Manipulation of the isoelectric point of polyampholytic smart hydrogels in order to increase the range and selectivity of continuous glucose sensors

Abstract

Continuous glucose sensors based upon polyampholytic smart hydrogels (PSHs) have been intensively studied for biomedical and bioprocess applications. Here we focus on the chemistry of PSHs designed for bioprocess monitoring, an application for which the relevant glucose concentration and pH ranges (1–50mM and 6.8–7.8, respectively) are much wider than those required for biomedical monitoring. PSHs respond to glucose because they contain phenylboronic acid (PBA) moieties that become negatively charged when they reversibly bind to glucose. PSHs also contain positively charged amine groups. Several research groups have designed PSHs that shrink in response to increases in glucose concentration, yet swell in response to increases in fructose or lactic acid concentration. The shrinking behavior is usually attributed to an increase in reversible crosslink density that occurs when the hydrogel binds glucose. However, we show here for the first time that it is possible to design PSHs that shrink in response to increases in glucose, fructose or lactic acid concentration. This is significant because fructose and lactic acid, unlike glucose, are incapable of forming reversible crosslinks within the hydrogel. Therefore, reversible crosslinking cannot be the sole mechanism responsible for the shrinking response of PSHs. In order to obtain PSHs suitable for glucose sensing over wide pH and glucose concentration ranges, we show that it is important to adjust the isoelectric point (IEP) so that it always exceeds the environmental pH value.