The Roles of Exosomes upon Metallic Ions Stimulation in Bone Regeneration

Abstract

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.

Engineered Exosome-Functionalized Extracellular Matrix-Mimicking Hydrogel for Promoting Bone Repair in Glucocorticoid-Induced Osteonecrosis of the Femoral Head

“…8 Considering the tremendous treatment efficiencies of exosomes in regenerative medicine, strategies to enhance the release of exosomes or improve their functions in tissue regeneration have garnered increasing attention. 9 Physical or chemical methods, such as metallic ions, 9 bioglass, 10 and light stimuli, 11 have been applied to promote the release of exosomes or generate engineered exosomes to improve their functions in tissue regeneration. Lithium (Li), a trace metal in the human body, can promote osteogenic differentiation of BMSCs by activating the Wnt/GSK-3β signaling pathway.…”

“…Previous studies have demonstrated that bone marrow stem cells (BMSCs) can be involved in enhanced immunomodulation and tissue regeneration via exosomes, , and BMSC-derived exosomes can protect against ONFH by modulating the immune response, suppressing adipogenesis, and improving osteogenesis . Considering the tremendous treatment efficiencies of exosomes in regenerative medicine, strategies to enhance the release of exosomes or improve their functions in tissue regeneration have garnered increasing attention . Physical or chemical methods, such as metallic ions, bioglass, and light stimuli, have been applied to promote the release of exosomes or generate engineered exosomes to improve their functions in tissue regeneration.…”

Metal ions: the unfading stars of bone regeneration—from bone metabolism regulation to biomaterial applications

“…Bone tissue contains diverse metal elements, and metal ions play an indispensable role in bone regeneration at the molecular and cellular levels. 11 Therefore, metal ions may provide a more straightforward therapeutic signal of bone regeneration. Metal ions such as magnesium ion (Mg 2+ ), calcium ion (Ca 2+ ), strontium ion (Sr 2+ ), zinc ion (Zn 2+ ), lithium ion (Li + ), manganese ion (Mn 2+ ), copper ion (Cu 2+ ), cobalt ion (Co 2+ ), cerium ion (Ce 3+ ), iron ion (Fe 3+ ), and silver ion (Ag + ) are currently used for bone regeneration.…”

Metal Ion-Doped Hydroxyapatite-Based Materials for Bone Defect Restoration

“…For example, the ions of some metals, including titanium, magnesium, and silver, show great biological potentials as they commonly exist in the human body and participate in most metabolic reactions [7]. Doping with these metal ions can also bring some extra benefits like the antibacterial ability to ensure overall performance of HA [8,9].…”