Janet Tamada

Clinical evaluation of the GlucoWatch® biographer: a continual, non-invasive glucose monitor for patients with diabetes ☆

A device providing frequent, automatic, and non-invasive glucose measurements for persons with diabetes has been developed: the GlucoWatch biographer. This device extracts glucose through intact skin via reverse iontophoresis where it is detected by an amperometric biosensor. The biographer can provide glucose readings every 20 min for 12 h. The performance of this device was evaluated in two large clinical studies in a controlled clinical environment (n=231), and the home environment (n=124). Accuracy of the biographer was evaluated by comparing the automatic biographer readings to serial finger-stick blood glucose (BG) measurements. Biographer performance was comparable in both environments. Mean difference between biographer and finger-stick measurements was -0.01 and 0.26 mmol l(-1) for the clinical and home environments, respectively. The mean absolute value of the relative difference was 1.06 and 1.18 mmol l(-1) for the same studies. Correlation coefficient (r) between biographer and finger-stick measurements was 0.85 and 0.80 for the two studies. In both studies, over 94% of the biographer readings were in the clinically acceptable A+B region of the Clarke Error Grid. A slight positive bias is observed for the biographer readings at low BG levels. Biographer accuracy is relatively constant over all rates of BG changes, except when BG decreases more than 10 mmol l(-1) h(-1), which occurred for only 0.2% of points in the home environment study. Biographer precision, as measured by CV%, is approx. 10%. Skin irritation, characterized by erythema and edema, was either non-existent or mild in >90% of subjects and resolved in virtually all subjects without treatment in several days.

Measurement of glucose in diabetic subjects using noninvasive transdermal extraction

Results from the Diabetes Care and Complications Trial show that tight blood glucose control significantly reduces the long-term complications of diabetes mellitus1. In that study, frequent self-testing of glucose and insulin administration resulted in a significant reduction in long-term complications. This protocol, however, also resulted in a threefold increase in the frequency of hypoglycaemic incidents. Currently, self-testing requires a drop of blood for each measurement. The pain and inconvenience of self-testing, along with the fear and danger of hypoglycaemia has led to poor patient acceptance of a tight control regimen, despite the clear long-term advantages. A continuously worn, noninvasive method to periodically measure glucose would provide a convenient and comfortable means of frequent self-testing2,3. A continuously worn device could also alert the user of low glucose levels, thereby reducing the incidence of hypoglycaemia4,5. Guy et al. demonstrated a noninvasive method to transport glucose through the skin using low-level electrical current6,7. To provide a quantitative measurement, the flux of glucose extracted across the skin must correlate with serum glucose in a predictive manner. The results presented here show a quantitative relationship between serum and transdermally extracted glucose in diabetics.

Glucose monitoring by reverse iontophoresis

Glucose can be extracted through intact skin by electro‐osmotic flow (a process called ‘reverse iontophoresis’) upon the application of a low‐level electrical current. Recently we have combined iontophoretic extraction with an in situ glucose sensor in a device called the GlucoWatch® biographer. Clinical results with this device show close tracking of blood glucose over a range of 2.2 to 22.2 mmol/l for up to 12 h using a single blood glucose value as calibration. The biographer readings lag behind blood glucose values by an average of 18 min. An analysis of data from 92 diabetic subjects in a controlled clinical setting shows a linear relationship (r=0.88) between GlucoWatch biographer readings and blood glucose. The mean absolute relative difference between the two measurements was 15.6% and more than 96% of the data fell in the (A+B) regions of the Clarke error grid. Similar results have been obtained from subjects using the GlucoWatch biographer in an uncontrolled home environment.

The GlucoWatch biographer: a frequent automatic and noninvasive glucose monitor.

The GlucoWatch® (Cygnus, Inc, Redwood City, CA, USA) biographer provides automatic, frequent and noninvasive blood glucose measurements for up to 12 h. The device extracts glucose through intact skin where it is measured by an amperometric biosensor. Clinical trials in a variety of environments have shown that the biographer provides accurate and precise glucose measurements when compared with serial fingerstick blood glucose measurements. Mean difference between these measurements was 0.26 mmol/L in the home environment (r = 0.80). Over 94% of biographer readings were in the clinically acceptable A+B region of the Clarke Error Grid. A slight positive bias is observed for the biographer readings at low glucose levels. Biographer precision, as measured by coefficient of variation (CV)%, is approximately 10%. The low glucose alert function of the biographer was able to detect up to 75% of hypoglycaemic episodes with a low false alert level. Skin irritation, characterized by erythema and oedema was either nonexistent or mild in over 87% of subjects and resolved in virtually all subjects without treatment in several days. The GlucoWatch® biographer has been shown to be a safe and effective method to track glucose level trends and patterns, which should enable improved glycaemic control for many patients.

Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, τ = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm2) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm2 fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm2 without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.

