The inverse electron demand diels-alder (IEDDA): A facile bioorthogonal click reaction for development of injectable polysaccharide-based hydrogels for biomedical applications

Abstract

The inverse electron demand Diels-Alder (IEDDA) cycloaddition between tetrazines and strained dienophiles is recognized as a fast and specific reaction. The integrating tetrazines and strained dienophiles onto the backbone of polysaccharides yield appropriate water-soluble precursors for IEDDA cycloaddition. Due to the high specificity of the IEDDA reaction and its outstanding cytocompatibility, a range of cargos (live cells, peptides and pharmaceuticals) can be effectively encapsulated in polysaccharide solutions throughout the hydrogel formation. Within a few minutes, the interaction of aqueous solutions of tetrazine-polysaccharides with polysaccharide derivatives of dienophiles can form the hydrogel. The gelation time can be regulated by the structure of tetrazine/dienophile, degree of substitution, concentration of polysaccharide solutions, and temperature. The hydrogels are utilized in the fields of tissue engineering, cancer treatment, and wound healing. The embedding of stimuli-responsive functionalities within the hydrogel's architecture enhances the precision of its application for designated targets. This review begins by elucidating the principles of IEDDA and identifying the primary factors that influence the rate of cycloaddition. Subsequently, we discuss various strategies for integrating the reactants of IEDDA onto polysaccharides. Finally, the approaches for the fabrication of the relevant injectable hydrogels, their specific characteristics, and their implementation in different biomedical applications are elaborated.