CN118021250A - Hand-held noninvasive blood glucose measuring instrument - Google Patents
Hand-held noninvasive blood glucose measuring instrument Download PDFInfo
- Publication number
- CN118021250A CN118021250A CN202211394276.3A CN202211394276A CN118021250A CN 118021250 A CN118021250 A CN 118021250A CN 202211394276 A CN202211394276 A CN 202211394276A CN 118021250 A CN118021250 A CN 118021250A
- Authority
- CN
- China
- Prior art keywords
- stokes
- glucose meter
- blood glucose
- coherent anti
- light
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 81
- 239000008103 glucose Substances 0.000 title claims abstract description 81
- 210000004369 blood Anatomy 0.000 title claims abstract description 48
- 239000008280 blood Substances 0.000 title claims abstract description 48
- 230000001427 coherent effect Effects 0.000 claims abstract description 56
- 238000001069 Raman spectroscopy Methods 0.000 claims abstract description 47
- 230000002269 spontaneous effect Effects 0.000 claims abstract description 34
- 238000001237 Raman spectrum Methods 0.000 claims abstract description 21
- 230000005284 excitation Effects 0.000 claims abstract description 14
- 238000012545 processing Methods 0.000 claims abstract description 14
- 239000013307 optical fiber Substances 0.000 claims description 23
- 239000000523 sample Substances 0.000 claims description 19
- 238000003384 imaging method Methods 0.000 claims description 12
- 230000010287 polarization Effects 0.000 claims description 12
- 239000011521 glass Substances 0.000 claims description 11
- 230000008878 coupling Effects 0.000 claims description 9
- 238000010168 coupling process Methods 0.000 claims description 9
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 230000002441 reversible effect Effects 0.000 claims description 4
- 239000000919 ceramic Substances 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 238000013135 deep learning Methods 0.000 claims description 2
- 210000000624 ear auricle Anatomy 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims description 2
- 210000003813 thumb Anatomy 0.000 claims description 2
- 210000003462 vein Anatomy 0.000 claims description 2
- 238000005086 pumping Methods 0.000 abstract 2
- 238000000034 method Methods 0.000 description 20
- 238000001514 detection method Methods 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 8
- 238000000701 chemical imaging Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000000386 microscopy Methods 0.000 description 5
- 238000004867 photoacoustic spectroscopy Methods 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 206010033675 panniculitis Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 210000004304 subcutaneous tissue Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000004497 NIR spectroscopy Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001834 photoacoustic spectrum Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001360 synchronised effect Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001566 impedance spectroscopy Methods 0.000 description 1
- 238000012623 in vivo measurement Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000790 scattering method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000012549 training Methods 0.000 description 1
Landscapes
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
The invention discloses a handheld noninvasive blood glucose measuring instrument which comprises an excitation module, a scanning module, an acquisition module and a data processing module, wherein the excitation module is used for emitting Stokes light and pumping light; the scanning module is used for scanning a first position of an organism by utilizing the Stokes light and the pumping light and exciting a coherent anti-Stokes scattering signal at the first position; the acquisition module is used for acquiring the coherent anti-Stokes scattering signal, acquiring a spontaneous Raman signal at the first position and acquiring a spontaneous Raman spectrum of the first position; the data processing module is used for processing and analyzing according to the coherent anti-Stokes scattering signal and the spontaneous Raman spectrum.
Description
Technical Field
The invention relates to the field of biomedical optics, in particular to a handheld noninvasive blood glucose measuring instrument.
Background
Existing methods for noninvasive blood glucose detection include optical methods and non-optical methods. Non-optical transdermal methods such as transdermal impedance spectroscopy, ultrasound and iontophoresis techniques use physical energy (e.g., electrical, thermal or ultrasound) to obtain sugar molecular information of interstitial fluid or blood, but may alter skin characteristics and cause skin blistering, irritation or erythema. The optical method is mature in technology, convenient to use and capable of avoiding ionizing radiation injury to organisms, and is widely applied to medical research, so that the optical method is widely used at present to realize noninvasive blood glucose monitoring. The method for optically detecting noninvasive blood glucose mainly comprises a near infrared spectroscopy (NEAR INFRARED spline, NIR), a photoacoustic spectroscopy (photoacoustic spectroscopy) and a spontaneous Raman spectroscopy (Raman spectroscopy, RS).
