Osteomyelitis remains a global challenge in the field of orthopedics. Even after standard debridement and antibiotic-assisted treatment, the long-term recurrence rate remains at 20%-30%. Given the dynamic changes in immune responses and defense mechanisms during bone infection, as well as the complex “race for the surface” involving bacterial adhesion and host cells (macrophages and tissue cells) on implant surfaces, biomaterials with immunomodulatory functions have attracted considerable attention. Macrophages, as crucial components of the immune system, participate in the inflammatory regulation and tissue remodeling of bone infections through highly plastic polarization mechanisms after bacterial invasion. The different microenvironmental characteristics and therapeutic needs at different stages of bone infection highlight the promising applications of biomaterials capable of macrophage polarization remodeling and sequential regulation. In this review, we provide a detailed discussion of the complex immune regulatory patterns in the bone infection microenvironment and the critical functions of macrophage polarization. We then explore how implant surface properties influence bacterial adhesion and macrophage function, highlighting the importance of achieving precise and dynamic regulation of macrophage polarization based on the Race for the Surface theory. Furthermore, we focus on recent advances, potential challenges, and opportunities in biomaterial-mediated macrophage polarization remodeling and sequential modulation strategies across different stages of osteomyelitis, aiming to offer insights that may accelerate the clinical translation of novel biomaterial-based macrophage immunotherapies.

Kangfuxin has been widely recognized for its use in treating ulcerative conditions and mucositis, primarily due to its anti-inflammatory properties, which promote cell proliferation, granulation tissue growth, and angiogenesis. However, the exact mechanisms underlying these effects remain poorly understood. In this study, we employed high-throughput mass spectrometry to identify 11 compounds in Kangfuxin, including uracil, hypoxanthine, xanthine, inosine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, and lysine. Notably, the antipyretic and anti-inflammatory properties of inosine, one of these compounds, have not been well characterized. To address this gap, we induced fever in vivo using lipopolysaccharide (LPS) and conducted various experiments, including the analysis of endogenous mediators, inflammatory factors, quantitative polymerase chain reaction (QPCR), Western blotting, and hematoxylin and eosin (HE) staining. Our findings indicate that inosine significantly reduces LPS-induced fever, inhibits the expression of inflammatory factors, and alleviates the inflammatory response. These results suggest that inosine may serve as a potential therapeutic target for inflammatory diseases.

Staphylococcus aureus (SA)-induced osteomyelitis causes refractory infected bone defects characterized by impaired osteogenesis and excessive inflammatory bone destruction. Pyroptosis has emerged as an important driver of infection-related tissue injury, but the upstream regulators in osteoblasts and effective local therapeutic strategies remain poorly defined. This study investigated the role of the MIF-CD74/PI3K/AKT axis in SA-mediated osteoblast dysfunction and evaluated the ISO-1 sustained-release hydrogel for repairing infected bone defects. MIF expression was examined in human osteomyelitis sample. Bone destruction, inflammation, and osteogenesis were compared between wild-type and Mif^−/− mice using micro-CT, histology, ELISA, RT-qPCR, and immunohistochemistry. In vitro, SA-infected mouse bone marrow mesenchymal stem cells (mBMSCs) were used to assess proliferation, osteogenic differentiation, and pyroptosis, while MIF and CD74 were silenced with siRNA. RNA sequencing (RNA-seq) and co-immunoprecipitation (Co-IP) were employed to identify MIF downstream receptors and pathways, and PI3K/AKT involvement was verified using CD74 overexpression and the PI3K inhibitor LY294002. An injectable, photocrosslinkable ISO-1@β-CD/GelMA hydrogel was fabricated and characterized for structure, mechanics, and pH-responsive drug release, then implanted into rat femoral infected bone defects after debridement to evaluate bone regeneration and local inflammatory modulation. MIF was markedly upregulated in human osteomyelitis and its genetic deletion in mice significantly attenuated SA-induced bone loss, preserved trabecular microarchitecture, enhanced osteogenic marker expression, and reduced local pro-inflammatory cytokines. SA infection suppressed mBMSC proliferation and osteogenic differentiation while activating NLRP3/ASC/GSDMD-dependent pyroptosis. MIF or CD74 knockdown partially restored osteogenesis and decreased inflammatory cytokine release and pyroptotic markers. RNA-seq and Co-IP identified CD74 as a key MIF receptor, with PI3K/AKT as a critical downstream pathway regulating osteoblast fate. The ISO-1@β-CD/GelMA hydrogel showed favorable injectability, mechanical stability, and sustained ISO-1 release, and significantly improved bone volume, microarchitecture, and inflammatory microenvironment in rat infected bone defects. SA-induced osteomyelitis disrupts bone homeostasis via the MIF-CD74/PI3K/AKT axis, thereby suppressing osteogenesis and promoting NLRP3/ASC/GSDMD-mediated osteoblast pyroptosis. Targeting MIF with an ISO-1 sustained-release hydrogel remodels the inflammatory and pyroptotic microenvironment, enhances osteogenic differentiation, and effectively promotes repair of infected bone defects, providing a promising translational platform for osteomyelitis-related bone regeneration.

Methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds are difficult to heal because of persistent bacterial colonization, prolonged inflammato