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Despite advancements in surgical techniques, musculoskeletal infections (MSKI) remain severe complications following orthopedic surgery, imposing a substantial financial and personal burden on patients and healthcare systems globally. To establish the current state of knowledge in this field, International Consensus Meetings (ICM) were held in 2013, 2018, and 2025, including a Biofilm Section focused on establishing state-of-the-art basic science and translational research. The latest ICM utilized a 2-year-long Delphi process that commenced on May 31, 2023, and culminated in an in-person meeting involving voting on 30 questions by 47 delegates on May 8–10, 2025, in Istanbul, Turkey. Following the voting process, the Biofilm Section formed three workgroups (Biofilm Basic Science, Biofilm Treatment, and Research Priorities) to interpret the results and disseminate the findings in Consensus Articles that highlight priorities. The following is the summation of the Biofilm Treatment Workgroup, which aims to shape future pre-clinical MSKI research directions and grant funding with respect to: (1) elevating scientific rigor to ensure reproducibility and high-quality data in preclinical research; (2) transitioning mature therapeutic concepts into rigorous in vivo models to definitively prove their clinical feasibility; and (3) accelerating the development of novel molecular targets and advanced drug-delivery systems. Finally, the workgroup acknowledged a critical shift in the funding landscape. As government support faces future challenges, there is an urgent need for increased investment from industry and philanthropic partners. Such support is essential to develop effective treatments for serious orthopedic infections and to improve outcomes for patients facing life-altering illnesses.

Musculoskeletal infection (MSKI) is a leading cause of implant failure following orthopedic surgery for trauma or elective procedures and it is associated with catastrophic outcomes for patients and healthcare systems worldwide. International Consensus Meetings (ICM) aim to define state-of-the-art, influencing clinical standards of care and accelerating discoveries by setting research priorities. The 3rd ICM was held on May 8–10, 2025 in Istanbul (Turkey) and included a 2-year-long Delphi process that culminated with in-person voting by 1205 delegates on 102 General and 30 Biofilm-specific MSKI questions. Consistent with prior ICMs, a Research Priorities Workgroup was established after the voting to interpret the results and summarize the most important future directions. Here, the group reports on several critical research priorities that emerged, which should be addressed to advance the field. These include: (1) improving diagnostics through standardized patient sampling, advanced non-invasive imaging technologies, and biofilm-specific biomarkers; (2) developing clinically relevant in-vitro and in-vivo models to rigorously and reproducibly test antibiofilm strategies; (3) identifying high priority immunological research areas, including deciphering the role of T-cell immunity in biofilm persistence, and if T cell targeting therapies can be harnessed to disrupt chronic biofilm-associated infection; (4) clinically evaluating novel anti-biofilm technologies on larger cohorts of patients; and (5) addressing translational barriers through the use of multi-center data collection and large-scale data tools to accelerate clinical application. These research priorities aim to enhance the prevention, diagnosis, and treatment of biofilm-associated MSKI.

Musculoskeletal infection (MSKI) remains a major problem after trauma and elective orthopedic surgery. Chronic MSKI is related to the formation of biofilm, which impairs diagnosis and effective treatments. Therefore, to understand and communicate global standards and best practices, the 2025 International Consensus Meeting (ICM) on MSKI created a Biofilm Section to address crucial aspects of biofilm biology pertaining to its mechanisms of drug resistance and immune evasion, and potential approaches to overcome them. This featured a 2-year process, with final voting and discussion on May 8–10, 2025, in Istanbul, Turkey. This Consensus Article is the effort of the Biofilm Basic Mechanisms Workgroup, which interpreted the results on ICM questions related to (1) the infectious micro-environment; (2) appropriate inocula in preclinical research; (3) biofilm behavior in infected tissues; and (4) synergy within biofilms and with other comorbidities. Collectively, we find that this field has the necessary research tools to discover the pathophysiology of orthopedic implant-associated biofilm development and maturation, perform clinically relevant studies in animal models, and elucidate mechanisms that allow opportunistic infections in compromised tissues and patients with other health issues.

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 1×10³ 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.

Periprosthetic joint infection (PJI) occurs in 1%–2% of primary total hip and knee arthroplasties; the rate can reach 20% in individuals at risk. Due to the low local bioavailability of systemic antibiotics and possible off-target effects, localized drug delivery systems are of great importance. Our aim was the electrophoretic deposition (EPD) of gentamicin and chitosan in Titanium (Ti) nanotubes to establish a local, prolonged antibiotic delivery. Nanotubes were created on Ti wire with a two-step anodization process. For drug deposition, EPD and the air-dry methods were compared. For a prolonged drug release, gentamicin and crosslinked chitosan were deposited in a two-step EPD process. Drug release was quantified by fractional volume sampling. The Ti wires were tested against Staphylococcus aureus by agar dilution and liquid culture methods. MC3T3-E1 osteoblastic cell viability was determined with trypan blue. Nanotubes were characterized by a 100 nm diameter and 7 µm length. EPD allowed a higher amount of gentamicin deposited than the air-dry method. Drug deposition was controllable by adjusting the voltage and duration of the EPD process. The crosslinked chitosan layer allowed diffusion-driven release kinetics for up to 3 days. Gentamicin-loaded Ti wires significantly inhibited bacterial growth and resulted in a larger inhibition zone compared to unloaded wires. Twenty-four hours of incubation with loaded wires did not have a significant effect on osteoblast viability. Gentamicin-loaded Ti nanotubes represent a promising approach for PJI prevention, as well as a valuable preclinical tool for the investigation of localized drug delivery systems created on Ti surface.

Despite many preventive measures, including prophylactic antibiotics, periprosthetic joint infection (PJI) remains a devastating complication following arthroplasty, leading to pain, suffering, morbidity and substantial economic burden. Humans have a powerful innate immune system that can effectively control infections, if alerted quickly. Unfortunately, pathogens use many mechanisms to dampen innate immune responses. The study hypothesis was that immunomodulators that can jumpstart and direct innate immune responses (particularly neutrophils) at the surgical site of implant placement would boost immune responses and reduce PJI, even in the absence of antibiotics.

To test this hypothesis, N-formyl-methionyl-leucyl-phenylalanine (fMLP) (a potent chemoattractant for phagocytic leukocytes including neutrophils) was used in a mouse model of PJI with Staphylococcus aureus (S. aureus). Mice receiving intramedullary femoral implants were divided into three groups: i) implant alone; ii) implant + S. aureus; iii) implant + fMLP + S. aureus.

fMLP treatment reduced S. aureus infection levels by ~ 2-Log orders at day 3. Moreover, fMLP therapy reduced infection-induced peri-implant periosteal reaction, focal cortical loss and areas of inflammatory infiltrate in mice distal femora at day 10. Finally, fMLP treatment reduced pain behaviour and increased weight-bearing at the implant leg in infected mice at day 10.

Data indicated that fMLP therapy is a promising novel approach for reducing PJI, if administered locally at surgical sites. Future work will be toward further enhancement and optimisation of an fMLP-based therapeutic approach through combination with antibiotics and/or implant coating with fMLP.