Near infrared spectroscopy, the noninvasive blood glucose monitoring is realized through a glucose molecule specific spectral absorption peak (1600 nm). The near infrared spectrum signal of glucose molecules is derived from the frequency multiplication and dominant frequency absorption effects of the chemical bond vibration of the C-H-O molecules. However, compared with other molecular chemical bonds, the absorption spectrum has weaker specificity and is interfered by infrared absorption of other pigment molecules in tissues, so that the method has a plurality of in-vivo measurement challenges. Sabbir et al utilized mid-infrared absorption spectroscopy to achieve continuous noninvasive blood glucose monitoring, and the relative error of the detectable blood glucose concentration range of 80-160mg/dl can reach 16%.
The photoacoustic spectroscopy technology utilizes the excitation light of middle infrared to induce the thermal expansion of skin, so as to generate an ultrasonic signal, and detects the strong absorption signal of the C-H-O molecular chemical bond in the range of 800-1200 wave numbers. Compared with the traditional infrared absorption spectrum technology, the method has higher sensitivity and deeper detection depth, and can detect glucose molecular signals of the particle layer below the epidermis layer and tissue fluid in the acantha layer. However, due to the strong absorption mid-infrared spectrum signal in sweat, skin oils and trace components, the intra-skin components in mid-infrared spectrum can seriously affect the photoacoustic spectroscopic measurement of subcutaneous blood glucose molecules. JooYongSim et al realize photoacoustic imaging of the finger skin by using a photoacoustic spectroscopy imaging technology, find a strong signal position by spectroscopic imaging, realize accurate photoacoustic spectrum acquisition (two absorption peaks of measuring ranges 950-1250 wave numbers, 1070 and 1140 wave numbers), and average relative error of 8.27mg/dl by using the lowest blood glucose concentration 120mg/dl detectable by using a photoacoustic spectroscopy imaging method.
Raman spectroscopy uses raman scattering methods to quantitatively detect the chemical composition and concentration of a molecule in a single cell by detecting the vibration of the molecule itself, without the need for any exogenous markers. But spontaneous raman scattering is small in cross section and therefore the signal is typically weak. The raman shift (900-1500 wavenumber range, 911, 1060, 1125 wavenumbers, three raman characteristic peaks) of subcutaneous glucose molecules can be detected by the raman spectroscopy method, the lowest blood glucose concentration detectable by the spontaneous raman spectroscopy method is 75mg/dl, the correlation coefficient reaches 94%, and the average relative error absolute value (MARD) is 13.4%. Compared with the traditional infrared absorption spectrum method and the photoacoustic spectrum method, the Raman spectrum method has higher detection sensitivity. However, due to the spatial heterogeneity of subcutaneous sugar molecule concentration distribution, spontaneous raman signal is weak, spontaneous spectrum detection speed is slow, and the technology cannot realize in-vivo spectral imaging. Therefore, the spontaneous raman spectroscopy technology cannot distinguish the specific signals of glucose molecules at different positions, so that the specific signals cannot meet the index requirements of CFDA on blood glucose monitoring measurement errors and measurement ranges at present.
