Mechanically adaptive Mg-Ti composites guided by single-cell insights accelerate load-bearing bone regeneration via dual modulation of osteogenesis and osteoclastogenesis

The regeneration and repair of load-bearing bone defects require a delicate balance between mechanical stability and biological integration. Magnesium (Mg)-based materials are promising due to their bioactivity, but their rapid degradation often results in the premature loss of mechanical strength, which compromises their ability to provide structural support during the critical early stages of bone healing, particularly in load-bearing applications. To address this challenge, a Magnesium-Titanium (Mg-Ti) composite was designed, integrating the bioactivity of Mg with the mechanical stability of titanium (Ti). Single-cell RNA sequencing revealed that Mg selectively promoted Mesenchymal Stem Cells (MSCs) recruitment and osteogenic differentiation, while also arresting osteoclast precursors to retain a less differentiated state. These precursors secreted PDGF-BB, coupling osteogenesis with angiogenesis. The Ti scaffold, fabricated as a 3D-printed rhombic dodecahedron structure that mimicked trabecular bone, ensured mechanical support while allowing controlled Mg degradation. This design enabled the progressive adaptation of the composites' mechanical properties to those of natural bone over time, in accordance with Nielsen's law, thereby optimizing both short-term stability and long-term integration. Mg-Ti-1200 exhibited dual-regulatory effects of osteogenesis-osteoclastogenesis: enhancing MSCs osteogenesis via the PI3K-Akt pathway, while inhibiting osteoclast maturation through the PLCγ2-Calcineurin-NFATc1 pathway. <i>In vivo</i>, the Mg-Ti-1200 resulted in a 55 % increase in bone volume and exhibited mechanical properties comparable to those of natural bone after 8 weeks of implantation. This study presented a mechanism-guided biomaterial strategy that integrated both mechanical and biological optimization for the functional regeneration of load-bearing bone defects.