Reduced platelet activation and thrombosis in extracorporeal circuits coated with nitric oxide release polymers.

OBJECTIVE: To determine whether the use of nitric oxide (NO)-releasing polymers coated onto the inner surface of extracorporeal circuits can reduce platelet consumption and activation in the absence of systemic heparinization using a rabbit model of venovenous extracorporeal circulation. DESIGN: Prospective, controlled trial. SETTING: Research laboratory at an academic medical institution. SUBJECTS: New Zealand White Rabbits. INTERVENTIONS: Anesthetized, tracheotomized, and ventilated New Zealand White rabbits were injected with freshly prepared, 111In(oxine)3 labeled single donor platelets through the external jugular vein. After baseline measurements, these animals were placed on venovenous extracorporeal circulation through a 1-m control circuit or NO test circuit for 4 hrs at a blood flow rate of 109-118 mL/min via roller pump. Four groups were studied: systemically heparinized control circuits, systemically heparinized NO test circuits, nonheparinized control circuits, and nonheparinized NO test circuits. Platelet counts, fibrinogen levels, and plasma free indium levels were measured hourly. Circuits were rinsed and retained for gamma counting after the 4-hr run or when the circuit clotted. Four animals, one from each group, did not receive radiolabeled platelets so that the circuits could be preserved for scanning electron microscopic examination after the 4-hr study. MEASUREMENTS AND MAIN RESULTS: Platelet consumption was significantly reduced in both the heparinized and nonheparinized NO test groups when compared with the controls (p < .0001 and p < .0004, respectively). Platelet adhesion to the extracorporeal circuits was significantly reduced in the nonheparinized test circuits when compared with the controls (p < .05). Scanning electron microscopic examination of the circuits revealed that in the absence of heparin and in the presence of a NO-releasing surface, platelets retained their spherical nonactivated shape. CONCLUSIONS: The incorporation of NO into the surface of extracorporeal circuits reduces platelet consumption and eliminates the need for systemic heparinization in a rabbit model of extracorporeal circulation.

Conversion of a polysaccharide to nitric oxide-releasing form. Dual-mechanism anticoagulant activity of diazeniumdiolated heparin.

We describe heparin/diazeniumdiolate conjugates that generate nitric oxide (NO) at physiological pH. Like the heparin from which they were prepared, they inhibit thrombin-induced blood coagulation. Unlike heparin, they can also inhibit and reverse ADP-induced platelet aggregation (as expected for an NO-releasing agent), suggesting potential utility as dual-action antithrombotics.

Improving the thromboresistivity of chemical sensors via nitric oxide release: fabrication and in vivo evaluation of NO-releasing oxygen-sensing catheters.

The development and in vivo analytical performance of a nitric oxide (NO)-releasing amperometric oxygen sensor with greatly enhanced thromboresistivity are reported. Gas permeable coatings formulated with cross-linked silicone rubber (SR) containing NO-generating compounds (diazeniumdiolates) are shown to release NO for extended periods of time (> 20 h) while reducing platelet adhesion and activation. Oxygen-sensing catheters prepared by dip-coating the NO-releasing films over the outer SR tubes of the implantable devices display similar analytical response properties in vitro (sensitivity, selectivity, response times) when compared to analogous sensors prepared without the NO release coatings. Superior analytical accuracy (relative to blood PO2 values measured in vitro) and greatly reduced thrombus formation on the outer surface of the sensors are observed in vivo (in canine model) with the NO release PO2 sensors compared to control sensors (without NO release) implanted simultaneously within the same animals. Based on these preliminary studies, the use of NO release polymers to fabricate catheter-style chemical sensors may be a potential solution to lingering biocompatibility and concomitant performance problems encountered when attempting to employ such devices for continuous intravascular measurements of blood gases and electrolytes.

Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release.

The preparation of hydrophobic polymer films (polyurethane and poly(vinyl chloride)) containing nitric oxide (NO)-releasing diazeniumdiolate functions is reported as a basis for improving the thromboresistivity of such polymeric materials for biomedical applications. Several different approaches for preparing NO-releasing polymer films are presented, including: (1) dispersion of diazeniumdiolate molecules within the polymer matrix; (2) covalent attachment of the diazeniumdiolate to the polymer backbone; and (3) ion-pairing of a diazeniumdiolated heparin species to form an organic soluble complex that can be blended into the polymer. Each approach is characterized in terms of NO release rates and in vitro biocompatibility. Results presented indicate that the polymer films prepared by each approach release NO for variable periods of time (10-72 h), although they differ in the mechanism, location and amount of NO released. In vitro platelet adhesion studies demonstrate that the localized NO release may prove to be an effective strategy for improving blood compatibility of polymer materials for a wide range of medical devices.