Polydopamine Mediated Titanium Dioxide Nanotubes For Bivalirudin Loading And Its Biocompatibility Study

For blood contacting implants, the anticoagulant property is the main focus for biological compatibility research, yet in clinical applications, there is still no bio-medical material can achieve the long-term anticoagulant demand in vivo currently. According to the reports, titanium dioxide nanotubes (TiO2-NTs) not only can be used as drug carrier to release drug through the nanotube arrays, but also, adjusted by the micro/nano surface structures. NTs can promote cell adhesion, proliferation and migration. Therefore, weintegrate the two features of NTs by building a system of anticoagulant drug Bivaludin (BVLD) loaded and polydopamine (PDAM) modified titanium dioxide nanotubes. On one hand, BVLD loaded in the PDAM modified NTs could play an important role in the long-term anticoagulant effect, and on the other hand. NTs can promote the hyperplasia of endothelial cells and at the same time suppress the hyperplasia of smooth muscle cells through the topology of the NTs and the chemical cues of PDAM, finally realizes the multiple targets of anticoagulation, endothelial promotion and hyperplasia inhibit suppression on the NTs surface.In this study, NTs arrays were fabricated by anodie oxidation on pure titanium plate, and PDAM was creatively introduced to mediated the eluting of BVLD in NTs.The material characterization, the drug releasing behavior and the biocompatibility evaluation were investigated. The crystal structure and surface morphology of the nanotube arrays were analyzed by X-ray diffractometer (XRD) and scanning electron microscope (SEM). The element and hydrophilicity of the nanotube arrays were analyzed by X-ray photoelectron spectroscopy (XPS) and a standard goniorneterinstrument. Loading and adsorption of Bivarudin (BVLD) into the NTs was used to explore the in vitro release experiment of BVLD, and investigate the loading mass and elution time of BVLD. Meanwhile, hemocompatibility test and cell culture experiments were adopted to evaluate the targeted effectsincluding in vitro blood compatibility and cellular behavior of endothelial cells (ECs) and smooth muscle cells (SMCs).In this study, the results showed that highly ordered and uniformly sized nanotubes can be prepared on titanium surface, and the diameter and length of nanotubes are about110nm and1μm, respectively. In addition, after the heat treatmen at450℃for4h, titanium dioxide transferred from amorphous type to anatase crystal type. X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and contact angle measurements revealed the successful introduction of polydopamine (PDAM) and Bivarudin (BVLD) to TiO2nanotubes.In addition, supersonic elution experiments showed that the smooth titanium surface had a low adsorption capacity of BVLD. with only22.1μg/cm2. but the capacityof BVLD in nanotube based surfaces was larger. Almost89.0μg/cm2for untreated NTs and192.6μg/cm2for PDAM mediated NTs (PDAM/NTs). The static BVLD releasing test demonstrated that the cumulative release amount of BVLD was with the trend of supersonic elution experiments. Besides, it was also found from the release curve and the accumulative release percentage that the flat titanium surface had a short release period (not more than20days) and a quick release rate of BVLD. On the contrary, the drug release period was longer in nanotube siries, along with the lower release rate, about two months release period for untreated NTs and nearly three months for PDAM/NTs samples.In vitro blood compatibility tests showed that, compared with titanium, the introduction of BVLD to nanotube based surfaces (including BVLD-NTs and BVLD-PDAM/NTs) remarkably prolonged the clotting times, reduced platelet adhesion and activation of platelet. Besides, the activity of the thrombin adsorbed on these surfaces was effectively inhibited. Moreover, cell culture experiments showed that the BVLD-PDAM/NTs effectively enhanced ECs’ adhesion, proliferation, migration and the release of nitric oxide (NO), and at the same time, the system can inhibit the adhesion and proliferation of smooth muscle cells (SMCs).