Hyaluronic-acid based redox-responsive hydrogels using the Diels-Alder reaction for on-demand release of biomacromolecules

Abstract

Hydrogels are crosslinked, three-dimensional hydrophilic polymeric networks which possess similarity in structure to human soft tissue, and thus have found a great number of applications as biomaterials. Hydrogels can also act as depot for therapeutic cargo, where small molecule drugs to biomolecules can be encapsulated within their porous structure. The aim of this work is to fabricate redox-responsive hydrogels that can dissolve and release biomacromolecules upon exposure to a reducing environment. In particular, hyaluronic acid (HA), was modified with electron-rich furan groups to yield hydrogels through the Diels-Alder (DA) reaction with a maleimide group containing redox-responsive polyethylene glycol (PEG) based crosslinker. Redox-responsive hydrogels were obtained with high conversions (87–95%) at 37 °C, in a catalyst-free fashion. The stimuli-responsive degradation of hydrogels could be tuned by varying the amount of crosslinker. To examine the passive and on-demand delivery of biomacromolecules, a model protein, fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA), was encapsulated within the hydrogels. While a sustained passive release was observed in PBS, a rapid on-demand release was obtained upon exposure to the reducing agent 1,4-dithiothreitol (DTT). Furthermore, the complete dissolution of the hydrogel was accomplished upon exposure to a solution containing the reducing agent.

Graphical Abstract

Keywords:

• Hyaluronic acid
• hydrogel
• Diels-Alder
• disulfide
• PEG
• redox-responsive

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors would like to thank the Bogazici University Research Grant (Project No. 14825, 19B05M1) for financial assistance.