Injectable self-healing thermoresponsive hydrogel based on methylcellulose for localized delivery of hydrophobic bioactives.

Thermoresponsive injectable hydrogels are promising platforms for soft tissue repair because they enable minimally invasive administration and undergo sol-gel transition under physiological conditions. In this study, methylcellulose-based hydrogels were prepared using sodium sulfate as a thermogelation-promoting agent and functionalized with thiolated hyaluronic acid (HA-SH) and a β-cyclodextrin/curcumin (β-CD/CUR) inclusion complex. The β-CD/CUR complex improved curcumin compatibility and dispersion within the aqueous hydrogel matrix. All formulations exhibited shear-thinning behavior, supporting injectability, while qualitative self-healing tests showed recovery of structural continuity after mechanical disruption. HA-SH incorporation altered the hydration and porous structure, increasing water uptake while reducing porosity. CUR-loaded hydrogels provided sustained curcumin release under physiological conditions, reaching 67.94 ± 6.52% after 24 h for MC3.5/1.5-HA0.25/CUR0.5, with diffusion modeling indicating a diffusion-controlled mechanism. The released curcumin retained antioxidant activity, with the highest DPPH radical scavenging observed at the highest CUR loading. All hydrogels were cytocompatible with normal human fibroblasts, maintaining viability above 80% throughout the study and exceeding 100% after 72 h. CUR-loaded formulations also showed antibacterial activity against Staphylococcus aureus and Escherichia coli, with MC3.5/1.5-HA0.25/CUR0.5 exhibiting the strongest effect. IL-1β analysis showed no pronounced pro-inflammatory response, while CUR-loaded hydrogels reduced LPS-induced IL-1β secretion over time. Scratch assays further demonstrated enhanced fibroblast-mediated wound closure, particularly after 24 and 48 h. Overall, these HA-SH/CUR-loaded thermoresponsive hydrogels combine injectability, cytocompatibility, controlled release, antioxidant and antibacterial activity, and wound closure-supporting properties, highlighting their potential as bioactive platforms for various biomedical applications.