Polydopamine-Modified Copper-Doped Titanium Dioxide Nanotube Arrays for Copper-Catalyzed Controlled Endogenous Nitric Oxide Release and Improved Re-Endothelialization

The controllable release is necessary for ideal drug delivery technologies. Because of their high specific surface area and high porosity, titanium dioxide nanotubes (TNTs) have been widely used as drug carriers in medical devices. By loading copper as the catalyst, nitric oxide (NO) generation was facilitated by catalyzing the decomposition of renewable endogenous NO donors in vivo. Herein, the long-term controllable release profile of NO is highlighted owing to the multilayer polydopamine (PDA) cap structure. Different layers of PDA are used to adjust the NO release behavior, and the results show that three layers of PDA can not only effectively prevent the burst release of NO but also maintain long-term stable release of copper ion and NO. The bioactivity of the NO generated from three-layer PDA-modified copper-loaded TNTs (PDA-3L-NTCu2) and unmodified copper-loaded TNTs (NTCu2) are verified by our work, indicating effective inhibition of platelet activation, thrombosis, inflammation, and intimal hyperplasia. Importantly, the PDA-3L-NTCu2 show selectively promote the growth of endothelial cells in vitro and outstanding re-endothelialization for 4 weeks in vivo, as compared to NTCu2, TNTs, and 316L stain steel. This study suggests that copper-loaded with PDA modification helps us achieve controlled long-term stable local NO release with well-retained bioactivity and enhanced re-endothelialization.