3D Printed High‐Strength Hydrogel for Dual Release of Cu ²⁺ and Ag ⁺ Ions to Enhance Bone Repair and Antibacterial Properties

ABSTRACT Bone restoration is often hindered by the spatiotemporal dysregulation of immune and regenerative signals. Conventional bio‐inert implants, providing only passive support, fail to modulate this microenvironment, leading to infections and poor healing. To achieve proactive regulation of the osteo‐immune niche alongside robust antimicrobial defense, we developed a novel 3D‐printed, high‐strength hydrogel composed of methacrylated silk fibroin (SFMA), copper‐epigallocatechin gallate (Cu‐EGCG), and silver nanoparticles (AgNPs), characterized by dual‐ion release kinetics. A sophisticated staged‐release strategy was engineered wherein the rapid initial burst of Cu 2+ establishes an immediate antimicrobial barrier and initiates early immunomodulation, whereas the sustained, long‐term release of Ag + ensures continuous pathogen suppression. This “fast‐and‐slow” synergistic release profile effectively bridges the gap between acute‐phase infection control and the requirement for a stable environment during chronic tissue maturation. In vitro studies confirmed that the hydrogel possesses superior mechanical integrity, biocompatibility, and potent antibacterial activity, significantly promoting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo results demonstrated robust new bone formation, with near‐complete anatomical restoration of critical‐size bone defects achieved within 4 weeks in the experimental group. Transcriptomic analysis further elucidated the underlying mechanism, revealing that the SFMA/Cu‐EGCG/AgNPs hydrogel significantly reshaped gene expression profiles associated with immunity and osteogenesis. By activating immune‐regulatory pathways—specifically IL‐17 and TGF‐β—the hydrogel successfully orchestrated a pro‐regenerative immune microenvironment. Simultaneously, the significant enrichment of Wnt signaling and ossification‐related pathways confirmed its dual‐functional role in accelerating bone regeneration at the molecular level. In summary, this hydrogel facilitates a synergistic “infection control‐immunomodulation‐osteogenesis” tripartite repair strategy, offering a highly promising biomimetic approach for the clinical management of complex bone defects.