Enhancing thromboresistance of neurovascular nickel-titanium devices with responsive heparin hydrogel coatings

Abstract

Background: Neurointerventional devices, particularly laser-cut thin-strut stents made of self-expanding nickel-titanium alloy, are increasingly utilized for endovascular applications in intracranial arteries and dural venous sinuses. Preventing thrombosis and stroke necessitates systemic anticoagulant and antiplatelet therapies with the risk of bleeding complications. Antithrombotic coatings present a promising solution.

Methods: In this study, we investigated the potential of hydrogels composed of four-armed poly(ethylene glycol) (starPEG) and heparin, with or without coagulation-responsive heparin release, as coatings for neurovascular devices to mitigate blood clot formation. We evaluated the feasibility and efficacy of these coatings on neurovascular devices through in vitro Chandler-Loop assays and implantation experiments in the supra-aortic arteries of rabbits.

Results: Stable and coagulation-responsive starPEG-heparin hydrogel coatings exhibited antithrombotic efficacy in vitro, although with a slightly reduced thromboprotection observed in vivo. Furthermore, the hydrogel coatings demonstrated robustness against shear forces encountered during deployment and elicited only marginal humoral and cellular inflammatory responses compared with the reference standards.

Conclusion: Heparin hydrogel coatings offer promising benefits for enhancing the hemocompatibility of neurointerventional devices made of self-expanding nickel-titanium alloy. The variance in performance between in vitro and in vivo settings may be attributed to differences in low- and high-shear blood flow conditions inherent to these models. These models may represent the differences in venous and arterial systems. Further optimization is warranted to tailor the hydrogel coatings for improved efficacy in arterial applications.

Keywords: Material; Pharmacology; Stent.

Figure 1. Properties of the hydrogel coating. (A) Fluorescent scan of the stent retrievers with the fluorescently labeled hydrogel coating. No coating was applied to the delivery wires of the stent, which, therefore, appear pale and confirm the successful coating application on the stent. (B) Hydrogel degradation in thrombin solution. The non-responsive PHG sample shows virtually no release of fluorescently conjugated heparin compared with the high release from the thrombin-cleavable tcPHG sample.

Figure 2. Whole blood response to bare metal stent retrievers (BMS), stent retrievers with starPEG-Heparin hydrogel (PHG) or thrombin-cleavable starPEG-Heparin hydrogel (tcPHG) coating during 1 hour Chandler-Loop incubation compared with an empty Chandler-Loop without stent. (A) Principle of the Chandler-Loop: the stent is inserted in a silicon tube that is partly filled with blood. Rotation of the tube causes a blood flow due to gravity. (B) Activation of the coagulation cascade measured as the prothrombin fragment F1+2. (C) Platelet activation, measured as the release of platelet factor 4 (PF4). (D) Complement activation measured as the formation of the complement fragment C5a. (E) Granulocyte activation measured as exposure of the activation marker CD11b. Data are normalized to the response to 100 U/mL endotoxin.

Figure 3. Stent retrievers after 1 hour of Chandler-Loop incubation. (A) Fluorescent scan of SybrGreen stained stent fragment and quantitative evaluation. (B) Corresponding scanning electron microscopy images.

Figure 4. Stent retrievers after 1 hour of implantation in rabbit subclavian and carotid arteries. (A) X-Ray of the stents in the rabbit’s supra-aortic vessels. (B) Photographs of the stents. (C) Scans of fluorescent DiOC6 stents and quantitative evaluation (D) SEM images.