Medical Device Link.

Originally Published IVD Technology May 2003

Detection Technologies

Technology advances that are making life easier for diabetic patients include an approved device for frequent, automatic, and noninvasive glucose measurement.

Michael J. Tierney

Figure 1. The GlucoWatch G2 Biographer from Cygnus Inc.

Diabetes is a disease characterized by elevated blood glucose levels caused either by the body’s inability to produce sufficient insulin or by its resistance to insulin’s purpose of regulating glucose. About 17 million people in the United States—6.2% of the population—are diagnosed diabetics. This number, along with the discovery of a million new cases yearly, makes diabetes one of the most important national health issues.1 Worldwide, diabetes rates are increasing even faster, especially in developing countries. The global incidence of diabetes is expected to increase 170% between 1995 and 2025.2 Causes of this increase are complex and involve poor nutrition, obesity, and more-sedentary lifestyles.

The inability to control blood glucose leads to acute and chronic complications. Hypoglycemia, a condition in which blood glucose (glycemia) levels rapidly drop dangerously low, can cause mental confusion, convulsions, and even coma and death. Chronic hyperglycemia (excessive blood sugar) results in a wide range of long-term microvascular and neuropathic complications due to abnormally high levels of protein glycosylation.

A milestone clinical study of diabetes, the Diabetes Control and Complications Trial (DCCT), demonstrated that an intensive blood glucose control regimen lowers the incidence of such complications.3 However, this intensive insulin regimen to reduce average glucose levels was seen to result in a threefold increase in hypoglycemia. This outcome has likely hindered the widespread adoption by patients of the DCCT recommendations.

To effectively manage their disease, people with diabetes need to take glucose measurements. At first, the only measurement technology available for home use was the colorimetric urine glucose test strip, which was limited to diagnosing hyperglycemia. Colorimetric test strips developed later used blood obtained from a fingerstick to measure a wider range of glucose levels. These strips originally were read by eye, but handheld meters were soon introduced that could read strips with greater accuracy. A painful fingerstick was still required to obtain the necessary relatively large blood sample, however, and obtaining the measurement could take up to a minute.

Advancements in both meter and strip technologies have resulted in today’s state-of-the-art fingerstick meters, such as the Lifescan One Touch Ultra (a trademark of Johnson & Johnson Co.; New Brunswick, NJ), the FreeStyle (a trademark of TheraSense; Alameda, CA), and the BD Logic (a trademark of Becton Dickinson and Co.; Franklin Lakes, NJ). These devices use electrochemical biosensors that require less than a microliter of blood. Time to measurement is a few seconds. Such small blood samples allow measuring at sites other than the fingertip. The forearm is an example. The density of nerve endings in the arm is less than in the fingertip, and thus the pain caused by the sampling stick is less.

Technology developments in glucose monitoring have been targeted at reducing the pain and inconvenience of acquiring measurements so that glucose can be checked more often daily for better glycemic control. However, the glucose meters just discussed all use a blood sample and require user intervention to collect and measure that sample. Two new developmental approaches aim at making glucose measurement even easier and less painful than heretofore. Noninvasive measurement eliminates the need to violate the skin to acquire a usable sample. And continuous monitoring, where measurements are taken repeatedly and automatically over time, creates a long-range glycemic profile from those frequent readings.

Although a number of noninvasive and continuous monitoring technologies are in various stages of development, only one device has been approved by FDA so far as an automatic and noninvasive frequent-sampling glucose monitor—the GlucoWatch Biographer (a trademark of Cygnus Inc.; Redwood City, CA) (see Figure 1). This instrument received agency approval in March 2001 as an adjunctive device to supplement, not replace, blood glucose measurements. The second-generation GlucoWatch G2 Biographer was approved in March 2002 and again in August 2002 for pediatric use. The G2 Biographer is intended for detecting trends and tracking patterns in glucose levels in adults 18 and older and in children and adolescents between 7 and 17 who have diabetes. Data interpretation is based on these trends and patterns that emerge from the accumulation of sequential readings taken over a period of time.

