Soňa Kucharíková1, Evelien Gerits2, Katrijn De Brucker2, Annabel Braem3, Katerina Ceh4, Gregor Majdič4, Tanja Španič4, Estera Pogorevc4, Natalie Verstraeten2, Hélène Tournu1, Nicolas Delattin2, Frédéric Impellizzeri5, Martin Erdtmann6, Annika Krona7, Maria Lövenklev7, Miomir Knezevic8, Mirjam Fröhlich9, Jef Vleugels3, Maarten Fauvart2, Wander Jose de Silva10, Katleen Vandamme11, Jordi Garcia-Forgas12, Bruno P A Cammue13, Jan Michiels2, Patrick Van Dijck1, Karin Thevissen14. 1. Department of Molecular Microbiology, VIB, Kasteelpark Arenberg 31, Box 2438, 3001 Leuven, Belgium Laboratory of Molecular Cell Biology, KU Leuven, Kasteelpark Arenberg 31, Box 2438, 3001 Leuven, Belgium. 2. Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001 Leuven, Belgium. 3. Department of Materials Engineering (MTM), KU Leuven, Kasteelpark Arenberg 44, Box 2450, 3001 Leuven, Belgium. 4. Center for Animal Genomics, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia. 5. Biotech International, Allées de Craponne 305, 13300 Salon-de-Provence, France. 6. Hemoteq AG, Adenauerstrasse 15, 52146 Wuerselen, Germany. 7. SP Food and Bioscience, Department of Structure and Material Design, Box 5401, 402 29 Gothenburg, Sweden. 8. Educell, d.o.o., Prevale 9, 1236 Trzin, Slovenia. 9. Educell, d.o.o., Prevale 9, 1236 Trzin, Slovenia Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia. 10. Department of Oral Health Sciences-Biomaterials BIOMAT, KU Leuven, Kapucijnenvoer 33, Box 7001, 3000 Leuven, Belgium FOP-UNICAMP, Department of Prosthodontics and Periodontology, Av. Limeira, 901, 13414-903, Piracicaba-SP, Brazil. 11. Department of Oral Health Sciences-Biomaterials BIOMAT, KU Leuven, Kapucijnenvoer 33, Box 7001, 3000 Leuven, Belgium. 12. Alhenia AG, Täfernstrasse 39, 5405 Dättwil, Switzerland. 13. Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001 Leuven, Belgium Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium. 14. Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001 Leuven, Belgium karin.thevissen@biw.kuleuven.be.
Abstract
OBJECTIVES: Biofilm-associated implant infections represent a serious public health problem. Covalent immobilization of antimicrobial agents on titanium (Ti), thereby inhibiting biofilm formation of microbial pathogens, is a solution to this problem. METHODS: Vancomycin (VAN) and caspofungin (CAS) were covalently bound on Ti substrates using an improved processing technique adapted to large-scale coating of implants. Resistance of the VAN-coated Ti (VAN-Ti) and CAS-coated Ti (CAS-Ti) substrates against in vitro biofilm formation of the bacterium Staphylococcus aureus and the fungal pathogen Candida albicans was determined by plate counting and visualized by confocal laser scanning microscopy. The efficacy of the coated Ti substrates was also tested in vivo using an adapted biomaterial-associated murine infection model in which control-Ti, VAN-Ti or CAS-Ti substrates were implanted subcutaneously and subsequently challenged with the respective pathogens. The osseointegration potential of VAN-Ti and CAS-Ti was examined in vitro using human bone marrow-derived stromal cells, and for VAN-Ti also in a rat osseointegration model. RESULTS: In vitro biofilm formation of S. aureus and C. albicans on VAN-Ti and CAS-Ti substrates, respectively, was significantly reduced compared with biofilm formation on control-Ti. In vivo, we observed over 99.9% reduction in biofilm formation of S. aureus on VAN-Ti substrates and 89% reduction in biofilm formation of C. albicans on CAS-Ti substrates, compared with control-Ti substrates. The coated substrates supported osseointegration in vitro and in vivo. CONCLUSIONS: These data demonstrate the clinical potential of covalently bound VAN and CAS on Ti to reduce microbial biofilm formation without jeopardizing osseointegration.
OBJECTIVES: Biofilm-associated implant infections represent a serious public health problem. Covalent immobilization of antimicrobial agents on titanium (Ti), thereby inhibiting biofilm formation of microbial pathogens, is a solution to this problem. METHODS:Vancomycin (VAN) and caspofungin (CAS) were covalently bound on Ti substrates using an improved processing technique adapted to large-scale coating of implants. Resistance of the VAN-coated Ti (VAN-Ti) and CAS-coated Ti (CAS-Ti) substrates against in vitro biofilm formation of the bacterium Staphylococcus aureus and the fungal pathogen Candida albicans was determined by plate counting and visualized by confocal laser scanning microscopy. The efficacy of the coated Ti substrates was also tested in vivo using an adapted biomaterial-associated murine infection model in which control-Ti, VAN-Ti or CAS-Ti substrates were implanted subcutaneously and subsequently challenged with the respective pathogens. The osseointegration potential of VAN-Ti and CAS-Ti was examined in vitro using human bone marrow-derived stromal cells, and for VAN-Ti also in a rat osseointegration model. RESULTS: In vitro biofilm formation of S. aureus and C. albicans on VAN-Ti and CAS-Ti substrates, respectively, was significantly reduced compared with biofilm formation on control-Ti. In vivo, we observed over 99.9% reduction in biofilm formation of S. aureus on VAN-Ti substrates and 89% reduction in biofilm formation of C. albicans on CAS-Ti substrates, compared with control-Ti substrates. The coated substrates supported osseointegration in vitro and in vivo. CONCLUSIONS: These data demonstrate the clinical potential of covalently bound VAN and CAS on Ti to reduce microbial biofilm formation without jeopardizing osseointegration.
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