Adjuvant Immunomodulatory Therapy to Surgical Debridement in Osteomyelitis Associated with Staphylococcus aureus Biofilms: A Scoping Review and Evidence Gap Mapping

This scoping review aims to map and characterize the available preclinical and clinical evidence regarding pharmacological immunomodulatory therapies used as adjuncts to surgical debridement in the treatment of osteomyelitis associated with Staphylococcus aureus biofilms. The project is based on the premise that chronic staphylococcal osteomyelitis represents a complex therapeutic challenge in which biofilm formation, persistent bacterial reservoirs, immune evasion, and sustained inflammatory signaling may contribute to bone destruction and disease recurrence. The primary objective is to systematically map the evidence on immunomodulatory strategies used in conjunction with surgical debridement, with particular emphasis on modulation of the RANK/RANKL axis, pro-inflammatory cytokines, and mechanisms involved in bone remodeling and preservation. The review will also investigate whether studies evaluate microbiological and biofilm-related outcomes alongside immunological outcomes, as well as whether they address the safety of immunomodulation in the setting of active bone infection. The research question will be structured according to the Population, Concept, and Context (PCC) framework. The population will include experimental in vivo models and patients with chronic osteomyelitis or osteolysis associated with S. aureus biofilms. The concept will comprise pharmacological immunomodulatory therapy used concomitantly with or as an adjunct to surgical debridement, with emphasis on RANK/RANKL modulation, pro-inflammatory cytokines, and preservation of bone tissue. The context will encompass chronic bone infection associated with staphylococcal biofilms in both preclinical and clinical settings. The review will follow the methodological framework proposed by Arksey and O’Malley and subsequently advanced by Levac et al., with reporting guided by the PRISMA-ScR recommendations. Searches will be conducted in PubMed/MEDLINE, LILACS, ClinicalTrials.gov, the Cochrane Library, and SciELO, with complementary searches of grey literature, reference lists, and selected journals. Eligible evidence will include primary clinical and experimental in vivo studies, as well as systematic and scoping reviews used as secondary sources for mapping the existing state of knowledge. Studies will be selected by two independent reviewers, with disagreements resolved by consensus or consultation with a third reviewer. The evidence will be organized into two parallel streams. Stream A will comprise preclinical in vivo evidence, including animal models, immunomodulatory agents, doses, biological mechanisms, and reported immunological and bone-related outcomes. Stream B will comprise clinical evidence, including human studies, interventions, clinical and laboratory outcomes, and the characteristics of the available clinical evidence. The two streams will be synthesized descriptively and narratively rather than through quantitative meta-analysis, given the anticipated heterogeneity of study designs, populations, interventions, and outcomes. A central component of the project will be the development of an Evidence Gap Map. This map will systematically identify areas in which evidence is sufficient, limited, or absent, with particular attention to the clinical translation of immunomodulatory strategies. The analysis will examine the distribution of reported outcomes related to osteoclast activity, RANK/RANKL signaling, pro-inflammatory cytokines, bone preservation, and S. aureus biofilm control. It will also identify gaps concerning the safety of immunomodulatory interventions during active infection and the methodological barriers that may limit clinical translation. The expected results are a structured characterization of the current body of evidence, identification of the principal immunomodulatory strategies investigated in association with surgical debridement, and systematic mapping of the distribution and scarcity of evidence across preclinical and clinical research. The project is expected to clarify which biological mechanisms and outcomes have been most extensively investigated and which areas remain insufficiently studied. In particular, the Evidence Gap Map is expected to highlight deficiencies in clinical evidence and define methodological priorities for future investigations. The final products will include a comprehensive scoping review, a systematic evidence synthesis, and a visual and tabular Evidence Gap Map identifying priority knowledge gaps. The findings are expected to support the design of future preclinical and clinical studies and contribute to a clearer understanding of the potential role, limitations, and research needs surrounding adjunctive immunomodulation in S. aureus osteomyelitis. The protocol will be prospectively registered on the Open Science Framework (OSF), ensuring transparency, methodological traceability, and reproducibility throughout the research process.