Click chemistry is not a single specific reaction, but describes ways of generating products which emulate examples in nature. Click reactions occur in one pot, are not disturbed by water, generate minimal and inoffensive byproducts, and are characterized by a high thermodynamic driving force, driving the reaction quickly and irreversibly towards a high yield of a single reaction product. As a result, over the past 15 years it has become a very useful bio-orthogonal method for the preparation of chemical cross-linked biopolymer-based hydrogel, in the presence of e.g. growth factors and live cells, or in-vivo. Biopolymers are renewable and non-toxic, providing a myriad of potential backbone toolboxes for hydrogel design. The goal of this review is to summarize recent advances in the development of click chemistry-based biopolymeric hydrogels, and their applications in regenerative medicine. In particular, various click chemistry approaches, including copper-catalyzed azide-alkyne cycloaddition reactions, copper-free click reactions (e.g. the Diels–Alder reactions, the strain-promoted azide-alkyne cycloaddition reactions, the radical mediated thiol-ene reactions, and the oxime-forming reactions), and pseudo-click reactions (e.g. the thiol-Michael addition reactions and the Schiff base reactions) are highlighted in the first section. In addition, numerous biopolymers, including proteins (e.g. collagen, gelatin, silk, and mucin), polysaccharides (e.g. hyaluronic acid, alginate, dextran, and chitosan) and polynucleotides (e.g. deoxyribonucleic acid), are discussed. Finally, we discuss biopolymeric hydrogels, cross-linked by click chemistry, intended for the regeneration of skin, bone, spinal cord, cartilage, and cornea. This article provides new insights for readers in terms of the design of regenerative medicine, and the use of biopolymeric hydrogels based on click chemistry reactions.
