A novel dual pH- and temperature-responsive poly (N-isopropylacrylamide)/polyacrylamide/calcium alginate hydrogel with robust mechanical performance and biocompatibility for sustainable drug release

Abstract

Stimuli-responsive hydrogels show promising potential for drug delivery, but often fall short in complex environments due to their single responsiveness and inadequate mechanical properties. Herein, we introduce a dual thermo-/pH-responsive hydrogel carrier, poly(N-isopropylacrylamide)/polyacrylamide/Ca²⁺-coordinated sodium alginate (PNIPAM/PAM/Alg-Ca²⁺), distinguished by exceptional mechanical performance and biocompatibility. The developed PNIPAM/PAM/Alg-Ca²⁺ hydrogel has demonstrated exceptional performance, with a remarkable breaking elongation reaching 4900 % and a toughness of 6.5 MJ/m³, greatly outperforming traditional PNIPAM hydrogels that usually have an elongation of only 247 % and a toughness of 0.035 MJ/m³. It also showcased outstanding crack resistance, with a tearing energy of 212 J/m², far superior to the average of 10 J/m² for existing hydrogel carriers. Moreover, even hydrogel samples with notches can be stretched beyond 1000 %. Swelling tests revealed dual responsiveness (pH and thermo-responsiveness), along with a highly porous structure that supports high drug loading and cell proliferation. Importantly, the hydrogel showed non-cytotoxicity towards NIH-3T3 cells. In vitro release studies of dexamethasone from the hydrogel demonstrated sustained release at pH 7.0 and 37 °C, showing potential for application in drug delivery. Overall, this work highlights the transformative potential of the dual thermo-/pH-responsive PNIPAM/PAM/Alg-Ca²⁺ hydrogel carrier for advancing next-generation biomaterials with enhanced therapeutic efficacy and safety profiles.