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Development of a highly responsive needle-type glucose sensor using polyimide for a wearable artificial endocrine pancreas.

To produce a long-life, stable, miniature glucose sensor for a wearable artificial endocrine pancreas (WAEP), we developed a novel microneedle-type glucose sensor using polyimide, designated the PI sensor (outer diameter, 0.3 mm; length, 16 mm), and investigated its characteristics in vitro and in vivo. In the in vitro study, we tested the sensor in 0.9% NaCl solution with varying glucose concentrations and observed an excellent linear relationship between the sensor output and glucose concentration (range: 0-500 mg/100 ml). In in vivo experiments, the PI sensor was inserted into the abdominal subcutaneous tissue of beagle dogs (n = 5), and interstitial fluid glucose concentrations were monitored after sensor calibration. Simultaneously, blood glucose concentrations were also monitored continuously with another PI sensor placed intravenously. The correlation and time delay between subcutaneous tissue glucose (Y) and blood glucose concentrations (X: 30-350 mg/100 ml) were Y = 1.03X + 7.98 (r = 0.969) and 6.6 +/- 1.2 min, respectively. We applied the new WAEP system/PI sensor and an intravenous insulin infusion algorithm developed previously for glycemic control in diabetic dogs. The use of the WAEP system resulted in excellent glycemic control after an oral glucose challenge of 1.5 g/kg (post-challenge blood glucose levels: 176 +/- 18 mg/100 ml at 65 min and 93 +/- 23 mg/100 ml at 240 min), without any hypoglycemia. Thus, we confirmed that our new PI sensor has excellent sensor characteristics in vitro and in vivo. The new WAEP using this sensor is potentially suitable for clinical application.

Administration, Oral↗

Development of a miniaturized glucose monitoring system by combining a needle-type glucose sensor with microdialysis sampling method. Long-term subcutaneous tissue glucose monitoring in ambulatory diabetic patients.

OBJECTIVE: To develop a reliable and practical glucose monitoring system by combining a needle-type glucose sensor with a microdialysis sampling technique for long-term subcutaneous tissue glucose measurements. RESEARCH DESIGN AND METHODS: A microdialysis Cuprophan hollow-fiber probe (inner diameter, 0.20 mm; length, 15 mm) was perfused with isotonic saline solution (120 microliters/h) and glucose concentrations in the dialysate were measured by a needle-type glucose sensor extracorporeally. This system was tested both in vitro and in vivo. Subcutaneous tissue glucose concentrations were then monitored continuously in 5 healthy and 8 diabetic volunteers for 7 to 8 days. A hollow-fiber probe was inserted into the abdominal subcutaneous tissue. RESULTS: This monitoring system achieved excellent results in vitro. Subcutaneous tissue glucose concentrations were measured in a wide range from 1.7 to > 27.8 mM glucose, with a time delay of 6.9 +/- 1.2 min associated with a rise in glucose and 8.8 +/- 1.6 min with a fall in the glucose level (means +/- SE). The overall correlation between subcutaneous tissue (Y) and blood (X) glucose concentration was Y = 1.08X + 0.19 (r = 0.99). The subcutaneous tissue glucose concentration could be monitored precisely for 4 days without any in vivo calibrations and for 7 days by introducing in vivo calibrations. CONCLUSIONS: Glycemic excursions could be monitored precisely in the subcutaneous tissue by this microdialysis sampling method with a needle-type glucose sensor in ambulatory diabetic patients.

Adult↗

Glucose correlation with light scattering patterns--a novel method for non-invasive glucose measurements.

To correlate occlusion red near-infrared spectroscopy technology with intravenous and interstitial glucose levels, occlusion red near-infrared spectroscopy and glucose levels were measured in five subjects with diabetes mellitus during a stepped hyperinsulinemic hypoglycemic clamp. Validation was achieved using a standard error grid and linear correlations. During hyperinsulinemic hypoglycemic clamp linear correlation was significant at r = 0.836, and the intercept was 43.3 mg/dL. Of the glucose measurements, 94.3% were assigned to zones A and B of the standard error grid, the zones of the greatest therapeutic relevance. Expected interference from serum triglycerides, catecholamines, and cortisol was not apparent. These results demonstrate the applicability of occlusion red near-infrared spectroscopy for in vivo glucose monitoring. The technology has implications for continuous non-invasive glucose sensing.

Adult↗

Effects of microdialysis catheter insertion into the subcutaneous adipose tissue assessed by the SCGM1 system.

