Articles | Volume 11, issue 4
https://doi.org/10.5194/jbji-11-535-2026
© Author(s) 2026. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
https://doi.org/10.5194/jbji-11-535-2026
© Author(s) 2026. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
Feasibility of a rat femoral-defect model for immediate perioperative and delayed post-implantation implant-associated bone infections
Pardis Keikhosravani
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Michiel Croes
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Nada Ristya Rahmani
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Flurina Stabuli
Department of Maxillofacial Surgery, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Leonardo Cecotto
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
H. Charls Vogely
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Bart C. H. van der Wal
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Marianne Koolen
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Debby Gawlitta
Department of Maxillofacial Surgery, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Harrie Weinans
CORRESPONDING AUTHOR
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Department of Biomechanical Engineering, Delft University of Technology, 2628 CD, Delft, the Netherlands
Azin Khodaei
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Saber Amin Yavari
CORRESPONDING AUTHOR
Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands
Regenerative Medicine Centre Utrecht, Utrecht University, 3508 GA Utrecht, the Netherlands
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Yorrick P. Bourgonjen, J. Fred F. Hooning van Duyvenbode, Bruce van Dijk, F. Ruben H. A. Nurmohamed, Ewout S. Veltman, H. Charles Vogely, and Bart C. H. van der Wal
J. Bone Joint Infect., 6, 379–387, https://doi.org/10.5194/jbji-6-379-2021, https://doi.org/10.5194/jbji-6-379-2021, 2021
Short summary
Short summary
This study provides a comprehensive overview of a frequently used treatment strategy for chronic prosthetic joint infection of the hip and knee. Forty-seven patients met the inclusion criteria. Successful eradication was achieved in 36 of 47 cases. Multiple variables were analysed to explore their influence on the outcome of two-stage revision surgery. No variables were found to have a significant influence. Mean follow-up of over 10 years provides a good perspective of the long-term outcome.
Cited articles
Amin Yavari, S., Castenmiller, S. M., van Strijp, J. A. G., and Croes, M.: Combating Implant Infections: Shifting Focus from Bacteria to Host, Adv. Mater., 32, https://doi.org/10.1002/ADMA.202002962, 2020.
Arciola, C. R., Campoccia, D., and Montanaro, L.: Implant infections: Adhesion, biofilm formation and immune evasion, Nat. Rev. Microbiol., 16, 397–409, https://doi.org/10.1038/S41579-018-0019-Y, 2018.
Assefa, M. and Amare, A.: Biofilm-Associated Multi-Drug Resistance in Hospital-Acquired Infections: A Review, Infect. Drug Resist., 15, 5061, https://doi.org/10.2147/IDR.S379502, 2022.
Bahnasawy, S. M., Ahmed, H., Zeitlinger, M., Friberg, L. E., and Nielsen, E. I.: Plasma effects on bacterial time-kill dynamics: Insights from a PK/PD modelling analysis, Int. J. Antimicrob. Agents, 65, 107441, https://doi.org/10.1016/J.IJANTIMICAG.2024.107441, 2025.
Bakalakos, M., Vlachos, C., Ampadiotaki, M. M., Stylianakis, A., Sipsas, N., Pneumaticos, S., and Vlamis, J.: Role of Dithiothreitol in Detection of Orthopaedic Implant-Associated Infections, Journal of Personalized Medicine, 14, p. 334, https://doi.org/10.3390/JPM14040334, 2024.
Barat, B. and Shogan, B. D.: The Microbiome's Role in Driving Anastomotic Leak and Cancer Recurrence Following Colorectal Surgery, Surg. Clin. N. Am., https://doi.org/10.1016/J.SUC.2025.06.003, 2025.
Cabrera, K., Hoard, D. S., Gibson, O., Martinez, D. I., and Wunderlich, Z.: Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance, PLoS Pathog., 19, e1011567, https://doi.org/10.1371/JOURNAL.PPAT.1011567, 2023.
Campisi, J., Leem, T. H., and Fleshner, M.: Acute stress decreases inflammation at the site of infection: A role for nitric oxide, Physiol. Behav., 77, 291–299, https://doi.org/10.1016/S0031-9384(02)00861-2, 2002.
Chang, J. and Lee, G. W.: Late hematogenous bacterial infections of breast implants: Two case reports of unique bacterial infections, Ann. Plast. Surg., 67, 14–16, https://doi.org/10.1097/SAP.0B013E3181F3E387, 2011.
