The ultimate objective of this research is to understand further role of the material in the pathogenesis of the thromboembolic complications of cardiovascular implants such as vascular catheters or prostheses. Our immediate objectives are: (A) to understand the basis for the differences among materials (e.g., PE and PVA) in the platelet consumption as observed in our unique chronic canine arterio-venous shunt and (B) to study the mechanism underlying the transient contact of platelets with hydrogel (high water content) surfaces - contact that does not result in adhesion yet appears to yield to their premature consumption. It is hypothesized that hydrogel surfaces (e.g., PVA), being """"""""slippery"""""""", are less able to retain platelets on their surface yet the transient contact of platelets is sufficient to damage them and cause them to be removed from the circulation prematurely. Hence consumption is high but adhesion is low; the opposite is found with PE. We will (1) study the thrombogenicity (111In canine platelet lifespan, etc) of well characterized materials of different surface chemistries and thereby define the particular characteristics that distinguish PE from PVA. Special emphasis will be given to short chain alkylated surfaces, one of which (butylated PVA) has eliminated the platelet reactivity of the PVA in preliminary studies. We also propose to (2) prepare a partially alkylated surface with low platelet reactivity that can be subsequently heparinized to yield a surface which would also have high anticoagulant activity. This material may be uniquely suitable for the minimization of the thromboembolic complications of cardiovascular devices since the immobilized heparin can prevent fibrin formation while the low reactivity will not result in high platelet consumption. Additional control materials that differ from PVA in a single functional group will also be evaluated. Furthermore, we propose to better understand the mechanism of biomaterial associated platelet activation. We will (3) exploit the sensitivity of flow cytometry (FAFC) and immunologic platelet membrane markers to characterize human platelet activation after exposure to PVA, PE, etc and (4) assess the relationship among surface chemistry, protein adsorption and transient platelet contact through fluorescent videomicroscopy measurement of human platelet residence time distribution and platelet attachment/detachment dynamics. We expect to identify strategies suitable for the preparation and ultimately the clinical evaluation (i.e. by FAFC) of low thrombogenicity, platelet compatible materials for cardiovascular devices. By minimizing the thromboembolic consequences of surgical intervention, existing therapies can be made safer and new ones developed as a consequence of material development.
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