To monitor glucose in patients with diabetes continuously a microdialysis-based glucose sensor system (SCGM1 System, Roche Diagnostics GmbH, Mannheim, Germany) is under clinical development. This system allows monitoring of glucose levels in the subcutaneous interstitial fluid of patients with diabetes for a maximum duration of up to 120 h. The aim of the study was to determine the effect of microdialysis catheter insertion on the stability of the SCGM1 System glucose sensor signal. At four study sites, 47 experiments with the prototype of the novel SCGM1 System were performed in 42 patients with type 1 diabetes; two additional experiments were performed in two healthy volunteers. The microdialysis catheter was inserted in the subcutaneous adipose tissue of the patients in order to measure the glucose concentration in the interstitial fluid continuously. The catheter was perfused with a pump rate of 0.3 microL/min. For method comparison capillary blood glucose measurements were performed as reference values. In addition, the skinfold thickness was measured. Out of the total of 49 experiments 34 were usable. The average monitoring time in these experiments was 106.0 +/- 14.3 h (mean +/- SD). However, for this study the data from the first study day were evaluated in more detail. The analysis showed that during the first 12 h after catheter insertion the sensor signal increased 20% in comparison with the capillary blood glucose values (normalized calibration factor). This leads to a lower normalized calibration factor compared with the following study days. It remains stable in the time thereafter. The skinfold thickness showed no significant effect on the sensor signal. The observed increase in sensor signal in the first hours after insertion of the microdialysis catheter was probably due to a local trauma, which can induce an inflammation reaction. Thereafter, the signal registered by the SCGM1 System was stable and free of drift to the end of the experiment.

Adult↗

Glucose metabolism and cell size in continuous cultures of Saccharomyces cerevisiae.

A detailed analysis of the cell size, monitored as protein content, has been performed in glucose-limited continuous cultures, so as to obtain the values of the average protein content for various subpopulations at different cell cycle stages, as a function of the growth rate. Glucose metabolism appears to affect cell size, since there is an increase of the average protein content of the population when cells produce ethanol above the critical dilution rate. If the production of ethanol is forced at low growth rates by the addition of formate, the average protein content increases. These results indicate a link between glucose metabolism and cell size in budding yeast, as observed for mammalian cells.

DNA, Fungal↗

[Miniaturization capable, very sensitive polarimeter as detector of an implantable glucose probe. I. Optical amplification of the measuring value].

From a clinical point of view, an implantable telemetric probe for monitoring the blood glucose profile is highly desirable. It should be capable of monitoring the blood glucose level continuously or at regular brief intervals, if necessary requirement-controlled. Apart from blood, measurement can also be made in intercellular tissue fluid, for example, in subcutaneous connective and fatty tissue, because this fluid accurately reflects blood glucose levels after only a brief, but negligible, time lag. Since the functional lifespan of an implantable probe is of decisive importance, only physical sensors, but not bio-sensors can be considered. We are in the process of developing a very sensitive miniaturised detector based on polarimetry, capable of determining the measuring parameter--the spatial orientation of the in-plane vibration of a polarised light beam--with extreme accuracy. This is a very important point, since the physiological and pathological glucose levels modify the in-plane vibration by only a very tiny angle of rotation. The high level of accuracy is achieved by various specific optical amplification mechanisms, and amplification of the electric signal. Two purely optical amplification methods are described here. Simple linear elongation of the optical path of a laser beam within the sample, resulting in a proportional amplification of the measuring signal, is obviously strictly limited in an implantable probe. We therefore developed a technique that preserves the polarisation state of the light beam during reflection. This technique makes possible multiple passage of the light beam through the fluid being sensed, thus elongating the optical path by "folding" the light beam without the need to enlarge the measuring cuvette. In a second possibility, enlargement of the rotation angle can be achieved by reflecting the light beam from a suitable surface, when the orthogonal components of the polarised light beam are reflected to different extents.

Blood Glucose↗

The treatment of unstable type I diabetes: conventional versus portable pump insulin administration.

The treatment of unstable insulin-dependent diabetics (UIDD) is still an unsolved problem. A comparison was made between optimized conventional treatment (OCT) (Ultralente + Actrapid at breakfast, Actrapid at lunch and Actrapid at dinner) and continuous s.c. insulin infusion (CSII) for 30 days in 10 UIDD outpatients. Continuous 24-h blood glucose monitoring with an artificial pancreas, fasting values of HbA1, plasma lipids, growth hormone, glucagon, daily urinary glucose and protein excretion were recorded after each treatment; a daily blood glucose profile was determined every week. Daily mean blood glucose values dropped significantly (p less than 0.01): from 187.2 +/- 66.6 (OCT) to 111.6 +/- 27.0 mg/dl (CSII), and hypoglycemic and ketotic events disappeared during CSII. A significant improvement (p less than 0.01 - p less than 0.001) in all other parameters was also observed. It is suggested that CSII may help to improve metabolic control and the quality of life in UIDD.