Croes, M., de Visser, H., Meij, B. P., Lietart, K., van der Wal, B. C. H., Vogely, H. C., Fluit, A. C., Boel, C. H. E., Alblas, J., Weinans, H., and Amin Yavari, S.: Data on a rat infection model to assess porous titanium implant coatings, Data Brief, 21, 1642–1648, https://doi.org/10.1016/J.DIB.2018.10.157, 2018.
Daghighi, S., Sjollema, J., van der Mei, H. C., Busscher, H. J., and Rochford, E. T. J.: Infection resistance of degradable versus non-degradable biomaterials: An assessment of the potential mechanisms, Biomaterials, 34, 8013–8017, https://doi.org/10.1016/J.BIOMATERIALS.2013.07.044, 2013.
de Aguilar-Nascimento, J. E.: Probiotics and Prebiotics: Role in Surgery Recuperation?, Bioactive Foods in Promoting Health: Probiotics and Prebiotics, 171–179, https://doi.org/10.1016/B978-0-12-374938-3.00012-8, 2010.
Dong, J., Wang, W., Zhou, W., Zhang, S., Li, M., Li, N., Pan, G., Zhang, X., Bai, J., and Zhu, C.: Immunomodulatory biomaterials for implant-associated infections: from conventional to advanced therapeutic strategies, Biomater. Res., 26, 72, https://doi.org/10.1186/S40824-022-00326-X, 2022.
Fang, C., Wong, T. M., Lau, T. W., To, K. K. W., Wong, S. S. Y., and Leung, F.: Infection after fracture osteosynthesis – Part I: Pathogenesis, diagnosis and classification, Journal of Orthopaedic Surgery, 25, https://doi.org/10.1177/2309499017692712, 2017.
Frisch, E., Clavier, L., Belhamdi, A., Vrana, N. E., Lavalle, P., Frisch, B., Heurtault, B., and Gribova, V.: Preclinical in vitro evaluation of implantable materials: conventional approaches, new models and future directions, Front. Bioeng. Biotechnol., 11, 1193204, https://doi.org/10.3389/FBIOE.2023.1193204, 2023.
Fujimura, S., Sato, T., Hayakawa, S., Kawamura, M., Furukawa, E., and Watanabe, A.: Antimicrobial efficacy of combined clarithromycin plus daptomycin against biofilms-formed methicillin-resistant Staphylococcus aureus on titanium medical devices, J. Infect. Chemother., 21, 756–759, https://doi.org/10.1016/J.JIAC.2015.06.001, 2015.
Gatti, M., Barnini, S., Guarracino, F., Parisio, E. M., Spinicci, M., Viaggi, B., D'arienzo, S., Forni, S., Galano, A., and Gemmi, F.: Orthopaedic Implant-Associated Staphylococcal Infections: A Critical Reappraisal of Unmet Clinical Needs Associated with the Implementation of the Best Antibiotic Choice, Antibiotics, 11, 406, https://doi.org/10.3390/ANTIBIOTICS11030406, 2022.
Gbejuade, H. O., Lovering, A. M., and Webb, J. C.: The role of microbial biofilms in prosthetic joint infections: A review, Acta Orthop., 86, 147, https://doi.org/10.3109/17453674.2014.966290, 2015.
Giavaresi, G., Meani, E., Sartori, M., Ferrari, A., Bellini, D., Sacchetta, A. C., Meraner, J., Sambri, A., Vocale, C., Sambri, V., Fini, M., and Romanò, C. L.: Efficacy of antibacterial-loaded coating in an in vivo model of acutely highly contaminated implant, Int. Orthop., 38, 1505–1512, https://doi.org/10.1007/S00264-013-2237-2, 2014.
Gjini, E., Paupério, F. F. S., and Ganusov, V. V.: Treatment timing shifts the benefits of short and long antibiotic treatment over infection, Evol. Med. Public Health, 2020, 249–263, https://doi.org/10.1093/EMPH/EOAA033, 2020.
Gottenbos, B., Klatter, F., Van Der Mei, H. C., Busscher, H. J., and Nieuwenhuis, P.: Late Hematogenous Infection of Subcutaneous Implants in Rats, Clin. Diagn. Lab. Immunol., 8, 980, https://doi.org/10.1128/CDLI.8.5.980-983.2001, 2001.
Grari, O., Ezrari, S., El Yandouzi, I., Benaissa, E., Ben Lahlou, Y., Lahmer, M., Saddari, A., Elouennass, M., and Maleb, A.: A comprehensive review on biofilm-associated infections: Mechanisms, diagnostic challenges, and innovative therapeutic strategies, The Microbe, 8, 100436, https://doi.org/10.1016/J.MICROB.2025.100436, 2025.
