Development of Furan-Modified Hyaluronic Acid Using an Epoxide Ring Opening Reaction for Biomedical Applications

Smith, Emma

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Development of Furan-Modified Hyaluronic Acid Using an Epoxide Ring Opening Reaction for Biomedical Applications

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Hyaluronic acid (HA) is an abundant and modulatory biomaterial that has been investigated for drug and cell delivery for regenerative medicine applications. Due to the water solubility of HA, modifications and crosslinking are used to fabricate it into a hydrogel. Diels-Alder “click” chemistry has been used with furan-modified HA (F-HA), crosslinked with poly(ethylene glycol) bismaleimide [(MI)2PEG], to create a robust hydrogel. The current modification scheme modified the carboxylate group on the D-glucuronic acid of HA via furfurylamine (FFA). In this thesis, we propose a novel F- HA utilizing furfuryl glycidyl ether (FGE) that undergoes an epoxide ring-opening reaction to covalently conjugate furan onto the 6-position hydroxyl group on N-acetyl-D-glucosamine within HA. FGE-modified HA was synthesized alongside, previously characterized, FFA-modified HA. Alongside the synthesis of one FGE-HA formulation, three different FFA-HA formulations were synthesized to have an FFA-HA formulation with a similar degree of substitution (DOS) as the FGE-HA formulation. After identifying FFA-HA and FGE-HA formulations with comparable DOS, F-HA derivatives were cross-linked with (MI)2PEG to form hydrogels. Interestingly, with a similar DOS, the FGE-HA-(MI)2PEG hydrogel swelling properties were significantly different from FFA-HA-(MI)2PEG hydrogels; FGE-HA-(MI)2PEG hydrogels had wet weight swelling ratios and equilibrium swelling ratios that were greater. Rheological analysis revealed that the elastic moduli for the FFA-HA-(MI)2PEG hydrogels was higher than FGA-HA-(MI)2PEG hydrogels, suggesting a stiffer hydrogel. The FFA-HA-(MI)2PEG hydrogels exhibited faster gelation time than FGE-HA-(MI)2PEG hydrogels, as determined by time sweep rheology, a useful property for in situ crosslinking hydrogels. Both F-HA-(MI)2PEG hydrogels did not impact metabolic activity, a proxy for cell viability, of human fibroblasts. When evaluating the ROS scavenging potential of furan-HA, the F-HA products exhibited similar scavenging capability as unmodified HA. Taken together, this work developed a new method for modifying HA with furan that leaves the carboxylate available for further modification, increases the gelation time, does not result in a toxic hydrogel, and maintains ROS scavenging capability, which may be useful for in situ crosslinking hydrogels for biomedical applications.

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