Paper-Based In-Situ Gold Nanoparticle Synthesis for Colorimetric, Non-Enzymatic Glucose Level Determination

Abstract

Due to its properties, paper represents an alternative to perform point-of-care tests for colorimetric determination of glucose levels, providing simple, rapid, and inexpensive means of diagnosis. In this work, we report the development of a novel, rapid, disposable, inexpensive, enzyme-free, and colorimetric paper-based assay for glucose level determination. This sensing strategy is based on the synthesis of gold nanoparticles (AuNPs) by reduction of a gold salt precursor, in which glucose acts simultaneously as reducing and capping agent. This leads to a direct measurement of glucose without any enzymes or depending on the detection of intermediate products as in conventional enzymatic colorimetric methods. Firstly, we modelled the synthesis reaction of AuNPs to determine the optical, morphological, and kinetic properties and their manipulation for glucose sensing, by determining the influence of each of the reaction precursors towards the produced AuNPs, providing a guide for the manipulation of nucleation and growth. The adaptation of this synthesis into the developed paper platform was tested and calibrated using different standard solutions with physiological concentrations of glucose. The response of the colorimetric signals obtained with this paper-based platform showed a linear behavior until 20 mM, required for glycemic control in diabetes, using the Red × Value/Grey feature combination as a calibration metric, to describe the variations in color intensity and hue in the spot test zone. The colorimetric sensor revealed a detection limit of 0.65 mM, depending on calibration metric and sensitivity of 0.013 AU/mM for a linear sensitivity range from 1.25 to 20 mM, with high specificity for the determination of glucose in complex standards with other common reducing interferents and human serum.

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“…[49] Moreover, glucose-based AuNPs showed broader absorption bands than the citrate-based AuNPs, which can indicate a higher heterogeneity in size and/or shape of the glucose-based AuNPs. [46] This was confirmed by TEM imaging (Figure 1c,d) where spherical particles are visible on the citrate-based AuNPs, whereas the AuNPs prepared with glucose shows anisotropic shapes.…”

“…In addition, when glucose was used as RA, the syntheses were also performed at RT, without microwave irradiation, since it is reported in the literature, glucose-based AuNPs production promoted by an alkaline medium at room temperature. [45][46][47] However, the synthesis outcome showed a poor reproducibility as optical properties is concerned, with variable surface plasmon resonance (SPR) and maximum absorbance values (Figure S1). For this reason, this approach was disregarded in further optimizations.…”

“…The reaction for the synthesis of AuNPs by citrate and glucose reduction is based on the oxidation of the reducing agents to dicarboxy acetone and gluconic acid, respectively, with subsequent reduction of Au 3+ to Au 0 . [46,48] In both cases, the reducing agents act also as a capping agent, contributing to the formation of an outer shell of anionic charges (from the carboxylate groups in citrate) or hydroxyl groups (from glucose). [49,50] For both syntheses, the absorbance values obtained rose when higher concentrations of gold salt precursor were used (Figure 1a,b), which may be indicative of an increased number of AuNPs, when HAuCl 4 was in a higher concentration.…”

“…In fact, these deviations are observed in the glucose-based AuNPs, since this reducing agent renders AuNPs with higher heterogeneity in terms of shape and size, as it was corroborated by TEM imaging (Figure 1d). [46] The stability of the synthesized AuNPs was evaluated through visual inspection and direct comparison of the A SPR value after 3 months of production (Figure 3). Exceptional high stability of the gold nanoparticles produced through citrate-based synthesis is observed, which shows the higher stability efficiency of citrate when compared to glucose.…”

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“…The surface plasmon resonance (SPR) plays a vital role in light scattering and absorption, which causes different color detection of AuNPs. For example, as the size increases, the color of colloidal suspensions of AuNPs changes from red to blue or purple and vice versa [ 44 ]. This phenomenon occurs due to the effect of the SPR peak that shifts slightly toward the red region, which causes the absorption of red light.…”