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.
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