Non-invasive Glucose Measurement Research Articles

Noninvasive Electromagnetic Wave Sensing of Glucose.

Diabetic patients need long-term and frequent glucose monitoring to assist in insulin intake. The current finger-prick devices are painful and costly, which places noninvasive glucose sensors in high demand. In this review paper, we list several advanced electromagnetic (EM)-wave-based technologies for noninvasive glucose measurement, including infrared (IR) spectroscopy, photoacoustic (PA) spectroscopy, Raman spectroscopy, fluorescence, optical coherence tomography (OCT), Terahertz (THz) spectroscopy, and microwave sensing. The development of each method is discussed regarding the fundamental principle, system setup, and experimental results. Despite the promising achievements that have been previously reported, no established product has obtained FDA approval or survived a marketing test. The limitations of, and prospects for, these techniques are presented at the end of this review.

A comparative study of non-enzymatic glucose detection in artificial human urine and human urine specimens by using mesoporous bimetallic cobalt-iron supported N-doped graphene biosensor based on differential pulse voltammetry

Development of non-invasive glucose measurement allows future advancement of smart sensing platform for diagnostic technology. Especially for endocrine disorders, advanced kidney diseases, and diabetes, monitoring excessive glucose level in urine can provide invaluable information for clinical prognosis and preventive healthcare. Herein, we present a comparative electrochemical study of cobalt/iron (CoFe) catalyst on nitrogen-doped graphene (NG) for non-enzymatic glucose detection, carried out in physiological pH urine including (i) modified artificial urine medium (mAUM), (ii) commercial standard urine (Surine), and (iii) human urine specimens. With no requirement of strong alkaline addition, catalytic properties of CoFe-NG were assessed by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) on a glassy carbon rotating disk electrode. Upon successive glucose additions from 0 to 3 mM, DPV results revealed two anodic peaks at +0.18 V and +0.42 V versus Ag/AgCl, corresponding to Co3+ and Co4+ as a result of glucose binding in urine. By evaluating at +0.18 V, the sensitivities of CoFe-NG were estimated to be 16.77 (R2 = 0.987), 45.36 (R2 = 0.988), and 20.26 (R2 = 0.991) μA mM−1 cm−2 with the limit of detection of 0.25, 0.07, and 0.19 mM in mAUM, Surine, and human urine specimen with low serum creatinine, respectively. Furthermore, the effects of CoFe on graphene (G) and carbon Vulcan XC-72 (C) were also studied in comparison of NG on the bimetal. Interestingly, CoFe-C showed a good electrochemical trend in glucose detection in urine. However, negligible catalytic activity was presented in CoFe-G. Thus, electrochemical responses of CoFe-C were also further studied in the comparison of CoFe-NG in each type of urine. Overall, CoFe-NG outperformed CoFe-C in all types of urine and exhibited an excellent anti-interference property toward uric acid, thereby suggesting great potential for the next generation of glucose sensing platform in urine.

Overcoming Individual Discrepancies, a Learning Model for Non-Invasive Blood Glucose Measurement

Non-invasive Glucose Measurement (NGM) technology makes great sense for the blood glucose management of patients with hyperglycemia or hypoglycemia. Individual Discrepancies (IDs), e.g., skin thickness and color, not only block the development of NGM, but also become the reason why NGM cannot be widely used. To solve this problem, our solution is designing an individual customized NGM model that can measure these discrepancies through multi-wavelength and tune parameters for glucose estimating. In this paper, an NGM prototype is designed, and a learning model for glucose estimating with automatically parameters tuning based on Independent Component Analysis (ICA) and Random Forest (RF) is presented. The clinic trial proves that the correlation coefficient between estimation and reference Blood Glucose Concentration (BGC) can reach 0.5 after merely 10 times of learning, and rise to 0.8 after about 60 times of learning.

"Guide Star" Assisted Noninvasive Photoacoustic Measurement of Glucose.

A novel "guide star" assisted photoacoustic (GSPA) method for noninvasive glucose measurement has been proposed. Instead of receiving PA signals that are directly generated by tissue, a virtual photodiode is employed to amplify the PA signal difference regarding amplitude and peak arrival time caused by glucose concentration variations in an indirect way. Being different from traditional PA spectroscopy, this method can improve sensitivity and accuracy by optimizing optical path lengths (or tissue thickness). On the other hand, being superior to near-infrared (NIR) spectroscopy, it utilizes both optical absorption and acoustic propagation velocity information confered by PA signals. Theoretical analysis and simulation have been done to illustrate how the concentration change affects the PA waveform. In vitro experiments on aqueous glucose solution were conducted with concentrations varying in human physiological range (50-350 mg/dL). Performance of quartz cuvettes with 1 mm and 2 mm optical path lengths were compared in terms of correlation quality ( R2), degree of agreement (Bland-Altman plot), and clinical accuracy (Clarke's Error Grid analysis) to demonstrate the scalability of sensitivity provided by the indirect method. Longer optical length shows better sensitivity and accuracy in this case. Moreover, detection was also done on human blood serum to further prove the potential of the proposed method for clinical application. Our proposed method provides a solution to enhance sensitivity, facilitating development of portable and low-cost PA sensors with low power laser diodes for noninvasive glucose monitoring and other applications.