Transdermal Glucose Sampling and Detection

Figure 3. The CGMS continuous home glucose monitor from Medtronic MiniMed.

Worn on the forearm like a watch, the GlucoWatch Biographer samples glucose through intact skin, quantitates the amount of glucose extracted, and converts that measurement to a glucose-level value.

Overcoming the normal barrier function of human skin has been an object of study for many years with regard to transdermal drug delivery. Nicotine and hormone-replacement patches employ passive diffusion of the drug across skin. Active transport technologies also have been investigated. Iontophoresis is a mechanism by which charged drug molecules are delivered across the skin under the influence of an electric field.

When charged drug molecules flow into the skin, ions must flow out to maintain electroneutrality. This reverse iontophoresis is the basis of transdermal glucose sampling with the device under discussion. Because skin carries a net negative electrical charge, positive sodium (Na+) ions can migrate more freely and carry most of the iontophoretic current. Migrating Na+ ions create an electroosmotic fluid flow through the skin that carries neutral molecules such as glucose out of the body (see Figure 2). The amount of glucose collected by reverse iontophoresis correlates well with blood glucose, as will be shown, with an average lag time of 5 minutes.

Biosensor-Based Monitoring. Most glucose monitors based on biosensor technology operate on a single principle—glucose reacting with a glucose-specific enzyme produces a chemical species that is detected electrochemically. Commonly, the enzyme is glucose oxidase (GOx) which catalyzes the oxidation of glucose thus: 


where GOxred is the reduced form of the enzyme. The enzyme is reoxidized by oxygen as follows:

The hydrogen peroxide produced is detected on a platinum electrode:

The two electrons are measured on the electrode as an electric current by an external circuit.

For use in blood glucose measurement, this sensing scheme has some limitations. The glucose concentration in blood is higher than the O2 concentration; membranes are thus required to slow glucose transport in order to prevent an O2-limited reaction. Also, at the electrode potential necessary for detecting hydrogen peroxide, other blood components such as ascorbic acid can interfere with the measurement. Some blood glucose meter biosensors use chemistries that substitute for the enzyme’s natural O2/H2O2 redox couple a synthetic alternative in order to eliminate O2 limitations and problems caused by interfering species. Such electrochemical mediators as ferrocene and ferrocyanide act as redox couples to shuttle between the enzyme and electrode:

where Medox and Medred are the oxidized and reduced forms of the mediator, respectively.

The conditions under which the transdermal glucose monitor operates allow its biosensor to use the simple glucose oxidase and O2/H2O2 chemistry. The concentration of glucose it extracts from interstitial fluid—approximately 2.5–25 µmol in the hydrogel disks versus an average of 5.5 mmol in blood—is sufficiently low to avoid O2 limitations. Iontophoretic extraction also eliminates the problem of interference from many species that do interfere with measurements made directly in blood. In addition, many synthetic mediator systems are not viable options because they might be delivered into the body via the iontophoresis mechanism and create potential toxicity problems.

Transdermal Biosensing. Onboard amperometric biosensors used in the GlucoWatch Biographer consist of two hydrogel electrolyte disks that serve as the glucose collection reservoirs and contain the glucose oxidase enzyme, along with two sets of biosensor electrodes. Each electrode set includes a platinum-graphite-composite sensing electrode, a silver–silver chloride reference electrode, and a third that acts alternately as the counter electrode for the biosensor and the iontophoresis electrode.

