Borosilicate bioactive glass synergizing low-dose antibiotic loaded implants to combat bacteria through ATP disruption and oxidative stress to sequentially achieve osseointegration
Mengke Fan, Youliang Ren, Yanbin Zhu, Hao Zhang, Shuaijie Li, Chunyu Liu, Hongzhi Lv, Lei Chu, Zhiyong Hou, Yingze Zhang, Haobo Pan, Xu Cui, Wei Chen
Abstract
Bone infection is a catastrophe in clinical orthopedics. Despite being the standard therapy for osteomyelitis, antibiotic-loaded polymethyl methacrylate (PMMA) cement has low efficiency against bacteria in biofilms. Furthermore, high-dose antibiotic-loaded implants carry risks of bacterial resistance, tissue toxicity, and impairment of local tissue healing. By incorporating borosilicate bioactive glass (BSG) into low-dose gentamicin sulfate (GS)-loaded PMMA cement, an intelligent strategy that synergistically eradicates bacteria and sequentially promotes osseointegration, was devised. Results showed that BSG did not compromises the handling properties of the cement, but actually endowed it with an ionic and alkaline microenvironment, thereby damaging the integrity of bacterial cell walls and membranes, inhibiting ATP synthesis by disrupting the respiratory chain in cell membranes and glycogen metabolism, and elevating reactive oxygen species (ROS) levels by weakening antioxidant components (peroxisomes and carotenoids). These antibacterial characteristics of BSG synergistically reinforced the effectiveness of GS, which was far below the actual clinical dosage, achieving efficient bacterial killing and biofilm clearance by binding to the 30S subunit of ribosomes. Furthermore, the released GS and the ionic and alkaline microenvironment from the implants fostered the osteogenic activity of hBMSCs in vitro and coordinately enhanced osseointegration in vivo . Collectively, this study underscores that BSG incorporation offers a promising strategy for reducing antibiotic dosage while simultaneously enhancing the antibacterial activity and osteogenesis of implants. This approach holds potential for resolving the conflict between bacterial resistance and bone infection. Fig. 1 . Schematic illustration highlighting the preparation, application and antibacterial mechanism of bioactive antibacterial PMMA cement . (a) Fabrication of borosilicate bioactive glass and bioactive cement, the energy dispersive spectroscopy (EDS) mapping image demonstrates the uniform distribution of BSG in PMMA substrate. (b) After implanting cement into the infected femoral bone marrow cavity, there is a temporal transition from combating infection to promoting bone formation. (c) The antibacterial mechanism of bioactive antibacterial PMMA cement: the diagram illustrates how ions and alkaline microenvironment from BSG degradation disrupt bacterial cell walls and membranes, leading to intracellular ATP synthesis inhibition and ROS accumulation, ultimately resulting in bacterial eradication. (d) The osteogenic effect of bioactive antibacterial PMMA cement: This section showcases how bioactive antibacterial PMMA cement enhances osteogenesis and bone formation around the implant site. • Borosilicate bioactive glass is incorporated into PMMA cement loaded with a low dose of gentamycin sulfate. • Borosilicate bioactive glass and low-dose antibiotics synergistically enhance the antibiosis and osseointegration of implants. • Borosilicate bioactive glass eliminates bacterial infection by biofilm inhibition, oxidative stress and ATP disruption.