Grzeskowiak, R. M., Schumacher, J., Dhar, M. S., Harper, D. P., Mulon, P. Y., and Anderson, D. E.: Bone and Cartilage Interfaces With Orthopedic Implants: A Literature Review, Front. Surg., 7, 601244, https://doi.org/10.3389/FSURG.2020.601244/XML, 2020.
Guarch-Pérez, C., Riool, M., and Zaat, S. A. J.: Current Osteomyelitis Mouse Models, A Systematic Review, Eur. Cell. Mater., 42, 334–374, https://doi.org/10.22203/ECM.V042A22, 2021.
Han, A., Li, X., Huang, B., Tsoi, J. K. H., Matinlinna, J. P., Chen, Z., and Deng, D. M.: The effect of titanium implant surface modification on the dynamic process of initial microbial adhesion and biofilm formation, Int. J. Adhes. Adhes., 69, 125–132, https://doi.org/10.1016/J.IJADHADH.2016.03.018, 2016.
Harrasser, N., Gorkotte, J., Obermeier, A., Feihl, S., Straub, M., Slotta-Huspenina, J., Von Eisenhart-Rothe, R., Moser, W., Gruner, P., De Wild, M., Gollwitzer, H., and Burgkart, R.: A new model of implant-related osteomyelitis in the metaphysis of rat tibiae, BMC Musculoskel. Dis., 17, p. 152, https://doi.org/10.1186/S12891-016-1005-Z, 2016.
Holdbrook, R., Reavey, C. E., Randall, J. L., Andongma, A. A., Tummala, Y., Rice, A., Simpson, S. J., Smith, J. A., Cotter, S. C., and Wilson, K.: Combining in vivo and in vitro approaches to better understand host-pathogen nutritional interactions, J. Animal Ecol., 94, 657–669, https://doi.org/10.1111/1365-2656.70000, 2025.
Huang, S., Wen, J., Zhang, Y., Bai, X., and Cui, Z. K.: Choosing the right animal model for osteomyelitis research: Considerations and challenges, J. Orthop. Translat., 43, 47–65, https://doi.org/10.1016/J.JOT.2023.10.001, 2023.
Jahanmard, F., Croes, M., Castilho, M., Majed, A., Steenbergen, M. J., Lietaert, K., Vogely, H. C., van der Wal, B. C. H., Stapels, D. A. C., Malda, J., Vermonden, T., and Amin Yavari, S.: Bactericidal coating to prevent early and delayed implant-related infections, J. Control. Release, 326, 38–52, https://doi.org/10.1016/J.JCONREL.2020.06.014, 2020.
Keikhosravani, P.: Feasibility of a rat femoral-defect model for immediate perioperative and delayed post-implantation implant-associated bone infections, Zenodo [data set], https://doi.org/10.5281/zenodo.22009740, 2026.
Keikhosravani, P., Khodaei, A., Bollen, T., Nazmi, K., Bikker, F. J., van Steenbergen, M., van Nostrum, C. F., van Strijp, J., Weinans, H., and Amin Yavari, S.: Developing antibacterial HB43 peptide-loaded chitosan nanoparticles for biofilm treatment, Int. J. Biol. Macromol., 310, 143397, https://doi.org/10.1016/J.IJBIOMAC.2025.143397, 2025.
Khatoon, Z., McTiernan, C. D., Suuronen, E. J., Mah, T. F., and Alarcon, E. I.: Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention, Heliyon, 4, e01067, https://doi.org/10.1016/J.HELIYON.2018.E01067, 2018.
Lex, J. R., Koucheki, R., Stavropoulos, N. A., Michele, J. Di, Toor, J. S., Tsoi, K., Ferguson, P. C., Turcotte, R. E., and Papagelopoulos, P. J.: Megaprosthesis anti-bacterial coatings: A comprehensive translational review, Acta Biomater., 140, 136–148, https://doi.org/10.1016/J.ACTBIO.2021.11.045, 2022.
Li, Y. and Baldridge, M. T.: Modelling human immune responses using microbial exposures in rodents, Nat. Microbiol., 8, 363–366, https://doi.org/10.1038/S41564-023-01334-W, 2023.
