Sustained raloxifene release from hyaluronan-alendronate-functionalized titanium nanotube arrays capable of enhancing osseointegration in osteoporotic rabbits.

To enhance the localized bone remodeling at titanium-based implants under osteoporotic conditions, TiO2 nanotube arrays (TNT) were used as nanoreserviors for raloxifene (Ral) and then covered with the hybrid multilayered coating of chitosan and alendronate grafted hyaluronic acid (HA-Aln) via a spin-assisted layer-by-layer technique. The fabrication of this system (TNT/Ral/LBL-Aln) was characterized by field emission scanning electron microscopy (SEM), atomic force microscope (AFM) and X-ray photoelectron spectroscopy (XPS), respectively. The release test showed that the composited multilayers onto Ral-loaded TiO2 nanotube substrate (TNT/Ral) could prevent the burst release of Ral from TiO2 nanotube arrays and maintain stable Ral concentration at the implant site even after 192h. The TNT/Ral/LBL-Aln system demonstrated higher alkaline phosphatase (ALP) activity, mineralization capability in osteoblasts as well as lower tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts compared to both bare TiO2 nanotube and TNT/Ral substrate, respectively. Moreover, the in vivo tests of micro-CT, histological staining and push-out testing showed that TNT/Ral/LBL-Aln implant could efficiently enhance the formation of new bone around the implant and promote bone binding in osteoporotic rabbits. The study indicated the potential application of TNT/Ral/LBL-Aln system for bone remodeling under osteoporotic condition.