Sequential release of bioactive factors from functionalized metal-organic framework hydrogel enhances interfacial osseointegration of 3D-printed titanium alloy porous scaffolds

<b>Rationale:</b> Repairing bone defects in osteoporotic patients presents a significant clinical challenge due to inadequate osseointegration, persistent inflammation, and elevated oxidative stress. To overcome these barriers, this study proposes the development of a functionalized 3D-printed titanium alloy porous scaffold capable of sequentially releasing therapeutic agents to modulate the immune environment and enhance bone regeneration. <b>Methods:</b> A thermosensitive collagen hydrogel was integrated with a zeolitic imidazolate framework (ZIF-8) to construct a dual-release platform capable of delivering the immunomodulator 4-octyl itaconate (4-OI) and the osteogenic factor bone morphogenetic protein-9 (BMP-9) in a temporally controlled manner. The hydrogel facilitated early-phase release of 4-OI to inhibit M1 macrophage polarization and mitigate oxidative stress, while ZIF-8 enabled sustained BMP-9 release to induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Comprehensive in vitro assays and an osteoporotic rat model were employed to evaluate the scaffold's immunomodulatory properties, osteogenic capacity, and osseointegration performance. <b>Results:</b> The scaffold inhibited pro-inflammatory cytokine expression, attenuated osteoclast activity, and enhanced osteogenic marker levels in vitro. In vivo analysis revealed enhanced bone-implant interface integration and significantly accelerated bone regeneration in osteoporotic defects. Transcriptome analysis revealed suppression of NF-κB and TGF-β signaling, confirming the scaffold's combined immunomodulatory and osteoinductive effects. <b>Conclusions:</b> This ZIF-functionalized hydrogel scaffold with sequential release capability offers a potential strategy for clinical translation in osteoporotic bone defect repair. By orchestrating local immune modulation and promoting sustained osteogenesis, the system offers a clinically relevant approach to enhance osseointegration and facilitate long-term bone repair in osteoporotic conditions.