Hyaluronan Coatings for Engineered Vessels

 描述(申请人提供)：改进的生物血管移植物材料的开发是一项重大的医学需求，自20世纪80年代S以来一直在开发。我们已经开发出一种组织工程的细胞血管移植物，目前正在进行两项I/II期临床试验。在生物反应器中，人的血管平滑肌细胞被种植到可降解的聚合物上，并进行培养，以产生基于血管平滑肌的工程化动脉。在定量去细胞后，产生的动脉移植物缺乏细胞抗原，主要由胶原蛋白组成，并保留了原始细胞移植物的机械性能。利用这项技术，已将人体工程移植物作为动静脉移植物植入到总共60名血液透析患者体内。正在进行的临床试验的中期分析显示，6个月和12个月的一次通畅率分别为%和30%，而6个月和12个月的二次通畅率分别为97%和89%。PTFE移植物的继发通畅率分别为97%和89%，明显好于历史值，这意味着脱细胞移植物对感染和内膜增生都具有抵抗力。然而，脱细胞移植物容易发生血栓，需要血栓切除干预，其主要通畅性与报道的聚四氟乙烯相似。这些结果表明，移植物管腔上暴露的胶原蛋白触发了血小板的激活，导致急性血栓形成的发作。如果用于小直径(6 Mm)的外周或冠状动脉搭桥术，胶原蛋白触发的血小板激活也可能阻碍移植物功能。为了解决暴露的胶原蛋白和血小板活化的问题，我们开发了一种使用交联型透明质酸(HA)的新颖和创新的共价表面修饰。在体外，HA涂层保护了血小板免受胶原移植表面的影响，我们的初步数据显示，体内血栓形成减少。我们推测，脱细胞的工程移植物表面涂有交联型透明质酸，可以保护胶原不受血小板的影响，减少血栓形成，并允许移植物管腔内皮细胞的再生。为了验证这一假设，我们将进行一系列合理的体外和体内研究，使用门静脉移植模型来建立生物学效果。这种涂层的影响可能 未来将改善动静脉和小口径血管移植材料的功能，以及其他类型的血液接触表面。我们为该项目带来的专业知识包括一位血管组织工程领域的领导者(尼克森)、一位血管移植物重塑方面的专家(达迪克)，以及一位率先开发功能化HA分子的生物材料领域的领导者(普雷斯特维奇，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).