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Periprosthetic joint infection (PJI) is a leading cause and major complication of joint replacement failure. As opposed to standard-of-care systemic antibiotic prophylaxis for PJI, we developed and tested titanium femoral intramedullary implants with titania nanotubes (TNTs) coated with the antibiotic gentamicin and slow-release agent chitosan through electrophoretic deposition (EPD) in a mouse model of PJI. We hypothesized that these implants would enable local gentamicin delivery to the implant surface and surgical site, effectively preventing bacterial colonization. In the mouse PJI model, C57BL/6 mice received implants with TNTs coated with chitosan (chitosan group; control group) or with TNTs coated with chitosan and gentamicin (chitosan + gentamicin group; experimental group). Following implant placement, the surgical site was inoculated with 1 × 10 3 CFUs of Xen36 bioluminescent Staphylococcus aureus. All the mice in the chitosan group and none in the chitosan + gentamicin group had evidence of infection based on CFU analysis and bioluminescence imaging through the 14-day assessment postsurgery. Correspondingly, scanning electron microscopy analysis at the implant surface demonstrated bacterial biofilm only in the chitosan group. Furthermore, periosteal reaction and peri-implant bone loss at the femur were significantly reduced in the chitosan + gentamicin group. The chitosan + gentamicin group had reduced pain behavior, improved weight-bearing, and increased weight compared to the chitosan-control group. This study provides preclinical evidence supporting the efficacy of implants with TNTs coated with chitosan and gentamicin through EPD for preventing bacterial colonization and biofilm formation in a mouse model of PJI., (© 2024 Orthopaedic Research Society.)

In vitro and in vivo studies are critical for the preclinical efficacy assessment of novel therapies targeting musculoskeletal infections (MSKI). Many preclinical models have been developed and applied as a prelude to evaluating safety and efficacy in human clinical trials. In performing these studies, there is both a requirement for a robust assessment of efficacy, as well as a parallel responsibility to consider the burden on experimental animals used in such studies. Since MSKI is a broad term encompassing infections varying in pathogen, anatomical location, and implants used, there are also a wide range of animal models described modeling these disparate infections. Although some of these variations are required to adequately evaluate specific interventions, there would be enormous value in creating a unified and standardized criteria to animal testing in the treatment of MSKI. The Treatment Workgroup of the 2023 International Consensus Meeting on Musculoskeletal Infection was responsible for questions related to preclinical models for treatment of MSKI. The main objective was to review the literature related to priority questions and estimate consensus opinion after voting. This document presents that process and results for preclinical models related to (1) animal model considerations, (2) outcome measurements, and (3) imaging., (© 2024 Orthopaedic Research Society.)

Objective: Recognition of citrullinated antigens such as vimentin, fibrinogen, and α-enolase is associated with rheumatoid arthritis (RA). Emerging data suggest that the matrix protein aggrecan is also recognized as a citrullinated antigen. This study was undertaken to directly visualize Cit-aggrecan-specific T cells and characterize them in patients with RA., Methods: Citrullinated aggrecan peptides with likely DRB1*04:01 binding motifs were predicted using a previously published scanning algorithm. Peptides with detectable binding were assessed for immunogenicity by HLA tetramer staining, followed by single cell cloning. Selectivity for citrullinated peptide was assessed by tetramer staining and proliferation assays. Ex vivo tetramer staining was then performed to assess frequencies of aggrecan-specific T cells in peripheral blood. Finally, disease association was assessed by comparing T cell frequencies in RA patients and controls and correlating aggrecan-specific T cells with levels of aggrecan-specific antibodies., Results: We identified 6 immunogenic peptides, 2 of which were the predominant T cell targets in peripheral blood. These 2 epitopes were citrullinated at HLA binding residues and shared homologous sequences. RA patients had significantly higher frequencies of Cit-aggrecan-specific T cells than healthy subjects. Furthermore, T cell frequencies were significantly correlated with antibodies against citrullinated aggrecan., Conclusion: Our findings indicate that T cells that recognize citrullinated aggrecan are present in patients with RA and correlate with antibodies that target this same antigen. Consequently, aggrecan-specific T cells and antibodies are potentially relevant markers that could be used to monitor patients with RA or at-risk subjects., (© 2018, American College of Rheumatology.)