Hyaluronan Coatings for Engineered Vessels

用于工程船舶的透明质酸涂层

• 批准号: 9038008
• 负责人: LAURA E NIKLASON
• 金额: $ 61.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-22 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038008
• 关键词: Acute; Address; Aneurysm; Antigens; Arteries; Autologous; Biocompatible Materials; Biological; Bioreactors; Blood Platelets; Blood coagulation; Blood typing procedure; Caliber; Cells; Clinical; Clinical Trials; Coagulants; Coagulation Process; Collagen; Coronary Artery Bypass; Data; Development; Dialysis procedure; Dilatation - action; Endothelial Cells; Engineering; Family suidae; Figs - dietary; Future; Hemodialysis; Heparin; Human; Human Engineering; Hyaluronan; Hyaluronidase; Hyperplasia; Immune; Immune response; Implant; In Vitro; Infection; Inflammation; Inflammatory; Intervention; Length; Leukocytes; Mechanics; Medical; Modeling; Modification; Patients; Peripheral; Phase; Phase I/II Trial; Platelet Activation; Poland; Polytetrafluoroethylene; Property; Reporting; Resistance; Role; Rupture; Seroma; Smooth Muscle Myocytes; Surface; Surgeon; Surgical sutures; Techniques; Technology; Testing; Thrombectomy; Thrombosis; Time; Tissue Engineering; Tissues; Translations; Transplanted tissue; Ursidae Family; Vascular Endothelial Growth Factors; Vascular Graft; Vascular Smooth Muscle; base; biodegradable polymer; chemical stability; clinical application; crosslink; graft function; implantation; improved; improved functioning; in vivo; innovation; novel; public health relevance; response; shear stress; surface coating; vascular tissue engineering

 DESCRIPTION (provided by applicant): The development of improved biological vascular graft materials is a significant medical need that has under development since the 1980's. We have developed a tissue-engineered, cellular vascular graft that is currently being evaluated in two, Phase I/II clinical trials. Human vascular smooth muscle cells are seeded onto a degradable polymer in a bioreactor, and cultured to produce an engineered vascular smooth muscle-based artery. After quantitative decellularization, an arterial graft is produced which lacks cellular antigens, is composed primarily of collagens, and which retains the mechanical properties of the original, cellular graft. Using this technology, human, engineered grafts have been implanted as arteriovenous (AV) grafts into a total of 60 hemodialysis patients. Interim analysis of ongoing clinical trials has shown primary patency at 6 and 12 months is 64% and 30%, while secondary patency at 6 and 12 months is 97% and 89%, respectively. Secondary patencies of 97% and 89% are substantially better than historical values for PTFE grafts, implying that the acellular grafts are resistant both to infection and to intimal hyperplasia. However, acellular grafts are subject to thrombosis and require thrombectomy interventions, and their primary patency is similar to that reported for PTFE. These results imply that exposed collagen on the graft lumen triggers platelet activation, leading to episodes of acute thrombosis. Collagen-triggered platelet activation may also hamper graft function if they are used for small-diameter (< 6mm) peripheral or coronary artery bypass. To address this issue of exposed collagen and platelet activation, we have developed a novel and innovative covalent surface modification using cross-linked hyaluronan (HA). The HA coating shields platelets from the collagenous graft surface in vitro, and our pilot data show decreased thrombosis in vivo. We hypothesize that coating of acellular, engineered grafts with cross-linked HA will shield collagen from platelets, decrease thrombosis, and allow endothelial repopulation of the graft lumen. To test this hypothesis, we will perform a rational set of in vitro and in vivo studies, using a porcie model of arteriovenous grafting to establish biological efficacy. The impact of this coating could be to improve the function of arteriovenous and small- caliber vascular grafting materials, as well as other types of blood-contacting surfaces, in the future. The expertise that we have brought to bear on this project includes a leader in vascular tissue engineering (Niklason), a surgeon who is an expert in vascular graft remodeling (Dardik), and a leader in biomaterials who has pioneered the development of functionalized HA molecules (Prestwich, consultant).

 描述（由适用提供）：自1980年代以来，改善生物性血管移植物材料的发展是正在开发的重要医疗需求。我们已经开发了一种组织设计的细胞血管移植物，目前正在两期/II期临床试验中进行评估。人血管平滑肌细胞在生物反应器中播种到可降解的聚合物上，并培养以产生工程的血管平滑肌基。定量脱细胞后，产生了缺乏细胞抗原的伪影，由胶原蛋白组成，并保留原始细胞移植物的机械性能。使用这项技术，人类工程的移植物已被植入动静脉（AV）移植物成60例血液透析患者。对正在进行的临床试验的临时分析显示，在6和12个月时，初级通畅率为64％和30％，而6和12个月的次级通畅分别为97％和89％。 97％和89％的二级专辑明显优于PTFE图形的历史值，这意味着细胞移植对感染和内膜增生都具有抵抗力。然而，细胞移植受到血栓形成，需要进行血栓切除术，其主要通畅性与PTFE报道的相似。这些结果表明，在移植管腔触发血小板激活上暴露了胶原蛋白，导致急性血栓形成发作。如果使用胶原蛋白触发的血小板激活，则如果将其用于小直径（<6mm）外周或冠状动脉旁路，则可能是障碍物移植的功能。为了解决裸露的胶原蛋白和血小板激活问题，我们使用交联的透明质酸（HA）开发了一种新颖而创新的共价修饰。 HA涂层在体外屏蔽了胶原谷物表面的血小板，我们的试点数据显示体内血栓形成降低。我们假设具有交联HA的细胞，工程移植物将胶原蛋白屏蔽到血小板中，减少血栓形成，并允许对移植腔的内皮重群。为了检验这一假设，我们将使用动静脉嫁接的波尔奇模型来建立生物学效率，进行一组合理的体外和体内研究。这种涂层的影响可能 将来，要改善动脉静脉和小口径的血管嫁接材料以及其他类型的血液接触表面的功能。我们在该项目上带来的专家包括一位血管组织工程（Niklason）的领导者，他是一名外科医生，他是血管移植重塑（Dardik）的专家，也是生物材料的领导者，他们率先开发了功能齐全的HA Molecules（Prestwich，顾问，顾问）。