Liu, G., Guo, Y., Zhang, L., Wang, X., Liu, R., Huang, P., Xiao, Y., Chen, Z., and Chen, Z.: A standardized rat burr hole defect model to study maxillofacial bone regeneration, Acta Biomater., 86, 450–464, https://doi.org/10.1016/J.ACTBIO.2018.12.049, 2019.
Lucke, M., Schmidmaier, G., Sadoni, S., Wildemann, B., Schiller, R., Stemberger, A., Haas, N. P., and Raschke, M.: A New Model of Implant-Related Osteomyelitis in Rats, J. Biomed. Mater. Res. B Appl. Biomater., 67, 593–602, https://doi.org/10.1002/JBM.B.10051, 2003.
Meganathan, Y., Vishwakarma, A., and Ramya, M.: Biofilm formation and social interaction of Leptospira in natural and artificial environments, Res. Microbiol., 173, 103981, https://doi.org/10.1016/J.RESMIC.2022.103981, 2022.
Mishra, A., Aggarwal, A., and Khan, F.: Medical Device-Associated Infections Caused by Biofilm-Forming Microbial Pathogens and Controlling Strategies, Antibiotics, 13, 623, https://doi.org/10.3390/ANTIBIOTICS13070623, 2024.
Monaco, G., Cecchini, S., Gatto, M. R., and Pelliccioni, G. A.: Delayed onset infections after lower third molar germectomy could be related to the space distal to the second molar, Int. J. Oral Maxillofac. Surg., 46, 373–378, https://doi.org/10.1016/J.IJOM.2016.09.011, 2017.
Moriarty, T. F., Harris, L. G., Mooney, R. A., Wenke, J. C., Riool, M., Zaat, S. A. J., Moter, A., Schaer, T. P., Khanna, N., Kuehl, R., Alt, V., Montali, A., Liu, J., Zeiter, S., Busscher, H. J., Grainger, D. W., and Richards, R. G.: Recommendations for design and conduct of preclinical in vivo studies of orthopedic device-related infection, J. Orthop. Res., 37, 271–287, https://doi.org/10.1002/JOR.24230, 2019.
Njiké Ngamga, F. H., Fowa, A. B., Teboukeu, G. B., Mouokeu, R. S., and Womeni, H. M.: Effectiveness of boiled Chrysicthys nigrodigitatus against rats-induced Salmonella Typhi infection, Clinical Nutrition Open Science, 37, 25–34, https://doi.org/10.1016/J.NUTOS.2021.04.001, 2021.
Rao, T. S.: Bacterial Biofilms and Implant Infections: A Perspective, Archives of Orthopaedics, 1, 98–105, https://doi.org/10.33696/ORTHOPAEDICS.1.016, 2020.
Reizner, W., Hunter, J. G., O'Malley, N. T., Southgate, R. D., Schwarz, E. M., and Kates, S. L.: A systematic review of animal models for Staphylococcus aureus osteomyelitis, Eur. Cell. Mater., 27, 196–212, https://doi.org/10.22203/ECM.V027A15, 2014.
Schömig, F. and Putzier, M.: Clinical presentation and diagnosis of delayed postoperative spinal implant infection, Journal of Spine Surgery, 6, 772, https://doi.org/10.21037/JSS-20-499, 2020.
Seebach, E. and Kubatzky, K. F.: Chronic Implant-Related Bone Infections-Can Immune Modulation be a Therapeutic Strategy?, Front. Immunol., 10, 1724, https://doi.org/10.3389/FIMMU.2019.01724, 2019.
Shaw, J. D., Bailey, T. L., Ong, J., Brodke, D. S., Williams, D. L., Wawrose, R. A., Epperson, R. T., Kawaguchi, B., and Ashton, N. N.: Development and validation of a large animal ovine model for implant-associated spine infection using biofilm based inocula, Biofilm, 6, 100138, https://doi.org/10.1016/J.BIOFLM.2023.100138, 2023.
Shi, D., Mi, G., Wang, M., and Webster, T. J.: In vitro and ex vivo systems at the forefront of infection modeling and drug discovery, Biomaterials, 198, 228, https://doi.org/10.1016/J.BIOMATERIALS.2018.10.030, 2018.
Shiels, S. M., Mangum, L. H., and Wenke, J. C.: Revisiting the “race for the surface” in a pre-clinical model of implant infection, Eur. Cells Mater., 39, 77–95, https://doi.org/10.22203/eCM.v039a05, 2020.
Singhal, N., Maurya, A. K., Singh, N. S., Kumar, M., and Virdi, J. S.: Antimicrobial resistance and its relationship with biofilm production and virulence-related factors in Yersinia enterocolitica biotype 1A, Heliyon, 5, e01777, https://doi.org/10.1016/J.HELIYON.2019.E01777, 2019.
