Hydrolytic (In)stability of Methacrylate Esters in Covalently Cross-Linked Hydrogels Based on Chondroitin Sulfate and Hyaluronic Acid Methacrylate

Chondroitin sulfate (CS) and hyaluronic acid (HA) methacrylate (MA) hydrogels are under investigation for biomedical applications. Here, the hydrolytic (in)stability of the MA esters in these polysaccharides and hydrogels is investigated. Hydrogels made with glycidyl methacrylate-derivatized CS (CSGMA) or methacrylic anhydride (CSMA) degraded after 2-25 days in a cross-linking density-dependent manner (pH 7.4, 37 °C). HA methacrylate (HAMA) hydrogels were stable over 50 days under the same conditions. CS(G)MA hydrogel degradation rates increased with pH, due to hydroxide-driven ester hydrolysis. Desulfated chondroitin MA hydrogels also degrade, indicating that sulfate groups are not responsible for CS(G)MA's hydrolytic sensitivity (pH 7.0-8.0, 37 °C). This sensitivity is likely because CS(G)MA's N-acetyl-galactosamines do not form hydrogen bonds with adjacent glucuronic acid oxygens, whereas HAMA's N-acetyl-glucosamines do. This bond absence allows CS(G)MA higher chain flexibility and hydration and could increase ester hydrolysis sensitivity in CS(G)MA networks. This report helps in biodegradable hydrogel development based on endogenous polysaccharides for clinical applications.