Anti-Thrombogenic Membrane-Mimetic Assemblies

抗血栓形成膜模拟组件

• 批准号: 7142208
• 负责人: Elliot Chaikof
• 金额: $ 33.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142208
• 关键词: CD antigens; adenosinetriphosphatase; anticoagulants; antithrombins; antithrombogenic surface; artificial membranes; baboons; bioengineering /biomedical engineering; biomaterial development /preparation; biomaterial evaluation; biomaterial interface interaction; biomimetics; blood coagulation; blood vessel prosthesis; cell membrane; chemical kinetics; clinical research; fibrinogen; hemodynamics; human subject; lipid bilayer membrane; membrane model; membrane reconstitution /synthesis; membrane structure; molecular film; phospholipids; physiologic anastomosis; platelet activation; vascular endothelium

DESCRIPTION (provided by applicant): A clinically durable small diameter vascular graft may be achievable by identifying and incorporating into the prosthesis actively antithrombogenic mechanisms that are operative at the blood-material interface under a range of hemodynamic conditions. We believe that a membrane-mimetic assembly that contains CD39 (E- NTPDase-1) as an inhibitor of purinergic mediated platelet activation, aggregation, and recruitment provides a rational design strategy for such an approach. Specifically, we intend to: (1) Synthesize and characterize a membrane-mimetic thin film that incorporates CD39 as a mediator of an "on-demand" antiplatelet response. CD39 will be incorporated into polymerizable phospholipid vesicles and stable, substrate-supported, planar membrane assemblies will be produced and atomic level properties characterized. In the process, the extent to which the catalytic activity of the surface is dependent upon CD39 concentration, lipid membrane dynamics, and the local hemodynamic flow regime will be defined. (2) Define the role of the hemodynamic flow regime in modulating the effect of surface mediated purinergic pathway inhibition on platelet thrombus growth. The capacity of a CD39 based strategy to limit platelet activation and thrombus growth when initiated either by surface bound adhesive proteins or tissue factor will be evaluated using a parallel plate flow reactor under simulated arterial and venous flow conditions. (3) Determine the capacity of CD39 integrated into a membrane-mimetic interface to influence both thrombus formation and the development of anastomotic neointimal hyperplasia in vivo. Small diameter vascular prostheses will be functionalized with a membrane-mimetic film containing CD39. Initial studies will focus on acute platelet and fibrinogen deposition in a baboon ex vivo shunt model, as well as short-term biostability analysis. This will be followed by long-term primate studies of graft healing and patency. Lay summary: The control of thrombus formation on molecularly engineered surfaces may be an important step in the development of a small diameter arterial prosthesis critical to the fields of cardiac, plastic, and vascular surgery, as well as to the successful implantation of artificial organs and metabolic support systems.

描述（由申请人提供）：可以通过识别和纳入假体中的临床耐用小直径血管移植物可以实现，并在一系列血液动力学条件下积极地在血液材料界面上可在血液材料界面处有效。我们认为，包含CD39（E-NTPDase-1）作为嘌呤能介导的血小板激活，聚集和募集的膜模拟组装为这种方法提供了合理的设计策略。具体而言，我们打算：（1）合成并表征膜模拟薄膜，该膜将CD39融合为“按需”抗血小板反应的介体。 CD39将掺入可聚合的磷脂囊泡中，并将产生稳定的底物支持的平面膜组件，并表征原子水平的特性。在此过程中，将定义表面催化活性取决于CD39浓度，脂质膜动力学和局部血液动力学流动状态。 （2）定义了血流动力学方向在调节表面介导的嘌呤能途径抑制对血小板血栓生长的影响中的作用。当通过表面结合的粘合剂蛋白或组织因子引发时，基于CD39的策略限制血小板激活和血栓生长的能力将在模拟的动脉和静脉流动条件下使用平行板流动反应器进行评估。 （3）确定集成到膜模拟界面中的CD39的能力，以影响血栓形成和体内吻合的新内膜增生的发展。小直径的血管假体将用包含CD39的膜模拟膜功能化。最初的研究将集中于狒狒离体分流模型中的急性血小板和纤维蛋白原沉积，以及短期的生物稳定性分析。随后将进行长期对移植物愈合和通畅性的灵长类动物研究。摘要摘要：对分子工程表面上的血栓形成的控制可能是发展对心脏，塑料和血管外科田地至关重要的小型动脉假体以及成功植入人造器官和代谢支持系统的重要一步。