Recent progress in click-crosslinked bio-based hydrogels for biomedical applications

Hydrogels have emerged as versatile biomaterials owing to their high water content, tunable mechanical properties, and biocompatibility. Recent advancements in bio-based hydrogel design have focused on integrating renewable biopolymers with “Click” chemistry which are rapid, specific, and bioorthogonal reactions that enable efficient crosslinking under mild conditions. This review summarizes the latest developments in click-crosslinked bio-based hydrogels, emphasizing mainly copper-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, thiol-ene, thiol-Michael, Diels-Alder, and inverse electron-demand Diels-Alder reactions. Particular attention is given to the shift from copper-catalyzed to metal-free systems to enhance cytocompatibility and in vivo safety. The review discusses how these click strategies allow precise control of hydrogel structure, mechanical integrity, and degradation behavior, facilitating their application in drug delivery, tissue engineering, wound healing, and regenerative medicine. Emerging trends including multifunctional and interpenetrating network hydrogels highlight the potential of click-crosslinked biopolymers as sustainable and customizable platforms for next-generation biomedical materials.