Osteochondral defects include the damage of cartilage and subchondral bone, which are still clinical challenges. The general replacements are difficult to simultaneously repair cartilage and subchondral bone due to their various requirements. Moreover, appropriate printable bioactive materials were needed for 3D bioprinting personalized scaffolds for osteochondral repairing. Herein, the novel hydrogel was developed by hybridizing the alginate sodium (SA) and gellan gum (GG) with the inorganic thixotropic magnesium phosphate-based gel (TMP-BG) in the pre-crosslinking of Mg²⁺ to enhance osteochondral repairing. SA-GG/TMP-BG hybrid hydrogels possessed controllable rheological, injectable, mechanical properties and porosities by tuning their ratio. The shear-thinning of SA-GG/TMP-BG was responsible for its excellent injectability. SA-GG/TMP-BG hybrid hydrogels displayed good cell compatibility, on which MG-63 and BMSCs cells attached and spread well with the high proliferation and up-regulated osteogenic genes. In addition, the inorganic TMP-BG gel hybridized with SA-GG hydrogel released Mg²⁺ was conducive to recruiting BMSCs and promoting the osteogenic and chondrogenic differentiation of BMSCs. Histological results confirmed that SA-GG/TMP6040 significantly promoted the osteogenesis of subchondral bone and then further facilitated the cartilage repairing after being implanted in osteochondral defects of rabbits for 6 and 12 weeks.

Synthetic scaffolds with multifunctional properties, including angiogenesis and osteogenesis capacities, play an essential role in accelerating bone regeneration. In this study, various concentrations of Cu/Zn ions were incorporated into biphasic calcium phosphate (BCP) scaffolds, and then growth differentiation factor-5 (GDF-5)-loaded poly(lactide-co-glycolide) (PLGA) microspheres were attached onto the ion-doped scaffold. The results demonstrated that with increasing concentration of dopants, the scaffold surface gradually changed from smooth grain crystalline to rough microparticles, and further to a nanoflake film. Additionally, the mass ratio of β-tricalcium phosphate/hydroxyapatite increased with the dopant concentration. Furthermore, GDF-5-loaded PLGA microspheres attached onto the BCP scaffold surface exhibited a sustained release. In vitro co-culture of bone mesenchymal stem cells and vascular endothelial cells showed that the addition of Cu/Zn ions and GDF-5 in the BCP scaffold not only accelerated cell proliferation, but also promoted cell differentiation by enhancing the alkaline phosphatase activity and bone-related gene expression. Moreover, the vascular endothelial growth factor secretion level increased with the dopant concentration, and attained a maximum when GDF-5 was added into the ions-doped scaffold. These findings indicated that BCP scaffold co-doped with Cu/Zn ions exhibited a combined effect of both metal ions, including angiogenic and osteogenic capacities. Moreover, GDF-5 addition further enhanced both the angiogenic and osteogenic capacities of the BCP scaffold. The Cu/Zn co-incorporated BCP scaffold-derived GDF-5 sustained release system produced multifunctional scaffolds with improved angiogenesis and osteogenesis properties.

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.