Heparin thromboresistant surfaces

To circumvent many of these undesired side effects associated with systemic heparin administration, many investigators have endeavored to immobilize heparin to blood-contacting polymers to form thromboresistant surfaces. Considering that heparin binds to the endothelium following systemic injection (I), this approach appears attractive. 

The strategy we adopted in developing thromboresistant, heparin-immobilized surfaces is ... 

Haddad, Chitosan-heparin as a thromboresistant surface. in "Proc. Second Inti. Conference on Chitin Chitosan", S. Hirano and S. Tokura (Eds.), Japan Society for Chitin, Sapporo, Hokkaido, Japan (1982). 

It has been well documented that most artificial materials, whether hydrophilic, hydrophobic, made electroconductive by the dispersion of conductive particles in it, smooth, rough or heparinized, were covered with protein immediately following implantation into the cardiovascular system (1,2). Regardless of this protein coating, some of the materials had higher thromboresistance than others. Many theories have been proposed to explain these thrombo-resistant properties, but a definitive answer to these questions would be premature at this time. We have also found that not every protein surface shows thromboresistance however, when the protein surface was treated with an aldehyde or heat. It resulted in a reproducibly improved thromboresistant surface. 

A semi-interpenetrated network was obtained by bulk polymerization of 2-hydroxye-thyl methacrylate incorporated in DMF treated PET films by solvent-exchange technique, followed by treatment of films in e-lectrical discharges. Heparinization was accomplished by reacting glutaraldehyde with heparin and poly(2-hydroxyethyl methacrylate) present on the surface of modified polyester films. The immobilization of heparin was indirectly evidenced by chromatographying the silylated hydrolyza-tes of heparinized PET films and heparin, respectively. In vitro experiments demonstrated the enhanced thromboresistance of heparinized films. 

The thromboresistance of heparinized films, as shown in Table VI, was enhanced by higher hydrogel content since the concentration of hydroxylic groups on modified PET film surface, able to react with glutaralde-hyde in order to bind heparin, was higher. 

The results discussed in the previous Section permits to make some assumptions regarding the mechanism of enhanced thromboresistance of HCP. Two self-excluding viewpoints concerning the problem coexist in the literature. The first one implies the elution of heparin from a polymeric surface into the bloodstream which prevents clotting in a way common for the anticoagulant itself64,67 73). According to the second, the... 

Optimal stent implantation and new antiplatelet therapy have reduced the thrombotic complication after stent implantation, dramatically. However, thrombosis remains a challenge in some lesions and patient subgroups. As an initial and unavoidable event during stent implantation, thrombosis and platelet activation are also involved in the development of neointimal hyperplasia. Stents coated with heparin and other antithrombotic drugs have been demonstrated to decrease thrombotic complications, although their effect on neointimal hyperplasia remains uncertain. As heparin is attached to the stent surface, we divide thromboresistant stents as heparin-coated stents and drug-eluting thromboresistant stents. 

Wilson, at Bishop College, and Eberhart and Elkowitz at University of Texas (27) have irradiated a silicone substrate in the presence of chloromethylstyrene monomer to produce a reactive graft polymer that can be quarternized with pyridine and reacted with sodium heparin to produce a thromboresistant heparinized product that has a higher blood compatibility than the untreated silicone. The same group has used essentially the same methods to create a heparin grafted polyethylene surface. 

Other concerns regarding the practicality of surface bound heparin for the preparation of materials with long-term thromboresistance remain. Because the interaction of heparin with platelets is unclear (31), whether the immobilized heparin causes greater thrombosis under conditions where platelet deposition is more important than fibrin formation remains to be shown. The passivating effect of antithrombin III on platelet consumption caused by surface-bound heparin is a significant observation in this context (32, 33). 

The results reported here, in conjunction with earlier results, indicate that immobilized heparin need not necessarily be lost from a surface in order to impart thromboresistance to that surface. For heparin-PVA, and perhaps for other covalent reactions that do not inactivate the heparin, the irreversibly bound heparin can accelerate the formation of a surface-bound inactive thrombin-antithrombin III complex. Furthermore, our results suggest that the inactive complex is not itself permanently bound to the surface, but rather can be displaced by a component or components in plasma. 

Segmented polyurethanes have good resistance to thromboresistance plus exceptionally good physical properties which makes them unique. Also special surface treatment of the PU is not usually required for heparin anticoagulant attachment, hydrogel grafting, nor blood treatment with... 

Chitosan-heparin coated polymers display excellent thrombo-resistance properties. The lifetime of the thromboresistance can be extended by covalently binding the heparin to chitosan with the aid of sodium cyanoborohydride. This surface treatment is useful for biomedical applications requiring blood compatibility for periods as long as four days. 

Arnander, C., Bagger-Sjoebaeck, D., FrebeUus, S., Larsson, R., Swedenborg, J. Long-term stability in vivo of a thromboresistant heparinized surface. Biomaterials 8(6), 496-499 (1987)... 

Biologically modified surfaces - were a different approach in that if surface treatments could be found that were compatible, or at least thromboresistant, substrates could be chosen on the basis of suitability for the application. Because of the promise shown by the ionically-bonded heparinized surfaces, considerable study was devoted to methods of heparinization, by both ionic and covalent bonding. 

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