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Background: Titanium (Ti) implant-associated infection, which is mostly caused by bacterial adhesion and biofilm formation, may result in implant failure and secondary surgery. Thus it is an urgent issue to prevent bacterial infections at the earliest step. Purpose: To develop a novel surface strategy of polydopamine (PDA) and silver (Ag) nanoparticle-loaded TiO2 nanorods (NRDs) coatings on Ti alloy. Materials and methods: Ag-TiO2@PDA NRDs was fabricated on Ti alloy by hydrothermal synthesis. The antibacterial activity of Ag-TiO2@PDA NRDs against Escherichia coli and methicillin-resistant Staphylococcus aureus were tested by FE-SEM, Live/Dead staining, zone of inhibition, bacteria counting method and protein leakage analysis in vitro. In addition, an implant infection model was conducted and the samples were tested by X-ray, Micro-CT and histological analysis in vivo. Besides, cell morphology and cytotoxicity of Mouse calvarial cells (MC3T3-E1) were characterized by FE-SEM, immunofluorescence and CCK-8 test in vitro. Results: Our study successfully developed a new surface coating of Ag-TiO2@PDA NRDs. The selective physical puncture of bacteria and controlled release of Ag+ ions of Ag-TiO2@PDA NRDs achieved a long-lasting bactericidal ability and anti-biofilm activity with satisfied biocompatibility. Conclusion: This strategy may be promising for clinical applications to reduce the occurrence of infection in the implant surgeries

Yangmengfan Chen,1,* Ming Guan,1,* Ranyue Ren,1 Chenghao Gao,1 Hao Cheng,2 Yong Li,1 Biao Gao,3 Yong Wei,3 Jijiang Fu,3 Jun Sun,4 Wei Xiong1 1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 3The State Key Laboratory of Refractories and Metallurgy, School of Materials and Metallurgy, Wuhan University of Science and Technology, Wuhan 430081, People’s Republic of China; 4Department of Biochemistry and Molecular Biology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun SunDepartment of Biochemistry and Molecular Biology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaTel +86 189 7128 0215Email sunjun99@hotmail.comWei XiongDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of ChinaTel +86 132 1273 6006Email 1996tj0558@hust.edu.cnIntroduction: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant.Methods: In this study, we developed an antibacterial silver nanoparticle-loaded TiO2 nanotubes (Ag@TiO2-NTs) using an electrochemical anodization method to make the surface modification and investigated the influences of Ag@TiO2-NTs on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo.Results: The results showed that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, Ag@TiO2-NTs surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO2-NTs and polished Ti surfaces in vivo. These findings suggested that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization.Discussion: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.Keywords: silver nanoparticle, TiO2 nanotubes, immune response, glucose transport, autophagy