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Titania nanotube-based local drug delivery is an attractive strategy for combating implant-associated infection. In our previous study, we demonstrated that the gentamicin-loaded nanotubes could dramatically inhibit bacterial adhesion and biofilm formation on implant surfaces. Considering the overuse of antibiotics may lead to the evolution of antibiotic-resistant bacteria, we synthesized a new quaternized chitosan derivative (hydroxypropyltrimethyl ammonium chloride chitosan, HACC) with a 27% degree of substitution (DS; referred to as 27% HACC) that had a strong antibacterial activity and simultaneously good biocompatibility with osteogenic cells. Titania nanotubes with various diameters (80, 120, 160, and 200 nm) and 200 nm length were loaded with 2 mg of HACC using a lyophilization method and vacuum drying. Two standard strain, methicillin-resistant Staphylococcus aureus (American Type Culture Collection 43300) and Staphylococcus epidermidis (American Type Culture Collection 35984), and two clinical isolates, S. aureus 376 and S. epidermidis 389, were selected to investigate the bacterial adhesion at 6 h and biofilm formation at 24, 48, and 72 h on the HACC-loaded nanotubes (NT-H) using the spread plate method, confocal laser scanning microscopy (CLSM), and scanning electron microscopy (SEM). Smooth titanium (Smooth Ti) was also investigated and compared. We found that NT-H could significantly inhibit bacterial adhesion and biofilm formation on its surface compared with Smooth Ti, and the NT-H with 160 nm and 200 nm diameters had stronger antibacterial activity because of the extended HACC release time of NT-H with larger diameters. Therefore, NT-H can significantly improve the antibacterial ability of orthopedic implants and provide a promising strategy to prevent implant-associated infections.

Wen-tao Lin,1 Hong-lue Tan,1 Zhao-ling Duan,2 Bing Yue,1 Rui Ma,1 Guo He,2 Ting-ting Tang1 1Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 2State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China Abstract: Titania nanotubes loaded with antibiotics can deliver a high concentration of antibiotics locally at a specific site, thereby providing a promising strategy to prevent implant-associated infections. In this study we have fabricated titania nanotubes with various diameters (80, 120, 160, and 200 nm) and 200 nm length via electrochemical anodization. These nanotubes were loaded with 2 mg of gentamicin using a lyophilization method and vacuum drying. A standard strain, Staphylococcus epidermidis (American Type Culture Collection 35984), and two clinical isolates, S. aureus 376 and S. epidermidis 389, were selected to investigate the anti-infective ability of the gentamicin-loaded nanotubes (NT-G). Flat titanium (FlatTi) and nanotubes with no drug loading (NT) were also investigated and compared. We found that NT-G could significantly inhibit bacterial adhesion and biofilm formation compared to FlatTi or NT, and the NT-G with 160 nm and 200 nm diameters had stronger antibacterial activity because of the extended drug release time of NT-G with larger diameters. The NT also exhibited greater antibacterial ability than the FlatTi, while nanotubes with 80 nm or 120 nm diameters had better effects. Furthermore, human marrow derived mesenchymal stem cells were used to evaluate the effect of nanotubular topographies on the osteogenic differentiation of mesenchymal stem cells. Our results showed that NT-G and NT, especially those with 80 nm diameters, significantly promoted cell attachment, proliferation, spreading, and osteogenic differentiation when compared to FlatTi, and there was no significant difference between NT-G and NT with the same diameter. Therefore, nanotube modification and gentamicin loading can significantly improve the antibacterial ability and osteogenic activity of orthopedic implants. Keywords: titania nanotubes, gentamicin, bacteria adhesion, biofilm formation, osteogenic activity