The feasibility of ceria-incorporated materials for osteoporotic fracture treatment

Abstract

Polymethyl methacrylate (PMMA) bone filler provides mechanical support to a collapsed vertebral body. However, the disparity in compressive strength between PMMA and bones leads to stress shielding and an increased risk of secondary fractures. Furthermore, the heat generated during PMMA polymerization can cause thermal necrosis, implant loosening, and dislocation. Calcium-based bone fillers, while avoiding the risk of thermal necrosis and stress shielding, do not offer a long-term solution for fracture treatment. In this study, the healing effects of conventional biodegradable bone cement were first evaluated. Both fast- and slow-degrading magnesium (Mg)-containing calcium sulfate/phosphate cement (CSPC) were unable to provide complete recovery after fractures. The results showed that fast-degrading Mg-containing CSPC promoted higher rates of bone regeneration at the early stage (postoperative weeks 4-7), but bone void formation still occurred at week 12. Slow-degrading Mg-containing CSPC reduced the degradability and Mg release rate, resulting in lower rates of bone regeneration and a larger void formation after complete degradation. Thus, a new bone cement containing ceria nanoparticles (CNP) was proposed. The objectives of this study were to (1) assess the biocompatibility and toxicity of CNP; (2) to evaluate the impact of poly(ethylene glycol) diacrylate (PEGDA)-coated CNP on antioxidant capacity and cellular uptake; (3) to investigate the bone healing potential of PEGDA_CNP-containing hydrogel; (4) to examine the healing process of osteoporotic fractures treated with CNP-CSPC. CNP demonstrated good biocompatibility and did not induce toxicity at concentrations below 50 μg/ml in vitro. The superoxide dismutase (SOD)- and catalase (CAT)-mimetic effects of PEGDA_CNP was investigated and a low ratio of PEGDA: CNP coating exhibited higher SOD- and CAT-mimetic effect, oxidase- and peroxidase-like activity. The zeta potential of CNP was -13.64 mV, while PEGDA-coated CNP had a positive zeta potential of 10.91 mV, increasing cellular uptake efficiency. The bone healing effects of PEGDA_CNP-containing hydrogel and CNP-containing bone cement were investigated using an ovariectomy (OVX) and bone defect model in rats. A concentration of 1 mg/ml of CNP in gelatin methacrylate (GelMa) significantly enhanced the healing effect compared to the control group. However, a concentration of 2 mg/ml of CNP in GelMa reduced cell adhesion and induced toxicity to mesenchymal stem cells (MSC) in vitro, and the in vivo bone healing performance was worse than the GelMa group. 15 Wt% of CNP containing CSPC demonstrated great osteoconductivity, as evidenced by histological analysis showing multiple sites of mineralization at the cement core and increased osteoblast adhesion. Tartrate-resistant acid phosphatase (TRAP) staining results indicated higher osteoclastic activity around CNP clusters, but the bone mineral density (BMD) was unaffected in quantitative micro-CT analysis, suggesting a protective effect on newly formed bones. In conclusion, PEGDA-coated CNP improved particle dispersion and antioxidant capacity, making it a potential candidate for drug delivery. CNP-enriched bone cement improved the sustainability of bioactive bone filler and could be used in vertebroplasty, especially for patients with osteoporosis.