Hyaluronic acid-based IPN hydrogels with trigger-induced thermoresponsive behavior for drug delivery

Hyaluronic acid (HA)-based hydrogels are promising materials for drug delivery, but conventional single-network systems often exhibit limited mechanical stability and poor stimulus responsiveness. In this study, sequential interpenetrating polymer network (IPN) hydrogels combining pH- and temperature-sensitive properties were developed using HA, poly(methylvinylether-alt-maleic acid), and a thermosensitive copolymer, poly(N-isopropylacrylamide-co-N-hydroxyethyl acrylamide). The IPN structure was obtained through a solvent-free thermal crosslinking strategy, avoiding the use of potentially toxic crosslinking agents. The hydrogels exhibited ion-exchange capacities between 3.27 and 6.77 mmol -COOH g^-1, enabling efficient loading of the model drug hydroxyzine (HDZ), with loading capacities reaching up to ∼2 g HDZ g^-1 hydrogel depending on the HDZ/-COOH ratio. The presence of the ionizable drug molecule HDZ in the polymeric network and release medium actively influences internal network structure, swelling behavior, thermoresponsive properties, and drug release profiles. Release studies combined with kinetic modeling showed a diffusion-controlled release mechanism, while slightly higher Weibull β values (0.63-0.78) were observed in the presence of drug, indicating a partial relaxation of the polymer network due to drug-network interactions. Cytotoxicity assays confirmed a good cytocompatibility, with cell viability exceeding 100% in some cases. These results demonstrate that IPN hydrogels represent promising adaptable platforms for controlled drug delivery applications.