Design and Assessment of a Compliant Nanofibrous Vascular Graft

顺应性纳米纤维血管移植物的设计和评估

• 批准号: 8124591
• 负责人: Kelvin G.M. Brockbank
• 金额: $ 27.82万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124591
• 关键词: Animals; Aorta; Arteries; Behavior; Biocompatible Materials; Biomechanics; Biomimetics; Biopolymers; Bioreactors; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Carotid Arteries; Cells; Characteristics; Clinical; Clinical Trials; Collagen; Complex; Coronary artery; Data; Deposition; Development; Drug Formulations; Elastic Fiber; Elastin; Environment; Evaluation; Exhibits; Extracellular Matrix; Fiber; Future; Generations; Histology; Human; Hyperplasia; Implant; In Vitro; Lead; Marketing; Mechanics; Methods; Modification; Molecular Conformation; Morbidity - disease rate; Oryctolagus cuniculus; Outcome; Patients; Pattern; Penetration; Performance; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Polymers; Polytetrafluoroethylene; Polyurethanes; Preparation; Production; Property; Pulsatile Flow; Relaxation; Resistance; Sampling; Shapes; Simulate; Site; Small Business Innovation Research Grant; Stenosis; Stress; Surgical sutures; Testing; Time; Tissue Engineering; Translations; United States Food and Drug Administration; Vascular Graft; Work; base; biomaterial compatibility; dacron; design; functional restoration; graft failure; hemodynamics; implantation; in vivo; innovation; meetings; mortality; nanofiber; phase 2 study; polycaprolactone; preclinical safety; preclinical study; pressure; repaired; response; restenosis; safety testing; scaffold; shear stress; success

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.

描述（申请人提供）：临床上进行血管移植以修复或替换患病的冠状动脉和外周血管，以恢复正常的血流模式。由涤纶和发泡聚四氟乙烯等聚合物组成的合成移植物在小直径（<6 毫米）血管中效果不佳。此类移植物的通畅率较低，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随着内部血流动力学压力而变化。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。具有直构象的弹性纤维在低血管扩张水平下主导低弹性模量。虽然具有波状或螺旋取向的胶原纳米纤维在较低血管扩张值下几乎没有扩张阻力，但随着纳米纤维伸直，在较高血管扩张水平下主导高弹性模量。除了顺应性之外，拥有非血栓形成的内衬、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很重要。该提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（TEVG），它模仿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，移植物的设计将匹配每种需要置换的动脉类型的顺应性。我们的初步数据表明，我们有能力通过采用不可降解的类弹性蛋白纳米纤维和可降解的类胶原纳米纤维来制造合成纳米纤维复合材料，其整体机械性能与天然血管（主动脉）相匹配。在本提案中，这些材料将用于构建模仿兔子颈动脉的 TEVG，然后针对三个特定目标进行评估。这些目标包括生物力学和细胞移植接种，以及重塑轮廓的体外评估和机械性能的保留，包括随时间变化的顺应性、破裂强度和缝合拉力强度。最后，无细胞 TEVG 设计将通过体内血管移植进行评估。通畅性、定量组织学、机械特性和血管活性的发展将在植入后一个月后确定。进入 II 期 SBIR 研究的可行性将通过保留生物材料特性（通畅率达到 80%）、受体细胞向内生长后明显更好的颈动脉样血管活性的发展以及比对照（没有胶原样微结构的 TEVG）更少的吻合增生来证明。外植体。在第二阶段，我们将提出大型动物临床前研究和联邦监管机构批准人体试验所需的其他测试。 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基于复合纳米纤维的组织工程血管移植物。预计到 2013 年，全球潜在的血管移植市场将达到 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临床转化和市场渗透。