Design, development, and evaluation of a novel microneedle array-based continuous glucose monitor.

The development of accurate, minimally invasive continuous glucose monitoring (CGM) devices has been the subject of much work by several groups, as it is believed that a less invasive and more user-friendly device will result in greater adoption of CGM by persons with insulin-dependent diabetes. This article presents the results of preliminary clinical studies in subjects with diabetes of a novel prototype microneedle-based continuous glucose monitor. In this device, an array of tiny hollow microneedles is applied into the epidermis from where glucose in interstitial fluid (ISF) is transported via passive diffusion to an amperometric glucose sensor external to the body. Comparison of 1396 paired device glucose measurements and fingerstick blood glucose readings for up to 72-hour wear in 10 diabetic subjects shows the device to be accurate and well tolerated by the subjects. Overall mean absolute relative difference (MARD) is 15% with 98.4% of paired points in the A+B region of the Clarke error grid. The prototype device has demonstrated clinically accurate glucose readings over 72 hours, the first time a microneedle-based device has achieved such performance.

Effect of formulation factors on electroosmotic glucose transport through human skin in vivo.

Glucose transport through human skin can be facilitated by electroosmotic flow that results from the application of an electric current across the skin (iontophoresis). A series of studies on human volunteers examined how formulation factors (buffer type, pH, ionic strength, and buffer concentration) affect the amount of glucose extracted from interstitial fluid through the skin. Sampling cells were placed on subjects' forearms and a current of 0.25 mA/cm(2) was passed across the skin for 5 h. Samples were collected every 20 min and analyzed for glucose concentration. Two methods were used. In one method, subjects ingested glucose and one formulation was tested in each pair of sampling cells for the study duration. The ratio of transdermal glucose flux to blood glucose was determined and compared across formulations. In another method, subjects fasted through the study, and different formulations were sequentially tested in each sampling cell. Citrate was found to give higher flux than bicarbonate or phosphate buffers. Transport increased with increasing pH from 4.5 to 6.5 for citrate buffer and 6.5 to 7.5 for bicarbonate buffer. Increased salt concentration in the formulation decreased transport. Increased phosphate concentration increased transport. These results can be used to optimize electroosmotic transport through the skin.

Rates of glucose change measured by blood glucose meter and the GlucoWatch Biographer during day, night, and around mealtimes.

OBJECTIVE: The purpose of this study was to characterize the distribution of the rate of change of blood glucose for a diabetic population. RESEARCH DESIGN AND METHODS: The study population consisted of 124 adults with type 1 or type 2 diabetes requiring insulin. Study participants applied a GlucoWatch Biographer during the day at home for 5 consecutive days and took finger-prick blood glucose measurements hourly. Subjects kept a diary of meals. The Biographer frequently and automatically measured glucose up to three times per hour for up 12 h. Rates of glucose change were calculated for both Biographer and blood glucose measurements. Rates of glucose change during a separate study of 134 subjects were determined for daytime and nighttime use. RESULTS: -Mean (+/-SD) rates of change of glucose of -0.36 +/- 0.95 and 0.36 +/- 0.99 mg. dl(-1). min(-1) were found before and after lunch using blood glucose data and -0.31 +/- 1.23 and 0.43 +/- 1.26 using Biographer data. For both types of diabetes, rates of glucose change exceeded 2 mg. dl(-1). min(-1) before and after meals approximately 10% of the time. Periprandial glucose patterns showed some significant differences between type 1 and type 2 diabetic subjects. Glucose levels changed more gradually at night than during the day. CONCLUSIONS: Glucose values were almost equally unstable before and after meals. Glycemic instability around dinner was different in type 1 and type 2 diabetes. The GlucoWatch Biographer was found to be effective in tracking trends in glucose levels and yielded similar results as obtained by finger-prick blood samples.

The effect of preapplication of corticosteroids on skin irritation and performance of the GlucoWatch G2 Biographer.