Spontaneous raman scattering signals are usually weak, detection speed is slow, and coherent raman scattering microscopy is developed in order to obtain weak biological raman signals and realize rapid in-vivo spectral imaging. Coherent raman scattering microscopy, including Coherent anti-Stokes RAMAN SCATTERING (called CARS for short) and stimulated raman scattering (Stimulated RAMAN SCATTERING for short) microscopy, is an emerging class of molecular imaging techniques that do not require fluorescent markers. Compared with spontaneous Raman, the signal intensity of coherent Raman scattering is improved by 104-105 times. The coherent Raman scattering microscopy has high detection sensitivity (mM), high imaging capability (1 s/image) and high spatial resolution (0.5 mu m), so that the coherent Raman scattering microscopy is a biomedical imaging means with great potential. Compared with SRS, the coherent anti-Stokes scattering signal is separated from the excitation light wavelength, complex frequency modulation and phase-locked amplification are not needed, and the equipment is simple; the SRS system based on the optical fiber probe can generate the phenomenon of mixing excitation light and four waves of signals, so that extremely strong background noise is caused, and the handheld optical fiber CARS system based on hollow optical fiber coupling has higher signal-to-noise ratio due to the separation of the signals and the wavelengths of the excitation light; and the back reflection type epi-CARS system based on the fiber laser has smaller background noise and is easy to miniaturize. However, CARS itself has a non-resonant background, which causes spectrum distortion and is not easy to quantitatively analyze, so that development of a handheld CARS system based on hyperspectral imaging is required to remove the non-resonant background. The hyperspectral CARS system has great advantages in quantitative analysis capability, sensitivity, chemical specificity and the like, and particularly provides a brand-new research method for lipid, protein and sugar metabolism.
Aiming at the clinical requirement of blood glucose monitoring, the label-free coherent Raman spectrum imaging method based on hyperspectral CARS has great potential to provide a new method for noninvasive continuous accurate detection of blood glucose.
Disclosure of Invention
The present invention aims to provide a handheld noninvasive blood glucose meter which can solve one or more of the drawbacks of the prior art.
In order to achieve the above object, the present invention provides a handheld noninvasive blood glucose meter, comprising an excitation module for emitting stokes light and pump light; a scanning module for scanning a first location of a living being with the stokes light and the pump light, exciting a coherent anti-stokes scattering signal at the first location; the acquisition module is used for acquiring the coherent anti-Stokes scattering signal, acquiring a spontaneous Raman signal at the first position and acquiring a spontaneous Raman spectrum of the first position; and a data processing module for processing and analyzing according to the coherent anti-stokes scatter signal and the spontaneous raman spectrum.
The invention provides a handheld noninvasive blood glucose measuring instrument, which adopts a brand-new optical excitation mode and a scanning mode to scan and excite the concentration of glucose molecules under the skin of an organism at high speed, high spectrum and high resolution, realizes noninvasive coherent Raman scattering hyperspectral imaging and glucose molecule specific detection, comprehensively improves the detection sensitivity, simultaneously detects the spatial heterogeneity existing in the distribution of the glucose molecules through the spectral imaging, effectively improves the detection accuracy, reduces the relative error of blood glucose measurement, and simultaneously meets the requirements on blood glucose monitoring by using a noninvasive detection method.
Drawings
In order to more clearly illustrate the technical solution of the implementation of the present invention, the following description will briefly explain the drawings that are required to be used in the embodiments.
FIG. 1 is a schematic diagram of the structure of a handheld non-invasive glucose meter of the present invention;
FIG. 2a is a graph of coherent Raman scattering energy levels of the present invention;
FIG. 2b is a schematic diagram of a coherent Raman hyperspectral scanning of the present invention;
FIG. 3 is a schematic illustration of a handheld non-invasive glucose meter of the present invention for in vivo Raman spectroscopy acquisition;
FIG. 4a is a schematic diagram of the operation of the loop generation countermeasure network of the present invention;
FIG. 4b is a flow chart of the hyperspectral data quantification process of the present invention.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
Example embodiments will now be described more fully with reference to the accompanying drawings. However, the exemplary embodiments can be embodied in many forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the example embodiments to those skilled in the art. The same reference numerals in the drawings denote the same or similar structures, and thus detailed descriptions thereof will be omitted.
When introducing elements/components/etc. that are described and/or illustrated herein, the terms "a," "an," "the," and "at least one" are intended to mean that there are one or more of the elements/components/etc. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements/components/etc., in addition to the listed elements/components/etc. Furthermore, the terms "first," "second," and the like in the claims are used merely as labels, and are not intended to limit the numerals of their objects.
