Rapid gelation strategy for ion-doped hierarchical hollow hydroxyapatite microspheres with enhanced bioactivity for bone repair

The development of biomimetic microsphere systems holds great promise for advancing bone tissue engineering, yet challenges remain in achieving scalable synthesis of hierarchical structures with controlled bioactivity. Here, we report a rapid gelation-based strategy to fabricate hydroxyapatite (HAp) microspheres doped with biologically relevant ions (Mg, Sr, Zn, Fe). By exploiting the strong affinity between guar gum (GG) and trace copper ions, stable gel precursors were formed, enabling large-scale production of hollow microspheres. Structural characterizations confirmed that ion substitution preserved the HAp lattice while modulating crystallinity and particle growth. SEM analyses revealed the formation of well-defined hollow cores, with cavity size positively correlated with ion concentration. Thermogravimetric data suggested that hollow architectures arose from gel microstructure evolution during calcination. In vitro assays with bone marrow-derived mesenchymal stem cells (mBMSCs) demonstrated robust cell adhesion, spindle-like morphology, and active proliferation on the microsphere surfaces, confirming excellent cytocompatibility.