Molecular barriers to biomaterial thrombosis by modification of surface proteins with polyethylene glycol.

For cardiovascular biomaterials, thrombosis, thromboembolism and vascular graft occlusion are believed to be precipitated by the adsorption of proteins containing adhesive ligands for platelets. Polyethylene-glycol-diisocyanate(PEG-diisocyanate, 3400 MW) may potentially react with protein amines to form molecular barriers on adsorbed proteins on biomaterials, thereby masking adhesive ligands and preventing acute surface thrombosis. To test this notion, PE, PTFE, and glass microconduits were pre-adsorbed with fibrinogen and treated with PEG-diisocyanate, non-reactive PEG-dihydroxyl, or remained untreated. Following perfusion of 111In-labeled platelets in whole human blood for 1 min (wall shear rate = 312 s(-1)), PEG-diisocyanate treated surfaces experienced 96%(PE), 97%(PTFE) and 94% (glass) less platelet deposition than untreated surfaces. Similar reductions were seen for PEG-diisocyanate versus PEG-dihydroxyl treatment. Low shear perfusions of plasma for one hour prior to blood contact did not reduce the inhibitory effect of PEG-diisocyanate. Platelet adhesion onto collagen coated glass coverslips and platelet deposition onto preclotted Dacron was also reduced by treatment with PEG-diisocyanate (93 and 91%, respectively). Protein-reactive PEG may thus have utility in forming molecular barriers on surface associated proteins to inhibit acute thrombosis on cardiovascular biomaterials.

Molecular barriers to biomaterial thrombosis by modification of surface proteins with polyethylene glycol.

For cardiovascular biomaterials, thrombosis, thromboembolism and vascular graft occlusion are believed to be precipitated by the adsorption of proteins containing adhesive ligands for platelets. Polyethylene-glycol-diisocyanate (PEG-diisocyanate, 3400 MW) may potentially react with protein amines to form molecular barriers on adsorbed proteins on biomaterials, thereby masking adhesive ligands and preventing acute surface thrombosis. To test this notion, PE, PTFE, and glass microconduits were pre-adsorbed with fibrinogen and treated with PEG-diisocyanate, non-reactive PEG-dihydroxyl, or remained untreated. Following perfusion of 111In-labeled platelets in whole human blood for 1 min (wall shear rate = 312 s(-1)), PEG-diisocyanate treated surfaces experienced 96% (PE), 97% (PTFE) and 94% (glass) less platelet deposition than untreated surfaces. Similar reductions were seen for PEG-diisocyanate versus PEG-dihydroxyl treatment. Low shear perfusions of plasma for 1 h prior to blood contact did not reduce the inhibitory effect of PEG-diisocyanate. Platelet adhesion onto collagen-coated glass coverslips and platelet deposition onto preclotted Dacron were also reduced by treatment with PEG-diisocyanate (93 and 91%, respectively). Protein-reactive PEG may thus have utility in forming molecular barriers on surface-associated proteins to inhibit acute thrombosis on cardiovascular biomaterials.

Creating molecular barriers to acute platelet deposition on damaged arteries with reactive polyethylene glycol.

We report here a novel method for blocking acute platelet deposition at the site of vessel injury by molecularly masking thrombogenic vascular wall proteins with covalently attached polyethylene glycol (PEG). To evaluate this technique, blood containing 111In-labeled platelets was perfused over damaged human placental arteries for 2 min at a wall shear rate of 200 s-1. Denuded vessel segments were incubated for 30, 15, 5, and 1 min with a solution of either reactive PEG-diisocyanate (PEG-ISO) or nonreactive PEG-dihydroxyl (PEG-OH). Vessels treated with PEG-ISO for 1 min exhibited 87 +/- 12% less platelet deposition (p < 0.01) than untreated control vessels, and this reduction did not vary significantly among treatment times, indicating that this reaction occurs rapidly enough to be clinically applicable. To investigate the duration of this thrombotic barrier, denuded pig carotid arteries were treated with reactive PEG-ISO for 1 min, perfused with plasma for 30 min, and then perfused with blood containing radiolabeled platelets. PEG-ISO-treated arteries exhibited 84 +/- 9% less platelet deposition (p < 0.05) than untreated controls. These data demonstrate that damaged arterial surfaces can be rendered resistant to platelet deposition after short contact periods with reactive PEG. Molecular PEG barriers ultimately might find application following vascular procedures to sterically inhibit blood cell interaction with damaged vascular surfaces.