Computational Model Driven Design of Tissue Engineered Vascular Grafts

 描述(申请人提供)：尽管自体静脉移植物和合成移植物(用于大口径血管)在血管外科中作为替代管道普遍成功，但普遍缺乏合适的自体组织(特别是在最年轻和非常年长的患者中)和持续的高失败率仍然是显著的限制，尤其是对于小口径置换。因此，迫切需要另一种战略。在过去的几十年里，组织工程血管移植物(TEVGs)已经从台式设备发展到床边，目前正在对儿童和成年人进行临床试验。这些进展主要是通过对由不同表面化学成分、机械性能和几何特征(如孔径、纤维直径和孔隙率)定义的不同生物可降解聚合物支架进行艰苦的反复比较而产生的。临床前研究主要集中在安全性和有效性上，这主要意味着有足够的缝线保持和破裂压力，抗血栓，以及体内没有形成狭窄和动脉瘤。尽管取得了许多成功，但目前还没有正式的尝试来优化支架设计，以产生更接近天然生物力学性能并具有长期生物稳定性的生物力学性能。鉴于制造技术的不断进步，支架参数的几乎无限组合现在是可能的。然而，试错比较可能确定最佳组合，这是不可想象的。因此，我们提出了一种聚合物支架设计的新范式--我们将把无量纲化、参数敏感性和最优化的概念融合在一个新的已验证的体内新生细胞发育计算模型中，并与3个已验证的小鼠模型相结合，以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，包括由顺应性聚癸二酸甘油酯组成的内部多孔层，以促进细胞渗透，以及外部较少渗透、更坚硬的聚(e-己内酯)鞘，在内层快速降解和被肿瘤组织替代时支撑内层。计算模型将通过一系列小的初始实验来提供信息和改进，这些实验在体内揭示了在孔隙率、纤维直径和硬度方面的极端影响，同时描绘了炎症和机械介导的基质产生的重叠作用。使用无量纲化、参数敏感性、不确定性量化和优化的正式概念，然后我们将通过数千次模拟来确定最有希望的少数几个支架设计。这些设计将被制造成新的支架，并在小鼠体内进行长达两年的测试。与第一系列测试的结果进行比较，将会发现预测的设计是否确实明显更好；如果不是，我们可以重复这一过程。我们的目标的成功完成将为支架设计建立一种新的计算-实验范式，导致TEVG的显著改进，并通过新的实验方法、生物材料和建模为其他组织工程应用提供原型。

 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.