Non-invasive optical glucose detection faces significant challenges due to the need to identify and extract glucose-induced signals amidst continuous human variations and probing disturbances. To ensure stable near-infrared optical signal acquisition in vivo, we enhanced the design of a wearable detector and introduced strategies to mitigate human-induced variations, aiming to minimize unnecessary fluctuations and interferences. Our custom-designed multi-ring InGaAs detector, combined with a differential method, achieved a high signal-to-noise ratio (SNR) during in vivo data acquisition. The proposed posture-aiming method enabled continuous, high-stability data collection for 1-2 hours in vivo, even with slight human motion. These enhancements enable the direct acquisition of near-infrared optical signals modulated by blood glucose levels in vivo. Results from Monte Carlo (MC) simulations and data collected from fasting subjects validated the detection approaches’ capability for stable spectroscopic detection. We conducted 30 oral glucose tolerance tests (OGTT) involving 28 volunteers. At 1550 nm, we successfully extracted optical signals that were continuously synchronized with blood glucose fluctuations, achieving an average coefficient of determination (R2) of 0.82 across the 30 OGTT tests.
Position-based reference measurement method is taken as one of the most promising method in non-invasive measurement of blood glucose based on spectroscopic methodology. Selecting an appropriate source-detector separation as the reference position is important for deducting the influence of background change and reducing the loss of useful signals. Our group proposed a special source-detector separation named floating-reference position where the signal contains only background change, that is to say, the signal at this source-detector separation is uncorrelated with glucose concentration. The existence of floating-reference position has been verified in a three layer skin by Monte Carlo simulation and in the in vitro experiment. But it is difficult to verify the existence of floating-reference position on the human body because the interference is more complex during in vivo experiment. Aiming at this situation, this paper studies the determination of the best reference position on human body by collecting signals at several source-detector separations on the palm and measuring the true blood glucose levels during oral glucose tolerance test (OGTT) experiments of 3 volunteers. Partial least square (PLS) calibration model is established between the signals at every source-detector separation and its corresponding blood glucose levels. The results shows that the correlation coefficient (R) between 1.32 mm to 1.88 mm is lowest and they can be used as reference for background correction. The signal of this special position is important for improving the accuracy of near-infrared non-invasive blood glucose measurement.
A new approach for quantitative analysis of melamine in milk was proposed based on two-dimensional (2D) correlation
near-infrared spectroscopy and multi-way partial least squares (N-PLS) in this paper. 40 pure milk samples and 40 milk
samples adulterated with different contents of melamine were prepared. The near-infrared transmittance spectra of all
samples were measured at room temperature. Then 2D NIR-NIR correlation spectroscopy under the perturbation of
adulterant concentration was calculated and N-PLS model for the melamine concentration was established with 2D
correlation spectra (28x51x51). For the prediction set, the root mean square errors of prediction (RMSEP) for melamine
concentration was 0.067 g/L and the coefficient correlation between actual reference values and predicted values was
0.999, which means the model has good predictive ability. For comparison purpose, partial least squares (PLS) model
was also built using the conventional one-dimensional near-infrared spectra (28x51), where the RMSEP and the
coefficient correlation were 0.079 g/L and 0.998, respectively. The average relative prediction error was 22.9% for
N-PLS model; whereas it was 122.4% for PLS model. The N-PLS models yielded relatively low RMSEP and average
relative prediction error as compared to PLS model. Therefore, N-PLS method was more robust than PLS method for
accurate quantification of the concentration of melamine in milk.
Laser speckle imaging is widely used to monitor functional blood perfusion within tissue beds in vivo but traditionally has difficulty visualizing small blood vessels even when the exposure time of the detector is long. We report a simple method that uses the motion contrast of dynamic speckle patterns to noninvasively visualize the distribution of blood flow within tissue beds in vivo. We experimentally demonstrate that the motion contrast can significantly suppress the effect of static scattering, leading to enhanced visibility of the functional blood vessels, including capillaries when compared to the traditional laser speckle contrast imaging.
