First-generation glucose biosensors relied on the use of the natural oxygen cosubstrate and the production and detection of hydrogen peroxide and were much simpler, especially when miniaturized sensors are concerned. More sophisticated bioelectronic systems for enhancing the electrical response, based on patterned monolayer or multilayer assemblies and organized enzyme networks on solid electrodes, have been developed for contacting GOx with the electrode support. Electrochemical biosensors are well suited for satisfying the needs of personal (home) glucose testing, and the majority of personal blood glucose meters are based on disposable (screen-printed) enzyme electrode test strips, which are mass produced by the thick film (screen-printing) microfabrication technology. In the counter and an additional “baseline” working electrode, various membranes (mesh) are incorporated into the test strips along with surfactants, to provide a uniform sample coverage. Such devices offer considerable promise for obtaining the desired clinical information in a simpler, user-friendly, faster, and cheaper manner compared to traditional assays. Continuous ex-vivo monitoring of blood glucose was proposed in 1974 and the majority of glucose sensors used for in-vivo applications are based on the GOx-catalyzed oxidation of glucose by oxygen. The major factors that play a role in the development of clinically accurate in-vivo glucose sensors include issues related to biocompatibility, miniaturization, long-term stability of the enzyme and transducer, oxygen deficit, short stabilization times, in-vivo calibration, baseline drift, safety, and convenience.

Electrochemical Glucose Biosensors

In this review the phenomenon of proton conductivity in materials and the elements of proton conduction mechanismsproton transfer, structural reorganization and diffusional motion of extended moietiesare discussed with special emphasis on proton chemistry. This is characterized by a strong proton localization within the valence electron density of electronegative species (e.g., oxygen, nitrogen) and self-localization effects due to solvent interactions which allows for significant proton diffusivities only when assisted by the dynamics of the proton environment in Grotthuss and vehicle type mechanisms. In systems with high proton density, proton/proton interactions lead to proton ordering below first-order phase transition rather than to coherent proton transfers along extended hydrogen-bond chains as is frequently suggested in textbooks of physical chemistry. There is no indication for significant proton tunneling in fast proton conduction phenomena for which almost barrierless proton transfer is suggest...

Proton Conductivity: Materials and Applications

An analyte monitor includes a sensor, a sensor control unit, and a display unit. The sensor has, for example, a substrate, a recessed channel formed in the substrate, and conductive material disposed in the recessed channel to form a working electrode. The sensor control unit typically has a housing adapted for placement on skin and is adapted to receive a portion of an electrochemical sensor. The sensor control unit also includes two or more conductive contacts disposed on the housing and configured for coupling to two or more contact pads on the sensor. A transmitter is disposed in the housing and coupled to the plurality of conductive contacts for transmitting data obtained using the sensor. The display unit has a receiver for receiving data transmitted by the transmitter of the sensor control unit and a display coupled to the receiver for displaying an indication of a level of an analyte. The analyte monitor may also be part of a drug delivery system to alter the level of the analyte based on the data obtained using the sensor.

Analyte Monitoring Device And Methods Of Use

Wearable biosensors are garnering substantial interest due to their potential to provide continuous, real-time physiological information via dynamic, noninvasive measurements of biochemical markers in biofluids, such as sweat, tears, saliva and interstitial fluid. Recent developments have focused on electrochemical and optical biosensors, together with advances in the noninvasive monitoring of biomarkers including metabolites, bacteria and hormones. A combination of multiplexed biosensing, microfluidic sampling and transport systems have been integrated, miniaturized and combined with flexible materials for improved wearability and ease of operation. Although wearable biosensors hold promise, a better understanding of the correlations between analyte concentrations in the blood and noninvasive biofluids is needed to improve reliability. An expanded set of on-body bioaffinity assays and more sensing strategies are needed to make more biomarkers accessible to monitoring. Large-cohort validation studies of wearable biosensor performance will be needed to underpin clinical acceptance. Accurate and reliable real-time sensing of physiological information using wearable biosensor technologies would have a broad impact on our daily lives.

Wearable biosensors for healthcare monitoring.

Over 7,000 peer reviewed articles have been published on electrochemical glucose assays and sensors over recent years. Their number makes a full review of the literature, or even of the most recent advances, impossible. Nevertheless, this chapter should acquaint the reader with the fundamentals of the electrochemistry of glucose and provide a perspective of the evolution of the electrochemical glucose assays and monitors helping diabetic people, who constitute about 5 % of the world’s population. Because of the large number of diabetic people, no assay is performed more frequently than that of glucose. Most of these assays are electrochemical. The reader interested also in nonelectrochemical assays used in, or proposed for, the management of diabetes is referred to a 2007 excellent review of Kondepati and Heise [1].

Electrochemical glucose sensors and their applications in diabetes management.

A new miniaturized glucose oxidase based needle-type glucose microsensor has been developed for subcutaneous glucose monitoring. The sensor is equivalent in shape and size to a 26-guage needle (0.45-mm o.d.) and can be implanted with ease without any incision. The novel configuration greatly facilitates the deposition of enzyme and polymer films so that sensors with characteristics suitable for in vivo use (upper limit of linear range greater than 15 mM, response time less than 5 min, and sensitivity yielding a 5:1 signal-to-background ratio at normal basal glucose levels) can be prepared in high yield (greater than 60%). The sensor response is largely independent of oxygen tension in the normal physiological range. It also exhibits good selectivity against common interferences except for the exogenous drug acetaminophen.

