Understanding and Preventing the Spontaneous Gelation of Thiol-Norbornene Hydrogels

Typically, externally triggered initiators are required for norbornene-modified polysaccharides to undergo thiol-ene gelation into a hydrogel. However, anecdotal and reported evidence exists of these prehydrogel solutions undergoing spontaneous thiol-ene gelation without the trigger. Understanding the origin of this spontaneous process would improve the storage of prehydrogel solutions. We found that polysaccharides with carboxylic acids (e.g., carboxymethyl cellulose) can overcome the buffering capacity of phosphate-buffered saline (PBS), creating an acidic solution that is required for spontaneous gelation. Investigation using a small molecule model system revealed that acidic pH and trace metal ions increase the reaction rate and the conversion to the thiol-ene product. We concluded that the self-initiated thiol-ene reaction resulted from a Fenton-like reaction catalyzed by trace metal impurities, such as iron(II), that generate reactive oxygen species (ROS) that initiate the reaction. Using this knowledge, we developed strategies to inhibit spontaneous gelation and increase the working time of prehydrogel solutions.