Mechano-Triggered Release of Biomolecules from Supramolecular Hyaluronic Acid Hydrogels

Smart drug-delivery systems play an important role in the development of effective therapies and regenerative medicine. The precisely controlled release of bioactive molecules offers numerous advantages, such as reduced side effects and improved drug efficiency. In this work, we demonstrate an approach to load proteins into mechano-responsive hydrogels and release the payload via mechanical activation. For this, we synthesized hyaluronic acid hydrogels, which are cross-linked via supramolecular host–guest complexation. We varied the hyaluronic acid concentration between 100 and 150 mg mL^–1 and the host–guest ratio between 1:2 and 3:1. The reversible cross-linking strategy enables the hydrogel network to respond with changes in its internal structure when an external mechanical force is applied. For mechano-activation, we applied pressure of 1.3 N cm^–2 from the top. Hereby, we observed significantly enhanced protein release for the supramolecular gels, whereas no such behavior was seen for a conventional covalently cross-linked hydrogel. Further, we showed that, by adjusting the supramolecular hydrogels’ composition, their mechanical properties and distinctly related release profiles can be modulated (up to 32% higher release upon activation). Additionally, cytotoxicity tests showed excellent biocompatibility for the gels, making them promising candidates for applications in, for example, tissue engineering or personalized medical treatment.