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. The investigator believes that a membrane-mimetic assembly that contains thrombomodulin (TM) as an activator of the endogenous protein C anticoagulant pathway provides a rational design strategy for such an approach. Specifically, the investigator intends to: Synthesize and characterize a membrane-mimetic thin film incorporating thrombomodulin as a mediator of an """"""""on demand"""""""" anticoagulant response. TM will be incorporated into polymerizable phospholipid vescles and stable, substrate-supported, planar membrane assemblies will be produced and atomic level properties characterized. In the process, the relationship between lipid head composition, TM concentration, and membrane dynamics in the activation of protein C will be elucidated and the effect on thrombin generation defined. Define the role of the hemodynamic flow regime in modulating protein C activation and thrombin generation using membrane-mimetic model systems. The extent to which a TM based strategy generates an antithrombogenic environment under arterial and venous flow environments will be evaluated using a tubular flow reactor system. The role of wall shear rate in modulating the kinetic parameters for activated protein C production will be determined. In addition, we will define the capacity of these systems to limit thrombin generation when either the intrinsic or extrinsic coagulation pathways are initiated under varying flow conditions. Determine the capacity of thrombomodulin 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 incorporated TM. 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.
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