"Smart tattoo" glucose biosensors and effect of coencapsulated anti-inflammatory agents

Background

Minimally invasive glucose biosensors with increased functional longevity form one of the most promising techniques for continuous glucose monitoring. In the present study, we developed a novel nanoengineered microsphere formulation comprising alginate microsphere glucose sensors and anti-inflammatory-drug-loaded alginate microspheres.

Methods

The formulation was prepared and characterized for size, shape, in vitro drug release, biocompatibility, and in vivo acceptability. Glucose oxidase (GOx)- and Apo-GOx-based glucose sensors were prepared and characterized. Sensing was performed both in distilled water and simulated interstitial body fluid. Layer-by-layer self-assembly techniques were used for preventing drug and sensing chemistry release. Finally, in vivo studies, involving histopathologic examination of subcutaneous tissue surrounding the implanted sensors using Sprague–Dawley rats, were performed to test the suppression of inflammation and fibrosis associated with glucose sensor implantation.

Results

The drug formulation showed 100% drug release with in 30 days with zero-order release kinetics. The GOx-based sensors showed good enzyme retention and enzyme activity over a period of 1 month. Apo-GOx-based visible and near-infrared sensors showed good sensitivity and analytical response range of 0–50 mM glucose, with linear range up to 12 mM glucose concentration. In vitro cell line studies proved biocompatibility of the material used. Finally, both anti-inflammatory drugs were successful in controlling the implant–tissue interface by suppressing inflammation at the implant site.

Conclusion

The incorporation of anti-inflammatory drug with glucose biosensors shows promise in improving sensor biocompatibility, thereby suggesting potential application of alginate microspheres as “smart tattoo” glucose sensors with increased functional longevity.     

On-Chip Microdialysis System with Flow-Through Glucose Sensing Capabilities

Background

Microdialysis is a sampling technique based on controlling the mass transfer rate of different-sized molecules across a semipermeable membrane. Because the dialysis process has minimal effects on the surrounding fluid, it is viewed as a tool for continuous monitoring of human metabolites. In diabetes treatment, microdialysis probes have been used as sampling systems coupled to a glucose biosensor but may struggle to obtain high recoveries of analytes, as the sampling housing, probes, and glucose sensors are fabricated as separate pieces and then assembled, resulting in a large dead volume, which limits sensing frequency. An in situ combination of a miniaturized microdialysis probe with an integrated glucose sensor could help solve some of these problems.

Method

The system was fabricated by bonding a 6-μm-thick polycarbonate track-etch membrane with 100-nm-diameter pores onto microfluidic channels with the electrochemical glucose sensing electrodes patterned within the microchannels.

Results

In vitro experiments demonstrating glucose microdialysis with continuous sensing were conducted. The permeability of glucose to the polycarbonate membrane with a 100-nm-diameter pore size was obtained to be 5.44 μm/s. Glucose recovery of 99% was observed using this microdialysis system at a perfusion flow rate of 0.5 μl/min. Experiments monitoring fluctuating glucose concentrations in the time domain at 99% recovery were also performed. The lag time was measured to be 210 seconds with 45 seconds contributed by mass transfer limitations and the rest from dead volume within the experimental setup.

Conclusion

The electrochemical sensing component was able to continuously track concentration changes in the reservoir. This system is expected to have the proper sensitivity to track physiologically relevant concentration changes of glucose with a lag time of less than 1 minute and minimal amplitude reduction for continuous glucose monitoring for diabetes treatment.     

Contribution of an intrinsic lag of continuous glucose monitoring systems to differences in measured and actual glucose concentrations changing at variable rates in vitro

Background

Current continuous glucose monitoring (CGM) systems measure glucose levels in the interstitial fluid to estimate blood glucose concentration. A lag time has been observed between CGM system glucose readings and blood glucose levels when glucose levels are changing. Although this lag has been attributed to the time it takes glucose to equilibrate between blood and interstitial fluid compartments, it is unclear to what extent these inaccuracies reflect an intrinsic delay of the device itself.

