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WO2006036079A1 - Procede de mesure des caracteristiques de viscosite et d'elasticite des cellules d'objets biologiques, procede de diagnostic differentiel de maladies diffuses du foie d'origine virale ou alcoolique et dispositif pour mettre en oeuvre ces procedes - Google Patents

Procede de mesure des caracteristiques de viscosite et d'elasticite des cellules d'objets biologiques, procede de diagnostic differentiel de maladies diffuses du foie d'origine virale ou alcoolique et dispositif pour mettre en oeuvre ces procedes Download PDF

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Publication number
WO2006036079A1
WO2006036079A1 PCT/RU2004/000336 RU2004000336W WO2006036079A1 WO 2006036079 A1 WO2006036079 A1 WO 2006036079A1 RU 2004000336 W RU2004000336 W RU 2004000336W WO 2006036079 A1 WO2006036079 A1 WO 2006036079A1
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cell
cells
electric field
red blood
measuring
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PCT/RU2004/000336
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English (en)
Russian (ru)
Inventor
Vladimir Mikhailovich Generalov
Talgat Salmanovich Bakirov
Anton Vladimirovich Pak
Ivan Leonidovich Zvolsky
Margarita Vitalevna Kruchinina
Svetlana Arsentievna Kurilovich
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Bio-Id Diagnostics, Inc.
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Publication of WO2006036079A1 publication Critical patent/WO2006036079A1/fr

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/487Physical analysis of biological material of liquid biological material
    • G01N33/49Blood
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N11/00Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
    • G01N11/10Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by moving a body within the material
    • G01N11/16Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by moving a body within the material by measuring damping effect upon oscillatory body
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N2015/1006Investigating individual particles for cytology

