Chitosan content as a key modulator of gelation threshold and sustained fluconazole release in semi-IPN hydrogels.

The rational design of thermoresponsive hydrogels requires precise control of polymer-polysaccharide interactions to ensure injectability, rapid sol-gel transition, and sustained release. We engineered semi-interpenetrating polymer network (semi-IPN) hydrogels by incorporating increasing concentrations of chitosan (CS) into a fumaric acid-crosslinked poly(N-isopropylacrylamide) (pNIPAM) matrix for localized fluconazole delivery. CS incorporation markedly modified hydrogel structure and performance. Swelling increased fivefold with 15 % CS due to enhanced hydrogen bonding and free volume, while gelation time decreased from ∼50 s (control) to ∼33 s, reflecting accelerated network formation via CS-carboxyl interactions. Rheological sweeps showed reinforced viscoelasticity and earlier G'/G″ crossover, while SEM confirmed improved pore interconnectivity. A critical CS threshold (>15.4 % w/v) abolished thermoresponsive gelation, defining a design limit for clinical use. Drug release studies with mathematical modeling revealed a dual transport mechanism: diffusion dominated at low CS, whereas polymer relaxation contributed significantly in CS-rich matrices, producing slower, sustained fluconazole release over 168 h. These systems maintained antifungal activity against Candida albicans and fibroblast viability (>85 %), confirming biocompatibility. Overall, CS concentration emerged as a molecular lever controlling network formation, mechanical stability, and release kinetics, providing a framework for rational design of injectable semi-IPN hydrogels for prolonged antifungal therapy.