Fig. 1 shows the structure of a handheld non-invasive glucose meter 10 of the present invention. The handheld noninvasive blood glucose meter 10 comprises an excitation module 1, a scanning module 2, an acquisition module 3 and a data processing module (not shown), wherein the excitation module 1 adopts a form of a coherent raman scattering system excited by collinearly, and uses a laser 1-1 with two paths of synchronous output as a light source to respectively emit pump light and stokes light; the scanning module 2 scans a first position of a living body by using the Stokes light and the pump light through the optical fiber probe 2-1, and excites a coherent anti-Stokes scattering signal positioned at the first position; the acquisition module 3 comprises a photomultiplier tube 3-1 and a spectrometer 3-2, wherein the photomultiplier tube 3-1 acquires the coherent anti-Stokes scattering signal, and the spectrometer 3-2 is adopted to acquire spontaneous Raman signals of a first position of an organism, so as to acquire spontaneous Raman spectra of the first position; the data processing module processes and analyzes according to the coherent anti-Stokes scattering signal and the spontaneous Raman spectrum, and accurately quantifies the concentration of glucose molecules in skin tissues of an individual. According to the invention, the traditional microscope architecture is replaced by the optical fiber probe in the scanning module, the diameter of the optical fiber probe is less than or equal to 10mm, the volume of the scanning end is greatly reduced, the flexibility of the optical fiber probe in clinical and complex environments is increased, and the optical fiber probe is more suitable for in-vivo testing.
In some embodiments of the present invention, the laser 1-1 emits a pump light, the wavelength of which is adjusted within the range of 938nm±50nm, the repetition frequency is 80±1MHz, the pump light passes through the half-wavelength polarizer 4-1 (a), the polarization splitting prism 5-1 (a), the lenses 6-1 (a), and 6-2 (a) in sequence, and then passes through the first mirror 7-1, the first dichroic mirror 11-1, and the half-wavelength polarizer 4-2 to reach the polarization splitting prism 5-2, and since the pump light output from the laser 1-1 is linearly polarized, the half-wavelength polarizer 4-2 changes the polarization direction of the pump light, makes it reflected by the polarization splitting prism 5-2, and returns along the incident path after passing through the glass post 12, the second mirror 7-2, and the third mirror 7-3 in sequence, the glass post 12 is used for chirped (chirp) pump light, makes it pass through the polarization splitting prism 5-2 and the quarter-wavelength polarizer 4-2, and becomes linearly polarized at an angle of 90 ° with the incident polarization angle.
The laser 1-1 emits a beam of stokes light, which is a fixed wavelength near infrared light of 1045nm and has a repetition frequency of 80 + -1 MHz, which passes through the half wavelength polarizer 4-1 (b), the polarization splitting prism 5-1 (b), the lenses 6-1 (b), 6-2 (b) in this order, passes through the fourth mirror 7-4 and the polarization splitting prism 5-2, passes through the quarter wavelength polarizer 8, and becomes circularly polarized light.
In some embodiments of the present invention, the handheld non-invasive glucose meter 10 further comprises a resonant galvanometer 9, the pump light and stokes light passing through the quarter-wavelength polarizer 8 enter the resonant galvanometer 9, the resonant galvanometer 9 adjusts the time delay between the pump light and stokes light by the principle of spectrum focusing, and changes the spectrum focusing frequency position to excite the coherent raman spectrum signal in the 250 wave number range, and the scanning frequency of the resonant galvanometer 9 is 8KHz.
In some embodiments of the present invention, the pump light and stokes light adjusted by the resonant galvanometer 9 enter the glass column 12, and the glass column 12 chirps and widens the stokes light and the pump light to excite coherent anti-stokes scattering signals or stimulated raman scattering signals of 900-1150cm -1 in the wave number range.
In some embodiments of the present invention, the handheld non-invasive blood glucose meter 10 further comprises a coupling objective 13, the pump light and stokes light stretched by the glass column 12 are led into the optical fiber probe 2-1 through the coupling objective 13, an optical fiber 14 is arranged between the coupling objective 13 and the optical fiber probe 2-1, the optical fiber probe 2-1 comprises a piezoelectric ceramic tube 2-11, a hollow optical fiber 2-12 and a graded index lens 2-13, the piezoelectric ceramic tube 2-11 and the optical fiber 14 are combined to realize spiral movement of the optical fiber, the graded index lens 2-13 with high Numerical Aperture (NA) focuses the pump light and stokes light at a first position of an organism, and performs spiral scanning on the first position to excite a coherent anti-stokes scattering signal located at the first position.
