Gradient-Decalcified Cuttlebone Powder-Loaded Hierarchical Microneedles: A Synergistic Therapeutic Strategy for...

Chronic diabetic wounds suffer from a vicious cycle of persistent inflammation and bacterial infection. While natural cuttlebone powder (CBP) exhibits excellent hemostatic, anti-inflammatory, and pro-angiogenic properties, its topical utility is hindered by poor permeability and short retention. Furthermore, fabricating microneedles (MNs) from mineralized materials requires balancing mineral content for skin penetration against effective bioactive release. Herein, we fabricated three gradient-decalcified MNs via acetic acid treatment, namely undecalcified CBP MNs (UDCBP@MNs), partially decalcified CBP MNs (PDCBP@MNs), and completely decalcified CBP MNs (CDCBP@MNs). These MNs integrate CBP and silver nanoparticles within a gelatin methacryloyl (GelMA) matrix, backed by a chitosan hydrogel. Among them, PDCBP@MNs optimally balanced mechanical strength and the sustained release of Ag⁺ and bioactive components. In vitro, these MNs significantly inhibited Staphylococcus aureus and Pseudomonas aeruginosa while promoting cell proliferation, migration, and angiogenesis. In vivo studies in a diabetic mouse model demonstrated that PDCBP@MNs accelerated wound closure by alleviating local inflammation, promoting vascular maturation, and enhancing collagen deposition. This hierarchically designed system maximizes the therapeutic potential of CBP, offering a promising translational strategy for diabetic wound management.