Methods

Four Guardian^® REAL-Time CGM systems (CGMSs) (Medtronic Diabetes, Minimed, CA) and eight glucose sensors were tested in glucose solutions prepared in Krebs bicarbonate buffers at 37 °C. Glucose readings obtained from CGMSs were compared with actual glucose concentrations during controlled changes in glucose concentration performed at four rates (30, 90, and 220 mg/dl/hr^-1 and an instantaneous change of 110 mg/dl) using a linear gradient maker.

Results

Irrespective of the rate and direction of changes in glucose concentration, the readings obtained from CGMSs were significantly different from actual glucose levels. The faster the rise or fall in actual glucose concentration, the more pronounced the mismatch with CGMS glucose readings. Furthermore, the intrinsic lag times (8.3 to 40.1 min) were high enough to account for the lags reported in previous in vivo studies.

Conclusions

The lag intrinsic of the CGMS may make a significant contribution to the mismatch between CGM system readings and blood glucose concentrations.     

Flexible three-dimensional electrochemical glucose sensor with improved sensitivity realized in hybrid polymer microelectromechanical systems technique

Background

Continuous glucose monitoring for patients with diabetes is of paramount importance to avoid severe health conditions resulting from hypoglycemia or hyperglycemia. Most available methods require an invasive setup and a health care professional. Handheld devices available on the market also require finger pricking for every measurement and do not provide continuous monitoring. Hence, continuous glucose monitoring from human tears using a glucose sensor embedded in a contact lens has been considered as a suitable option. However, the glucose concentration in human tears is very low in comparison with the blood glucose level (1/10–1/40 concentration). We propose a sensor that solves the sensitivity problem in a new way, is flexible, and is constructed onto the oxygen permeable contact lens material.

Methods

To achieve such sensitivity while maintaining a small sensor footprint suitable for placement in a contact lens, we increased the active electrode area by using three-dimensional (3-D) electrode micropatterning. Fully flexible 3-D electrodes were realized utilizing ordered arrays of pillars with different shapes and heights.

Results

We successfully fabricated square and cylindrical pillars with different height (50, 100, and 200 μm) and uniform metal coverage to realize sensor electrodes. The increased surface area produces high amperometric current that increases sensor sensitivity up to 300% using 200 μm tall square pillars. The sensitivity improvement closely follows the improvement in the surface area of the electrode.

Conclusions

The proposed flexible glucose sensors with 3-D microstructure electrodes are more sensitive to lower glucose concentrations and generate higher current signal than conventional glucose sensors.     

A disposable tear glucose biosensor--part 3: assessment of enzymatic specificity

Background

A concept for a tear glucose sensor based on amperometric measurement of enzymatic oxidation of glucose was previously presented, using glucose dehydrogenase flavin adenine dinucleotide (GDH-FAD) as the enzyme. Glucose dehydrogenase flavin adenine dinucleotide is further characterized in this article and evaluated for suitability in glucose-sensing applications in purified tear-like saline, with specific attention to the effect of interfering substances only. These interferents are specifically saccharides that could interact with the enzymatic activity seen in the sensor''s performance.

Methods

Bench top amperometric glucose assays were performed using an assay solution of GDH-FAD and ferricyanide redox mediator with samples of glucose, mannose, lactose, maltose, galactose, fructose, sucrose, and xylose at varying concentrations to evaluate specificity, linear dynamic range, signal size, and signal-to-noise ratio. A comparison study was done by substituting an equivalent activity unit concentration of glucose oxidase (GOx) for GDH-FAD.

Results

Glucose dehydrogenase flavin adenine dinucleotide was found to be more sensitive than GOx, producing larger oxidation currents than GOx on an identical glucose concentration gradient, and GDH-FAD exhibited larger slope response (-5.65 × 10^-7 versus -3.11 × 10^-7 A/mM), signal-to-noise ratio (18.04 versus 2.62), and linear dynamic range (0–30 versus 0–10 mM), and lower background signal (-7.12 versus -261.63 nA) than GOx under the same assay conditions. GDH-FAD responds equally to glucose and xylose but is otherwise specific for glucose.

Conclusion

Glucose dehydrogenase flavin adenine dinucleotide compares favorably with GOx in many sensor-relevant attributes and may enable measurement of glucose concentrations both higher and lower than those measurable by GOx. GDH-FAD is a viable enzyme to use in the proposed amperometric tear glucose sensor system and perhaps also in detecting extreme hypoglycemia or hyperglycemia in blood.     

