3D ‐Printed Ordered Porous CSMA / GelMA Hydrogel Scaffolds Enhance ADSC Reparative Function With FAK – YAP ‐Related Mechanotransductive Changes

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Chronic diabetic wounds persist in a hostile microenvironment that compromises the survival and reparative activity of transplanted stem cells. Here, we developed a structurally defined 3D-printed ordered porous chitosan methacrylate/gelatin methacryloyl (CSMA/GelMA) hydrogel scaffold platform to test whether topological order acts as a structurally relevant biomaterial cue for adipose-derived mesenchymal stem cell (ADSC) regulation. To enrich for topology-dependent effects, ordered and disordered scaffolds were fabricated from the same photocrosslinkable chitosan methacrylate/gelatin methacryloyl precursor system and subjected to the same crosslinking and lyophilization-rehydration workflow, while differing in spatial pore organization. Among the ordered architectures tested, the 200 μm scaffold showed the most favorable early biological performance and was selected for subsequent studies. Ordered topology induced ADSC polarization, directional F-actin organization, and nuclear elongation/alignment, indicating coordinated cytoskeletal-nuclear remodeling. Mechanistically, ordered scaffolds increased FAK phosphorylation and enhanced YAP nuclear localization, whereas pharmacological inhibition of FAK attenuated YAP-related responses and the reparative paracrine advantage conferred by ordered topology. On this basis, sustained SDF-1α presentation further enhanced the reparative secretory profile, at least partly through CXCR4-AKT/ERK-associated signaling. In an STZ-induced diabetic full-thickness skin wound model, the integrated ordered scaffold strategy improved wound closure, histological reconstruction, collagen deposition, and CD31- and CD206-associated reparative changes, with the greatest benefit observed when combined with ADSCs. These findings support a topology-mechanotransduction-function axis within this scaffold system and provide a rationale for biomaterial-guided stem-cell therapy in diabetic wound healing.