Biomaterials derived from decellularized extracellular matrix (dECM) contain a complex mixture of proteins, proteoglycans, and signaling molecules that mimic the native tissue microenvironment and provide important cues for regulating cell function. However, dECM-based materials often lack mechanical integrity and tuneability, which limits their applications in tissue engineering. In this study, we modified skin-derived dECM with methacryloyl functional groups (MA-dECM) to support photo-crosslinking and the formation of mechanically tunable hydrogels with up to a 30-fold increase in the elastic modulus. In addition, we generated granular MA-dECM hydrogels by fragmentation into microgels and compaction by centrifugation. Granular MA-dECM hydrogels displayed shear-thinning properties, were compatible with extrusion 3D printing, and could be stabilized by secondary photo-crosslinking. In vitro studies confirmed good adhesion, viability, and proliferation of endothelial cells in both the bulk and granular gels. In skin wound healing studies in mice, application of either bulk or granular MA-dECM gels to the wound bed significantly increased wound closure compared to untreated control mice, and this response was associated with elevated vascularization at early time points. These findings demonstrate that modification of dECM materials with photo-crosslinkable moieties introduces mechanical tuneability and compatibility with advanced biofabrication processes, while retaining their unique biological activity. MA-dECM hydrogels may therefore be attractive biomaterials for improving wound healing and skin repair. STATEMENT OF SIGNIFICANCE: Biomaterials derived from decellularized extracellular matrix (dECM) contain a rich mix of biologically active macromolecules but often lack the mechanical integrity and tunability required for regenerative medicine applications. In this study, we develop robust methods to modify and process dECM from the skin into granular hydrogels with tunable mechanical properties and improved printability compared to unmodified dECM-based materials. We further demonstrate that skin-derived ECM is not only biocompatible but also accelerates healing in acute wounds in vivo. The granular dECM hydrogels may therefore have therapeutic potential for promoting skin repair and regeneration in the future.
