# Versatility of Click Chemistry in Hydrogel Synthesis: From Molecular Strategies to Applications in Regenerative Medicine

## TL;DR

This review explores how click chemistry is used to create biocompatible hydrogels for tissue regeneration, focusing on safer and more efficient methods.

## Contribution

The paper highlights the shift from toxic copper-based click reactions to biocompatible alternatives like SPAAC for hydrogel synthesis.

## Key findings

- Copper-catalyzed reactions are inefficient and toxic for in vivo applications.
- Biorthogonal reactions like SPAAC improve biocompatibility and reduce fibrosis.
- Thiol-ene and Diels–Alder reactions are effective for creating functional hydrogels.

## Abstract

Click chemistry is highly valued in the design of polymeric biomaterials due to its ability to generate complex structures and localized surface modifications. However, prominent mechanisms in click chemistry, such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), are inefficient for the synthesis and/or modification of biomaterials because they present significant limitations for in vivo applications. The presence of residual copper in the material is toxic and requires extensive purification, increasing production costs and hindering scalability and availability for in vivo applications. To overcome these limitations and ensure the safety and biocompatibility of materials, biorthogonal reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have been developed. Thiol-ene/thiol-yne and Diels–Alder mechanisms are also relevant for the formation of robust polymer networks with specific characteristics and attractive advantages for generating biocompatible materials. These reactions not only improve cell integration and reduce fibrosis in in vivo applications but also enable the creation of functional structures for tissue regeneration. This review provides a comprehensive analysis of advances in the synthesis of biomaterials for tissue regeneration using hydrogels designed via click chemistry, as well as the various mechanisms and structural considerations.