Dynamically Cross-Linked Granular Hydrogels for 3D Printing and Therapeutic Delivery

Granular hydrogels have recently emerged as promisingbiomaterialsfor tissue engineering and 3D-printing applications, addressing thelimitations of bulk hydrogels while exhibiting desirable propertiessuch as injectability and high porosity. However, their structuralstability can be improved with post-injection interparticle cross-linking.In this study, we developed granular hydrogels with interparticlecross-linking through reversible and dynamic covalent bonds. We fragmentedphoto-cross-linked bulk hydrogels to produce aldehyde or hydrazide-functionalizedmicrogels using chondroitin sulfate. Mixing these microgels facilitatedinterparticle cross-linking through reversible hydrazone bonds, providingshear-thinning and self-healing properties for injectability and 3Dprinting. The resulting granular hydrogels displayed high mechanicalstability without the need for secondary cross-linking. Furthermore,the porosity and sustained release of growth factors from these hydrogelssynergistically enhanced cell recruitment. Our study highlights thepotential of reversible interparticle cross-linking for designinginjectable and 3D printable therapeutic delivery scaffolds using granularhydrogels. Overall, our study highlights the potential of reversibleinterparticle cross-linking to improve the structural stability ofgranular hydrogels, making them an effective biomaterial for use intissue engineering and 3D-printing applications.