Hierarchical Therapeutic Ion‐Based Microspheres with Precise Ratio‐Controlled Delivery as Microscaffolds for In Situ Vascularized Bone Regeneration

Abstract Therapeutic ions, such as Si and Mg, play vital roles in regulating metabolism and promoting tissue repair, hence providing an efficient strategy in tissue engineering. The regenerative outcome is strongly dependent on the targeted delivery and controlled release of therapeutic ions. Nevertheless, it remains challenging to deliver multiple ions at controlled manners and ratios. Herein, hierarchical therapeutic ion‐based microspheres are fabricated. The coordinated release of Mg and Si ions at pre‐set ratios is achieved, based on which, Mg favors osteogenesis by inducing highly efficient cell recruitment and angiogenesis, and Si promotes massive collagen secretion and biomineralization to accelerate the bone maturation process. These therapeutic ion‐based microspheres (namely PNM2) can steadily release Mg and Si ions at an optimized ratio of 2:1, which shows the most significant synergistic effect on angiogenesis and osteogenesis. Furthermore, in a rat calvarial defects model, the volume and maturity of the vascularized neo‐bone tissue regenerated with PNM2 microspheres are comparable with or even surpassing those defects regenerated with growth factors and/or cell‐laden scaffolds. Overall, this platform provides a controllable strategy for the coordinated delivery of Mg/Si ions, opening a new avenue for developing therapeutic ion‐based microscaffold for tissue engineering.