物降解的管状支架的自然进化， 细胞到由天然细胞和细胞外基质组成的新血管代表了第一个真正“生长”的移植物 潜在的”，这可以消除与躯体过度生长有关的问题， 他们的嫁接。然而，这些TEVG治疗儿童的广泛临床适应性 先天性心脏病已经被“狭窄”的高发病率所减缓， 用于安全地处理这种并发症。然而，我们小组最近的研究结果表明， 被解释为狭窄的TEVG的早期狭窄实际上可以自然地和简单地解决 这是正常自然史的一部分，因此不需要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血管形成的自然历史。 为此，我们开发了一种大型动物（绵羊）模型，其中植入TEVG表型模仿人类 也就是说，一些移植物会变窄，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（体内几何学和血液动力学、体外生物力学、细胞生物学和组织学） 需要建立一个新的计算模型的TEVG发展和（ii）这样的计算 模型可以提供独特的洞察TEVG发展的自然历史，以及预测 能够就潜在的介入治疗（血管成形术）做出更明智的决策 在TEVG开发过程中。为此，我们提出的“流体-固体-生长”模型将整合验证 在三维中进行受试者特定的流体-固体相互作用以及血管生长和重塑模拟， 量化体内TEVG发展的自然史，包括潜在的狭窄和治疗的需要。 无论是否进行血管成形术。该模型将使用体内绵羊数据进行通知和验证，其预测性 在前瞻性模型引导血管成形术中验证了该能力。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 改善先天性手术中TEVG的使用和未来设计，并具有预测 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 机制等这项工作将通过汇集三个互补小组的专门知识来完成， 有先前成就的跟踪记录，以促进使用有前途的技术， 可能会对患有先天性心脏异常的人的健康产生重大影响。