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

Abstract

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 Nacetyl-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.

Creating a Functional Biomimetic Cartilage Implant Using Hydrogels Based on Methacrylated Chondroitin Sulfate and Hyaluronic Acid

“…This observation proved our hypothesis that making a hybrid hydrogel combining CSMA and HAMA could result in formulations with tunable swelling behaviors. It should be noted that CSMA-only-based gels degraded within ~3 weeks (15 wt%, pH 7.4), as reported previously [ 50 ], whereas those based on HAMA (10 wt%) could not be formulated due to the excessive solution viscosity.…”

“…It was important that the DM of HAMA exceeded 30%, as the crosslinking points deriving from HA methacrylate groups are considered to be responsible for the stability features of hydrogels. This notion is related to the higher stability of the ester methacrylate groups on HA polymers as compared to CSMA polymers [ 50 ].…”

“…The hydrogels based on CSMA exhibited higher swelling potential and faster degradation rates compared to those based on HAMA (at comparable DM) due to the combined effects of the higher flexibility and hydrophilicity of CSMA compared to HAMA, rendering the microenvironment around the methacrylate esters in CSMA more hydrophilic and thus more sensitive to hydrolysis. This ester instability in CSMA eventually leads to a decreased crosslinking density, and thus causes more swelling [ 39 , 50 , 55 , 56 , 57 , 58 ]. The swelling profile observed in the formulations with a lower content of HAMA indicates a higher swelling capacity of the gels, which is most likely due to the more predominant CSMA component.…”

Viscoelastic Chondroitin Sulfate and Hyaluronic Acid Double-Network Hydrogels with Reversible Cross-Links

“…Hydrogel discs were fabricated either as free or confined gels before testing (Figure A). Swelling capacity was calculated as the ratio between the weight of the swollen gel and its initial weight and was defined as the swelling ratio (SR). ,, Figure B shows the swelling ratio of SN-DA and DN hydrogels in time. Under free swelling in PBS and at 37 °C, both hydrogels steadily absorbed water in time, as observed from the increase of the corresponding swelling ratios.…”

“…Sodium hyaluronate was obtained from Lifecore Biomedical (82 kDa as measured with GPC, Chaska, MN). Chondroitin 4-sulfate sodium salt (bovine trachea, lyophilized powder suitable for cell culture, molecular weight 19.9 kDa as measured previously 34 ) was purchased from Sigma-Aldrich (Zwijndrecht, the Netherlands). All other reagents were obtained from either Sigma-Aldrich (Zwijndrecht, the Netherlands) or TCI Europe N.V. and were used as received.…”