Comparative Evaluation of Curcumin Derivatives Loaded 3D Printable Chitosan/Gelatin Hydrogels: Release Behaviour, Antimicrobial, Antioxidant, and Immunomodulatory Properties

The development of multifunctional scaffolds with improved mechanical strength, swelling resistance, antibacterial activity and cytocompatibility is crucial for tissue engineering. In this study, chitosan–gelatin (CH GT) scaffolds were reinforced with curcumin (Cur), nano-curcumin (nCur), and PLGA-encapsulated curcumin (PLGA_Cur) to enhance physicochemical and biological properties. SEM micrographs confirmed uniform, interconnected pores with reduced pore wall disruption upon Cur incorporation. Mechanical testing revealed that the highest tensile strength and tensile modulus for CH GT nCur were observed at 34 kPa and 58 kPa, respectively. Swelling studies showed a significant reduction in equilibrium swelling ratio from ~ 675% (CH GT) to ~ 340% (CH GT_nCur), correlating with enhanced hydrogen bonding and physical crosslinking. Antibacterial assays indicated significant inhibition against S. aureus (~ 94%) and E. coli (~ 92%) for CH GT_nCur. Cytocompatibility tests showed > 85% cell viability across all formulations, with CH GT_nCur supporting superior cell attachment and cell migration capabilities compared to controls. Cur release from CH GT Cur and CH GT nCur hydrogel scaffolds resulted in antioxidant activity; however it was slightly impeded by rapid release. In the PLGA-based system, antioxidant activity is enhanced with sustained release. CH GT Cur and CH GT nCur enhanced M2 macrophage polarization (p < 0.001) compared to CH GT Cur hydrogels, which successfully decreased inflammation and oxidative stress. Notably, despite a delayed M2 response, the PLGA-encapsulated Cur system (CH GT PLGA_Cur) demonstrated sustained decrease of ROS levels and iNOS expression, suggesting extended anti-inflammatory effect. These results demonstrate the promise of CH GT-based hydrogels, particularly the PLGA_Cur system, for oxidative stress management and regulated immunomodulation in therapeutic settings.