Hydrogel Synthesis and Stabilization via Tetrazine Click‐Induced Secondary Interactions

Abstract

The discovery of tetrazine click‐induced secondary interactions is reported as a promising new tool for polymeric biomaterial synthesis. This phenomenon is first demonstrated as a tool for poly(ethylene glycol) (PEG) hydrogel assembly via purely non‐covalent interactions and is shown to yield robust gels with storage moduli one to two orders of magnitude higher than other non‐covalent crosslinking methods. In addition, tetrazine click‐induced secondary interactions also enhance the properties of covalently crosslinked hydrogels. A head‐to‐head comparison of PEG hydrogels crosslinked with tetrazine‐norbornene and thiol‐norbornene click chemistry reveals an approximately sixfold increase in storage modulus and unprecedented resistance to hydrolytic degradation in tetrazine click‐crosslinked gels without substantial differences in gel fraction. Molecular dynamic simulations attribute these differences to the presence of secondary interactions between the tetrazine‐norbornene cycloaddition products, which are absent in the thiol‐norbornene crosslinked gels.