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• A multifunctional and novel coating of TNT-ZO is successfully fabricated. • TNT-ZO substrates exhibit excellent antibacterial activity for MRSA elimination. • TNT-ZO substrates improve the crosstalk between RAW264.7 and MSCs via multiple paracrine signaling. • TNT-ZO substrates present the excellent osseointegration of peri‑implants in vivo. The bacterial infection, especially for methicillin-resistant Staphylococcus aureus (MRSA), and the associated severe inflammatory response could extremely limit the crosstalk of RAW264.7 cells and mesenchymal stem cells (MSCs) and lead to the undesirable osseointegration of peri‑implants. It is highly demanded to modify the surface of titanium (Ti) implant to improve its anti-bacterial and anti-inflammatory properties and facilitate its disabled osseointegration. Herein, in our study, a multifunctional coating of zeolitic imidazolate frameworks-67 encapsulated osteogenic growth peptide (OGP) (ZO) was fabricated on titanium dioxide nanotubes (TNT) substrates (TNT-ZO) via the electrophoresis deposition (EPD) approach. The TNT-ZO substrates exhibited excellent antibacterial activity indicated by the reactive oxygen species (ROS) generation, outer membrane (OM) and inner membrane (IM) permeabilization change, adenosine triphosphate (ATP) decrease, and intracellular compounds (DNA/RNA) leakage. Importantly, the regulation effects of TNT-ZO coating modified titanium substrates on the RAW264.7-MSCs crosstalk could induce the anti-inflammatory and osteogenic microenvironment via multiple paracrine signaling of Runx2, BMP2, VEGF, and TGF-β1. The promoted effects of coating structure were investigated in vivo, including antibacterial effect, osteogenic differentiation of mesenchymal stem cells, and anti-inflammation of RAW264.7 cells, as well as infected bone regeneration and repair in bone defect transplantation model. The results demonstrated that MRSA was effectively eliminated by the hydrolysis of ZIF-67 nanoparticles on TNT-ZO substrates. Furthermore, the excellent osseointegration of peri‑implants was realized simultaneously by modulating the crosstalk of RAW264.7-MSCs. This study could provide a novel approach to designing a multifunctional coating on the Ti implants for infected bone regeneration in orthopedic applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • Biofilm formation is one of the obstacles for bacterial infection treatment. • Antibiotic-free approaches are promising for combating the implant-associated infection. • Antibacterial surface of titanium implant would simultaneously promote bone formation. • Phototherapy has potential for eradication of the formed-biofilms on titanium implants. Titanium (Ti) and titanium alloys have become widely used as biomedical materials in orthopedics because of their good machinability, corrosion resistance, low elastic modulus and excellent biocompatibility. However, when Ti-based implants are used for bone repair and replacement, they are easy to cause bacteria adhesion and aggregation, which leads to postoperative infection. In addition, Ti and its alloys, as bio-inert materials, cannot induce desirable tissue responses such as osseointegration after implantation, which will eventually lead to implant loosening. Postoperative bacterial infection and lack of osseointegration directly lead to the failure of implantation surgery and are not conductive to the long-term service of titanium-based implants. Recently, researchers have made many attempts to focus on the surface modification of multifunctional Ti-based implants to endow them with both antibacterial activity and simultaneous osteoinductive property. In this review, we primarily highlighted the recent progresses in the surface design of Ti implants with both antimicrobial and osteoinductive properties for orthopedic applications. First, the challenges for treating implant-associated infections were briefly introduced such as the emergence of antibiotic resistance, the formation of biofilms, and the construction of cell-selective surfaces. Some of the essential fundamentals were concisely introduced to address these emerging challenges. Next, we intended to elaborate the potential strategies of multifunctional surface design to endow good osseointegration for antibacterial Ti implants and highlighted the recent advances of the implants. We hope that this review will provide theoretical basis and technical support for the development of new Ti implant with antibacterial and osteogenic functions. [ABSTRACT FROM AUTHOR]