Design and Assessment of a Compliant Nanofibrous Vascular Graft

描述（由申请人提供）：血管移植在临床上用于修复或替换病变的冠状动脉和外周血管，以恢复正常的血流模式。由聚合物（如涤纶和膨胀聚四氟乙烯）组成的合成移植物在小直径（<6 mm）血管中效果不佳。这种移植物表现出低的通畅率，并且在很大程度上由于顺应性不匹配而失败。顺应性描述了血管移植物的机械性能如何作为内部血液动力学压力的函数而变化。天然血管显示出复杂的非线性“J形”应力-应变生物力学行为，这是细胞外基质弹性蛋白和胶原纳米纤维的函数。在低水平血管扩张时，具有直构型的弹性纤维主导低弹性模量。而具有波浪形或螺旋形取向的胶原纳米纤维在较低的血管扩张值下对扩张几乎没有阻力，而随着纳米纤维变直，在较高水平的血管扩张下主导高弹性模量。除了顺应性之外，具有非血栓形成内衬、生物相容性以及受体细胞向内生长后的血管活性对于血管移植物的长期功能也是重要的。该提案的创新在于设计和制造基于复合纳米纤维的组织工程血管移植物（TEVG），其模拟潜在植入部位的动脉细胞外基质微观结构和机械性能。换句话说，移植物将被设计为匹配需要替换的每种类型的动脉的顺应性。我们的初步数据表明，我们有能力通过采用不可降解的弹性蛋白样纳米纤维和可降解的胶原蛋白样纳米纤维来制造具有与天然血管（主动脉）的整体机械性能相匹配的整体机械性能的合成纳米纤维复合材料。在该提案中，这些材料将用于构建模仿兔颈动脉的TEVG，然后在三个特定目标中进行评估。这些目标包括生物力学和细胞移植物接种以及体外评估重塑特征和机械性能保留，包括顺应性、爆破强度和缝线抗拉强度随时间的变化。最后，将通过体内血管移植评估无细胞TEVG设计。将在植入后1个月确定通畅性、定量组织学、机械性能和血管活性的发展。将通过保留生物材料特性（e80%通畅率）、受体细胞向内生长后颈动脉样血管活性显著更好以及取出时吻合口增生比对照组（无胶原样微结构的TEVG）更少来证明进展至II期SBIR研究的可行性。在第二阶段，我们将提出大型动物临床前研究和其他测试所需的联邦监管批准的人体试验。 公共卫生相关性：心血管疾病是患者发病和死亡的主要原因。有效的小直径血管移植物是未满足的临床需求。该项目的潜在影响是为需要小直径动脉修复或置换的患者设计和生产有效的复合纳米纤维组织工程血管移植物。到2013年，全球血管移植物的潜在市场预计为1，657，000个单位，价值25.88亿美元。我们提出的方法的简单性，多功能性和可扩展性将允许快速的临床翻译和市场渗透。

DESCRIPTION (provided by applicant): Vascular grafting is performed clinically to repair or replace diseased coronary artery and peripheral vessels to restore normal blood flow patterns. Synthetic grafts composed of polymers such as Dacron and expanded polytetrafluoroethylene do not work well in small diameter (<6 mm) vessels. Such grafts exhibit low patency rates and fail, in large part, due to compliance mismatch. Compliance describes how the mechanical properties of a vascular graft change as a function of the internal hemodynamic pressure. Natural blood vessels display a complex non-linear 'J-shaped' stress-strain biomechanical behavior which is a function of extracellular matrix elastin and collagen nanofibers. Elastic fibers with straight conformation dominate the low elastic modulus at low levels of vessel distention. While collagen nanofibers with a wavy or helical orientation, with little resistance to expansion at lower values of vessel distention, dominate the high elastic modulus at higher levels of vessel distention as the nanofibers straighten. In addition to compliance, possession of a non-thrombogenic inner lining, biocompatibility and, after recipient cell ingrowth, vasoactivity is important for long term function of vascular grafts. The innovation in this proposal is design and manufacturing of composite nanofiber-based tissue-engineered vascular grafts (TEVGs) which mimic the potential implant site's arterial extracellular matrix microstructure and mechanical properties. In other words the grafts will be designed to match the compliance of each type of artery that requires replacement. Our preliminary data has demonstrated our ability to fabricate synthetic nanofibrous composite materials with overall mechanical properties matching those of a natural blood vessel (aorta) by employing a non-degradable elastin-like nanofiber and degradable collagen-like nanofibers. In this proposal these materials will be used in the construction of TEVGs mimicking the rabbit's carotid artery followed by evaluation in three specific aims. These aims include biomechanics and graft seeding with cells and in vitro assessment of remodeling profiles and retention of mechanical properties including compliance, burst strength and suture pull strength over time. Finally, cell-free TEVG designs will be assessed by vascular grafting in vivo. Patency, quantitative histology, mechanical properties and development of vasoactivity will be determined after one month post-implantation. Feasibility for progression to Phase II SBIR studies will be demonstrated by retention of biomaterial properties with e80% patency, the development of significantly better carotid-like vasoactivity after ingrowth of recipient cells and less anastomotic hyperplasia than controls (TEVGs without collagen-like microstructures) at explant. In Phase II we will propose large animal preclinical studies and other testing required for federal regulatory clearance for human trials. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is a leading cause of patient morbidity and mortality. Effective small diameter vascular grafts are an unmet clinical need. The potential impact of this project is design and production of effective composite nanofiber-based tissue-engineered vascular grafts for patients requiring small diameter artery repair or replacement. The potential world-wide market for vascular grafts is predicted to be 1,657,000 units valued at $2,588M by the year 2013. The simplicity, versatility, and scalability of our proposed approach will allow rapid clinical translation and market penetration.