Spatial organization of magnetic nanoparticles in chitosan-gelatin hydrogels enables enhanced magnetic actuation and cell response under dynamic stimulation

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Magnetically responsive hydrogels have emerged as promising platforms for remotely modulating HFF-1 fibroblasts behavior through dynamic mechanical stimulation; however, the influence of magnetic nanoparticle spatial organization on magnetic actuation and cell response remains unexplored. Herein, we report the development of chitosan-gelatin magnetic hydrogels with controlled Fe 3 O 4 nanoparticle distribution including homogeneously dispersed, and spatially patterned configurations, as a strategy to engineer localized mechanotransduction and magnetic actuation. The role of nanoparticle organization on the physicochemical, magnetic, and biological properties of the hydrogels has been analyzed. Structural characterization confirmed the successful incorporation of Fe 3 O 4 nanoparticles while preserving their crystalline inverse spinel structure. Morphological and topographical analyses revealed that patterned hydrogels exhibit well-defined nanoparticle-rich and nanoparticle-free regions, generating pronounced microscale heterogeneity throughout the material. The incorporation and spatial confinement of Fe 3 O 4 nanoparticles significantly influenced the hydrogel properties, increasing stiffness, reducing swelling capacity, and enhancing magnetic responsiveness. Notably, patterned hydrogels displayed higher saturation magnetization and magnetic susceptibility than homogeneously dispersed systems, indicating that nanoparticle confinement promotes cooperative magnetic interactions and more efficient magnetic actuation. Biological studies demonstrated excellent cytocompatibility for all hydrogel formulations. While static magnetic stimulation slightly reduced fibroblast proliferation, dynamic magnetic stimulation significantly enhanced cell proliferation, spreading, and cytoskeletal organization, particularly in patterned hydrogels. These effects are attributed to cyclic mechanical cues generated by amplified magnetic-to-mechanical transduction within the patterned magnetic domains. Overall, this study demonstrates that nanoparticle spatial organization is a key design parameter for engineering magnetically responsive hydrogels with tunable magnetic actuation and controllable cellular responses for tissue engineering applications.