First clinical evaluation of a new long-term subconjunctival glucose sensor

Background

To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for glucose monitoring in humans, we investigated the in vivo performance of the sensor in a clinical trial with five patients.

Methods

The new SGMS consists of an implantable ocular mini implant (OMI) and a hand-held fluorescence photometer. The implantable subconjunctival glucose sensor is composed of a fluorescence resonance energy transfer system based on Concanavalin A chemistry, embedded in a nelfilcon polymer hydrogel disk. Blood glucose changes in humans were induced by oral glucose intake and insulin injections.

Results

The in vivo response of the new SGMS was tested in a first human clinical study with five diabetes patients. The OMI was well tolerated in the eyes of the patients. The SGMS exhibited high correlation coefficients (>0.88) with blood glucose changes and a good stability of the sensor response to glucose for the study period of 2 weeks. Lag times were in the range of 5–10 min. A total of 98% of all data pairs was in the clinical acceptable ranges A and B of the consensus error grid.

Conclusions

For the first time, the possibility to measure glucose in vivo in the subconjunctival interstitial fluid for a period of 2 weeks was demonstrated in a human clinical trial.     

Comparing the Performance of the Optical Glucose Assay Based on Glucose Binding Protein with High-Performance Anion-Exchange Chromatography with Pulsed Electrochemical Detection: Efforts to Design a Low-Cost Point-of-Care Glucose Sensor

Background

The glucose binding protein (GBP) is one of many soluble binding proteins found in the periplasmic space of gram-negative bacteria. These proteins are responsible for chemotactic responses and active transport of chemical species across the membrane. Upon ligand binding, binding proteins undergo a large conformational change, which is the basis for converting these proteins into optical biosensors.

Methods

The GBP biosensor was prepared by attaching a polarity-sensitive fluorescent probe to a single cysteine mutation at a site on the protein that is allosterically responsive to glucose binding. The fluorescence response of the resulting sensor was validated against high-performance anion-exchange chromatography (HPAEC) with pulsed electrochemical detection. Finally, a simple fluorescence reader was built using a lifetime-assisted ratiometric technique.

Results

The GBP assay has a linear range of quantification of 0.100–2.00 μM and a sensitivity of 0.164 μM⁻¹ under the specified experimental conditions. The comparison between GBP and HPAEC readings for nine blind samples indicates that there is no statistical difference between the analytical results of the two methods at the 95% confidence level. Although the methods of fluorescence detection are based on different principles, the response of the homemade device to glucose concentrations was comparable to the response of the larger and more expensive tabletop fluorescence spectrophotometer.

Conclusions

A glucose binding protein labeled with a polarity-sensitive probe can be used for measuring micromolar amounts of glucose. Using a lifetime-assisted ratiometric technique, a low-cost GBP-based micromolar glucose monitor could be built.     

Effects of a sodium glucose co‐transporter 2 selective inhibitor,ipragliflozin, on the diurnal profile of plasma glucose in patients with type 2 diabetes: A study using continuous glucose monitoring

Aims/Introduction

To assess the effects of sodium glucose co-transporter 2 inhibitor therapy on the pathophysiology of type 2 diabetes.

Materials and Methods

We administered ipragliflozin to 21 inpatients with type 2 diabetes for 7 days, and analyzed the diurnal profiles of plasma glucose and 3-hydroxybutyrate. A total of 21 age-, sex- and body mass index-matched diabetic patients served as controls.

Results

Continuous glucose monitoring showed that the 24-h glucose curve was shifted downward without hypoglycemia by the administration of ipragliflozin. The average glucose level was reduced from 182 ± 54 mg/dL to 141 ± 33 mg/dL (P < 0.0001). The magnitude of the reduction was highly correlated with the baseline average glucose level. Homeostasis model assessment of insulin resistance was decreased, and homeostasis model assessment of β-cell function was increased during the treatment. Urinary glucose excretion was correlated with the average glucose level both on day 0 and on day 7, although the regression line was steeper and shifted leftward on day 7. The ipragliflozin-treated patients lost more weight than the control patients (1.4 ± 0.5 vs 0.5 ± 0.6 kg, P < 0.0001). Plasma levels of 3-hydroxybutyrate were significantly increased with peaks before breakfast and before dinner. Patient age and bodyweight loss were negatively and positively correlated with the peak levels of 3-hydroxybutyrate on day 7, respectively.