Noninvasive, continuous, real-time glucose measurements compared to reference laboratory venous plasma glucose values

Purpose: Current modalities for glucose monitoring are invasive and inconvenient. The search for a noninvasive technique is still ongoing, without a clinically viable product. The aim of our study was to evaluate the safety and accuracy of a novel non-invasive continuous glucometer – the Wizmi™ device.Methods: Prospective, observational, controlled clinical trial. We included healthy pregnant women designated to undergo a 3-hour oral glucose tolerance test. Each participant underwent synchronous and simultaneous glucose measurement by venous sampling of plasma glucose and non-invasive glucose by Wizmi device. Primary outcome was the accuracy of the Wizmi device as assessed by comparing between paired measurements, i.e. non-invasive glucose measurements by Wizmi versus standard plasma glucose levels, which were taken at the exact same time.Results: Thirty-two women underwent oral glucose tolerance test (OGTT), contributing 224 paired glucose measurements. Of the 224 paired measurements, all were within the clinically appropriate zones of the Clarke error grid analysis zones −208 (93%) in Zone A and 16 (7%) in zone B. Mean absolute relative difference of the Wizmi non-invasive glucose versus plasma glucose laboratory reference was 7.23% or 9.66 mg/dl. Overall, for all 224 paired measurements, across all Wizmi glucose ranges, the agreement was 86.6, 92.0, 97.8 and 99.5% for deviations within ±15, 20, 30, 40% (if glucose >80 mg/dl) or mg/dl (if glucose ≤80 mg/dl).Conclusions: Wizmi device is novel non-invasive continuous glucose monitor, safe to use, with overall high accuracy compared to a gold standard reference of plasma glucose.

NON-INVASIVE BLOOD GLUCOSE ANALYSIS BASED ON GALVANIC SKIN RESPONSE FOR DIABETIC PATIENTS

Diabetes is a chronic disease due to the lack of production of hormone insulin by the beta cells in the islets of Langerhans. Many diabetic patients often draw a small amount of blood to measure the glucose level every day. This vital information is needed to control their daily food intake. One such method could cause infection and discomfort to the patient. Non-invasive glucose measurement techniques overcome these challenges to monitor blood glucose level continuously. The aim and objective of this study are as follows: (i) to correlate the skin resistance based on Galvanic skin response (GSR) and blood glucose level for diabetic and non-diabetic subject and (ii) to estimate the blood glucose value based on GSR voltage and resistance using stepwise linear regression model. About 50 diabetic and 50 non-diabetic subjects were included in this study. Blood glucose level is recorded using the minimally invasive device called accu-chek for all the subjects. GSR resistance and GSR voltage were recorded using the designed instrumentation setup. In diabetic subjects, the measured blood glucose level shows negative correlation with the GSR voltage ([Formula: see text], [Formula: see text]) and GSR resistance ([Formula: see text], [Formula: see text]). The estimated blood glucose level can be predicted with good sensitivity (94%) and accuracy (92%) using age and GSR voltage, or by the combination of age and GSR resistance in the evaluation of diabetic subjects.

Nonlinear transfer function’s approach to non-invasive glucose measurement

In this paper a non invasive glucose sensor Fast Fourier Transform FFT base is suggested using the relatively new concept of nonlinear transfer function From the conceptual idea to the electronic schematic circuit showing some in vivo measurements this paper opens the discussion for a new idea improving the necessity of demanding for a reliably portable non invasive glucose sensor moreover being of low cost

Sensory Elements and Devices Operational Diagnostic Blood Glucose Using Near Infrared Radiation

The article describes a method for measuring the concentration of glucose in human blood by the non-invasive methods using near-infrared optical technology. In medical practice, glucose concentration in the blood in most cases is measured by invasive methods involving the collection of blood from the finger or vein, while non-invasive devices for determining the level of glucose preserve the operational measurement of blood-borne levels. Invasive methods are expensive and painful. Frequent piercing of fingers causes corns on the skin, and also increases the risk of spreading infectious diseases. Thus, the development of a system of non-invasive measurement of glucose in the blood will be useful for patients with diabetes mellitus. The proposed system consists of emitters of signals with a wavelength of 940 nm. These optical signals are sent through the earlobe, and the rays passing through it are fixed by a phototransistor located on another part of the device. The concentration of glucose in the blood is determined by analyzing the intensity variation obtained after passing the signal. The accuracy of the measurements of the proposed system can be improved by integrating its sensitive and emitting elements based on the SOI of the CMOS structures.