KEYWORDS: Glucose, Blood, Monte Carlo methods, Mathematical modeling, Near infrared spectroscopy, Data modeling, Stomach, Mode conditioning cables, Statistical modeling, Matrices
Previous studies have shown the limitations of taking OGTT (Oral Glucose Tolerance Test) as the
glucose adjustment protocol for non-invasive blood glucose sensing. Previous studies built a
mathematical model of glucose metabolism system-IMM (the Integrated Minimal Model) to probe
other available adjustment methods. In this talk, a further study would be focused on more detailed combination options of different glucose input types for glucose adjustment projects in non-invasive blood glucose sensing. And predictive models of blood glucose concentration have been established by means of partial least squares (PLS) method, which could be used to evaluate the quality of different glucose adjustment options. Results of PLS modeling suggested that predictive models under combined glucose input types, compared with OGTT, show a great enhancement in the stability. This would finally improve the precision of non-invasive blood glucose sensing.
KEYWORDS: Glucose, Spectroscopy, Blood, Absorption, Mid-IR, In vitro testing, In vivo imaging, Attenuated total reflectance, Signal detection, Spectroscopes
Glucose specificity is the premise of spectroscopic measurements for blood glucose concentration, and it is also
paramount for feasibility study of a spectral measurement method. Two-dimensional correlation spectroscopy
technology is widely used in many fields such as inter-/intra-molecular reaction, material phase transition and
information extraction because of its high resolution and the effective "sequential order" rules (Noda's rule). By using 2D
correlation spectroscopy analysis, we aim at exploring glucose specificity for noninvasive glucose measurements from
mid-infrared spectra collected from human beings. The study is mainly divided into two parts. The first part is to prove
the realizability of the method by 2D correlation analysis of in vitro solutions which all contain glucose. And the second
part is validating characteristic information of glucose from mid-infrared ATR spectra of human fingers by use of the 2D
correlation spectroscopy technology. The conclusion is that glucose specific spectral information is really present in
noninvasive mid-infrared in vivo spectra. So the feasibility of mid-infrared spectroscopy in noninvasive measurements of
blood glucose concentration is demonstrated fundamentally.
The adulteration of milk with harmful substances is a threat to public health and beyond question a serious crime. In
order to develop a rapid, cost-effective, high-throughput analysis method for detecting of adulterants in milk, the
discriminative analysis of melamine is established in milk based on the two-dimensional (2D) correlation infrared
spectroscopy in present paper. Pure milk samples and adulterated milk samples with different content of melamine were
prepared. Then the Fourier Transform Infrared spectra of all samples were measured at room temperature. The
characteristics of pure milk and adulterated milk were studied by one-dimensional spectra. The 2D NIR and 2D IR
correlation spectroscopy were calculated under the perturbation of adulteration concentration. In the range from 1400 to
1800 cm-1, two strong autopeaks were aroused by melamine in milk at 1464 cm-1 and 1560 cm-1 in synchronous
spectrum. At the same time, the 1560 cm-1 band does not share cross peak with the 1464 cm-1 band, which further
confirm that the two bands have the same origin. Also in the range from 4200 to 4800 cm-1, the autopeak was shown at
4648 cm-1 in synchronous spectrum of melamine in milk. 2D NIR-IR hetero-spectral correlation analysis confirmed that
the bands at 1464, 1560 and 4648 cm-1 had the same origin. The results demonstrated that the adulterant can be discriminated correctly by 2D correlation infrared spectroscopy.
Since the beginning of the 21st century, the issue of food safety is becoming a global concern. It is very important to
develop a rapid, cost-effective, and widely available method for food adulteration detection. In this paper, near-infrared
spectroscopy techniques and pattern recognition were applied to study the qualitative discriminant analysis method. The
samples were prepared and adulterated with one of the three adulterants, urea, glucose and melamine with different
concentrations. First, the spectral characteristics of milk and adulterant samples were analyzed. Then, pattern recognition
methods were used for qualitative discriminant analysis of milk adulteration. Soft independent modeling of class analogy
and partial least squares discriminant analysis (PLSDA) were used to construct discriminant models, respectively.
