Design and Assessment of a Compliant Nanofibrous Vascular Graft

描述(申请人提供)：血管移植在临床上是为了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。由涤纶和膨胀聚四氟乙烯等聚合物组成的合成移植物在小直径(&lt；6 mm)的容器中不能很好地工作。这类移植物的通畅率较低，并在很大程度上由于合规不匹配而失败。顺应性描述了血管移植物的机械特性如何随着内部血流动力学压力的变化而变化。天然血管表现出复杂的非线性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。在血管扩张程度较低的情况下，弹性纤维以直线构象为主。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时几乎不抵抗扩张，而在较高水平的血管扩张时，随着纳米纤维的伸直，占主导地位的是高弹性系数。除了依从性，拥有无血栓形成的内衬，生物相容性，以及在受体细胞植入后，血管活性对于血管移植物的长期功能是重要的。这一方案的创新之处在于设计和制造了基于复合纳米纤维的组织工程血管移植物(TEVGs)，它模拟了潜在植入部位的动脉细胞外基质的微观结构和机械性能。换句话说，移植物的设计将与每一种需要替换的动脉的顺应性相匹配。我们的初步数据表明，通过使用不可降解的弹性蛋白样纳米纤维和可降解的胶原样纳米纤维，我们能够制造出综合机械性能与天然血管(主动脉)相当的合成纳米纤维复合材料。在这项提案中，这些材料将用于构建模拟兔颈动脉的TEVGs，然后在三个具体目标上进行评估。这些目标包括生物力学和细胞移植种植，以及重塑轮廓的体外评估和力学性能的保留，包括顺应性、破裂强度和随时间推移的缝合拉力。最后，无细胞TEVG设计将通过体内血管移植进行评估。植入后一个月将确定通畅性、定量组织学、机械特性和血管活性的发展情况。进展到第二阶段SBIR研究的可行性将通过保持E80%通畅率的生物材料特性、在受体细胞植入后发展出显著更好的颈动脉样血管活性以及在外植体处比对照(没有胶原样微结构的TEVGs)更少的吻合口增生来证明。在第二阶段，我们将提出大型动物临床前研究和其他测试，以获得联邦监管机构对人体试验的批准。 公共卫生相关性：心血管疾病是患者发病率和死亡率的主要原因。有效的小直径血管移植物是临床上尚未满足的需求。该项目的潜在影响是为需要小直径动脉修复或替换的患者设计和生产有效的基于纳米纤维的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将达到1,657,000台，价值25.88亿美元。我们建议的方法的简单性、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.