Accurate viscosity measurements of flowing aqueous glucose solutions with suspended scatterers using a dynamic light scattering approach with optical coherence tomography.

The viscosity of turbid colloidal glucose solutions has been accurately determined from spectral domain optical coherence tomography (OCT) M-mode measurements and our recently developed OCT dynamic light scattering model. Results for various glucose concentrations, flow speeds, and flow angles are reported. The relative "combined standard uncertainty" uc(η) on the viscosity measurements was ±1% for the no-flow case and ±5% for the flow cases, a significant improvement in measurement robustness over previously published reports. The available literature data for the viscosity of pure water and our measurements differ by 1% (stagnant case) and 1.5% (flow cases), demonstrating good accuracy; similar agreement is seen across the measured glucose concentration range when compared to interpolated literature values. The developed technique may contribute toward eventual noninvasive glucose measurements in medicine.

Infrared reflectometry of skin: Analysis of backscattered light from different skin layers

We have recently reported infrared spectroscopy of human skin in vivo using quantum cascade laser excitation and photoacoustic or photothermal detection for non-invasive glucose measurement . Here, we analyze the IR light diffusely reflected from skin layers for spectral contributions of glucose. Excitation of human skin by an external cavity tunable quantum cascade laser in the spectral region from 1000 to 1245cm−1, where glucose exhibits a fingerprint absorption, yields reflectance spectra with some contributions from glucose molecules. A simple three-layer model of skin was used to calculate the scattering intensities from the surface and from shallow and deeper layers using the Boltzmann radiation transfer equation. Backscattering of light at wavelengths around 10μm from the living skin occurs mostly from the Stratum corneum top layers and the shallow layers of the living epidermis. The analysis of the polarization of the backscattered light confirms this calculation. Polarization is essentially unchanged; only a very small fraction (<3%) is depolarized at 90° with respect to the laser polarization set at 0°. Based on these findings, we propose that the predominant part of the backscattered light is due to specular reflectance and to scattering from layers close to the surface. Diffusely reflected light from deeper layers undergoing one or more scattering processes would appear with significantly altered polarization. We thus conclude that a non-invasive glucose measurement based on backscattering of IR light from skin would have the drawback that only shallow layers containing some glucose at concentrations only weakly related to blood glucose are monitored.

IR-spectroscopy of skin in vivo: Optimal skin sites and properties for non-invasive glucose measurement by photoacoustic and photothermal spectroscopy.

We have reported two methods to analyze glucose in the interstitial fluid of skin based on mid-infrared excitation with a tunable quantum cascade laser and photoacoustic or photothermal detection. These methods were evaluated for optimum skin locations to obtain reproducible glucose information. The lower part of the arm, the hypothenar, the tips of the index finger and the thumb were tested. The thumb appears to be the optimal skin location, followed by the index finger. Basic requirements for an optimum site are good capillary blood perfusion, low Stratum corneum thickness and the absence of fat layers. To obtain a correlation on such a site, spectra were recorded on volunteers continuously after blood glucose manipulation. However, continuous measurements on an in vivo sample such as the skin have to cope with physiological alterations such as the formation of sweat. We have used both detection schemes to investigate the acid mantle reformation after washing during time scales similar to continuous measurements for calibration spectra. We found that reconstitution of the acid mantle of skin may be seen in less than one hour. Precleaning of the measurement site may thus be useful for intermittent, but not for long term continuous measurements.

Statistical properties of dynamic speckles from flowing Brownian scatterers in the vicinity of the image plane in optical coherence tomography.

A closed-form analytical expression is obtained for the spatio-temporal correlation function of the scattered radiation detected in fiber-based optical coherence tomography (OCT), assuming a clean optical system arrangement in the OCT sample arm. It is shown that the transverse flow component causes purely translational speckle motion with the predicted speckle velocity 2x higher than the velocity of the flowing particles as would be observed in the image plane under incoherent illumination. It is also shown that both speckle velocity and speckle radius do not depend on the position of the scattering volume relative to the focal plane, hence the derived correlation function is independent of the position of the scattering volume relative to the focal plane. Although the analytical results are obtained for a clean optical system arrangement, they can be used with high accuracy in most practical implementations of fiber based OCT. Validation experiments in control scattering phantoms with varying liquid viscosities show excellent agreement with the developed theoretical model, under both no-flow and flow conditions. Accurate viscosity determinations enabled by this methodology may have applications to non-invasive glucose measurements in medicine.