Adolescent↗

Feedback-controlled dextrose infusion during surgical management of insulinomas.

Through the use of a feedback-controlled dextrose infusion system, we obtained continuous monitoring of the blood glucose level in a patient undergoing surgery for multiple pancreatic beta-cell tumors. In addition, this device infused dextrose at variable rates to maintain a predetermined euglycemic level of 90 mg/dl. Before locating the source of excessive insulin production, the maximum dextrose infusion rate of 400 mg/min was required; but after extirpation of multiple insulinomas, the dextrose-infusion rate declined whereas the blood glucose level rose above the preselected level. These results emphasize the usefulness of a monitoring and infusion system not only in protecting the patient from the hazard of hypoglycemia under anesthesia but also as an aid in determining whether all insulin-secreting tumors have been removed.

Adenoma, Islet Cell↗

Continuous subcutaneous insulin infusion in patients with diabetes mellitus.

During the last quarter of a century continuous subcutaneous insulin infusion (CSII) with external portable insulin pumps has been increasingly used in selected type 1 diabetic subjects and also in some patients with type 2 diabetes mellitus. The treatment of diabetes mellitus with insulin pumps has become more and more popular and accepted by diabetic patients as well as by medical professionals worldwide. Published trials have shown that, in most patients, mean blood glucose concentration and glycated hemoglobin (HbA1c) percentages are either slightly lower or similar on CSII versus an optimized therapy with multiple daily insulin injections. Hypoglycemic episodes seem to be less frequent and ketoacidoses occur at a comparable rate to that during intensive injection therapy. Moreover, nocturnal glycemic control can be improved with insulin pumps, and automatic basal rate changes help to minimize a prebreakfast blood glucose increase (often called 'the dawn phenomenon'). For many patients, CSII provides greater flexibility in timing of meals with the result of better quality of life and higher treatment satisfaction. However, despite these promising data, and although many patients with diabetes mellitus with well-defined clinical problems are likely to benefit substantially from CSII, either in respect to glycemic control, acute complications or quality of life and treatment satisfaction, we are still far away from reaching'dream diabetes management', the fully automatic closed-loop system. Presently, the most difficult problem concerns not the design of an 'optimal' insulin pump, but rather the development of a system which is able to provide continuous and reliable blood glucose monitoring. Hence, because this problem has not been solved with maximum satisfaction, the development of a feedback-controlled 'artificial pancreas' is one of the main goals in diabetes management in the new millennium.

Blood Glucose↗

Opportunities at the skin interface for continuous patient monitoring: a reverse iontophoresis model tested on lactate and glucose.

Skin has the potential to provide an important noninvasive route for diagnostic monitoring of human subjects for a wide range of applications. Dimensions of surface features in skin suggest that nanodevices and microdevices could be utilized to monitor molecules and ions extracted from the skin. Methods of enhancing extraction from the skin for diagnostics are being developed including reverse iontophoresis, electroporation and sonophoresis. A model system for the simulation of in vivo extraction of molecules and ions by reverse iontophoresis is described here that displays similar behavior to skin both in terms of molecular flux levels and electrical impedance characteristics. The device has potential for use in the development of complete reverse iontophoresis/sensor systems, allowing sensor and extraction systems to be studied and optimized before being tested in the complex in vivo environment. The system has been tested using glucose and lactate and the results are reported and discussed.

Animals↗

[Propofol anesthesia for a patient with insulinoma].

We experienced the anesthetic management of a 47-year-old woman with insulinoma. Removal of the tumor was performed under propofol, nitrous oxide, and epidural anesthesia. We tried the continuous infusion of glucose to maintain normal blood glucose level and to avoid intraoperative hypoglycemic event. The blood glucose and immunoreactive insulin (IRI) level were measured intermittently. After the removal of the insulinoma, the IRI level decreased rapidly to the normal range. In this case, neither hyperglycemic nor hypoglycemic episode was observed. The perioperative course was uneventful. Propofol has not been shown to significantly affect the release of insulin and glucose regulation. This case suggests that under the condition of continuous glucose infusion and blood glucose monitoring, propofol is an useful anesthetic agent for a patient with insulinoma.

Anesthesia↗

Recording of subcutaneous glucose dynamics by a viscometric affinity sensor.