Fig. 2a is an energy level diagram of coherent raman scattering, and fig. 2b is a schematic diagram of coherent raman hyperspectral scanning, where a coherent anti-stokes scattering signal at a first location can be excited by two simultaneous beams of pump light and stokes light illuminating the first location of a living body, as shown in fig. 2a and 2 b. In the stimulated raman scattering phenomenon, if the frequency difference between the two laser beams corresponds to a specific molecular vibration frequency, the raman signal is enhanced by a factor r proportional to ω, where ω is related to the raman shift only and to the photon densities of the Pump light (Pump) and Stokes light (Stokes), respectively. Therefore, the Raman signal intensity under the condition of Stokes light irradiation is many orders of magnitude higher than that under the condition of no Stokes light irradiation, and can reach more than 10 4 under the normal condition. In this process, the resulting coherent anti-stokes scatter signal has a non-resonant background signal. The handheld noninvasive blood glucose meter 10 of the invention can test the content and distribution of different molecules in subcutaneous tissue at a first position of an organism through detection of molecular chemical bonds, irradiates the first position of the organism through two synchronous pump light and Stokes light, wherein ωp is the frequency of the pump light, ωs is the frequency of the Stokes light, and 2x ωp- ωs accords with the chemical bond vibration frequency of the detection molecules, and can excite anti-Stokes signals of specific chemical bonds and carry out resonance enhancement on the anti-Stokes signals to form coherent anti-Stokes scattering signals.
In some embodiments of the present invention, the acquisition module 3 comprises a spectrometer 3-1 and a photomultiplier tube 3-2, the handheld noninvasive blood glucose meter 10 further comprises a second dichroic mirror 11-2, a fifth reflecting mirror 7-5 and a first filter 15-1, the second dichroic mirror 11-2 is located between the third reflecting mirror 7-3 and the coupling objective 13, the coherent anti-stokes scattering signal returned from the first position passes through the second dichroic mirror 12-2, the fifth reflecting mirror 8-5 and the lens 6-4 and enters the photomultiplier tube 3-1 after being filtered by the first filter 15-1, and the photomultiplier tube 3-1 amplifies the coherent anti-stokes scattering signal.
In some embodiments of the present invention, the handheld non-invasive glucose meter 10 further comprises a reversible mirror 16 and a second filter 15-2, and the handheld non-invasive glucose meter 10 is coupled with 785nm excitation light in a reduction position, the optical fiber probe 2-1 is used for scanning the first position, spontaneous raman signals at the first position are excited, the spontaneous raman signals returned from the first position are reflected by the reversible mirror 16 after passing through the second dichroic mirror 11-2 and the fifth mirror 7-5 and filtered by the second filter, and then enter the spectrometer 3-2, and the spectrometer 3-2 generates spontaneous raman spectra according to the spontaneous raman signals.
The handheld non-invasive glucose meter 10 of the present invention further comprises a data acquisition system that acquires the coherent anti-stokes scatter signal output by the photomultiplier tube 3-1 and the spontaneous raman spectrum acquired by the spectrometer 3-2, and an automatic imaging platform. The automatic imaging platform is used for reconstructing a coherent anti-Stokes scattering signal image according to the coherent anti-Stokes scattering signal acquired by the data acquisition system and mainly comprises a programmable electric displacement table and an automatic focusing system. The programmable electric displacement table can automatically image a specific track of a sample, particularly a large-size biological sample according to actual requirements, an experimenter can carry out overall image jigsaw according to the track path after acquiring image data, the workload of the experimenter is reduced, the acquired data can be parameterized and tidied, subjective errors of operators are avoided, and the repeatability of experimental operation is ensured. Meanwhile, the automatic focusing system can automatically focus the selected layer, so that the problem of defocusing caused by micro deformation of the sample due to environmental temperature, humidity and other environmental problems is avoided, and the automatic focusing system can coexist with an anti-Stokes light signal, so that the data acquisition speed is further improved. The automatic imaging platform realizes the automation, integration and miniaturization of CARS equipment, and can be transplanted to clinical medical environment from laboratory environment. The operator can use the operation interface and the data acquisition interface more easily without complicated specialized training. The CARS is integrated and miniaturized, and meanwhile, the equipment cost is greatly reduced, so that the CARS is suitable for clinical application and popularization.
