In Situ-Forming Glucose-Responsive Hydrogel from Hyaluronic Acid Modified with a Boronic Acid Derivative

Hydrogels are a promising class of biomaterials for sustained drug release applications. The use of covalently cross-linked hydrogels for drug delivery applications may be limited due to their manufacturing complexity and the high injection forces required for their administration. Stimulus-responsive hydrogels, which are engineered to respond to stimuli such as pH, temperature, ionic strength, or chemical potential, may overcome these shortcomings and enable the development of injectable hydrogels. This study presents a strategy for forming hydrogels such that a sol-gel transition occurs in response to physiologically relevant glucose concentrations. A hyaluronic acid (HA) polymer backbone is modified with 3-aminophenylboronic acid, which is able to reversibly bind glucose with a 2:1 stoichiometry. The boronic acid-functionalized polymer is demonstrated to be glucose responsive, as indicated by its spontaneous hydrogelation and subsequent increase in stiffness as a function of glucose concentration. Furthermore, the transient nature of the boronic acid-glucose cross-linking enables the hydrogel to self-heal after physical rupture. A proof-of-concept gelation in alkaline conditions is demonstrated, but the system may be adapted for gelation at physiological pH using modified boronic acids. These HA-boronic acid conjugates have potential utility as in situ-forming hydrogels for sustained drug release applications.