The clinical application of magnesium (Mg) and its alloys for bone fractures has been well supported by in vitro and in vivo trials. However, there were studies indicating negative effects of high dose Mg intake and sustained local release of Mg ions on bone metabolism or repair, which should not be ignored when developing Mg-based implants. Thus, it remains necessary to assess the biological effects of Mg implants in animal models relevant to clinical treatment modalities. The primary purpose of this study was to validate the beneficial effects of intramedullary Mg implants on the healing outcome of femoral fractures in a modified rat model. In addition, the mineralization parameters at multiple anatomical sites were evaluated, to investigate their association with healing outcome and potential clinical applications. Compared to the control group without Mg implantation, postoperative imaging at week 12 demonstrated better healing outcomes in the Mg group, with more stable unions in 3D analysis and high-mineralized bridging in 2D evaluation. The bone tissue mineral density (TMD) was higher in the Mg group at the non-operated femur and lumbar vertebra, while no differences between groups were identified regarding the bone tissue volume (TV), TMD and bone mineral content (BMC) in humerus. In the surgical femur, the Mg group presented higher TMD, but lower TV and BMC in the distal metaphyseal region, as well as reduced BMC at the osteotomy site. Principal component analysis (PCA)-based machine learning revealed that by selecting clinically relevant parameters, radiological markers could be constructed for differentiation of healing outcomes, with better performance than 2D scoring. The study provides insights and preclinical evidence for the rational investigation of bioactive materials, the identification of potential adverse effects, and the promotion of diagnostic capabilities for fracture healing.

Historically, the rapid degradation and massive gas release from magnesium (Mg) implants resulted in severe emphysema and mechanical failure. With the advent of new alloys and surface treatment methods, optimized Mg implants have re-entered clinics since last decade with reliable performance. However, the optimization aims at slowing down the degradation process, rather than exemption of the gas release. This study involved a systematic evaluation of current preclinical and clinical evidence, regarding the physical signs, symptoms, radiological features, pathological findings and complications potentially associated with peri‑implant gas accumulation (PIGA) after musculoskeletal Mg implantation. The literature search identified 196 potentially relevant publications, and 51 papers were enrolled for further analysis, including 22 preclinical tests and 29 clinical studies published from 2005 to 2023. Various Mg-based materials have been evaluated in animal research, and the application of pure Mg and Mg alloys have been reported in clinical follow-ups involving multiple anatomical sites and musculoskeletal disorders. Soft tissue and intraosseous PIGA are common in both animal tests and clinical follow-ups, and potentially associated with certain adverse events. Radiological examinations especially micro-CT and clinical CT scans provide valuable information for quantitative and longitudinal analysis. While according to simulation tests involving Mg implantation and chemical processing, tissue fixation could lead to an increase in the volume of gas cavity, thus the results obtained from ex vivo imaging or histopathological evaluations should be interpreted with caution. There still lacks standardized procedures or consensus for both preclinical and clinical evaluation of PIGA. However, by providing focused insights into the topic, this evidence-based study will facilitate future animal tests and clinical evaluations, and support developing biocompatible Mg implants for the treatment of musculoskeletal disorders.