Conclusions

The ipragliflozin treatment improved the 24-h glucose curve without causing hypoglycemia. The close correlation between the magnitude of glucose reduction and the baseline plasma glucose concentration suggests that the risk of hypoglycemia is likely low. It might be prudent to monitor ketone body levels in younger patients and in patients with rapid weight loss.     

Sensors & Algorithms for Continuous Glucose Monitoring: Putative Delays in Interstitial Fluid (ISF) Glucose Kinetics Can Be Attributed to the Glucose Sensing Systems Used to Measure Them Rather Than the Delay in ISF Glucose Itself

Background

Since the advent of subcutaneous glucose sensors, there has been intense focus on characterizing the delay in the interstitial fluid (ISF) glucose response and the effect of insulin to alter the plasma-to-ISF glucose gradient. The Medtronic MiniMed continuous glucose monitoring system (CGMS) has often been used for this purpose; however, many of the studies have used experimental conditions that fall outside its intended use, for example, studies that have assessed the delay during rapid glucose excursions brought about by intravenous infusion of glucose or insulin. Under these conditions, it is possible that the rate of glucose change may exceed that allowed by CGMS filtering routines. If so, the estimated delay may be because of the filter rather than the ISF. Also, sensor characteristics, such as nonspecific offset current or stability, may have been inadvertently attributed to changes in the plasma-to-ISF gradient. The potential for these issues to have confounded the understanding of ISF glucose delay and gradient is investigated.

Methods

An in vitro preparation in which no delay or gradient exists between sensor and measurement solution was used to recreate a rapidly changing glucose profile from a previously published in vivo study. The CGMS system (N = 6 sensors) was then used to estimate any artifactual delay and gradient introduced by the system per se.

Results

One-point calibration resulted in an apparent change in gradient as glucose was lowered from ∼100 to 50 mg/dl. After a two-point calibration, sensor glucose followed the glucose profile as it was decreased slowly from ∼100 to ∼60 mg/dl; however, when the glucose level was subsequently increased rapidly to ∼150 mg/dl, CGMS filtering routines limited the rate of change of sensor glucose and introduced a delay similar to that previously attributed to ISF glucose equilibration delay.

Conclusions

Studies that have previously used the Medtronic MiniMed CGMS system to assess changes in the plasma-to-ISF glucose gradient may need to be reassessed to ensure that the offset current was estimated accurately. Studies that have used the system to assess ISF glucose delay during rapid, unphysiologic changes in glucose and did not remove the CGMS smoothing filters may have attributed CGMS filter delay to ISF glucose equilibration.     

Aluminum Gallium Nitride (GaN)/GaN High Electron Mobility Transistor-Based Sensors for Glucose Detection in Exhaled Breath Condensate

Background

Immobilized aluminum gallium nitride (AlGaN)/GaN high electron mobility transistors (HEMTs) have shown great potential in the areas of pH, chloride ion, and glucose detection in exhaled breath condensate (EBC). HEMT sensors can be integrated into a wireless data transmission system that allows for remote monitoring. This technology offers the possibility of using AlGaN/GaN HEMTs for extended investigations of airway pathology of detecting glucose in EBC without the need for clinical visits.

Methods

HEMT structures, consisting of a 3-μm-thick undoped GaN buffer, 30-Å-thick Al_0.3Ga_0.7N spacer, and 220-Å-thick silicon-doped Al_0.3Ga_0.7N cap layer, were used for fabricating the HEMT sensors. The gate area of the pH, chloride ion, and glucose detection was immobilized with scandium oxide (Sc₂O₃), silver chloride (AgCl) thin film, and zinc oxide (ZnO) nanorods, respectively.

