Click Chemistry-Based Hydrogels for Tissue Engineering.

Abstract

Click chemistry has become a powerful and flexible approach for designing hydrogels used in tissue engineering thanks to its high specificity, fast reaction rates, and compatibility with biological systems. In this review, we introduce the core principles of click chemistry, including efficiency, orthogonality, and modularity, and highlight the main types of reactions commonly used in hydrogel formation, such as azide-alkyne c-cloadditions, thiol-ene/yne reactions, Diels-Alder cycloadditions, and tetrazine-norbornene couplings. These chemistries allow researchers to create covalently crosslinked hydrogels that are injectable, responsive to environmental stimuli, biodegradable, or multifunctional. We also explore strategies to enhance bioactivity, such as incorporating peptides, growth factors, or extracellular matrix components, and enabling precise spatial and temporal control over biological cues. Click-based hydrogels have shown promise across a wide range of tissue engineering applications, from cartilage and skin repair to neural regeneration, corneal healing, and cardiovascular scaffolds, as well as in 3D bioprinting technologies. Despite the many advantages of click chemistry such as mild reaction conditions and customizable material properties, some challenges remain, including concerns around copper toxicity, the cost of specialized reagents, and scalability. Finally, we discuss the status of clinical translation, regulatory considerations, and future directions, including integration with advanced bio fabrication methods, the design of dual-click systems, and the emerging role of in vivo click chemistry in creating next-generation biomaterials.