Local environment-dependent kinetics of ester hydrolysis revealed by direct 1H NMR measurement of degrading hydrogels

We have demonstrated the use of a simple H-1 NMR spectrometry-based method to directly measure the pseudo first-order hydrolytic cleavage rate constant (k(obs)) of methacrylate-derived ester crosslinkers in hydrogels composed of PEG, dextran, carboxymethyl dextran (CM-dextran) and hyaluronic acid (HA). Using this technique, we systematically examined how the local environment in the hydrogel influenced the rate of ester hydrolysis. Within the formulations being studied, the esters in the crosslinked polymer network (gel state) degraded 1.8 times faster than esters of similar chemistry in soluble polymers (solution state). Furthermore, the value of k(obs) was independent of the polymer concentration or the hydrogel network structure, although these parameters affected the swelling profiles in response to the hydrolytic degradation. On the other hand, the presence of the negatively charged carboxylate groups in the polymer chains decreased k(obs) in gel state, while only minimally affecting k(cobs) in solution state. Hydrogels composed of negatively charged polymers (HA and CM-dextran) had a k(obs) about 30% smaller than hydrogels composed of neutral polymers (dextran and PEG). The reported method provides a reliable tool to resolve conflicting views about hydrogel degradation, and to guide the rational design of degradable hydrogel. Statement of significance Degradable hydrogels are widely used in biological applications. A common degradation mechanism of the crosslinked polymer is by hydrolytic cleavage. However, the hydrogel micro-milieu do affect the behavior of the hydrolysable bonds, for example esters. There have been several conflicting speculations on how hydrogel composition would affect the macroscopic degradation behavior. In this report, we simply, but innovatively applied ordinary H-1 NMR spectrometry-based method to probe the rate of ester cleavage in the native hydrogel milieu. We tried to answer whether these parameters will have direct influence on ester cleavage, or have indirect effect on the overall network disintegration behavior. This study provides quantitative evidences to assist theoretical modeling and to guide rational formulation design. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.