Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbornene chemistry. Academic Article uri icon


  • The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell-instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new cross-linking chemistry for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addition, the cytocompatibility of the polymerization led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochemistry. These advantages, combined with the synthetic accessibility of the tetrazine molecule compared to other bio-orthogonal click reagents, make this cross-linking chemistry an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications.

published proceedings

  • Biomacromolecules

altmetric score

  • 12

author list (cited authors)

  • Alge, D. L., Azagarsamy, M. A., Donohue, D. F., & Anseth, K. S.

citation count

  • 188

complete list of authors

  • Alge, Daniel L||Azagarsamy, Malar A||Donohue, Dillon F||Anseth, Kristi S

publication date

  • April 2013