Hyaluronate–Gold Nanoparticle/Glucose Oxidase Complex for Highly Sensitive Wireless Noninvasive Glucose Sensors

Abstract

Noninvasive real-time biosensors to measure glucose levels in the body fluids have been widely investigated for continuous glucose monitoring of diabetic patients. However, they suffered from low sensitivity and reproducibility due to the instability of nanomaterials used for glucose biosensors. Here, we developed a hyaluronate−gold nanoparticle/glucose oxidase (HA− AuNP/GOx) complex and an ultralow-power application-specific integrated circuit chip for noninvasive and robust wireless patchtype glucose sensors. The HA−AuNP/GOx complex was prepared by the facile conjugation of thiolated HA to AuNPs and the following physical binding of GOx. The wireless glucose sensor exhibited slow water evaporation (0.11 μL/min), fast response (5 s), high sensitivity (12.37 μA•dL/mg•cm 2 ) and selectivity, a low detection limit (0.5 mg/dL), and highly stable enzymatic activity (∼14 days). We successfully demonstrated the strong correlation between glucose concentrations measured by a commercially available blood glucometer and the wireless patch-type glucose sensor. Taken together, we could confirm the feasibility of the wireless patch-type robust glucose sensor for noninvasive and continuous diabetic diagnosis.

Hyaluronic Acid Allows Enzyme Immobilization for Applications in Biomedicine

“…One developing approach to reduce such limitations is through enzyme immobilization. In particular, enzyme immobilization is seen as a viable means to provide greater user controllability through specific localization strategies and control of enzymes’ catalytic activity using physical [ 66 ] or chemical [ 67 ] bounding to or within synthetic platforms including but not limited to hydrogels [ 17 , 18 , 19 , 20 ], particles [ 15 , 16 , 22 ], nanotubes [ 23 ], or frameworks [ 66 ]. Meanwhile, the recyclability of enzymes can also increase through such immobilization approaches, thus resulting in their repeatable use and reduction in application costs [ 66 ].…”

“…This compound is easily linked to the development of amphiphilic complexes with strong immobilization functionality in addition to its ability to breakdown in governable fashions and periods of time, as beneficial in drug delivery, tissue engineering, and wound healing processes [ 15 , 16 , 17 , 18 , 20 ]. Particularly in the biosensing sector, HA’s biocompatibility and moisture-retaining properties offer anti-fouling advantages to sensing composites; HA has also shown to improve electrical conductivity for biosensors in which it is applied [ 21 , 22 , 23 ]. HA has high market potential with current analysis projecting roughly doubling incomes (i.e., an increase in the size of the HA market from USD 9.6 billion in 2020 to USD 16.6 billion in 2027) representative of an expected compound annual growth rate (CAGR) of 8.1% [ 68 ].…”

“…Placing enzymes within synthetic microenvironments, as characteristic of immobilization processes, was for instance shown to oftentimes increase their stability and reusability, qualities greatly desired for a biosensor [ 11 , 77 , 78 , 79 , 80 ]. Kim et al, developed a glucose sensor using hyaluronate (the salt form of HA), AuNPs, GOx, and an integrated circuit chip; the sensor was intended to process sweat glucose data collected at its interface [ 22 ]. HA’s integration inhibited the interference of otherwise detrimental molecules including lactic acid and L-ascorbic acid.…”

“…As a result of these benefits, accurate and specific measurement, non-invasiveness, stability, sensitivity, and feasibility were enabled when monitoring continuous diabetes detection in mice. As shown in Figure 6 a, the complex consisted of enzyme and HA-coated AuNPs attached to the surface of a functional electrode via binding of each element with 1,2, ethanedithiol [ 22 ].…”

“…Subsequently, particular attention is directed towards enzyme immobilization using hyaluronic acid (HA) scaffolds, a polysaccharide consisting of alternating β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine rings known for its high biocompatibility, biodegradability, viscoelasticity, and hydrophilicity [ 12 , 13 , 14 ], to thus help emphasize enzymes’ implementation in biomedical applications. Discussions are in support of specific applications in drug delivery [ 15 , 16 , 17 ], tissue engineering including wound healing [ 18 , 19 , 20 ] and biosensors [ 21 , 22 , 23 , 24 ], respectively. Challenges associated with enzymes exploitations in synthetic environment are analyzed.…”