Furthermore, the optimization method of the model was studied. The best spectral pretreatment methods and the optimal
band were determined. In the optimal conditions, PLSDA models were constructed respectively for each type of
adulterated sample sets (urea, melamine and glucose) and all the three types of adulterated sample sets. Results showed
that, the discrimination accuracy of model achieved 93.2% in the classification of different adulterated and unadulterated
milk samples. Thus, it can be concluded that near-infrared spectroscopy and PLSDA can be used to identify whether the
milk has been adulterated or not and the type of adulterant used.
Non-invasive blood glucose monitoring using NIR light has been suffered from the variety of optical background that is
mainly caused by the change of human body, such as the change of temperature, water concentration, and so on. In
order to eliminate these internal influence and external interference a so called floating-reference method has been
proposed to provide an internal reference. From the analysis of the diffuse reflectance spectrum, a position has been
found where diffuse reflection of light is not sensitive to the glucose concentrations. Our previous work has proved the
existence of reference position using diffusion equation. However, since glucose monitoring generally use the NIR light
in region of 1000-2000nm, diffusion equation is not valid because of the high absorption coefficient and small source-detector
separations. In this paper, steady-state high-order approximate model is used to further investigate the existence
of the floating reference position in semi-infinite medium. Based on the analysis of different optical parameters on the
impact of spatially resolved reflectance of light, we find that the existence of the floating-reference position is the result
of the interaction of optical parameters. Comparing to the results of Monte Carlo simulation, the applicable region of
diffusion approximation and higher-order approximation for the calculation of floating-reference position is discussed at
the wavelength of 1000nm-1800nm, using the intralipid solution of different concentrations. The results indicate that
when the reduced albedo is greater than 0.93, diffusion approximation results are more close to simulation results,
otherwise the high order approximation is more applicable.
Adulteration of milk and dairy products has brought serious threats to human health as well as enormous economic
losses to the food industry. Considering the diversity of adulterants possibly mixed in milk, such as melamine, urea,
tetracycline, sugar/salt and so forth, a rapid, widely available, high-throughput, cost-effective method is needed for
detecting each of the components in milk at once. In this paper, a method using Fourier Transform Infrared spectroscopy
(FTIR) combined with two-dimensional (2D) correlation spectroscopy is established for the discriminative analysis of
adulteration in milk. Firstly, the characteristic peaks of the raw milk are found in the 4000-400 cm-1 region by its original
spectra. Secondly, the adulterant samples are respectively detected with the same method to establish a spectral database
for subsequent comparison. Then, 2D correlation spectra of the samples are obtained which have high time resolution
and can provide information about concentration-dependent intensity changes not readily accessible from
one-dimensional spectra. And the characteristic peaks in the synchronous 2D correlation spectra of the suspected samples
are compared with those of raw milk. The differences among their synchronous spectra imply that the suspected milk
sample must contain some kinds of adulterants. Melamine, urea, tetracycline and glucose adulterants in milk are
identified respectively. This nondestructive method can be used for a correct discrimination on whether the milk and
dairy products are adulterated with deleterious substances and it provides a new simple and cost-effective alternative to
test the components of milk.
KEYWORDS: Glucose, Monte Carlo methods, Diffuse reflectance spectroscopy, Absorption, Scattering, Water, Data corrections, In vitro testing, Single photon emission computed tomography, Interference (communication)
As an effective noninvasive method for glucose doesn't come into clinical realization due to the weakness of glucose
unique signal and complexity of background noise, a method based on a floating reference point and a measuring point,
where the diffuse reflectance intensity is insensitive and most sensitive to the variation of glucose concentration,
respectively, is applied. In this paper, the data processing method based on the information of reference point was
investigated to improve the precision of glucose sensing. The diffuse reflectance of intralipid solution with different
glucose concentration in different source-detector distances was obtained by Monte-Carlo simulation. And the radial
region selection of reference position and measuring position were discussed. Then in order to simulate the actual
measurement condition, the random noise and linear drift were added on the simulated spectra. And the spectra in the
proper measuring region corrected by that in the reference point were used to build the multivariate model. Further more,
the corresponding optical probe was designed according to the distribution of light intensity in the radial distance and an
in vitro experiment about intralipid solution with different glucose concentration was conducted to verify the effect of the
data correction based on the information from the reference point. Results showed that, three different measuring regions
should be determined in the wavelength of 1100nm-1700nm according to the wavelength characteristic of reference
point. And the measuring region should be about 0.2-0.3mm far away from the reference region. For the simulation and
in vitro experiment, after the correction by the information from the reference point, the prediction error for glucose was
reduced by 46.2% and 23.2%, respectively.
