Amino-acid-specific thiol-ene coupling governs hydrogel crosslinking mechanism and cell behavior

The thiol-ene reaction is widely utilized in the functionalization of biomaterials, with research focusing either on the function of peptides that direct cell behavior (e.g., cell adhesion governed by RGD peptide and biodegradation regulated by protease -sensitive peptides) or on the improvement of thiol-ene reaction kinetics by using electron -rich alkenes like norbornene. However, it remains unknown whether peptides could play a role in the thiol-ene reaction or alkene moieties could potentially affect cell behavior. In the current work, we observe that norbornene-modified polyvinyl alcohol crosslinked with peptides that offer different sensitivities to matrix metalloproteinases (KCGPQGIWGQCK, KCVPMSMRGGCK) probably underwent chain -growth- and step -growth -dominated polymerization, respectively, which was found to be determined by tryptophan that acts as radical stabilizer and thereby dictates hydrogel properties and cell behavior. This work thus contributes to a more comprehensive understanding of thiol-ene-based peptide functionalization of hydrogels and to a more accurate control of hydrogel design for tissue engineering applications.