AIMS/HYPOTHESIS: To provide a nonenzymatic sensor for glucose monitoring in subcutaneous tissue. METHODS: A continuously working affinity sensor based on the glucose-dependent viscosity of a sensitive liquid containing dextran and concanavalin A has been designed by arranging a microdialysis probe, two flow-resisting capillaries and two pressure transducers in a linear flow system. It allows synchronous processing of the viscosity of the sensitive liquid at the standard glucose concentration and the glucose concentration to be measured. In preliminary human trials the sensor was implanted into the subcutaneous tissue of the forearm and its read-out was compared with capillary blood concentrations. RESULTS: In vitro, the viscometric sensor shows a linear and long-term stable dependence on the glucose concentration without detectable drift. At the applied flow rate of the sensitive liquid (about 5 microliters/h) the technical delay is 5 to 10 min. The read-out of the implanted sensor followed the dynamics of the capillary blood glucose concentrations with a time-shift of 10 to 15 min but showed a systematic error when based on precalibration with polymer-free glucose solutions. After appropriate in vivo calibration, the read-out was in good or acceptable coincidence with capillary blood concentrations according to the error grid method and did not show any detectable reduction of sensitivity during the periods of measurement (up to 44 h). CONCLUSION/INTERPRETION: The viscometric-affinity sensor is an efficient tool for current research on glucose monitoring in the subcutaneous tissue and can potentially be further developed for routine clinical use.

Blood Glucose↗

Development and evaluation of a wearable blood glucose monitor.

Complex operation, prolonged set-up time, reliability problems, high cost, and excessive size limits the use of currently available extracorporeal continuous blood glucose analyzers. A self-calibrating, wearable blood glucose monitor has been developed to overcome these impediments. The wearable blood glucose monitor is a 410 g forearm-mounted instrument with three miniature pumps for blood sampling, calibration, and insulin infusion, and a flow cell containing an enzyme-electrode sensor capable of determining plasma glucose levels accurately and precisely in undiluted whole blood. The unit is connected to a computer controller with graphics display. Venous blood is drawn from a 21 gauge single lumen cannula through the sensor flow cell. A rate determination of glucose is completed in 20 sec and the blood is returned to the arm vein. Heparinized saline wash solution follows. No blood loss or significant systemic heparinization occurs. Cycle time is set from 2 to 5 min. The method is linear to at least 300 mg/dl glucose, independent of hematocrit, and free of interferences from blood constituents at normal venous pO2 with a coefficient of variation of 1-3% between calibrations. The sensor has a service life of at least 3 weeks. This wearable blood glucose monitor, with its high performance sensor, reduced size, and ease of operation, shows promise for evaluating and treating diabetes.

Animals↗

Anesthetic management of a parturient with carnitine palmitoyltransferase II deficiency.

PURPOSE: To report the anesthetic management of a patient with carnitine palmitoyltransferase II deficiency who presented for labour and delivery. CLINICAL FEATURES: A 30-yr-old primiparous woman with known carnitine palmitoyltransferase II deficiency and a past history of exercise induced muscle pain, weakness and myoglobinuria presented in active labour. Management consisted of an early epidural for labour and continuous dextrose infusion with frequent blood sugar monitoring. She had an uneventful spontaneous vaginal delivery. She experienced a single asymptomatic episode of hypoglycemia on the first postpartum day. Her serum creatine kinase was six times normal at 24 hr post-delivery and remained elevated for three days without evidence of rhabdomyolysis. The remainder of her postpartum course was uneventful. CONCLUSION: Labour and delivery is a potential precipitant of rhabdomyolysis in patients with carnitine palmitoyltransferase II deficiency. The normal postpartum creatine kinase elevation (two to four times baseline at 24 hr) must be taken into account when monitoring these patients. On the basis of the physiologic principles, institution of early epidural analgesia to blunt the stress response to labour and delivery, continuous dextrose infusion and frequent glucose monitoring during labour and postpartum are the mainstays of management.

Adult↗

Kinetics of glucose delivery to subcutaneous tissue in rats measured with 0.3-mm amperometric microsensors.

The time between intravenous injection of a glucose bolus and the time the glucose concentration peaked in the subcutaneous tissue was measured in pentobarbital-anesthetized rats with implanted 290-microns-diameter amperometric sensors. Boluses of 100, 200, and 400 mg/kg body wt were injected. The glucose concentration in the jugular vein was monitored by frequent withdrawal and analysis of samples. The glucose concentration in the subcutaneous tissue was continuously monitored with the sensors. The times required for the subcutaneously implanted sensor to reach its maximum current, corrected for sensor response times, were 7.5 +/- 3.9, 9.8 +/- 5.5, and 10.0 +/- 4.4 min for the smallest to the largest dose, respectively. The shorter delay in response to the smallest dose was statistically significant (P < 0.03). The results were consistent with dilution of the bolus in the cardiovascular system and transport of glucose by both diffusion and facilitated transport via a saturable mediator. An understanding of the differences in the dynamics of venous vs. subcutaneous response to a glucose dose is important in developing algorithms for the control of blood glucose based on a subcutaneous measurement.

