Computational Model Driven Design of Tissue Engineered Vascular Grafts

组织工程血管移植物的计算模型驱动设计

• 批准号: 9111979
• 负责人: Jay D. Humphrey
• 金额: $ 49.47万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111979
• 关键词: Abdomen; Accounting; Acute; Adjuvant; Adult; Advocate; Aneurysm; Animals; Area; Attention; Autologous; Beds; Biocompatible Materials; Biological; Biomechanics; Bioreactors; Blood Circulation; Blood Vessels; Bypass; Caliber; Cardiovascular Diseases; Cardiovascular system; Cellular Infiltration; Characteristics; Chemistry; Child; Childhood; Clinical Trials; Collaborations; Computer Simulation; Developed Countries; Development; Devices; Dilatation - action; Disease Progression; Educational workshop; Engineering; Evaluation; Evolution; Failure; Fiber; Future; Glycolates; Goals; Growth; Health; Homeostasis; Human; Implant; In Vitro; Inflammatory; Life; Mechanics; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Operative Surgical Procedures; Performance; Polymers; Population; Porosity; Prevalence; Procedures; Process; Production; Property; Rattus; Role; Safety; Series; Side; Stenosis; Surface; Surgical sutures; Techniques; Testing; Thrombosis; Thrombus; Time; Tissue Engineering; Tissues; Uncertainty; United States Food and Drug Administration; United States National Institutes of Health; Validation; Vascular Graft; Vein graft; Venous; Work; base; caprolactone; cost; cost efficient; design; engineering design; graft failure; hemodynamics; implantation; improved; in vivo; mortality; mouse model; novel; novel strategies; older patient; poly(glycerol-sebacate); preclinical study; pressure; research study; scaffold; simulation; success; treatment strategy

 DESCRIPTION (provided by applicant): Despite the general success of autologous vein grafts and synthetic grafts (for large caliber vessels) as replacement conduits in vascular surgery, both the common lack of suitable autologous tissue (especially in the youngest and very oldest of patients) and the continuing overall high failure rates remain as significant limitations, especialy for small caliber replacements. There is, therefore, a pressing need for another strategy. Over the past few decades, tissue engineered vascular grafts (TEVGs) have advanced from benchtop to bed- side, with clinical trials now underway in both children and adults. These advances have arisen primarily via laborious trial-and-error comparisons of different biodegradable polymeric scaffolds defined by different surface chemistries, mechanical properties, and geometric characteristics (e.g., pore sizes, fiber diameters, and porosities). Pre-clinical studies have necessarily focused on safety and efficacy, which has primarily meant sufficient suture retention and burst pressure, thrombo-resistence, and the lack of formation of stenosis and aneurysm in vivo. Notwithstanding these many successes, there has yet to be a formal attempt to optimize scaffold design to yield biomechanical properties closer to native and having long-term biological stability. Given the continued advances in fabrication techniques, an almost limitless combination of scaffold parameters is now possible. It is inconceivable, however, that trial-and-error comparisons can possibly identify an optimal combination. Hence, we suggest a new paradigm for polymeric scaffold design - we will meld concepts of nondimensionalization, parameter sensitivity, and optimization within a novel validated computational model of in vivo neovessel development with 3 proven mouse models to identify and test a new optimal scaffold design. Toward this end, we will seek a bilayered design consisting of an inner porous layer of compliant poly(glycerol sebacate) that encourages cellular infiltration and an outer less porous, stiffer poly(e-caprolactone) sheath that supports the inner layer during its rapid degradation and replacement with neotissue. The computational model will be informed and refined via a small series of initial experiments that reveal in vivo the effects o extremes in porosity, fiber diameter, and stiffness while delineating overlapping roles of inflammatory- and mechano- mediated matrix production. Using formal concepts of nondimensionalization, parameter sensitivity, uncertainty quantification, and optimization, we then will identify via thousands of simulations those few scaffold designs that are most promising. These designs will be fabricated as new scaffolds and tested in vivo in mice for up to 2 years. Comparisons with results from the first series of tests will reveal if the predicted desigs are indeed significantly better; if not, we can iterate the process. Successful completion of our aims will establish a new computational-experimental paradigm for scaffold design, result in a much improved TEVG, and serve as an archetype for other tissue engineering applications via novel experimental methods, biomaterials, & modeling.

 描述（由适用提供）：尽管自体静脉移植物和合成移植物（对于大口径vissels）作为血管手术中的替换管道取得了普遍的成功，但两者通常缺乏合适的自体组织（尤其是在最年轻的患者和最古老的患者中），并且是持续的总体高失败率，尤其是对小能量的较高的限制。因此，迫切需要另一种策略。在过去的几十年中，组织工程的血管移植物（TEVG）已从台式上延伸到床位，现在在儿童和成人中进行了临床试验。这些进步通过实验室试验和错误比较产生了不同的可生物降解聚合物支架，这些比较由不同的表面化学，机械性能和几何特性（例如，孔径，纤维直径和孔隙率）定义。临床前的研究必然关注安全性和效率，这主要意味着足够的持续保留和爆发压力，抗血栓性抗性以及体内缺乏狭窄和动脉瘤的形成。尽管取得了许多成功，但尚未进行正式尝试优化脚手架设计，以产生更接近天然和具有长期生物学稳定性的生物力学特性。鉴于制造技术的持续进展，现在几乎可以使用脚手架参数的无限组合。但是，不可想象的是，试验和错误的比较可能可以识别出最佳组合。因此，我们为聚合物支架设计提供了一种新的范式 - 我们将在新型验证的体内Neovessel开发的新型计算模型中融合非二敏化，参数敏感性和优化的概念，并使用3个可靠的鼠标模型来识别和测试新的最佳支架设计。为此，我们将寻求一种双层设计，该设计由内部多孔的多孔聚（甘油甲酸甘油）组成，该层鼓励细胞浸润和外部多孔，僵硬的僵硬的聚（E-Caprolactone）鞘，在其快速降解和替代Neotissue的过程中支持内层。计算模型将通过一系列初始实验来通知和完善，这些实验在体内揭示了O极端孔隙，纤维直径和刚度的影响，同时描述了炎症性和机械介导的基质产生的重叠作用。然后，我们将使用非二等化，参数灵敏度，不确定性定量和优化的概念，然后通过数千个模拟来识别那些最有前途的少数脚手架设计。这些设计将被制成新的脚手架，并在小鼠中在体内进行了2年的测试。与第一系列测试的结果的比较将揭示预测的设计是否确实更好。如果没有，我们可以迭代过程。成功完成我们的目标将为脚手架设计建立新的计算实验范式，从而改善了TEVG，并通过新型的实验方法，生物材料和建模来为其他组织工程应用提供原型。