A hierarchical dexamethasone-loaded zeolitic imidazolate framework-8 hybrid coating on biodegradable ZnCu alloys for coordinated immuno-angiogenic-osteogenic and antibacterial regulation in inflammation-impaired fracture healing.

Abstract

Bone fracture healing under inflammatory conditions remains a major clinical challenge due to immune dysregulation, impaired vascularization, delayed osteogenesis, and increased infection risk. Zinc-copper (ZnCu) alloys offer biodegradability, mechanical support, and bioactivity, but suffer from insufficient degradation rate, local cytotoxicity from burst Zn²⁺ release, and uneven corrosion. To address these issues, we constructed a dexamethasone-loaded metal-organic framework hybrid coating (DEX@ZIF-8) in situ on ZnCu intramedullary nails (IMNs) via hydrothermal oxidation and subsequent coordination-driven ZIF-8 assembly with DEX loading, enabling controllable drug release and adaptive degradation. Materials characterization confirmed a compact, well-adhered coating with a distinct hierarchical structure composed of uniformly distributed, polyhedral ZIF-8 crystals tightly integrated with the ZnCu substrate. Electrochemical and immersion results confirmed that the coating accelerated corrosion while maintaining uniform degradation, enabling controlled dual release of Zn²⁺ and DEX without local burst. In vitro, Zn²⁺ and DEX synergistically promoted macrophage polarization toward the anti-inflammatory M2 phenotype by up-regulating CD206 and Arg-1. Angiogenesis was enhanced through Zn²⁺-induced HIF-1α activation, while osteogenic differentiation was associated with PI3K/Akt and MAPK signaling, as confirmed by transcriptomic up-regulation of BMP-2, COL1A1, OPN. In a rat inflammatory femur fracture model, coated IMNs maintained mechanical integrity over 12 weeks and significantly accelerated bone regeneration without signs of fracture or local toxicity. This study offers a promising surface engineering approach for Zn-based IMNs to meet the complex demands of inflammatory bone repair.