Microgel-Crosslinked, thermo- and mechano- dual Responsive, Ketoprofen-Loaded hydrogels with high mechanical properties and rapid response.

Smart hydrogels have advanced rapidly in recent years. However, systems responsive to a single stimulus are typically triggered by specific cues, limiting their adaptability in complex and dynamic biological environments. To overcome this limitation, this study developed a dual-responsive hydrogel sensitive to both temperature and mechanical stress. The hydrogel consists of a poly(N-isopropylacrylamide) (PNIPAM) matrix crosslinked with ketoprofen-loaded, vinyl-functionalized PNIPAM microgels (MGVs), engineered as a transdermal platform for dynamically regulated drug release. The PNIPAM-based hydrogel exhibits temperature sensitivity, while the incorporated MGVs serve a dual function as both drug carriers and crosslinkers, reinforcing the hydrogel mechanically. Increasing MGV content from 1 % to 3 % elevated the compressive strength from 14.2 ± 4.5 kPa to 435.5 ± 20.9 kPa. Ketoprofen release can be precisely controlled by both temperature and mechanical compression. At 37 °C, increasing compressive strain from 40 % to 60 % significantly accelerated drug release, requiring only 35 cycles to release 372.5 ± 4.2 µg of ketoprofen, compared to 90 cycles for 360.7 ± 38.0 µg under 40 % strain. Under 60 % strain, reducing the temperature to 25 °C markedly reduced the release amount to 313.7 ± 0.9 µg over 90 cycles, demonstrating the hydrogel's effective dual-stimulus responsiveness. Ex vivo tissue permeation studies confirmed that both elevated temperature and applied mechanical force significantly accelerate drug release and enhance drug permeation into tissues. In vitro assays verified the hydrogel's cytocompatibility. Overall, the dual-stimulus-responsive hydrogel offers a versatile and robust platform for transdermal drug delivery, with strong potential for application in advanced therapeutic systems.