© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 5678 wileyonlinelibrary.com COMMUNICATION Linear and Fast Hydrogel Glucose Sensor Materials Enabled by Volume Resetting Agents Chunjie Zhang, Gerry G. Cano, and Paul V. Braun* C. Zhang, Prof. P. V. Braun Department of Materials Science and Engineering Frederick Seitz Materials Research Laboratory, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign Urbana, IL 61801, USA E-mail: pbraun@illinois.edu Dr. G. G. Cano Vytrace Corporation Pittsburgh, PA 15237, USA DOI: 10.1002/adma.201401710 bind with two PBAs generating a 2:1 PBA–glucose complex, forming a crosslinker that shrinks the hydrogel volume. As the glucose concentration increases, the 2:1 complex breaks into two charged 1:1 PBA–glucose complexes resulting in hydrogel swelling. [14,15,22] The combination of 2:1 and 1:1 complexes results in a non-linear correlation between the hydrogel volume and glucose concentration, and even over clinically relevant glu- cose range, the hydrogel may have the same volume at two dif- ferent concentrations (Supporting Information, Figure S1a). In previous work, we studied the response of hydrogels modified with ca. 20 chemically distinct PBAs. [14] Out of all these PBAs, the only PBAs that exhibited linear responses over the clinically relevant glucose concentration range had slow kinetics and sig- nificant hysteresis upon a cyclic sweep of glucose concentration. The PBAs that showed fast response kinetics were all highly non-linear within the clinical range. It was our hypothesis that to achieve linearity and fast kinetics, the coexistence of the 2:1 and 1:1 PBA–glucose complexes had to be eliminated. Here we demonstrate the concept of using a volume resetting agent to minimize the competing effects of these two complexes, and add a stored elastic energy into the hydrogel, yielding sensor materials that show linear and fast responses over the clinically relevant glucose concentration range under simulated physi- ological conditions. To provide an optical readout of the volume change, the hydrogel was formed into a polymerized crystal- line colloidal array (PCCA) photonic crystal, [23] whose optical reflection wavelength is a function of the hydrogel volume. [14,24] As the glucose concentration is determined only by the peak position, not the intensity of the diffraction, rather precise and accurate readings could be obtained. It is known that PBAs have lower affinities to 1,3-diols than 1,2-diols (e.g. glucose), and therefore, 1,2-diol appended mol- ecules can displace 1,3-diols from a preformed 1,3-diol-PBA complex. [25–28] Since the 2:1 complex (the complex that leads to contraction of the hydrogel through crosslinking) is preferen- tially formed at low glucose concentrations, we hypothesized that it would be possible to crosslink most of the PBA func- tionalities at zero glucose concentration by adding a molecule with multiple 1,3-diols to the hydrogel, so that glucose only leads to expansion of the hydrogel through 1:1 complex for- mation ( Figure 1a and Supporting Information, Figure S1b). During sensor operation, any added glucose essentially only results in the elimination of preformed crosslinks. We term the added 1,3-diol the ‘volume resetting agent’ based on its func- tion of reducing the hydrogel volume as it crosslinks the PBA functionalities on the hydrogel backbone. To accomplish this approach, the binding affinity of the volume resetting agent with PBA needs to be appropriate. If the PBA significantly pre- fers the volume resetting agent, glucose could not dissociate Glucose monitoring, coupled with insulin therapy, can often regulate blood glucose levels for diabetic patients and people who suffer from traumatic events and critical illnesses. [1–3] Real-time continuous measurement of blood glucose levels is important for making optimal therapeutic decisions, [4] and as such continuous glucose monitoring (CGM) technologies, have received considerable interest. To maximize their usefulness, CGM devices must provide high precision, accuracy, and sensi- tivity over the clinically relevant glucose range of 40–700 mg/dL (2.2–38.9 mM), reflecting the requirements for the corre- sponding sensor materials. [5,6] Over the past few decades, enzyme-based glucose electrodes have witnessed impressive progress toward long-term in vivo applications, however, tight control of diabetes has not been fulfilled. [7] As an alternative, or perhaps complimentary to glucose oxidase-based designs, phe- nylboronic acid (PBA) based designs should be considered for CGM. It is well known that PBAs can bind with cis-diols in glu- cose, leading to fluorescence changes in PBA-modified fluoro- phores and volumetric changes in PBA-modified hydrogels. [8,9] PBA-modified hydrogels have a number of attractive attributes for CGM. The hydrogel matrix can immobilize the PBA moie- ties and may limit biofouling, providing the potential for long- term operation. PBAs exhibit high operational stability. [10,11] Finally, the versatility of boronic acid chemistry offers the flex- ibility to customize sensor materials to operate over a wide glu- cose concentration and pH range for a diverse set of clinical as well as industrial applications. A continuing concern with PBA- based glucose sensors is the possibility for undesired responses to α-hydroxy acids and other diol-appended molecules that may be present in blood. A few reports have indicated the selectivity of PBA-modified fluorophores for glucose over other monosac- charides, [12,13] however, this still remains a challenge. Despite many attractive features, prior to this report, PBA- based hydrogel glucose sensors appeared to suffer from an intrinsic limitation, a highly non-linear glucose-response, due to the complexity of PBA binding with glucose. [14–21] Because glucose contains two cis-diols, at low concentrations it can Adv. Mater. 2014, 26, 5678–5683 www.advmat.de www.MaterialsViews.com