Manivannan Suresh Kannan, Govindaraj Sabarees
Hydrogels have emerged as a versatile class of biomaterials for a wide range of biomedical applications; however, conventional crosslinking strategies often lack precise control over network dynamics, degradation behavior, and functionality. In recent years, Diels–Alder (DA) chemistry, including both classical and inverse electron demand Diels–Alder (iEDDA) reactions, has gained significant attention as a bioorthogonal and catalyst-free approach for engineering advanced hydrogel systems. This review provides a comprehensive overview of the design and development of multifunctional hydrogels based on DA chemistry, with a particular focus on tunable degradation, dynamic mechanical properties, and on-demand therapeutic delivery. We discuss key molecular design strategies, including the selection of functionalized polymers (e.g., polyethylene glycol, hyaluronic acid, gelatin) and the modulation of crosslinking density, which enable precise control over hydrolytic and stimuli-responsive degradation profiles. Recent advances in DA-crosslinked hydrogels demonstrate highly tunable degradation kinetics ranging from days to months, along with excellent cytocompatibility and in vivo biocompatibility. In addition, the reversible nature of DA bonds facilitates dynamic mechanical behaviors such as self-healing, shear-thinning, and mechanoresponsive properties, enhancing their suitability for injectable and minimally invasive applications. Furthermore, the integration of stimuli-responsive mechanisms including redox, thermal, enzymatic, and ultrasound triggers has enabled the development of smart hydrogels capable of controlled and on-demand release of therapeutic agents, proteins, and cells. These features position DA-based hydrogels as promising platforms for drug delivery, tissue engineering, biofabrication, and regenerative medicine. Finally, current challenges and future perspectives are highlighted, including the need for improved reaction kinetics, long-term stability, and clinical translation. Overall, Diels–Alder chemistry offers a powerful and modular toolkit for designing next-generation multifunctional hydrogels with precisely tunable properties for advanced biomedical applications.