Noninvasive photoacoustic measurement of glucose by data fusion.

We proposed a novel noninvasive method for glucose detection using a photoacoustic (PA) technique utilizing both the peak-to-peak value and peak arrival time delay information. Without increasing apparatus and system complexity, we demonstrated the accuracy enhancement of 29.5% and 33.63% for high (0-7 g dL-1) and low (0-350 mg dL-1) concentration of glucose solution, compared to conventional amplitude-based prediction.

Depth-selective photothermal IR spectroscopy of skin: potential application for non-invasive glucose measurement

An infrared spectroscopic technique is described that employs a mid-IR broadband (980-1245 cm-1) tunable quantum cascade laser (QCL) to produce a pump beam, and a detection method based on photothermal deflection, enhanced by total internal reflection. The IR spectra thus obtained are depth-dependent by modulating the pump beam with different frequencies between 10 Hz and 500 Hz. A model system consisting of glucose and a polymer film is used to demonstrate the depth selectivity of this technique. We also apply this photothermal depth profiling method to record in vivo IR spectra of the human epidermis at different depths. This information can be used for a non-invasive glucose monitoring on diabetes patients, which is also demonstrated. Beyond biomedical infrared spectroscopy, there are numerous applications for total internal reflection enhanced photothermal deflection spectroscopy (TIR-PTDS). The high penetration depth of mid-IR light compared to the traditional ATR-FTIR technique and the easy sample access make this technique appropriate for in situ measurements, such as in industrial quality control. The depth selectivity of TIR-PTDS may be a convincing argument for its use in the analysis of multilayered samples or for the analysis of artwork, where the layers of interest are covered by a layer of varnish.

Dual-modulation, dual-wavelength, optical polarimetry system for glucose monitoring.

A dual modulation optical polarimetry system utilizing both laser intensity and polarization modulation was designed, built, and tested. The system was designed to reduce complexity and enhance the speed in order to facilitate the reduction of motion-induced time-varying birefringence, which is one of the major limitations to the realization of polarimetry for glucose monitoring in the eye. The high-speed less complex technique was tested using in vitro phantom studies with and without motion artifact introduced. The glucose concentration ranged from 0 to 600 mg/dl and the glucose measurements demonstrated a standard error of prediction to within 8.1 mg/dl without motion and to within 13.9 mg/dl with motion. Our feedback control systems took less than 10 ms to reach stabilization, which is adequately fast to eliminate the effect of time-varying birefringence. The results indicate that this new optical polarimetric approach has improved the speed and reduced the complexity, showing the potential for it to be used for noninvasive glucose measurements.

In-vitro Measurement of Glucose Concentration in Human Blood Plasma Mixed Intralipid Phantom Samples by Using Modulated Ultrasound and Infrared Light

Non-invasive blood glucose measurement is one of most innovative domain in Biomedical Engineering. Multiple methodologies have-been introduced over last few decades to fulfil the clinical requirement for non-invasive glucose measurement in human beings, however, without a successful breakthrough. This research article uses modulated ultrasound with infrared light-based technique to study glucose-induced variations in human blood plasma mixed Intralipid TM phantom samples using infrared light of 940 nm and 40 kHz central frequency based ultrasonic transmitter unit. The test uses blood samples of 30 study subjects during oral glucose tolerance test and fasting, postprandial and random stages based blood glucose tests respectively. The result as obtained from oral glucose tolerance tests and fasting, postprandial and random stages blood Original Research Article

NIR photoacoustic spectroscopy for non-invasive glucose measurement.

The use of near infra red (NIR) photoacoustic spectroscopy (PAS) for continuous non-invasive glucose measurement is outlined in the paper. A photoacoustic (PA) measurement apparatus was constructed and PA measurements were made on glucose solutions at multiple NIR excitation wavelengths. A variety of time and frequency domain features, including amplitude and area based features, were extracted from the PA measurements. These features were observed to be proportional to the glucose concentration of the sample. PA measurements from samples of whole blood at different glucose concentrations showed similar results. Subsequently, in vivo PA measurements made on a cohort of 30 volunteers were calibrated using a quadratic fit, and the results were compared to reference glucose concentrations made using a regular blood glucose meter. A comparison of 196 measurement pairs of predicted and reference glucose concentrations using a Clarke Error Grid gave a point distribution of 87.24% and 12.76% over zones A and B of the grid, with no measurement pairs falling in unacceptable zones C-E of the error grid. The predicted measurements had a mean absolute difference (MAD) of 12.57 ± 13.90 mg/dl and a mean absolute relative difference (MARD) of 9.61% ± 10.55%. This is an improvement over previous results obtained using PAS and other non-invasive techniques, validating the potential of PAS for continuous noninvasive glucose monitoring.