Application of the Mixtures of Experts algorithm for signal processing in a noninvasive glucose monitoring system

Abstract The theory of Mixtures of Experts (MOE) [M. Jordan, R. Jacobs, Hierarchical mixtures of experts and the EM algorithm, Neural Computation 6 (2) (1994) 181–214; S.R. Waterhouse, D.J.C. MacKay, et al., in: D.S. Touretzky (Ed.), Bayesian methods for Mixtures of Experts, Advances in Neural Information Processing Systems, Vol. 8, MIT Press, Cambridge, MA, 1996, pp. 351–357; S.R. Waterhouse, Classification and regression using Mixtures of Experts, PhD Thesis, Cambridge University, Cambridge, 1997] was applied to the signal from a noninvasive glucose monitor for the purpose of converting raw signal data into blood glucose values. The MOE algorithm can be described as a generalized predictive method of data analysis. This method uses a superposition of multiple linear regressions, along with a switching algorithm, to predict outcomes. Any number of input/output variables are possible. The unknown coefficients in this method are determined by an optimization technique called the Expectation Maximization (EM) algorithm. The noninvasive GlucoWatch® biographer operation has been described [R.T. Kurnik, B. Berner, et al., Design and simulation of a reverse iontophoretic glucose monitoring device, J. Electrochem. Soc. 145 (12) (1998) 4119–4125]. Briefly, a small electrical current results in the transport of glucose beneath the skin to a hydrogel placed on the skin surface. Within the hydrogel, the glucose reacts with the enzyme glucose-oxidase to produce hydrogen peroxide. This hydrogen peroxide then diffuses to a platinum-based electrode, where it reacts to produce a current. The integral of this current (charge) over the sensing time is the signal used to measure extracted glucose. This process is repeated, yielding up to three measurements per hour. The data used for this analysis were obtained from diabetic subjects wearing the biographer over a 15-h period. The MOE inputs consisted of elapsed time, integrated current, blood glucose value at the calibration point, and a calibrated signal. The output was the value of blood glucose at each measurement. These training data were used to determine the unknown parameters in the MOE by the EM algorithm. Using a 3-h time point for calibrating the biographer, the mean absolute error (MAE) between the actual blood glucose and the blood glucose predicted with the MOE, was 14.4%.

Effect of Acetaminophen on the Accuracy of Glucose Measurements Obtained with the GlucoWatch Biographer

BACKGROUND Improved glycemic control significantly reduces long-term microvascular complications of diabetes mellitus associated with chronic hyperglycemia. The GlucoWatch biographer is designed to facilitate intensive diabetes management by providing automatic, frequent, and noninvasive glucose readings up to three times per hour for as long as 12 hours. METHODS The device extracts glucose through intact skin using reverse iontophoresis and measures the extracted glucose with an electrochemical biosensor. A clinical trial was performed to assess the effect of acetaminophen, a potential interference for traditional blood glucose meters, on the accuracy of the GlucoWatch biographer in adult subjects with diabetes (n = 18). One thousand milligram doses of acetaminophen were administered to subjects in two groups: one to achieve Cmax (peak acetominophen concentration) at the time of biographer calibration and the other to achieve Cmax during the measurement period. The biographer readings were compared to serial fingerstick blood glucose measurements. RESULTS Time profiles over 9 hours show close tracking of the biographer glucose results with fingerstick blood glucose measurements for all groups. The mean difference between the two measurements is between 8 and 12 mg/dL for all groups. The mean absolute value of the relative difference is less than 20%, and more than 93% of the points were in the clinically acceptable (A+B) region of the Clarke Error Grid. No statistically significant differences were found for any accuracy measurement across all groups. CONCLUSIONS The GlucoWatch Biographer provides frequent measurements of glucose over a 12-hour period with high accuracy. No effect of therapeutic dosage of acetaminophen on the accuracy of the glucose readings was found.

Electroanalysis of Glucose in Transcutaneously Extracted Samples

Glucose can be extracted through intact skin by electroosmosis upon application of a low-level electrical current. The amount of glucose extracted has been shown previously to correlate with blood glucose level. An amperometric, GOx-based biosensor was used to measure the amount of glucose in samples extracted from a nondiabetic volunteer every twenty minutes for five hours. The blank-subtracted current output from this sensor accurately tracked blood glucose changes and correlated with the capillary blood glucose values (average r>0.93) and a time lag of twenty minutes. This proof-of-feasibility is a prerequisite to the development of an integrated, wearable glucose monitor for diabetics combining both biosensor and iontophoresis functions.

Design and Simulation of a Reverse Iontophoretic Glucose Monitoring Device

Mathematical modeling is presented for a combined iontophoretic device and biosensor used to analyze glucose concentration in transdermally extracted fluid that is correlated to blood glucose. This device works as follows: an electric current (iontophoresis) is used to extract glucose across the skin into a hydrogel. Within the hydrogel, the extracted glucose undergoes a reaction with the enzyme, glucose oxidase (GOx), to produce gluconic acid and hydrogen peroxide in the presence o oxygen. The hydrogen peroxide then further diffuses to and reacts on a platinum electrode to produce two electrons, water, and oxygen. The measured electrical current is proportional to the flux of glucose entering the hydrogel. Modeling for this device involves the diffusion of (a- and β-) glucose and hydrogen peroxide in the hydrogel, as well as the reaction of β-glucose with GOx, the mutarotation of the α-, β-anomeric pair, and the oxidation of hydrogen peroxide on a platinum catalyst/electrode. The reaction-diffusion problem exhibits both axial and radial diffusion as well as discontinuous boundary conditions, requiring the use of finite element methods to perform the simulations.

Use of the GlucoWatch biographer in children and adolescents with diabetes.

Abstract: Objective:  This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch® biographer in children and adolescents with diabetes.