Metallic ions have been widely investigated and incorporated into bone substitutes for bone regeneration owing to their superior capacity to induce angiogenesis and osteogenesis. Exosomes are key paracrine mediators that play a crucial role in cell-to-cell communication. However, the role of exosomes in metallic ion-induced bone formation and their underlying mechanisms remain unclear. Thus, this review systematically analyzes the effects of metallic ions and metallic ion-incorporated biomaterials on exosome secretion from mesenchymal stem cells (MSCs) and macrophages, as well as the effects of secreted exosomes on inflammation, angiogenesis, and osteogenesis. In addition, possible signaling pathways involved in metallic ion-mediated exosomes, followed by bone regeneration, are discussed. Despite limited investigation, metallic ions have been confirmed to regulate exosome production and function, affecting immune response, angiogenesis, and osteogenesis. Although the underlying mechanism is not yet clear, these insights enrich our understanding of the mechanisms of the metallic ion-induced microenvironment for bone regeneration, benefiting the design of metallic ion-incorporated implants.

Implant-related infection (IRI) is a major problem in orthopedics. Copper (Cu) is an essential trace element with strong bactericidal activity and, thus, presents potential for reducing IRI. The present study explored a straightforward strategy for releasing Cu²⁺ from titanium (Ti) implants, and we conducted a preliminary study to assess the feasibility of this approach in clinical translation. Polylactic acid (PLA) coatings containing different concentrations of copper ions were prepared on Ti discs. The antibacterial activity and biocompatibility of the copper ion-incorporated Ti implants were evaluated using Staphylococcus aureus (S. aureus), bone marrow mesenchymal stem cells (BMSCs) and animal models. In vitro, the coatings produced burst release of Cu²⁺ in 12 h, and inhibited S. aureus growth in a dose-dependent manner. The coatings prepared from PLA solutions containing 0.5 or 1.0 mg/mL reduced the viability and osteogenic differentiation of BMSCs, but these effects were negated after the coatings were immersed in culture medium for 6 h. Four weeks after implantation, the Cu-free K-wires challenged with S. aureus had persistent infection and inferior fracture healing to the other three groups, while Cu-coated wires had no evidence of infection. Furthermore, the Cu-coated wires placed in rabbits without S. aureus challenge showed superior fracture healing to the other three groups. These results suggest that PLA coatings containing Cu²⁺ may be an effective design for reducing IRI without adversely affecting adjacent bone healing.

Background: Iron overload-related osteoporosis has garnered significant attention, yet its pathological mechanisms remain unclear. Traditional two-dimensional (2D) culture systems often fail to recapitulate the extracellular matrix (ECM) microenvironment, leading to discrepancies between in vitro and in vivo findings. Methods: We developed a three-dimensional (3D) culture system using methacrylated gelatin (GelMA) microspheres to culture preosteoblastic cells, simulate the bone microenvironment under iron overload conditions, and systematically examine changes in cellular morphology, viability, function, and gene expression. Results: Iron overload impaired cell viability, induced oxidative stress, and inhibited osteogenesis in both 2D and 3D cultures. However, cells in 3D exhibited enhanced resilience, including reduced ROS levels, higher viability, preserved cytoskeletal integrity, and less apoptosis and G1-phase arrest. Compared to 2D, 3D-cultured cells showed downregulated expression of ITGA1 and ITGB1, decreased adhesion function, and promoted proliferation. Transcriptomics further revealed activation of NF-κB signaling and DNA replication pathways in 3D, while key pathways such as Hippo, focal adhesion, and Wnt were suppressed. Discussion: The GelMA microsphere-based 3D system provides a physiologically relevant model for studying iron overload. These findings offer not only mechanistic insights but also suggest potential microenvironment-targeted therapeutic strategies for iron overload-associated osteoporosis.