Phase Controllable Hyaluronic Acid Hydrogel with Iron(III) Ion–Catechol Induced Dual Cross-Linking by Utilizing the Gap of Gelation Kinetics

Abstract

Metal complexation-based gelation imparts load-bearing hydrogels with striking properties like reversibility, self-healing, and mechanical tunability. Using a bio-inspired metal–catechol complex, these properties have been introduced to a variety of polymer hydrogels, except hyaluronic acid, which is widely used in biological applications. In this research, we developed two different hyaluronic acid (HA) hydrogels by regulating the gelation kinetics of Fe3+ and a catechol cross-linker, including Fe3+-induced covalent bonding and coordination bonding. Dual roles of Fe3+ in catechol-modified HA (HA-CA), Fe3+–catechol coordination, and catechol oxidation followed by a coupling reaction were selectively applied for different gelations. Phase-changeable HA-CA gel was attributed to dominant Fe3+–catechol coordination with immediate pH control. Alternatively, allowing a curing time to form catechol coupling bonds resulted in color-changeable HA-CA gels with pH control. The gel structure is then preserved by dual cross-linking through covalent catechol-coupling-based coordinate bonds and electrostatic interactions between Fe3+ and HA-CA. The hydrogels showed enhanced cohesiveness and shock-absorbing properties with increasing pH due to coordinate bonds inspired by marine mussel cuticles. The present gelation strategy is expected to expand the utility of HA hydrogels in biological applications, offering easy control over the phase, gel network, and viscoelastic properties.