Skin irritation due to iontophoresis may limit the frequency of use of devices for drug delivery or transdermal extraction of analytes of clinical interest. This study examined whether preapplication of corticosteroid preparations could reduce skin irritation from iontophoresis used by the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA) in monitoring interstitial glucose levels frequently and automatically. Numerous corticosteroid preparations were screened to identify formulations that did not interfere with adhesion of the Biographer to the skin or glucose sensing. Kenalog (Westwood-Squibb Pharmaceuticals, Inc., Buffalo, NY) (triamcinolone acetonide) and Cortizone-10 Quick Shot (Pfizer, Inc., New York, NY) (hydrocortisone) sprays were selected and, in a double-masked, randomized, controlled trial, were applied to the forearms of 66 subjects with diabetes and allowed to dry. Biographers were applied and worn for 15 h, and home blood glucose measurements were taken every 30 min to assess accuracy. Irritation was assessed periodically by trained observers and study subjects. Skin irritation was reduced by both corticosteroid sprays, with the fraction of subjects who experienced moderate irritation reduced by 57% and 43% for the Kenalog and Cortizone-10 Quick Shot sprays, respectively. The treatment effect persisted at the 1-week assessment. Preapplication of these preparations did not affect the clinical utility of interstitial glucose readings. Preapplication of Kenalog or Cortizone-10 Quick Shot sprays significantly reduced skin irritation due to iontophoresis, and did not interfere with glucose measurements. This approach may enable the minority of users who experience moderate to severe skin irritation to use the Biographer more frequently for diabetes management.

Physiological differences between interstitial glucose and blood glucose measured in human subjects.

OBJECTIVE: This study investigated whether glucose readings from a sensor sampling in interstitial fluid differ substantially from blood glucose (BG) values measured at the same time. RESEARCH DESIGN AND METHODS: We have evaluated the relationship between BG and glucose extracted from interstitial fluid using the GlucoWatch (Cygnus, Redwood City, CA) biographer, a device that collects glucose from subcutaneous interstitial space through intact skin by application of a low electric current. We evaluated the relative change in the interstitial glucose (IG) signal (IGS) as measured by the biographer versus BG using a normalized two-point sensitivity index (NSI). RESULTS: The results show that biographer measures of IG differ in time and magnitude from the corresponding BG values. In particular, the biographer values were shifted in time due to instrumental and physiological lag. Results show an average total lag of 17.2 +/- 7.2 min for all subjects evaluated. The instrumental lag was 13.5 min, suggesting that physiological lag is approximately 5 min. In addition, when glucose was increasing, the change in IGS was less than that in BG, while when BG was decreasing, the change in IGS was greater than that in BG. CONCLUSIONS: Similar results have been reported for other measures of IG, suggesting that differences reflect physiological variation in glucose uptake, utilization, and elimination in blood and interstitial space. This further evidence of the difference between IG and BG should be considered when interpreting glucose measurements from devices that sample interstitial fluid.

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 automatic, frequent, and non-invasive measurements obtained with the GlucoWatch biographer provide substantially more information about glucose levels than do the current fingerstick methods. This information can be used for improved decisions about all aspects of diabetes management.

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

OBJECTIVE: This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch biographer in children and adolescents with diabetes. METHODS: Accuracy was assessed by comparing biographer glucose measurements with hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was evaluated by examining the biographer application sites immediately upon removal of the devices, and then at regular intervals. RESULTS: Sixty-six subjects each wore three biographers at sites including the forearm, upper arm, leg, and torso. For forearm biographers, the mean absolute relative difference between biographer readings and blood glucose was 21%. Ninety-five per cent of biographer readings fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B regions of the consensus error grid. Data from biographers worn at the alternative sites were similar to data from the forearm biographers. Two strong reactions to the adhesive pad of the biographer AutoSensor were observed. Most skin reactions were mild. CONCLUSIONS: The GlucoWatch biographer is well tolerated by children and adolescents with diabetes. Performance is similar when the device is worn at different anatomical sites, and is similar to the performance on the forearm, previously reported in adults.