Soe, N. H., Jensen, N. V., Nürnberg, B. M., Jensen, A. L., Koch, J., Poulsen, S. S., Pier, G., and Johansen, H. K.: A novel knee prosthesis model of implant-related osteomyelitis in rats, Acta Orthop., 84, 92–97, https://doi.org/10.3109/17453674.2013.773121, 2013.
Steinmetz, S., Wernly, D., Moerenhout, K., Trampuz, A., and Borens, O.: Infection after fracture fixation, EFORT Open Rev., 4, 468, https://doi.org/10.1302/2058-5241.4.180093, 2019.
Top Hartmann, K., Lund Nielsen, R., Mikkelsen, F. C., Aalbæk, B., Lichtenberg, M., Holm Jakobsen, T., Bjarnsholt, T., Kvich, L., Ingmer, H., Odgaard, A., Elvang Jensen, H., and Kruse Jensen, L.: Bacterial micro-aggregates as inoculum in animal models of implant-associated infections, Biofilm, 7, https://doi.org/10.1016/j.bioflm.2024.100200, 2024.
Wang, Y., Cheng, L. I., Helfer, D. R., Ashbaugh, A. G., Miller, R. J., Tzomides, A. J., Thompson, J. M., Ortines, R. V., Tsai, A. S., Liu, H., Dillen, C. A., Archer, N. K., Cohen, T. S., Tkaczyk, C., Stover, C. K., Sellman, B. R., and Miller, L. S.: Mouse model of hematogenous implant-related Staphylococcus aureus biofilm infection reveals therapeutic targets, P. Natl. Acad. Sci. USA, 114, E5094, https://doi.org/10.1073/PNAS.1703427114, 2017.
Wang, Y., Gou, Z., Ma, S., Jin, Z., Chen, S., Ye, J., Nie, Z., Wan, Z., Zhang, C., Ye, Y., Yu, X., Ye, Z., and Ren, Y.: Remote eradication of delayed infection on orthopedic implants via magnesium-based total morphosynthesis of biomimetic mineralization strategy, Mater. Des., 233, 112233, https://doi.org/10.1016/J.MATDES.2023.112233, 2023.
Witso, E.: Infections in Orthopaedics and Fractures, European Surgical Orthopaedics and Traumatology, 331–363, https://doi.org/10.1007/978-3-642-34746-7_17, 2014.
Zhang, H. and Jin, Z.: Antibacterial activities of titanium dioxide (TiO2) nanotube with planar titanium silver (TiAg) to prevent orthopedic implant infection, J. Orthop. Surg. Res., 19, 1–8, https://doi.org/10.1186/S13018-024-04596-0, 2024.
Zhang, S., Long, J., Chen, L., Zhang, J., Fan, Y., Shi, J., and Huang, Y.: Treatment methods toward improving the anti-infection ability of poly(etheretherketone) implants for medical applications, Colloids Surf. B Biointerfaces, 218, 112769, https://doi.org/10.1016/J.COLSURFB.2022.112769, 2022.
Zhang, S., Yang, H., Wang, M., Mantovani, D., Yang, K., Witte, F., Tan, L., Yue, B., and Qu, X.: Immunomodulatory biomaterials against bacterial infections: Progress, challenges, and future perspectives, The Innovation, 4, 100503, https://doi.org/10.1016/J.XINN.2023.100503, 2023.
Zhao, A., Sun, J., and Liu, Y.: Understanding bacterial biofilms: From definition to treatment strategies, Front. Cell. Infect. Microbiol., 13, 1137947, https://doi.org/10.3389/FCIMB.2023.1137947, 2023.
Zimmerli, W. and Sendi, P.: Role of rifampin against staphylococcal biofilm infections in vitro, in animal models, and in orthopedic-device-related infections, Antimicrob. Agents Chemother., 63, https://doi.org/10.1128/AAC.01746-18, 2019.
Zimmerli, W., Trampuz, A., and Ochsner, P. E.: Prosthetic-joint infections, N. Engl. J. Med., 351, https://doi.org/10.1056/NEJMRA040181, 2004.
Short summary
This study delivers a practical rat model for both early and delayed implant‑site infections. We show which bacterial doses and states produce consistent infections at each time point, creating a dependable platform to evaluate new materials and treatments that prevent or clear implant infections.
This study delivers a practical rat model for both early and delayed implant‑site infections....