Biophysiochemically favorable, antithrombotic and pro-endothelial coordination compound nanocoating of copper (II) with protocatechuic acid & nattokinase on flow-diverting stents

Abstract

Neurovascular flow-diverting stents (FDSs) are revolutionizing the paradigm for treatment of intracranial aneurysms, but they still face great challenges like post- implantation acute thrombosis and delayed reendothelialization. Surface modification is of crucial relevance in addressing such key issues. In this study, we fabricated an ultrathin nanocoating out of copper (II) together with protocatechuic acid (PCA) and nattokinase (NK) bioactive molecules on NiTi FDSs via a coordination chemistry approach, with favorable biophysiochemical interactions, to fulfill this goal. This coating was identified as covalently-anchored and compactly covering the FDSs substrate, with unique nano-structured morphology as well as superhydrophilicity. The in vitro coagulation and whole blood assays demonstrated that the modified FDS's surfaces showed improved antithrombogenicity, with reduced platelet and fibrinogen adhesion, as well as their aggregation and activation, and consequently prolonged clotting time leading to decreased thrombosis occurrence. Human umbilical vein endothelial cell cultures confirmed the modified capability of FDSs to promote endothelial cell proliferation and migration. The ex vivo experiments verified that modified FDSs had clearly in-stent patency without thrombi formation, as compared to the bare FDSs bearing thromboembolic blockage. It was postulated that these enhanced biocompatibilities can be attributable to the copper-catalyzed nitric oxide (NO) released as a functional mediator, the nature of the PCA and NK molecules, as well as the synergic biophysiochemical surface/interface interactions. Our strategy may not only open a new avenue for surface-functionalizing neurovascular FDSs for medical purpose but also help better-understand interfacial phenomena on the advanced biomaterials.