Programmable viscoelastic hydrogels exhibit antimicrobial and regenerative properties to promote cell migration,...

The growing challenges of conventional ECM bio-inks for 3D cell culture underscore the development of novel hydrogels that fully recapitulate specialized in vivo cell microenvironments. We developed HA-gel-dex hydrogels by double-crosslinking ECM components (hyaluronic acid and gelatin) with synthetic dextran. Engineered with irreversible amide bonds and dynamic imine crosslinks, the HA-gel-dex enables viscoelastic property modifications to replicate native ECM characteristics, with the highest yield ratio reaching ~1000%. This programmability derive from tunable crosslinking architectures and network dynamics, where controlled HA-gel to dex-CHO ratios and peptide functionalization yield optimized hydrogel viscoelasticity and predictable bioprinting performance. Functionalization with selective cell-ligation groups (RGD, collagen, and laminin peptides) strengthened cell-matrix interaction, promoting increased cell proliferation, differentiation, and micro-organo-sphere formation. Moreover, rheological analyses revealed significantly enhanced stress-relaxing and self-healing hydrogel properties; while showing cytocompatibility, increased cell viability, bioprinting capacity, significant biofilm inhibition properties, and synergism with antimicrobials. Further assays on BALB/c mice showed remarkably improved wound healing, hair follicle regeneration, and nature ECM production abilities, the performance of which are further augmented with the presence and encapsulation of therapeutic mesenchymal stem cells (MSCs). The study shows their future promise as wound dressings and potentially antibiotic treatment scaffolds for infection-associated wounds. Above all, HA-gel-dex hydrogels provide an improved ECM-like, reproducible, and cost-effective alternative to traditional ECM bio-inks for 3D cell culture, 3D bioprinting, and tissue repair studies - advancing synthetic ECM alternatives for translational applications.