In the noninvasive blood glucose sensing using near-infrared spectroscopy, the physiological noise was one of the
biggest challenges. In order to efficiently reduce the influence of the physiological background variations on the diffuse
reflectance spectra, the floating-reference method was used by differentially processing two signals from reference point
and measuring point. In this paper, the wavelength-dependent characteristic of the floating-reference point was discussed
by simulation and primary experiment. First, the wavelength-dependent characteristic of intralipid- 5% solution was
investigated in the wavelength range of 1300-1600nm. And source-detector distance for reference point in the
wavelength of 1300nm was conducted by different concentration of scatter media including 2%, 5% and 10% intralipid
solution. Then the single-layer and three layers skin model were built to investigate the wavelength characteristic of
reference point. The water displacement coefficients and relative large change in glucose concentration were considered
in the simulation. Finally, the primary experiment of intralipid model was conducted to validate the wavelength
dependence of reference point. The result showed that, the floating reference will not exist in the strong absorption
region (near 1450nm) and the region where the change of absorption coefficient is positive (high than 1525nm) due to
the corporate influence of scattering and absorption coefficient. And the wavelength-dependent characteristic is
consistent for intralipid solution and the skin model.
KEYWORDS: Glucose, Temperature metrology, Diffuse reflectance spectroscopy, Monte Carlo methods, Absorbance, Blood, Tissue optics, Near infrared spectroscopy, Spectroscopy, Transmittance
The use of near-infrared spectroscopy for the monitoring of blood glucose concentration is limited by many ambiguous factors, which leads to the prediction precision is not satisfied. Due to the weak interested signal and the difficulty to quantify the physiological noise directly, the absorbance induced by glucose concentration and temperature was analyzed based on Beer-Lambert Law and displacement between glucose and water. Then the transmittance of glucose aqueous solution in different temperatures was measured by spectrometer to investigate the influence of glucose concentration and temperature. As it's difficult to distinguish the influence of temperature from the diffuse reflectance, the Monte Carlo simulation was used to compute the light intensity induced by the change in glucose concentration and physiological temperature. Finally, the influence of actual physiological temperature on the prediction model of glucose concentration was estimated based on the oral glucose tolerance tests of two diabetics. The result showed that, near the normal physiological temperature, the intensity of diffuse reflectance caused by -0.1 °C change in temperature was equivalent to that caused by 2.7 mmol/L change in glucose concentration. Moreover, the proportion of prediction error induced by temperature to the total error was more than 50%.
Noninvasive and minimally invasive blood glucose sensing is one of most interesting research fields. For the noninvasive measurement using near-infrared spectroscopy, the optical signal was impaired by the uncertain physiological noise and systematical drift. A floating reference method by differentially processing two signals from reference point and measuring point was used to deal with these uncertain noises. For the minimally invasive measurement, interstitial fluid extracted by ultrasound and vacuum is investigated. Low-frequency ultrasound was applied to enhance the skin permeability to interstitial fluid by disrupting the stratum corneum lipid bilayers. In this paper, a kind of protein absorbing the glucose specifically called D-galactose/D-glucose Binding Protein (GGBP) was introduced to construct a novel surface plasmon resonance (SPR) measuring system. By immobilizing GGBP onto the surface of the SPR sensor, a new detecting system for glucose testing in mixed solution was developed. The experimental result indicated that, the SPR system succeeded in distinguishing glucose resolution of 0. 1 mg/L, and had linear relationship between 0.5 mg/L and 5 mg/L.
KEYWORDS: Glucose, Blood, Temperature metrology, Near infrared spectroscopy, Error analysis, In vivo imaging, Calibration, Tolerancing, Spectroscopy, Near infrared
In the sensing of blood glucose by the near-infrared spectroscopy, building a robust and effective model is the precondition to obtain an accurate and reasonable prediction result of glucose concentration. In the chemometrics analysis, training set should be representative, reasonable distribution and cover the scope of prediction set. So the experiment designs became one of most difficult challenges for the noninvasive glucose sensing, especially for the in vivo experiments. In this paper, the oral glucose tolerance tests of two diabetics were carried out. The transcutaneous diffuse reflectance spectra were collected by a custom-build spectrometer and the glucose reference were measured by an invasive portable glucose meter. Then the influence of different experiment designs including the error in the references, the time delay between glucose in blood and interstitial fluid, the change in physiological temperature and different validation methods were analyzed. The result showed that, the error induced by the uncertainty in the reference was lower than that by the time delay, which could be up to 15.4%. And the proportion of error induced by temperature change is more than 50%, which is the most significant. Furthermore, the prediction error was restricted by the validation set selection and the way to change the blood glucose concentration.
In the area of noninvasive human blood glucose concentration detecting, it has always been a critical task to extract the
glucose-specific signal from the highly overlapped and disturbed near-infrared spectrum. In this paper, the methodology
of effective glucose-specific signal extraction in complicated non-scattering sample is studied. By analyzing the impact
of water displacement upon dissolution of glucose, the relationship between glucose concentration and absorption
coefficient of the sample is deduced. Then, the reference wavelength where the absorption coefficient is insensitive to the
changes of glucose concentration is put forward theoretically. Accordingly, the validating experiments in aqueous
glucose solutions are executed. Both the theoretical and laboratorial results show that the reference wavelength of
glucose appears at 1525nm. Based on the reference wavelength, an effective method for extracting the glucose-specific
signal in complicated non-scattering samples is proposed and the corresponding validating experiments are constructed
with different glucose and albumin concentration. Two different methods, traditional and the novel reference wavelength
method are used to extract glucose signal and the corresponding root mean square error of prediction are 19.86mg/dl and
9.87mg/dl respectively. The experiment results indicate that the reference wavelength method can effectively eliminate
the influence of various noises on the glucose-specific signal extraction, and thus can remarkably improve the measuring
precision in noninvasive near-infrared glucose detecting.
KEYWORDS: Glucose, Signal to noise ratio, Blood, Absorption, Scattering, Near infrared spectroscopy, Monte Carlo methods, Diffuse reflectance spectroscopy, Interference (communication), Tissue optics
Weak signal and great background variation have been the major challenges for noninvasive measurement of blood glucose. Two kinds of noise are analyzed, and it is found out that, when instruments achieve a high level of signal to noise ratio, physiological variation other than glucose concentration becomes the dominant over instrument noise. After analyzing the sensitivity of glucose concentration on diffuse reflectance spectroscopy at different source-detector separation, floating-reference method is proposed firstly. This method discusses how to extract signal relating to glucose and signal only relating to background variation respectively, by making use of two special points, reference point and measuring point. Experiments on phantom and Monte Carlo simulations have been performed to validate the feasibility of floating-reference method.
KEYWORDS: Glucose, Photons, Absorption, Scattering, Diffuse reflectance spectroscopy, Blood, Monte Carlo methods, Tissue optics, Near infrared spectroscopy, Near infrared
Non-invasive glucose monitoring with optical methods has obtained increasing interest, in that the methods have shown great benefit for diabetes. Nevertheless, low sensitivity and signal to noise ratio (ratio of effective photons) are two major difficulties in non-invasively NIR spectral monitoring of blood glucose concentration. Designing the optical probe properly is one of the effective ways to improve measuring sensitivity and ratio of effective photons. In this paper, definition about ratio of effective photons in measurement of glucose is introduced. And then effect of glucose on optical properties of human skin is analyzed, based on this, two kind of sensitivities for diffuse reflectance, namely sensitivity to absorption and that to scattering, is derived. To investigate the ratio of effective photons and sensitivities, Monte Carlo simulations have been performed on a three-layered media with optical parameters similar to those of human skin. The results have shown that (1) high ratio of effective photons, even as high as 60%, can be obtained by choosing proper the separation between source and detector; (2) sensitivity of diffuse reflectance to absorption and scattering has different dependence on source-detector separation, which enables one can have different options by making use of different effect from glucose level changing. In the end, some suggestions have been put forward to improve precision of measurement of blood glucose.
