Pathological Environment Regulation And Treatment Of Osteomyelitis Based On MIF Pathway

Objective(s):The number of patients with osteomyelitis increases year by year with the rise in the incidence of traumatic fractures.As a common and intractable infectious disease in orthopedics,osteomyelitis is mostly caused by Staphylococcus aureus infection,which usually leads to the formation of inflammatory bone defects in local lesions.When the pathogenic bacteria develop resistance or enter the incubation period,osteomyelitis will occur repeatedly and is difficult to cure.Therefore,the search for key therapeutic targets in the pathogenesis of chronic osteomyelitis is particularly important,and macrophage migration inhibitory factor(MIF)has been linked to inflammatory and immune-mediated diseases such as systemic vasculitis,systemic lupus erythematosus,and rheumatoid arthritis.MIF can also promote the release of various inflammatory cytokines,including TNF-α,IL-1,IL-6,IL-8 and IL-12,and promote the synthesis of matrix metalloproteinase-1(MMP-1),MMP-3,MMP-9 and MMP-13,as well as the expression of adhesion factor(ICAM).However,there have been no relevant studies on the specific role and mechanism of MIF in osteomyelitis.This study aims to deeply explore the molecular biological mechanism of MIF in the pathological process of osteomyelitis,and on this basis,study and evaluate the therapeutic effect of surface modified filler implants on infected bone defects.Methods:1.Establishment and identification of rat Osteomyelitis model.2.By constructing a rat model of Osteomyelitis in vivo,based on high-throughput analysis and biotechnology,we explored the mechanism of the pathological environment of Osteomyelitis.3.A 3D printed Ti-6Al-4V implant modified by copper and strontium ions combined with natural polymers was designed,combined with targeted inhibitors of key factors in previous studies,to treat infection and osseointegration disorders caused by osteomyelitis.Through the above in vivo and in vitro experiments,we can reveal the regulatory mechanism of the pathological environment of Osteomyelitis based on the MIF pathway,and provide experimental basis and a new perspective for the diagnosis and treatment of Osteomyelitis and infectious bone defects.Results:1.When the animal model of chronic femoral Osteomyelitis was made by using high-speed dental drill to inject bacteria and bone wax to seal the gap,the amount of bacteria injected reached 1 × 108 CFU can achieve obvious radiological,Bacteriology and histological changes,which is suitable for model preparation in the study of chronic Osteomyelitis;2.Proteomic data of Osteomyelitis rats on the 21 st day after infection showed that MIF and CD74 may be the key targets for early diagnosis and treatment of Osteomyelitis,and calreticulin and Cathepsin S were expected to become new targets for early diagnosis and adjuvant treatment of Osteomyelitis;3.Cu-sr-modified 3D printed scaffold can regulate macrophage M1 polarization,osteogenic factor secretion and other immune regulation through ion release,and copper strontium ion can induce macrophage M1 polarization to achieve immune phagocytosis against bacteria.Copper strontium ions were used to induce macrophages to secrete bone factors and promote bone integration,thus producing excellent antibacterial and osteogenic effects.In 21-day chronic osteomyelitis model,combined with MIF inhibitor ISO-1 produced better bone integration effects than the control group.Conclusion(s):As an important targeted factor that promotes inflammation and osteoclast differentiation,MIF plays an important anti-inflammatory role in the early stage of osteomyelitis.However,when osteomyelitis enters the chronic stage,the expression of MIF may not be conducive to osteogenic repair.Therefore,in the stage of osteoplastic formation,the expression of MIF should be inhibited to facilitate bone healing in the bone defect area.on this basis,the modified microporous titanium implant has also been proved to be better able to promote bone growth,which is worthy of further research and eventual application in the treatment of clinical infectious bone defects.