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ICE Krakow

ICE Krakow

ul. Marii Konopnickiej 17 30-302 Kraków


Gegenschatz-Schmid, Katharina


Due to their favorable elastic properties, corrosion resistance and biocompatibility blood-contacting Nitinol is the material of choice for devices to treat cardiovascular diseases. A major drawback however is their strong thrombogenicity, making the use of systemic anticoagulation inevitable. Therefore, there is an urgent clinical need for reducing the thrombogenicity of Nitinol. We describe a simple surface treatment including the removal of surface contaminations and functionalizing the surface with phosphate ions. This treatment rendered commercially available Nitinol highly hydrophilic and anti-thrombotic. We investigate here the efficacy and mechanism of this treatment by comparing standard and surface treated Nitinol samples in terms of blood contact activation, cell adhesion, protein adsorption and endothelialization.

Nitinol discs and braids were tested. Discs were electropolished and passivated whereas the braids were thermally oxidized after electropolishing. These Standard (S) samples were washed with 0.9% NaCl prior to usage. Treated (T) samples were additionally treated with oxygen plasma, functionalized with KH2PO4, sealed with trehalose and washed with Hanks prior to usage.
The surface chemistry was analyzed by X-ray photoelectron spectroscopy (XPS) and its wettability by water contact angle measurements.
To investigate blood activation and clot formation, T and S braids were incubated statically and dynamically for 1h in fresh, minimally heparinized whole human blood. Blood activation was quantified by measuring thrombin-antithrombin complex (TAT) and β-Thromboglobulin (β-TG) concentrations in the blood plasma. Adherent human blood components were visualized by immunofluorescence and by scanning electron microscopy.
Blood plasma proteins adsorbed on S and T disks were analyzed by a standard proteomic work flow.
To study the mechanism of blood activation, S and T braids were pre-coated with 50 nM and 200 nM active FX (FXa) and inactive FX for 1 h in Hanks prior to static blood incubation tests. In whole human blood FX and FXII were inhibited by addition of Rivaroxaban (1-25 µg/ml) and FXII900 (1-100µM), respectively.
Endothelialization on S and T disks was evaluated by observing cell coverage of GFP-HUVECs over 4 days and quantifying the fluorescence signal.

T surfaces show significantly lower water contact angles (≤ 10°) than S surfaces (70°-90°). XPS measurements revealed increased amounts of phosphate, calcium, and magnesium ions on T. Static and dynamic blood incubation tests showed a drastic reduction of thrombus formation, decreased TAT and β-TG concentrations, and reduced fibrin fiber deposition on T devices. Proteomic analysis of adsorbed proteins showed reduced protein abundance on T compared to S surfaces, including proteins of the complement pathway. Interestingly, the treatment increased the adsorption of calcium-binding vitamin K-dependent proteins including FX. Static blood incubation tests with FXa precoated braids resulted in blood activation on T surfaces while Rivaroxaban and FXII900 inhibited blood activation on S surfaces. The endothelialization was not altered upon surface treatment.

The herein presented treatment made Nitinol surface ultra-hydrophilic and anti-thrombotic. We propose that the strong hydrophilicity and the presence of phosphate and calcium ions steer the adsorption, conformation, and activation of blood proteins. We propose that this surface treatment might be applicable to all titanium alloys.

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