A non-invasive and continuous blood glucose monitoring would be of great advantage for diabetic patients. Many techniques have been proposed for the purpose. But so far, none of these methods has been proven to be reliable and precise enough for in vivo monitoring. In non-invasive glucose measurement using near-infrared (NIR) spectroscopy, the difficulty is that the spectral variations due to the glucose concentration are extremely small compared with other sources of variations. Therefore extracting the variation signal of glucose in complicated background is challenging. We investigated the relationship between sample complexity and prediction accuracy, which was the fundamental research of non-invasive sensing and a kind of method to determine whether the OGTT or non-invasive sensing can achieve the required accuracy of clinic. A series of in vitro experiments had been conducted with different complex samples and same measurement system to analyze the relation between the sample complexity and the prediction accuracy, and some conclusions had been drawn. In general, the increase of sample complexity doesn’t lead to the distinct increase of prediction error.
Non-invasive glucose measurement by near-infrared spectroscopy is mainly based on the absorption of glucose. However, for non-invasive blood glucose measurement, the diffuse reflectance spectra are influenced not only by the absorption coefficient, but also by the scattering coefficient, anisotropy factor, and refractive index, which are normally nonlinear with the glucose concentrations. Furthermore, the variations of spectra depend on the relative changing direction of the absorption coefficient and scattering coefficient. In this paper, using the simulated samples of human tissues with different glucose concentrations in different conditions, we discussed the rules of how the glucose concentrations affected the absorption coefficient and scattering coefficient, respectively. The relations between the diffuse reflectance spectra and the absorption coefficient, as well as and the scattering coefficient were also investigated. Thus, we confirmed which of the optical parameters and measurement conditions would affect the diffuse reflectance spectra significantly. Based on the above results, proper methods could be selected to measure blood glucose concentration non-invasively according to different conditions, then the information of glucose absorption would be extracted more effectively, and higher measurement precision would be expected.
KEYWORDS: Glucose, Signal analyzers, Blood, Absorption, In vivo imaging, Absorbance, Diffuse reflectance spectroscopy, Calibration, In vitro testing, Near infrared
Near infrared spectroscopy has been proposed as an effective way for measuring blood glucose non-invasively. However the change of spectrum due to an increase in glucose level is very small compared to the changes due to other variations such as absorption of major blood components, skin surface reflectance, temperature and pressure and so on. So the complexity of spectrum makes it difficult to identify unique glucose information. In this paper, the effect of background correction is discussed firstly. Then a simple substitution is proposed to compute the net analyte signal of glucose using the subspace spanned by the background spectra. For the in vitro experiment, the net analyte signals of glucose using the traditional methods and the subspace spanned by background have the same peaks in the absorption peaks of glucose for the glucose aqueous solution. For in vivo experiment, there is significant spectral difference between the subject who took OGTT test and the subject who took no glucose or water. And the net analyte signal of glucose is computed for OGTT test based on the subspace spanned by the spectra of subject who didn’t take glucose. Results show that, the spectral information induced by glucose taking is quite significant but it does not have the same peak at the absorption peak of glucose in near-infrared region.
Bi2Sr2Ca1Cu2O7-x(BSCCO) superconducting films were deposited on Si substrates with buffer layers of Y- stabilized ZrO2 films (YSZ) by magnetic sputtering. The critical temperature (Tc) of BSCCO film on YSZ/Si was 82 K. The microstructure of BSCCO/YSZ/Si was studied by scanning electronic microscope (SEM) and atom force microscope (AFM), the growing model of spiral nucleation was verified. Fractal images were found in the micrographs, and their growth mechanism was presented.
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