To sample and measure glucose, the transdermal monitor first passes a 0.3-mA iontophoresis current for 3 minutes. The glucose is collected at the iontophoretic cathode where it reacts with GOx in the hydrogel, producing hydrogen peroxide. At the end of the collection period the iontophoresis current is stopped, and the biosensors are biased at a potential of 0.42 V relative to the silver–silver chloride reference electrode. The current obtained from the detection of hydrogen peroxide is integrated over 7 minutes. (The biosensor at the iontophoretic anode also is activated during this period to remove interfering species collected at that electrode, but the current is not sampled.) The iontophoretic current polarity then is reversed, and a second sample and measurement cycle is performed. The two measurements are averaged using a rolling-average scheme and the result is used to calculate glucose level.

Although the biosensors in the monitor employ relatively simple sensing chemistry, the electrodes, hydrogel electrolytes, and signal processing have been specifically designed for this application. To accurately measure glucose concentrations some three orders of magnitude lower than those in blood (micromolar versus millimolar) from a sample collected through a 1-cm2 area of skin necessitates using a large sensing electrode in order to detect essentially all of the glucose extracted during each cycle. Catalytic electrode materials with high sensitivity and low background currents were developed to attain high signal-to-noise ratios. The thickness, pH, and buffer strength of the hydrogel electrolyte were optimized to minimize lag time and maintain stability over many measurements. 

Helpfully, the barrier properties of the skin and the current polarities used in the iontophoretic extraction combine to create a virtual permselective membrane to prevent high-molecular-weight compounds, negatively charged compounds, and nonhydrophilic species from being extracted at the glucose-measuring biosensor. Operating the biosensor at a rather low applied potential for the detection of hydrogen peroxide and integrating the current over time to transform the amperometric measurement into a coulometric measurement also serves to improve the signal-to-noise ratio. This sense-to-depletion scheme cleans the glucose, hydrogen peroxide, and interfering species out of both hydrogels during each cycle, readying them for the next measurement cycle.

Figure 4. A nocturnal hypoglycemic episode recognized and alarmed as a function of continuous glucose measurement.

Data Gathering and Reading. Unlike fingerstick blood glucose meters that are typically resting on a table when the measurement is taken, the GlucoWatch Biographer is worn on the subject’s forearm, an unpredictable environment susceptible to mechanical shocks and temperature fluctuations. Data integrity checks of the raw biosensor data ensure that any glucose measurements presented to the user are valid. If any of several characteristics of the biosensor signals or device operational parameters exceed preset thresholds, the monitor will not calculate a glucose reading. Skin temperature and skin conductivity are also monitored, for extreme conditions in the first case and for the presence and extent of perspiration in the second. If temperature limits are breached or the presence of excessive perspiration‚which contains glucose enough to affect the measurement—is detected, again the glucose reading will be skipped. The monitor will continue with its sample-and-measure cycle until conditions become stable.

Once the raw data have been accepted, glucose readings are calculated and displayed. The monitor requires a one-point calibration after operating for 2 hours. This is effected by entering a fingerstick glucose value into the device. This blood glucose value is paired with the most recent set of biosensor readings to determine a calibration factor that mainly accounts for variation in skin permeability and thus the amount of glucose collected at a given blood glucose level. The calibration factor is used by the data conversion software in the second-generation G2 device to provide glucose measurements every 10 minutes for up to 13 hours. (The first-generation monitor did not use a rolling-average scheme and presented data every 20 minutes for 12 hours after a 3-hour calibration period.)

Continuous Glucose Monitors in Use

Data from more than 600 trial users of the GlucoWatch Biographer were collected as part of the FDA approval process.4 The most pertinent test of the monitor’s performance involved the 124 subjects who used the device daily for five days as they went through their usual routines. Their home-use experiences would replicate real-world operation. Hourly fingerstick glucose measurements were taken for comparison. Overall, the mean difference between readings taken from the transdermal monitor and blood glucose values was 4.7 mg/dl, and the mean absolute percent difference was 21.3%. The correlation coefficient between the measurements was 0.80. Approximately one-quarter of the potential glucose readings were skipped after data integrity checks. These and other statistics demonstrated that the device offered clinically acceptable accuracy over the entire glucose measurement range. Dermatological assessments showed that some skin irritation was associated with its use. However, the level of irritation for about 90% of the subjects was scored as either none or mild. Comfort problems in nearly all cases were resolved without treatment after several days. No contact sensitization reactions were observed.