The handheld noninvasive blood glucose meter 10 obtains coherent anti-Stokes scattering signals at a first position of an organism through the principle of spectrum focusing scanning, so as to obtain coherent Raman scattering characteristic distribution information of different molecules. Fig. 3 is a schematic diagram of the handheld non-invasive blood glucose meter 10 for living body raman spectrum acquisition according to the present invention, wherein the scanning module 2 is used to scan a first location of a living body, for example, a location corresponding to an earlobe, an inner side of an arm, a thumb nail or a median elbow vein of a human body. The spatial distribution of the individual molecules in the subcutaneous tissue at the first location of the organism is likely to be different, for example glucose molecules are commonly present in the interstitial fluid (THE INTERSTITIAL fluid, ISF) below the epidermis layer, resulting in a spectrum of glucose molecules characteristic of coherent raman scattering, with a large number of lipid molecules, protein molecules, DNA molecules being enriched in the cytoplasm and DNA molecules being enriched in the nucleus in the epidermis and dermis cells. Thus, testing using the handheld non-invasive glucose meter 10 of the present invention enables a more comprehensive, accurate database of optical characteristics of subcutaneous tissue to be established.
As shown in fig. 4a, since the coherent anti-stokes scattering signal has a non-resonant background, the spontaneous raman spectrum detection has no non-resonant background, the coherent anti-stokes scattering signal without the non-resonant background can be extracted by generating an anti-network modeling, the problems of spectrum distortion and difficult quantitative analysis of the coherent anti-stokes scattering signal are overcome, and the accurate quantification of the concentration distribution of molecules is realized. The data processing module of the handheld noninvasive blood glucose meter 10 firstly generates an anti-network according to a spontaneous raman spectrum of a first position based on an AI deep learning algorithm to remove a non-resonance background of a coherent anti-stokes scattering signal, then as shown in fig. 4b, utilizes an MCR algorithm to distinguish spectrum signals of different molecules, quantifies glucose molecule specific concentration distribution, has strong spatial heterogeneity of glucose molecules and the like, and needs to perform component analysis on molecular characteristic maps of lipid molecules, protein molecules, DNA molecules and the like to further distinguish the molecular concentration distribution; the data processing module also utilizes PLS algorithm to fit the relation between the glucose molecular concentration distribution and the blood glucose concentration at different positions in space, and the result shown in fig. 4b shows that the handheld noninvasive blood glucose measuring instrument has the capability of quantifying the subcutaneous glucose molecular concentration distribution in real time, so that the blood glucose concentration can be continuously and accurately monitored.
In summary, the invention provides a brand-new handheld noninvasive blood glucose measuring instrument, which comprises an excitation module, a scanning module, an acquisition module and a data processing module, wherein a brand-new optical excitation mode and a scanning mode are adopted to acquire a coherent anti-stokes signal and a spontaneous raman spectrum of a first position of an organism, glucose molecular signals are jointly determined by removing the coherent anti-stokes signal of a non-resonance background and the spontaneous raman spectrum detected in situ, and the subcutaneous glucose molecular concentration of the organism is scanned and excited at a high speed, a high spectrum and a high resolution, so that the noninvasive coherent raman scattering hyperspectral imaging and the sugar molecular specificity detection are realized.
The exemplary embodiments of the present invention have been particularly shown and described above. It is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims (15)
1. A handheld noninvasive blood glucose meter, comprising:
The excitation module is used for emitting Stokes light and pump light;
A scanning module for scanning a first location of a living being with the stokes light and the pump light, exciting a coherent anti-stokes scattering signal at the first location;
the acquisition module is used for acquiring the coherent anti-Stokes scattering signal, acquiring a spontaneous Raman signal at the first position and acquiring a spontaneous Raman spectrum of the first position; and
And the data processing module is used for processing and analyzing according to the coherent anti-Stokes scattering signal and the spontaneous Raman spectrum.