Animals↗

Interpretation of glycosuria in the teenage diabetic patient.

More than 700 insulin-dependent diabetic patients of both sexes and all ages have attended an education and stabilization course. Twelve adult females and four adult males were subsequently issued the means to monitor their blood glucose in their homes. Two of the adult females were pregnant, while the other 14 patients had one or more of the following: renal failure, an abnormal renal threshold, diabetic retinopathy, or continued and unexplained instability. A number of children were also issued Ames reflectometers. Eleven out of 13 male patients between the ages of 12 and 18 yr had no special difficulties except for a poor correlation between minor degrees of glycosuria and blood glucose estimations. One youth had a renal threshold of 17 mmol/L, while a recently diagnosed youth had a varying renal threshold. Eleven out of 17 teenage female diabetic patients had no correlation between urinary and blood glucose estimations with an apparant varying renal threshold being common. Four of these patients had a reflectometer on loan for 6--8 wk, but in three there was continued instability. Two others, who had continued use of home monitoring of blood glucose, had normoglycemia upon review. One of these patients had what appeared to be a varying renal threshold while unstable but a normal threshold with diabetic stability. Regardless of the cause of the disparity between blood and uninary glucose estimations, it appears that the unstable teenage female diabetic patient cannot rely upon urinalysis as a guide to insulin dosage.

Adolescent↗

Postprandial silent ischaemia following a fatty meal in patients with recently diagnosed coronary artery disease.

Silent myocardial ischaemia (SI) is recognised as an important prognostic factor in patients with coronary artery disease (CAD). Postprandial angina is related to severity of CAD. The effect of postprandial metabolic changes in the pathogenesis of SI is unclear. We studied the postprandial changes in glucose, insulin and triglyceride, and non-esterified fatty acids (NEFA) in relation to postprandial SI and exercise capacity, in patients with CAD. Forty elderly volunteers (63 +/- 1 years) mean age +/- s.e.m., with a history of angina were selected on the basis of a Rose questionnaire and a positive exercise stress test (modified Bruce protocol). The test meal contained 45% fat. The meal was consumed at 9.00 am and hourly blood samples were taken for glucose, insulin, triglyceride and NEFA. Continuous Holter monitoring for SI was conducted using a Spacelabs 2000 monitor. Twenty-five percent of the subjects had episodes of silent ischaemia. Postprandial glucose, insulin, triglyceride, and NEFA were not significantly different in the patients with SI (group 1, n = 10) compared with those without SI (group 2, n = 30). The mean exercise time was 6.1 +/- 0.8 min in group 1 compared with 6.8 +/- 0.5 minutes in group 2 (P = 0.48). The time to onset of ST depression during exercise test was also not significantly different in the two groups. The occurrence of postprandial SI cannot be related to changes in plasma levels of glucose, triglyceride, insulin, and NEFA. The explanation is not apparent from this study but may relate to a haemodynamic changes such as mesenteric steal. Journal of Human Hypertension (2000) 14, 391-394

Aged↗

On-chip microdialysis system with flow-through sensing components.

Microdialysis probes have been used for diabetes treatment as continuous monitoring system coupled to a glucose sensor. An on-chip microdialysis system with in-line sensing electrodes is demonstrated. As a first step towards greater biosensor integration with this miniaturized microdialysis system, a stacked system with in-line sensing electrodes was developed. Impedance electrodes sputtered within the microchannels were used to determine fluid electrical resistance from a dialyzed phosphate buffered saline (PBS) solution, which characterizes solution conductivity as a function of PBS concentration. The permeability of the membrane to the salt ions was obtained as 0.246+/-0.028 microm/s (15 nm pores). Subsequently, experiments measuring PBS dialysis in the time-domain at 64.4% recovery were conducted. The PBS concentration of the reservoir was changed in both a step response and sinusoidally with an 800 s period. The subsequently measured impedance indicates that the system is able to continuously track concentration changes in the reservoir with a 210 s system response delay. Most of this delay is due to the dead volume within the tubing between the syringe pumps and the microsystem. In addition, the predicted response was modeled using linear systems theory and matches the experimental measurements (r=0.98). This system is expected to have the proper sensitivity to track physiologically relevant concentration changes of biomolecules such as glucose (which has a physiological maximum change rate of approximately 4 mg/dl min with a periodicity of 1h or greater) with minimal lag time and amplitude reduction.

Electrochemistry↗