pH-Responsive Reversible Granular Hydrogels Based on Metal-Binding Mussel-Inspired Peptides

Taking advantage of their thixotropic behavior, microporosity,and modular properties, granular hydrogels formed from jammed hydrogelmicroparticles have emerged as an exciting class of soft, injectablematerials useful for numerous applications, ranging from the productionof biomedical scaffolds for tissue repair to the therapeutic deliveryof drugs and cells. Recently, the annealing of hydrogel microparticlesin situ to yield a porous bulk scaffold has shown numerous benefitsin regenerative medicine, including tissue-repair applications. Currentannealing techniques, however, mainly rely either on covalent connections,which produce static scaffolds, or transient supramolecular interactions,which produce dynamic but mechanically weak hydrogels. To addressthese limitations, we developed microgels functionalized with peptidesinspired by the histidine-rich cross-linking domains of marine musselbyssus proteins. Functionalized microgels can reversibly aggregatein situ via metal coordination cross-linking to form microporous,self-healing, and resilient scaffolds at physiological conditionsby inclusion of minimal amounts of zinc ions at basic pH. Aggregatedgranular hydrogels can subsequently be dissociated in the presenceof a metal chelator or under acidic conditions. Based on the demonstratedcytocompatibility of these annealed granular hydrogel scaffolds, webelieve that these materials could be developed toward applicationsin regenerative medicine and tissue engineering.