Design and Assessment of a Compliant Nanofibrous Vascular Graft

描述（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周围血管，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接枝在小直径（<6毫米）血管中效果不佳。这种移植物表现出低通畅率和失败，在很大程度上是由于依从性不匹配。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。天然血管在细胞外基质弹性蛋白和胶原纳米纤维的作用下表现出复杂的非线性“j型”应力-应变生物力学行为。具有直构象的弹性纤维在低水平血管扩张时占主导地位。而胶原纳米纤维呈波浪状或螺旋状取向，在较低的血管扩张值下几乎没有膨胀阻力，当纳米纤维拉直时，在较高的血管扩张水平上具有高弹性模量。除了顺应性外，具有非血栓性内层、生物相容性以及受体细胞向内生长后的血管活性对血管移植物的长期功能也很重要。该方案的创新之处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（TEVGs），它模拟了潜在植入部位动脉细胞外基质的微观结构和力学性能。换句话说，移植物的设计将与需要替换的每种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类弹性蛋白纳米纤维和可降解的类胶原纳米纤维，我们有能力制造出整体机械性能与天然血管（主动脉）相匹配的合成纳米纤维复合材料。在本提案中，这些材料将用于构建模拟兔子颈动脉的TEVGs，并在三个具体目标下进行评估。这些目标包括生物力学和细胞移植物播种，以及体外评估重塑概况和机械性能的保留，包括顺应性、破裂强度和缝合拉力随时间的变化。最后，无细胞TEVG设计将通过血管移植在体内进行评估。通畅度、定量组织学、力学特性和血管活性的发展将在植入后一个月后进行测定。进展到II期SBIR研究的可行性将通过以下方面来证明：生物材料特性的保留（e80%的通畅性）、受体细胞长入后颈动脉样血管活性的显著提高以及移植体中吻合口增生的减少（没有胶原样微结构的TEVGs）。在第二阶段，我们将提出大型动物临床前研究和其他联邦监管机构批准的人体试验所需的测试。

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.