Hyaluronan Coatings for Engineered Vessels

 描述（由申请人提供）：自20世纪80年代以来，改进的生物血管移植物材料的开发是一项重要的医疗需求。我们已经开发了一种组织工程化的细胞血管移植物，目前正在两个I/II期临床试验中进行评估。将人血管平滑肌细胞接种到生物反应器中的可降解聚合物上，并培养以产生基于血管平滑肌的工程化动脉。在定量脱细胞化之后，产生动脉移植物，其缺乏细胞抗原，主要由胶原组成，并且保留原始细胞移植物的机械性质。使用这项技术，人类，工程移植物已被植入作为动静脉（AV）移植到总共60例血液透析患者。正在进行的临床试验的中期分析显示，6个月和12个月的一期通畅率分别为64%和30%，而6个月和12个月的二期通畅率分别为97%和89%。97%和89%的二次通畅率明显优于PTFE移植物的历史值，这意味着无细胞移植物对感染和内膜增生均有抵抗力。然而，脱细胞移植物易发生血栓形成，需要血栓切除术干预，其一期通畅率与PTFE报告的相似。这些结果意味着移植物管腔上暴露的胶原蛋白触发血小板活化，导致急性血栓形成。如果用于小直径（<6 mm）外周或冠状动脉搭桥术，胶原触发的血小板活化也可能妨碍移植物功能。为了解决暴露的胶原蛋白和血小板活化的问题，我们已经开发了一种新颖的和创新的共价表面改性使用交联透明质酸（HA）。HA涂层在体外保护血小板不受胶原移植物表面的影响，我们的试验数据显示体内血栓形成减少。我们假设，涂层的无细胞，工程移植物与交联HA将屏蔽胶原血小板，减少血栓形成，并允许内皮细胞再生的移植管腔。为了验证这一假设，我们将使用猪动静脉移植模型进行一组合理的体外和体内研究，以确定生物学疗效。 这种涂层的影响可能 在未来，可以改善动静脉和小口径血管移植材料以及其他类型的血液接触表面的功能。我们为该项目带来的专业知识包括血管组织工程的领导者（Niklason），血管移植物重塑专家的外科医生（Dardik）以及率先开发功能化HA分子的生物材料领导者（Prestwich，顾问）。

 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).