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Design and in vitro studies of a needle-type glucose sensor for subcutaneous monitoring.

Implantable enzymatic sensors (25, 43, 44) for biochemicals such as glucose are provided having an ideal size and geometry for optional long term implantation and linear responses over the concentration ranges of interest. The sensors (25, 43, 44) include an elongated body (10, 26, 46) supporting an indicating electrode section having an appropriate enzyme immobilized thereon to present an enzymatic indicating surface (21, 33, 54). A permeable synthetic polymer membrane (24, 42, 56) is applied over the sensor body (10, 26, 46) to protect the enzyme and regulate diffusion of analyte therethrough, to ensure linearity of sensor response. The sensors (25, 43) are of flexible design and can be implanted using a catheter. Alternately, the sensor (44) includes an internal indicating electrode body (46) housed within an apertured, hollow needle (48). A holder (66) affixed to the needle (48) allows for easy manipulation and implantation of the sensor (44).

Implantable glucose sensor

We have developed a miniaturized glucose sensor which has been shown previously to function adequately when implanted in the subcutaneous tissue of rats and dogs. Following a glucose load, the sensor output increases, making it possible to calculate a sensitivity coefficient to glucose in vivo, and an extrapolated background current in the absence of glucose. These parameters are used for estimating at any time the apparent subcutaneous glucose concentration from the current. In the previous studies, this calibration was performed a posteriori, on the basis of the retrospective analysis of the changes in blood glucose and in the current generated by the sensor. However, for clinical application of the system, an on line estimation of glucose concentration would be necessary. Thus, this study was undertaken in order to assess the possibility of calibrating the sensor in real time, using a novel calibration procedure and a monitoring unit which was specifically designed for this purpose. This electronic device is able to measure, to filter and to store the current. During an oral glucose challenge, when a stable current is reached, it is possible to feed the unit with two different values of blood glucose and their corresponding times. The unit calculates the in vivo parameters, transforms every single value of current into an estimation of the glucose concentration, and then displays this estimation. In this study, 11 sensors were investigated of which two did not respond to glucose. In the other nine trials, the volunteers were asked to record every 30 s what appeared on the display during the secondary decrease in blood glucose. The results were analysed by comparing these readings (approximately 220 measurements per trial) to the changes in plasma glucose, measured every 15 min. The Error Grid Analysis indicated that 84.1±3.6% of the measurements were in zone A (accurate) and 15±3.6% were in zone B (acceptable). Considering each individual trial, the differences between the displayed value and the concomitant plasma glucose concentration ranged between −1.7 and 0.69 mmol/l. These excellent results were due to the absence of any significant lag between the changes in plasma glucose concentration and the changes in the result on the display. We conclude that this glucose monitoring system, based on subcutaneous sensing of glucose, is able to provide a direct on line estimation of blood glucose concentration.

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A glucose monitoring system for on line estimation in man of blood glucose concentration using a miniaturized glucose sensor implanted in the subcutaneous tissue and a wearable control unit.

The development of an electrochemically based implantable sensor for glucose is described. The sensor is needle-shaped, about the size of a 28-gauge needle. It is flexible and must be implanted subcutaneously by using a 21-gauge catheter, which is then removed. When combined with a monitoring unit, this device, based on the glucose oxidase-catalyzed oxidation of glucose, reliably monitors glucose concentrations for as long as 10 days in rats. Various design considerations, including the decision to monitor the hydrogen peroxide produced in the enzymatic reaction, are discussed. Glucose constitutes the most important future target analyte for continuous monitoring, but the basic methodology developed for glucose could be applied to several other analytes such as lactate or ascorbate. The success in implementation of such a device depends on a reaction of the tissue surrounding the implant so as not to interfere with the proper functioning of the sensor. Histochemical evidence indicates that the tissue response leads to enhanced sensor performance.

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Progress toward the development of an implantable sensor for glucose.

Acetaminophen has been one of the most serious electrochemical interferences to oxidase-based amperometric biosensors that measure H2O2. A study was carried out to investigate various polymer materials for their selectivity as the sensor inner membrane. A composite membrane of cellulose acetate and Nafion was found to eliminate acetaminophen and other electrochemical interferences effectively while at the same time maintaining reasonable diffusivity for hydrogen peroxide. The excellent in vivo performance of the sensor was attributed not only to significantly reduced steady-state sensitivity to acetaminophen but also to very slow acetaminophen response. These features, combined with rapid acetaminophen clearance pharmacokinetics, led to the decreased response as demonstrated in the rat.

Yanan Zhang

Papers

Design and in vitro studies of a needle-type glucose sensor for subcutaneous monitoring.

Implantable glucose sensor

A glucose monitoring system for on line estimation in man of blood glucose concentration using a miniaturized glucose sensor implanted in the subcutaneous tissue and a wearable control unit.

Progress toward the development of an implantable sensor for glucose.

Elimination of the Acetaminophen Interference in an Implantable Glucose Sensor