2. The hand-held, non-invasive blood glucose meter of claim 1, wherein the blood glucose meter comprises,
The scanning module comprises a fiber optic probe.
3. The hand-held, non-invasive blood glucose meter of claim 2, wherein the blood glucose meter,
The device also comprises a first reflecting mirror, a second reflecting mirror, a third reflecting mirror, a fourth reflecting mirror, a first dichroic mirror, a half-wave plate, a quarter-wave plate, a polarization beam splitter prism and a glass column;
The pump light enters the polarization splitting prism after passing through the first reflecting mirror, the first dichroic mirror and the half-wavelength polaroid, and returns along an incident path after passing through the glass column, the second reflecting mirror and the third reflecting mirror in sequence after being reflected by the polarization splitting prism, and enters the quarter-wavelength polaroid;
the Stokes light enters the quarter-wave polarizer after passing through the fourth reflector and the polarization splitting prism.
4. The hand-held, non-invasive blood glucose meter of claim 3,
The device also comprises a resonance galvanometer, wherein the pump light and the Stokes light enter the resonance galvanometer after passing through the quarter-wavelength polaroid, and the resonance galvanometer is used for adjusting the time delay between the pump light and the Stokes light.
5. The handheld non-invasive glucose meter of claim 4, wherein the pump light and the stokes light enter the glass column after being adjusted by the resonance galvanometer, and the glass column is used for stretching the stokes light and the pump light to excite a coherent anti-stokes scattering signal or an stimulated raman scattering signal with a wave number range of 900-1150cm -1.
6. The handheld non-invasive glucose meter as set forth in claim 5, wherein,
The optical fiber probe comprises a glass column, and is characterized by further comprising a coupling objective lens, wherein the pump light and the Stokes light enter the coupling objective lens after being stretched by the glass column, and the coupling objective lens is used for guiding the pump light and the Stokes light into the optical fiber probe.
7. The hand-held, non-invasive blood glucose meter of claim 6, wherein,
The optical fiber probe comprises a piezoelectric ceramic tube, a hollow optical fiber and a graded index lens, wherein the graded index lens focuses the pump light and the Stokes light at the first position, the optical fiber probe carries out spiral scanning on the first position, and a coherent anti-Stokes scattering signal at the first position is excited.
8. The handheld non-invasive glucose meter of claim 7, wherein the device comprises,
The acquisition module comprises a photomultiplier tube, the handheld noninvasive blood glucose meter further comprises a second dichroic mirror and a first filter, the second dichroic mirror is located between the third reflecting mirror and the coupling objective lens, and the coherent anti-Stokes scattering signal returned from the first position enters the photomultiplier tube after being reflected by the second dichroic mirror and filtered by the first filter.
9. The hand-held, non-invasive blood glucose meter of claim 8,
The optical fiber probe scans the first position and excites spontaneous raman signals at the first position.
10. The handheld non-invasive glucose meter as set forth in claim 9, wherein,
The acquisition module comprises a spectrometer, the handheld noninvasive blood glucose meter further comprises a reversible reflector and a second filter, the spontaneous Raman signal returned from the first position is reflected by the second dichroic mirror, reflected by the reversible reflector and filtered by the second filter and enters the spectrometer, and a spontaneous Raman spectrum of the first position is generated.
11. The handheld noninvasive blood glucose meter of claim 10, further comprising:
The data acquisition system is used for acquiring the coherent anti-Stokes scattering signal output by the photomultiplier and the spontaneous Raman spectrum; and
An automated imaging platform for reconstructing a coherent anti-stokes scatter signal image from a coherent anti-stokes scatter signal output by the photomultiplier tube, comprising:
a programmable electric displacement table for automatically imaging the specific track of the living body; and
An autofocus system that autofocus selected levels of the living being.
