Crosslinkers for polysaccharides and proteins: Synthesis conditions, mechanisms, and crosslinking efficiency, a review

Polysaccharides and proteins are important macromolecules for developing hydrogels devoted to biomedical applications. Chemical hydrogels offer chemical, mechanical, and dimensional stability than physical hydrogels due to the chemical bonds among the chains mediated by crosslinkers. There are many crosslinkers to synthesize polysaccharides and proteins based on hydrogels. In this review, we revisited the crosslinking reaction mechanisms between synthetic or natural crosslinkers and polysaccharides or proteins. The selected synthetic crosslinkers were glutaraldehyde, carbodiimide, boric acid, sodium trimetaphosphate, N,N'-methylene bisacrylamide, and polycarboxylic acid, whereas the selected natural crosslinkers included transglutaminase, tyrosinase, horseradish peroxidase, laccase, sortase A, genipin, vanillin, tannic acid, and phytic acid. No less important are the reactions involving click chemistry and the macromolecular crosslinkers for polysaccharides and proteins. Literature examples of polysaccharides or proteins crosslinked by the different strategies were presented along with the corresponding highlights. The general mechanism involved in chemical crosslinking mediated by gamma and UV radiation was discussed, with particular attention to materials commonly used in digital light processing. The evaluation of crosslinking efficiency by gravimetric measurements, rheology, and spectroscopic techniques was presented. Finally, we presented the challenges and opportunities to create safe chemical hydrogels for biomedical applications.