Mechano-Triggered\nRelease of Biomolecules from Supramolecular\nHyaluronic Acid Hydrogels

Smart drug-delivery\nsystems play an important role in\nthe development\nof effective therapies and regenerative medicine. The precisely controlled\nrelease of bioactive molecules offers numerous advantages, such as\nreduced side effects and improved drug efficiency. In this work, we\ndemonstrate an approach to load proteins into mechano-responsive hydrogels\nand release the payload via mechanical activation. For this, we synthesized\nhyaluronic acid hydrogels, which are cross-linked via supramolecular\nhost–guest complexation. We varied the hyaluronic acid concentration\nbetween 100 and 150 mg mL<sup>–1</sup> and the host–guest\nratio between 1:2 and 3:1. The reversible cross-linking strategy enables\nthe hydrogel network to respond with changes in its internal structure\nwhen an external mechanical force is applied. For mechano-activation,\nwe applied pressure of 1.3 N cm<sup>–2</sup> from the top.\nHereby, we observed significantly enhanced protein release for the\nsupramolecular gels, whereas no such behavior was seen for a conventional\ncovalently cross-linked hydrogel. Further, we showed that, by adjusting\nthe supramolecular hydrogels’ composition, their mechanical\nproperties and distinctly related release profiles can be modulated\n(up to 32% higher release upon activation). Additionally, cytotoxicity\ntests showed excellent biocompatibility for the gels, making them\npromising candidates for applications in, for example, tissue engineering\nor personalized medical treatment.