Corrigendum to Comparative Study of different Measurement Sites Using NIR Based Non-invasive Glucose Measurement System

Corrigendum to Comparative Study of different Measurement Sites Using NIR Based Non-invasive Glucose Measurement System

Comparative Study of Different Measurement Sites Using NIR Based Non-invasive Glucose Measurement System

Abstract In Diabetes, self-monitoring of blood glucose is crucial for effective treatment since it can help to identify and prevent unwanted episodes of hypoglycemia and hyperglycemia. Aim of the present work is to design and develop a non invasive gluco-meter using near infrared LED (940 nm). Three different designs of probes (arm, finger and ear lobe) were fabricated to measures in-vivo blood glucose. In addition, we also carried out experiments to study the interaction with glucose molecules in solution under plane polarized light. The polarizers were used at three different angles(450, 900 and 1800) to know the behavior of glucose interaction with polarized light of 640 nm and 740 nm with varying concentration of glucose in the solution. The polarization results showed that at 1800 the glucose has maximum polarization (1.12) and at 900 and 450 it has comparatively less polarization values 0.9 and 0.35 respectively. The polarization results helped us to design the probes. Therefore, we placed photodiodes at three angles (450, 900 and 1800). The results as expected were better at 1800 by showing maximum variation in photodiode voltage output. The results were in the correlation of the polarization studies. A comparative study of three measurement sites has also been carried out. The primary result of current sensor system is promising and with further improvement a robust system for glucose sensing can be realized.

3D-networked carbon nanotube/diamond core-shell nanowires for enhanced electrochemical performance

A boron-doped diamond/carbon nanotube (BDD–CNT) hybrid material with a core-shell three-dimensional random network structure was fabricated using the electrostatic self-assembly of nanodiamond. In general, CNTs are easily etched out as hydrocarbons or transformed to graphitic clusters at defect sites in hydrogen-rich environments (that is, the typical conditions employed for diamond deposition). However, attaching a dense layer of nanodiamond particles to the outer wall of the CNTs suppressed CNT etching and promoted BDD growth. To attach the dispersed nanodiamond particles on the CNT surface, we used an electrostatic self-assembly technique in which the surface charges on the CNTs and the nanodiamond were controlled using cationic and anionic polymers. Following BDD deposition, the electrochemical properties of the BDD–CNT structures were examined by cyclic voltammetry and electrochemical impedance spectroscopy. The results indicated that the BDD–CNTs exhibited enhanced electron transport efficiency, large effective surface areas and high sensitivity, with a remarkably low detection limit. Researchers in South Korea have coated carbon nanotubes with nanodiamonds to form a highly sensitive glucose biosensor. The team, led by Dae-Soon Lim at Korea University, deposited a layer of boron-doped diamond nanoparticles onto the outer walls of multiwalled carbon nanotubes. They then confirmed the structure of the resultant nanowires using an electron microscope and measured their electrochemical properties. Next, the team demonstrated that the nanowires exhibit a higher sensitivity to glucose — as well as a significantly lower detection limit — than other existing electrodes. The new nanowires could potentially be used for the noninvasive detection of glucose in human body fluids containing lower concentrations of glucose than blood, such as saliva, tears or sweat. They could help to estimate the size of bacteria populations in sea water, as many bacteria use glucose as an energy source. 3D-networked boron-doped diamond/carbon nanotube (BDD–CNT) core-shell nanowires were fabricated using the electrostatic self-assembly of nanodiamond. Although CNTs are easily etched out at their defect sites in hydrogen-rich environments, densely attached nanodiamond particles suppressed the etching of the CNTs and promoted BDD growth. After BDD deposition, 3D-networked BDD–CNT nanowires were successfully developed. In comparison to other electrodes, the BDD–CNT electrode exhibited better electrochemical performances, that is, low electron transfer resistance, large effective surface area and high sensitivity with significantly low detection range (8.7 mA mM−1 in the range 0.65–83.75 nM). The improvement in the performances of the BDD–CNT electrode could be attributed to the geometry and electron pathways offered by CNTs as well as to the synergistic material properties of BDD and CNT. The BDD–CNT electrode shows promise for application in the noninvasive measurement of glucose in living beings as well as for environmental monitoring in sea water.