Molecular modulation of cell migration via chitosan-based hydrogels: Toward smart biomaterial for wound regeneration

Chitosan-derived hydrogels offer a highly tunable scaffold for orchestrating the multifaceted process of wound repair, yet their full potential hinges on an integrated understanding of biochemical and biophysical cues. Here, we provide a concise yet comprehensive analysis of design parameters that govern cell-matrix interactions, focusing on polymer backbone modification, crosslinking density, and incorporation of bioactive ligands. We demonstrate how precise control of viscoelastic properties viscoelastic properties, including stiffness and stress relaxation, achieved through reversible covalent bonds and supramolecular assemblies regulates YAP/TAZ nuclear localization and downstream PI3K/Akt and MAPK/ERK signaling to differentially promote coordinated keratinocyte migration, fibroblast proliferation, and endothelial angiogenesis. Functionalization with RGD peptides and heparin-binding motifs further amplifies receptor-mediated adhesion and growth factor sequestration, creating a pro-regenerative microenvironment. We critically appraise the kinetic profiles of growth factor release and immunomodulatory payloads, underscoring the necessity of spatiotemporal precision in smart hydrogel systems and summarize preclinical and clinical evidence demonstrating accelerated wound closure in diabetic and burn models. Finally, we identify pivotal challenges including the quantitative decoupling of mechanical versus molecular influences in vivo, long-term biocompatibility of modified chitosan derivatives, and translation of high-throughput screening data into clinical contexts and propose a roadmap leveraging single-cell transcriptomics and advanced imaging, and AI-driven modeling to overcome translational challenges. This synthesis delivers actionable guidelines for the development of next-generation, personalized wound therapies.