12. The handheld non-invasive glucose meter of claim 11, wherein the data processing module generates an countermeasure network from the spontaneous raman spectrum using an AI deep learning algorithm to remove non-resonant background of the coherent anti-stokes scatter signal in the coherent anti-stokes scatter signal image.
13. The handheld non-invasive glucose meter according to claim 12, wherein the data processing module uses MCR algorithm to distinguish the coherent anti-stokes scatter signals of different molecules with non-resonant background removed, quantifies glucose molecule-specific concentration profiles, and fits the relationship between glucose molecule concentration profiles and glucose concentration at different locations in space using PLS algorithm.
14. The hand-held, non-invasive blood glucose meter of claim 2, wherein the blood glucose meter,
The diameter of the optical fiber probe is less than or equal to 10mm.
15. The hand-held, non-invasive blood glucose meter of claim 1, wherein the blood glucose meter comprises,
The first location is located at an earlobe, an inner side of an arm, a thumb nail, and a median elbow vein of the living being.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211394276.3A CN118021250A (en) | 2022-11-08 | 2022-11-08 | Hand-held noninvasive blood glucose measuring instrument |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211394276.3A CN118021250A (en) | 2022-11-08 | 2022-11-08 | Hand-held noninvasive blood glucose measuring instrument |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118021250A true CN118021250A (en) | 2024-05-14 |
Family
ID=90988181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211394276.3A Pending CN118021250A (en) | 2022-11-08 | 2022-11-08 | Hand-held noninvasive blood glucose measuring instrument |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118021250A (en) |
-
2022
- 2022-11-08 CN CN202211394276.3A patent/CN118021250A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105377134B (en) | Equipment for carrying out non-invasive somatometry by Raman spectrum | |
| US6352502B1 (en) | Methods for obtaining enhanced spectroscopic information from living tissue, noninvasive assessment of skin condition and detection of skin abnormalities | |
| Motz et al. | Real-time Raman system for in vivo disease diagnosis | |
| Wang et al. | Mapping lipid and collagen by multispectral photoacoustic imaging of chemical bond vibration | |
| US9658440B2 (en) | Optical probe for measuring light signals in vivo | |
| US20060181791A1 (en) | Method and apparatus for determining a property of a fluid which flows through a biological tubular structure with variable numerical aperture | |
| US20050043597A1 (en) | Optical vivo probe of analyte concentration within the sterile matrix under the human nail | |
| Huang et al. | Optical clearing of porcine skin tissue in vitro studied by Raman microspectroscopy | |
| US20160341668A1 (en) | Angled confocal spectroscopy | |
| Nogueira et al. | Broadband extraction of tissue optical properties using a portable hybrid time-resolved continuous wave instrumentation: characterization of ex vivo organs | |
| JP4618341B2 (en) | A method for measuring the amount of substances in a living body using coherent anti-Stokes Raman scattering light | |
| Schleusener et al. | Fiber-based SORS-SERDS system and chemometrics for the diagnostics and therapy monitoring of psoriasis inflammatory disease in vivo | |
| Rinia et al. | Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering | |
| US20230148312A1 (en) | Device for non-invasive blood glucose concentration measurement | |
| CN110857908B (en) | Biological sample analysis and test system based on off-axis digital holographic microscopy and spectral analysis method | |
| CN118021250A (en) | Hand-held noninvasive blood glucose measuring instrument | |
| Qi et al. | Simultaneous dual-wavelength source raman spectroscopy with a handheld confocal probe for analysis of the chemical composition of in vivo human skin | |
| WO2004090510A1 (en) | Optical fibre needle for spectroscopic analysis of liquids | |
| US10495516B2 (en) | Dedicated transformation spectroscopy | |
| Lin et al. | Optical clearing and Raman spectroscopy: In vivo applications | |
| EP3317625B1 (en) | Dedicated transformation spectroscopy | |
| Chen | Fiber-optic Raman Sensing on Tissue Identification and Bladder Cancer Diagnosis | |
| Yu | Excitation/emission spectroscopy with multi-channel imaging guidance for skin disease diagnosis | |
| Wang | Infrared attenuated total reflection spectroscopy for monitoring biological systems | |
| JPH0218851B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |