Zinc Silicate Modulates Bone Substitute Degradation Following Macrophage Activation via the JAK/STAT Pathway and Expedites the Initiation of Bone Repair: In Vitro and In Vivo Studies

Abstract Repairing segmental bone defects remains difficult because conventional bone substitutes rarely integrate immunomodulation with efficient tissue regeneration. To address this limitation, zinc-silicate-collagen-hydroxyapatite (ZCH) composites were developed wherein the incorporation of zinc allows controlled material degradation and imparts immunoreactive properties. The addition of moderate concentrations of zinc silicate (<0.337 M) maintained good biocompatibility while enabling tuneable degradation rates and bioactivity. Among the composites, the composite containing 0.224 M zinc silicate (10ZCH) exhibited the most favourable balance between material degradation and bone regeneration and promoted accelerated angiogenesis and osteogenesis. Mechanistic studies revealed that 10ZCH transiently activated M1 macrophages and promoted their polarization towards the proregenerative M2 phenotype by activating the JAK/STAT pathway. These findings demonstrate that rational zinc incorporation can orchestrate immune responses, improve material resorption, and promote rapid tissue repair. This work provides an innovative design concept for fabricating immune-responsive and resorbable bone graft substitutes that couple degradation dynamics with regenerative efficacy.