The only other FDA-approved continuous home glucose monitor is the CGMS (a trademark of Medtronic MiniMed; Sylmar, CA) (see Figure 3). This system consists of a small, subcutaneously implanted sensor connected to a belt-worn controller. Implantation caused no reaction in 85% of trial subjects.5 The device accumulates measurements for three days, after which the data are downloaded, calibrated with fingerstick glucose measurements taken over the same period, and displayed. Although the monitoring time is longer than for the GlucoWatch Biographer, the CGMS does not provide real-time data to the user. Medtronic MiniMed is continuing to develop the system so that it will be able to do so.

Advantages of Continuous Readings

With continuous glucose readings come two advantages over episodic blood glucose measurements: timeliness and the ability to track changes between readings. Timely readings can usefully warn the diabetic person when blood glucose levels are above or below preset limits. For example, in the transdermal monitor trial mentioned above, 75% of hypoglycemic episodes were detected (with a 10% false-alarm rate), compared with only 14% detected by prebreakfast and predinner fingersticks and 39% detected by four daily fingersticks.4 The ability of continuous glucose monitors to provide a hypoglycemia alarm should facilitate maintenance of stricter glycemic control while removing the fear of associated hypoglycemia. An alarm is especially useful for people who tend to be unaware of asymptomatic hypoglycemic conditions. It also is valuable during periods of sleep when nocturnal hypoglycemia often goes unnoticed unless severe enough to cause acute symptoms such as seizures (see Figure 4).

Figure 5. Postmeal hyperglycemic excursions that fingersticks would miss are tracked by the continuous transdermal glucose monitor.

Regularly repeated measurement also allows rising and falling glucose-level trends to be displayed, which is impossible with single measurements. Knowing, in addition to the absolute measurement, that the glucose level is consistently rising or falling enables the user to take appropriate action. For example, a glucose level of 80 mg/dl and falling may indicate a potential hypoglycemic episode, while 80 mg/dl and rising is not critical.

Another advantage of continuous monitoring is the ability to examine patterns in glycemic levels over time retrospectively. By downloading and examining the data (possible with both the GlucoWatch Biographer and the CGMS), users and their caregivers can fine-tune treatment to reduce glycemic excursions. Standard premeal fingersticks may completely miss postmeal hyperglycemia, for example (see Figure 5). Repeated observation of such occurrences may prompt alteration in meal composition or insulin type or dosage in order to eliminate the pattern. Similarly, observation of typical nighttime glycemic patterns might induce changes in basal insulin dosages or bedtime snacks.

On the Horizon

The unmet needs of people with diabetes continue to motivate technology researchers to work toward the twin goals of noninvasive and continuous glucose measurement. A quick Internet search turns up more than 50 companies that have been active in this area. The devices being developed can be categorized as implantable, transdermal, and spectroscopic sensors.

Implantable systems have been under development for more than 20 years, and the CGMS device, as mentioned, has received FDA approval for retrospective data collection. This technology offers the benefit of continuous glucose measurement, but the necessary subcutaneous implantation would seem to be a disincentive. TheraSense, iSense Corp. (Portland, OR), and DexCom Inc. (San Diego) also have implantable sensors in various stages of development, which are based on their own designs and sensing chemistries. Medtronic MiniMed is developing a long-term implantable sensor that the company envisions connecting to an implanted insulin pump to create a closed-loop glucose sensing and insulin-delivery system. The technical requirements of such a system are demanding, as a malfunction could result in delivery of an inappropriate insulin dosage and serious consequences.

Besides the reverse iontophoresis technique on which the Cygnus monitor is based, other methods for extracting glucose through the skin are being incorporated into devices. (These are sometimes termed minimally invasive techniques to differentiate them from truly noninvasive spectroscopic systems.) All of these transdermal devices can potentially perform continuous glucose measurement without invading the body. A device being developed by SpectRx Inc. (Norcross, GA) features laser poration of the stratum corneum of the skin, followed by vacuum extraction of interstitial fluid to an electrochemical sensor. Sontra Medical Corp. (Cambridge, MA) is developing a similar device that pretreats the skin with ultrasound to optimize its permeability. An electrochemical sensor placed on the pretreated site measures the extracted glucose. Both devices have undergone preliminary clinical trials.

The field of noninvasive glucose monitoring originated with the idea that near-infrared light (NIR) could be used to measure glucose levels through the skin. Such measurements are complicated, however, by low absorbance of glucose in the NIR region and by the overlapping spectra of proteins, fats, and other analytes. Software algorithms must be employed to distinguish glucose signals from the noise, and to correlate these spectral features with blood glucose concentrations. Despite these difficulties, a number of companies persevered and have prototype devices in clinical trials. Sensys Medical Inc. (Chandler, AZ; formerly Instrumentation Metrics) has a first-generation device that measures glucose from a forearm that is placed in a desktop reader. It has shown promise in a small clinical trial. The company now is working on a universal calibration system for the device to simplify operation. LifeTrac Systems Inc. (Biddeford, ME) is developing an NIR earpiece that measures across the earlobe. Its first-generation device would provide single measurements; however, future products could provide continuous glucose monitoring.

Other spectroscopic technologies are under development at Pendragon Medical Ltd. (Adliswil, Switzerland), Animas Corp. (Frazer, PA), and CIBA Vision Corp. (Duluth, GA). Pendragon Medical is developing a device that correlates radio-frequency measurements on the skin with blood glucose levels through a not-yet-understood mechanism. Animas is combining spectroscopic measurement with an implanted system to detect blood glucose levels across a vein for long-term monitoring. CIBA Vision has presented preliminary data generated by a fluorescent contact lens that measures glucose in tears when interrogated by a handheld light source.

Conclusion

One FDA-approved glucose monitor that provides frequent, automatic, and noninvasive glucose measurements for people with diabetes is commercially available. Clinical trials with children and adults have shown that the glucose readings taken with this transdermal device have clinically acceptable accuracy. Continuous glucose monitors of this type can sound an alert if the user’s glucose level is hypo- or hyperglycemic, at any time of day or night. Frequent measurement also lets users track trends and patterns in their daily glucose levels. The technology should enable patients and their healthcare providers to tailor treatment for improved glycemic control without risking hypoglycemic episodes.

Michael J. Tierney, PhD, is principal scientist at Cygnus Inc. (Redwood City, CA). He can be contacted at mtierney@cygn.com.

Whether they obtain it by traditional fingerstick blood measurements or by a continuous or noninvasive monitoring system, people with diabetes need as much information as possible to manage their disease, reduce long-term complications from it, and improve their quality of life. The more convenient and less painful it becomes to acquire glucose measurements, the better the outcomes for millions of people living with this condition.

References

1. Centers for Disease Control and Prevention, National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2000 (Atlanta: U.S. Dept. of Health and Human Services, 2002).

2. H King, RE Aubert, and WH Herman, “Global Burden of Diabetes, 1995–2025: Prevalence, Numerical Estimates, and Projections,” Diabetes Care 21, no. 9 (1998): 1414–1431.0

3. The Diabetes Control and Complications Trial Research Group, “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus,” New England Journal of Medicine 329 (1993): 977–986.

4. MJ Tierney et al., “The GlucoWatch Biographer: A Frequent, Automatic and Noninvasive Glucose Monitor,” Annals of Medicine 32, no. 9 (2000): 632–641.

5. J Mastrototaro, “The MiniMed Continuous Glucose Monitoring System (CGMS),” Journal of Pediatric Endocrinology Metabolism 12 (1999): 751–758. 

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