Photothermal-Controlled Release of IL-4 in IL-4/PDA-Immobilized Black Titanium Dioxide (TiO2) Nanotubes Surface to Enhance Osseointegration: An In Vivo Study

Host immune response has gradually been accepted as a critical factor in achieving successful implant osseointegration. The aim of this study is to create a favorable immune microenvironment by the dominant release of IL-4 during the initial few days after implant insertion to mitigate early inflammatory reactions and facilitate osseointegration. Herein, the B-TNT/PDA/IL-4 substrate was established by immobilizing an interleukin-4 (IL-4)/polydopamine (PDA) coating on a black TiO2nanotube (B-TNT) surface, achieving on-demand IL-4 release under near infrared (NIR) irradiation. Gene Ontology (GO) enrichment analyses based on high-throughput DNA microarray data revealed that IL-4 addition inhibited osteoclast differentiation and function. Animal experiment results suggested that the B-TNT/PDA/IL-4+Laser substrate induced the least inflammatory, tartrate-resistant acid phosphatase, inducible nitric oxide synthase and the most CD163 positive cells, compared to the Ti group at 7 days post-implantation. In addition, 28 days post-implantation, micro-computed tomography results showed the highest bone volume/total volume, trabecular thickness, trabecular number and the lowest trabecular separation, while Hematoxylin-eosin and Masson-trichrome staining revealed the largest amount of new bone formation for the B-TNT/PDA/IL-4+Laser group. This study revealed the osteoimmunoregulatory function of the novel B-TNT/PDA/IL-4 surface by photothermal release of IL-4 at an early period post-implantation, thus paving a new way for dental implant surface modification.Keywords:photothermal;controlled release;IL-4;PDA;TiO2nanotubes;osseointegration;near-infrared laser;titanium