Results

The Sc₂O₃-gated sensor could detect the pH of solutions ranging from 3 to 10 with a resolution of ∼0.1 pH. A chloride ion detection limit of 10^-8 M was achievedt with a HEMT sensor immobilized with the AgCl thin film. The drain–source current of the ZnO nanorod-gated AlGaN/GaN HEMT sensor immobilized with glucose oxidase showed a rapid response of less than 5 seconds when the sensor was exposed to the target glucose in a buffer with a pH value of 7.4. The sensor could detect a wide range of concentrations from 0.5 nM to 125 μM.

Conclusion

There is great promise for using HEMT-based sensors to enhance the detection sensitivity for glucose detection in EBC. Depending on the immobilized material, HEMT-based sensors can be used for sensingt different materials. These electronic detection approaches with rapid response and good repeatability show potential for the investigation of airway pathology. The devices can also be integrated into a wireless data transmission system for remote monitoring applications. This sensor technology could use the exhaled breath condensate to measure the glucose concentration for diabetic applications.     

Effect of short-term use of a continuous glucose monitoring system with a real-time glucose display and a low glucose alarm on incidence and duration of hypoglycemia in a home setting in type 1 diabetes mellitus

Background

The objective of this study was to examine whether setting the low glucose alarm of a Guardian^® REAL-Time continuous glucose monitoring system (CGMS) to 80 mg/dl for 3 days and providing instructions to users reduce the risk of hypoglycemia under free-living conditions in individuals with type 1 diabetes mellitus (T1DM).

Methods

Fourteen participants with T1DM aged 26.1 ± 6.0 years (mean ± standard deviation) were fitted with a CGMS and assigned for 3 days to either an alarm [low and high blood glucose (BG) alarms set at 80 and 200 mg/dl, respectively] or no alarm condition, with each treatment administered to all participants following a counterbalanced design. All participants were given detailed instructions on how to respond appropriately to low glucose alarms.

Results

The CGMS with alarm reduced the incidence of hypoglycemia (CGMS readings ≤65 mg/dl) by 44% as well as the time spent below this hypoglycemic threshold by 64% without increasing average BG levels. However, the CGMS with alarm had no effect on the incidence of symptomatic hypoglycemia.

Conclusions

Short-term use of the CGMS with alarm, together with appropriate instructions for users, reduces the incidence and duration of hypoglycemia, but only to a limited extent, in part because it overestimates BG in the low glucose range.     

Agreement between Glucose Trends Derived from Three Simultaneously Worn Continuous Glucose Sensors

Background

Sensors detect the rate and direction of glucose trend. They need to be accurate and reproducible as could be evidenced by strong agreement between multiple sensors. We evaluated this relationship through simultaneously worn glucose sensors using several methods of slope analysis.

Methods

Ten type 1 diabetic, insulin pump-treated subjects were studied while simultaneously wearing three CGMS^® Gold sensors each. Sensors were placed in the right abdomen (reference), left abdomen, and left upper arm. Sensors were calibrated and chronologically aligned. Data were only interpreted and included if there were 24 hours of data simultaneously obtained from all three sensors.

Results

Using a two-point derived slope, increasing the duration of the trend from 5 to 60 minutes improved agreement between sensors. Using a 20-minute rolling average trend (using every 5-minute glucose value during the 20 minutes) improved the agreement to 94.3%. Finally, using whichever of the two comparator sensor rolling average trends was closest to the reference (better of two), the agreement improved to 98.2%. However, for these trend analysis methods, when the absolute reference rate of change was more than 1 mg/dl/min, the agreement decreased. Even with the best analysis approach, at an absolute reference sensor rate of change of >2 mg/dl/min, the agreement between sensors was only 40.0%.

Conclusion

Despite several methods of analysis, trend agreement from multiple sensors diminishes as the absolute rate of change of reference glucose increases.     

Continuous glucose monitoring considerations for the development of a closed-loop artificial pancreas system

Background

Commercialization of a closed-loop artificial pancreas system that employs continuous subcutaneous insulin infusion and interstitial fluid glucose sensing has been encumbered by state-of-the-art technology. Continuous glucose monitoring (CGM) devices with improved accuracy could significantly advance development efforts. However, the current accuracy of CGM devices might be adequate for closed-loop control.

Methods

The influence that known CGM limitations have on closed-loop control was investigated by integrating sources of sensor inaccuracy with the University of Virginia Padova Diabetes simulator. Non-glucose interference, physiological time lag and sensor error measurements, selected from 83 Enlite™ glucose sensor recordings with the Guardian® REAL-Time system, were used to modulate simulated plasma glucose signals. The effect of sensor accuracy on closed-loop controller performance was evaluated in silico, and contrasted with closed-loop clinical studies during the nocturnal control period.

Results

Based on n = 2472 reference points, a mean sensor error of 14% with physiological time lags of 3.28 ± 4.62 min (max 13.2 min) was calculated for simulation. Sensor bias reduced time in target for both simulation and clinical experiments. In simulation, additive error increased time <70 mg/dl and >180 mg/dl by 0.2% and 5.6%, respectively. In-clinic, the greatest low blood glucose index values (max = 5.9) corresponded to sensor performance.

Conclusion

Sensors have sufficient accuracy for closed-loop control, however, algorithms are necessary to effectively calibrate and detect erroneous calibrations and failing sensors. Clinical closed-loop data suggest that control with a higher target of 140 mg/dl during the nocturnal period could significantly reduce the risk for hypoglycemia.     

Effects of cigarette smoke, nicotine and cotinine on red blood cell hemolysis and their -SH capacity

BACKGROUND:

Smoking is a leading cause of premature death. Red blood cell (RBC) membrane lipids are rich in polyunsaturated fatty acids; therefore, the effect of oxygen on RBC membranes is more prominent than on other body tissues. The attachment of peroxidants to RBC membranes can result in hemolysis.

OBJECTIVES:

The present study was conducted to assess the sensitivity of RBCs to 2,2′-azo-bis-(2-amidinopropane) dihydrochloride in smokers and nonsmokers. The effect of cigarette smoke, nicotine (1 μg/mL, 1.5 μg/mL and 2.5 μg/mL) and cotinine (1.25 μg/mL, 2.5 μg/mL and 5 μg/mL) on RBC hemolysis was also examined.

RESULTS:

RBC hemolysis in smokers was 21.6% higher than in non-smokers (P<0.05). Cigarette smoke increased 2,2′-azo-bis-(2-amidino-propane) dihydrochloride-induced RBC hemolysis by 281.7%. Nicotine inhibited RBC hemolysis by 36.7% at the highest concentration used, but increased RBC hemolysis at the lower concentrations. Cotinine caused a 13.8% increase in RBC membrane peroxidation at the highest concentration used and its effects were dose-dependent. At their highest concentrations, nicotine and cotinine decreased -SH groups by 50%.

CONCLUSIONS:

The present study confirms the results from previous studies of the oxidative and destructive effects of cigarette smoke, which are detrimental to the health of both active and passive smokers.     

No relevant relationship between glucose variability and oxidative stress in well-regulated type 2 diabetes patients

Background

A strong relationship between glycemic variability and oxidative stress in poorly regulated type 2 diabetes (T2DM) on oral medication has been reported. However, this relationship was not seen in type 1 diabetes. The purpose of this study is to reexamine the relation between glycemic variability and oxidative stress in a cohort of T2DM patients on oral medication.

Methods

Twenty-four patients with T2DM on oral glucose lowering treatment underwent 48 hours of continuous glucose monitoring (CGMS^® System Gold^TM, Medtronic MiniMed) and simultaneous collection of two consecutive 24-hour urine samples for determination of 15(S)-8-iso-prostaglandin F_2α (PGF_2α) using high-performance liquid chromatography tandem mass spectrometry. Standard deviation (SD) and mean amplitude of glycemic excursions (MAGE) were calculated as markers of glycemic variability.

Results

Included in the study were 66.7% males with a mean age (range) of 59 (36–76) years and a mean (SD) HbA1c of 6.9% (0.7). Median [interquartile range (IQR)] urinary 15(S)-8-iso-PGF_2α excretion was 176.1 (113.6–235.8) pg/mg creatinine. Median (IQR) SD was 31 (23–40) mg/dl and MAGE 85 (56–106) mg/dl. Spearman correlation did not show a significant relation for SD (ρ = 0.15, p = .49) or MAGE (ρ = 0.23, p = .29) with 15(S)-8-iso-PGF_2α excretion. Multivariate regression analysis adjusted for age, sex, HbA1c, and exercise did not alter this observation.

Conclusions

We did not find a relevant relationship between glucose variability and 15(S)-8-iso-PGF_2α excretions in T2DM patients well-regulated with oral medication that would support an interaction between hyperglycemia and glucose variability with respect to the formation of reactive oxygen species.     

Predicting subcutaneous glucose concentration using a latent-variable-based statistical method for type 1 diabetes mellitus

Background

Accurate prediction of future glucose concentration for type 1 diabetes mellitus (T1DM) is needed to improve glycemic control and to facilitate proactive management before glucose concentrations reach undesirable concentrations. The availability of frequent glucose measurements, insulin infusion rates, and meal carbohydrate estimates can be used to good advantage to capture important information concerning glucose dynamics.

Methods

This article evaluates the feasibility of using a latent variable (LV)-based statistical method to model glucose dynamics and to forecast future glucose concentrations for T1DM applications. The prediction models are developed using a proposed LV-based approach and are evaluated for retrospective clinical data from seven individuals with T1DM and for In silico simulations using the Food and Drug Administration-accepted University of Virginia/University of Padova metabolic simulator. This article provides comparisons of the prediction accuracy of the LV-based method with that of a standard modeling alternative. The influence of key design parameters on the performance of the LV-based method is also illustrated.

Results

In general, the LV-based method provided improved prediction accuracy in comparison with conventional autoregressive (AR) models and autoregressive with exogenous input (ARX) models. For larger prediction horizons (≥30 min), the LV-based model with exogenous inputs achieved the best prediction performance based on a paired t-test (α = 0.05).

Conclusions

The LV-based method resulted in models whose glucose prediction accuracy was as least as good as the accuracies of standard AR/ARX models and a simple model-free approach. Furthermore, the new approach is less sensitive to changing conditions and the effect of key design parameters.     

Evaluation of different disinfectants on the performance of an on-meter dosed amperometric glucose-oxidase-based glucose meter

Background

Off-meter dosed photometric glucose-oxidase-based glucose meters have been reported to be susceptible to interference by hydrogen-peroxide-based disinfecting agents. The objective of this study was to determine if a single application of hydrogen-peroxide-containing Accel® wipe to disinfect an on-meter dosed amperometric glucose-oxidase-based glucose meter will influence its performance.

Method

The performance of five on-meter dosed amperometric glucose-oxidase-based glucose meters was determined before and after disinfecting the devices with a single application of either CaviWipes® (14.3% isopropanol and 0.23% diisobutyl-phenoxy-ethoxyethyl dimethyl benzyl ammonium chloride) or Accel (0.5% hydrogen peroxide) wipes. Replicate glucose measurements were conducted before disinfecting the devices, immediately after disinfecting, and then 1 and 2 min postdisinfecting, with measurements in triplicate. Analysis was sequentially completed for five different meters. Results were analyzed by a two-way analysis of variance (Analyze-it software).

Results

No clinical (<0.3 mmol/liter) or statistical differences (p > .05) in glucose concentration were detected when the on-meter dosed amperometric glucose-oxidase-based glucose meters were disinfected with either CaviWipes or Accel wipes and measured immediately or 1 or 2 min postdisinfecting. No clinically significant difference in glucose concentration was detected between meters (<0.3 mmol/liter).

Conclusion

The on-meter dosed glucose oxidase amperometric-based glucose meters are not analytically susceptible to interference by a single application of hydrogen-peroxide-containing Accel disinfectant wipes.     

Numerical Simulation of the Effect of Rate of Change of Glucose on Measurement Error of Continuous Glucose Monitors

Background

A 5-day in-patient study designed to assess the accuracy of the FreeStyle Navigator® Continuous Glucose Monitoring System revealed that the level of accuracy of the continuous sensor measurements was dependent on the rate of glucose change. When the absolute rate of change was less than 1 mg•dl⁻¹•min⁻¹ (75% of the time), the median absolute relative difference (ARD) was 8.5%, with 85% of all points falling within the A zone of the Clarke error grid. When the absolute rate of change was greater than 2 mg•dl⁻¹•min⁻¹ (8% of the time), the median ARD was 17.5%, with 59% of all points falling within the Clarke A zone.

Method

Numerical simulations were performed to investigate effects of the rate of change of glucose on sensor measurement error. This approach enabled physiologically relevant distributions of glucose values to be reordered to explore the effect of different glucose rate-of-change distributions on apparent sensor accuracy.

Results

The physiological lag between blood and interstitial fluid glucose levels is sufficient to account for the observed difference in sensor accuracy between periods of stable glucose and periods of rapidly changing glucose.

Conclusions

The role of physiological lag on the apparent decrease in sensor accuracy at high glucose rates of change has implications for clinical study design, regulatory review of continuous glucose sensors, and development of performance standards for this new technology. This work demonstrates the difficulty in comparing accuracy measures between different clinical studies and highlights the need for studies to include both relevant glucose distributions and relevant glucose rate-of-change distributions.     

Noninvasive polarimetric-based glucose monitoring: an in vivo study

Background:

Since 1990, there has been significant research devoted toward development of a noninvasive physiological glucose sensor. In this article, we report on the use of optical polarimetry for the noninvasive measurement of physiological glucose concentration in the anterior chamber of the eye of New Zealand white (NZW) rabbits.

Method:

Measurements were acquired using a custom-designed laser-based optical polarimetry system in a total of seven NZW rabbits anesthetized using an isoflurane-only anesthesia protocol. Aqueous humor-based polarimetric measurements were obtained by coupling light through the anterior chamber of the eye. Blood glucose levels were first stabilized and then altered with intravenous dextrose and insulin administration and measured every 3–5 min with a standard glucometer and intermittently with a YSI 2300 glucose analyzer. Acquired polarimetric glucose signals are calibrated to measured blood glucose concentration.

Results:

Based on a total of 41 data points, Clarke error grid analysis indicated 93% in zone A, 7% in zone B, and 0% in zones C and D, with reference concentrations between 93 and 521 mg/dl. Errors in prediction are shown to be related to gross movement of the rabbit during the procedures, incurring time-varying corneal birefringence effects that directly affect the measured polarimetric signal. These effects can be compensated for with appropriate design modifications.

Conclusions:

An optical polarimetry technique was used for in vivo physiological glucose monitoring. The technique demonstrated provides a basis for the development of a noninvasive polarimetric glucose monitor for home, personal, or hospital use.     

Automated near-continuous glucose monitoring measured in plasma using mid-infrared spectroscopy

Objective

There are increasing calls for a precise, automated system to enable tight glycemic control and to avoid hypoglycemia in an intensive care unit setting. OptiScan Biomedical has developed a glucose monitor based on mid-infrared spectroscopy that withdraws blood samples (120 µl) and measures plasma glucose. The goal of this study was to validate the performance of the OptiScan Model 5000 over a wide range of glycemic levels in patients.

Research Design and Methods

Sixty people with type 1 (n = 18) or type 2 (n = 42) diabetes who were otherwise healthy were connected to OptiScanners. Their blood glucose concentrations were kept in a euglycemic, hypoglycemic (<75 mg/dl), and hyperglycemic (>180 mg/dl) range by intravenous administrations of insulin and glucose. OptiScanner venous blood samples were automatically withdrawn every 15 minutes. Reference measurements were done using the YSI 2300 glucose analyzer.

Results

The aggregate data points (1155 paired readings) were within International Organization for Standardization standards, with 98.6% of the glucose values within ±20% above 75 mg/dl and ±15 mg/dl below this value. A Clarke error grid analysis showed a total of 1139 points (98.6%) in zone A. Points outside of A exceeded the A zone boundary by an average of 4.3%. The r² was 0.99. The total coefficient for variance was 6.4%.

Conclusions

These results show that the OptiScanner is highly accurate in healthy patients with diabetes across a wide range of glucose values. Mid-infrared spectroscopy may become the method of choice for highly accurate, high frequency, automated glucose measurements and may thus enable better glycemic control in critically ill patients.