Definitions

  • the invention relates to the field of virology and medicine.
  • the proposed methods and device can be used for laboratory analysis of the physiological state of cells, for example, red blood cells and white blood cells, with the aim of early diagnosis of deviations from the normal state (detection of infected or cancerous) cells in the blood of humans and animals, as well as to determine the stage of liver disease (hepatitis, cirrhosis ) and its etiology (viral, alcoholic).
  • red blood cells must have high elasticity in order to penetrate the capillaries. Tight contact between the walls of the capillary and the erythrocyte membrane facilitates gas exchange of oxygen and carbon dioxide, which contributes to the full provision
  • Differential diagnosis of diffuse liver diseases of alcoholic and nonalcoholic origin is based on a complex of clinical, biochemical, and morphological features.
  • biological markers include: activity of aminotransferases (ALT, ACT), their ratio, activity of gamma glutamyl transpeptidase (GGTP), alkaline phosphatase (ALP), ratio of GGTP / ALP, ferritin level, carbohydrate deficient 5 transferrin, phosphatidylethanol level, epinephrine hydrogenase, alcohol erythrocyte volume, high density lipoprotein cholesterol (HDL HDC) [S.
  • ALT aminotransferases
  • GGTP gamma glutamyl transpeptidase
  • ALP alkaline phosphatase
  • ferritin level carbohydrate deficient 5 transferrin
  • phosphatidylethanol level phosphatidylethanol level
  • epinephrine hydrogenase alcohol erythrocyte volume
  • Serum alcohol enzymes appear as early
  • non-enzymatic methods for studying the morphological and functional safety of the liver are more indicative: determination of protein, immunoglobulin fractions and serum lipids, sedimentary samples (thymol, sublimate), indicators, excretory and metabolizing functions (plasma clearance of dyes, antipyrine index) .
  • the mismatch of the degree of violation of the listed non-enzymatic parameters and the normal or decreasing activity of serum enzymes underlines the degree of decompensation of the organ as a result of chronic damage to alcohol.
  • the disadvantages of using these indicators for the differential diagnosis of liver diseases are their lack of sensitivity and specificity, as well as the high complexity, the duration of the analyzes and obtaining the source materials for a number of markers.
  • the closest analogue (prototype) for measuring viscoelastic characteristics is a method and apparatus for measuring viscoelastic characteristics, red blood cells in an electric field created by a high-frequency generator between electrodes in series [H. Ephelhardt, E. Sackmapp. On th Qurex, E. Sackmapp. On th Qurex, E. Sackmapp. On th Qurex, E. Sackmapp. On th Quresen, E. Sackmapp. On th Qureus measuremet GmbH elastivic moduli apt visreteositi institutionss republicf e , irerutrosose ident .
  • Biorhus. J.- 1988, v. 54: 495-508 a method and apparatus for measuring viscoelastic characteristics, red blood cells in an electric field created by a high-frequency generator between electrodes in series
  • the method includes filling a working cell volume with a suspension of measuring cells with electrodes sequentially installed in it, applying an inhomogeneous alternating electric field to the suspension, computer recognition of the maximum size of an erythrocyte attracted to the electrode, calculation of the force stretching the cell according to the model of a conducting ellipsoid.
  • the disadvantage of the described method and device is the low accuracy of measuring the stiffness and viscosity of the cell, due to the error in calculating the tensile force according to the model of the conductive ellipsoid and the error associated with the fact that the cell has direct contact with the surface of the electrode. This changes the physiological state of the cell membrane.
  • the method and device have a low productivity of the process of measuring the visco-elastic characteristics of the cell.
  • the closest analogue (prototype) of the method for the diagnosis of liver diseases is the method of differential diagnosis of diffuse liver diseases of alcoholic and non-alcoholic nature by measuring the average radius and the average corpuscular volume of red blood cells (SKOE), (MCV) [T. Wötherlipg, R. Kapitz, H.
  • SKOE SKOE with prolonged alcoholization
  • a persistent change in this indicator with alcohol damage was noted.
  • the liver RMSE measurement is usually carried out using a conductometric hemisphere analyzer (particle counter) based on measuring the electrical resistance of a thin capillary through which the flow of red blood cells passes.
  • the closest technical solution (prototype) of a device for the differential diagnosis of diffuse liver diseases is a particle counter of the French company "Soulter" [FR, 2092378, 1972], containing a cuvette with an electrically conductive suspension of particles and a vertically located measuring tube with a calibrated input in the lower part a hole, the upper end of the measuring tube being connected by a pneumatic conduit to a vacuum source (a manual piston pump), an internal electrode is installed in the measuring tube, and in the cell eshny electrode. The electrodes are connected to a current source and an electronic unit for measuring and processing data.
  • the disadvantage of these methods for diagnosing diseases and the device for its implementation is the low reliability of the differential diagnosis of diseases due to the narrow spectrum of measured parameters of human red blood cells (determining only the size of red blood cells and characteristics directly related to the size of red blood cells), as well as large errors in measuring the size of red blood cells with high degree of aggregation.
  • the technical result of the invention is to increase the accuracy of measuring the viscoelastic characteristics of cells of biological objects and increase the reliability and specificity of the differential diagnosis of liver diseases and reduce the time of diagnosis by providing the ability to measure the following parameters of human red blood cells without changing the physiological state of the membrane of red blood cells: average cell radius, K ⁇ - ratio the average polarizability ⁇ 0 1 and sc at two frequencies, for example, 100 kHz and 1 MHz, membrane conductivity and capacitance erythrocytes, erythrocyte stiffness and viscosity, erythrocyte aggregation index, erythrocyte destruction coefficient in an electric field.
  • the specified technical result is achieved by the fact that in the method of measuring the visco-elastic characteristics of cells of biological objects, including sampling cells of biological objects, diluting them with an isotonic solution that supports cell activity, with a given coefficient k, determining the dynamic viscosity ⁇ w of a suspension of red blood cells in the specified isotonic solution and transferring a mixture of the studied red blood cells with a given concentration of cells into a measuring cell, according to the invention, a heterogeneous shape is formed in the cell th alternating electric field with a frequency / from 10 kHz to 5 MHz and an average electric field strength E 0 in the gap between the electrodes in the range from 10 4 to 10 6 Volt / m, measure the average speed V c the movement of each cell in suspension and their average radius R at certain time intervals during the period of exposure to the electric field and after it is turned off after a period of time t by video recording the image of the movement of cells and changing their size, the obtained data are digitally input and processed
  • is the intensity of the external electric field
  • ⁇ o is the dielectric constant of the vacuum
  • force (F el ) a stretching cell, in the direction of the electric field vector:
  • strain ⁇ x after turning off the electric field t-time after turning off the electric field
  • is the strain value Ax after turning off the electric field
  • the optimal frequency, amplitude and duration of exposure to an electric field are selected under the condition of a given value of cell deformation.
  • the specified technical result is also achieved by the fact that in the method of differential diagnosis of liver diseases, which includes taking samples of red blood cells, diluting them with an isotonic solution that supports the vital functions of red blood cells, with a given coefficient k, determining the dynamic viscosity ⁇ w of a suspension of red blood cells in a specified isotonic solution and transferring a mixture of the studied red blood cells with a given cell concentration to a measuring cell, according to the invention, an inhomogeneous alternating electric field with a frequency / from 10 kHz to 5 MHz and an average intensity E 0 electric field in the gap between the electrodes in the range of 10 4 to 10 6 V / m, measured average traffic speed V c of each cell in the slurry and minimum radius R mun mean radius R and ma maximum DUTY radius R MAX at regular intervals during the action of the electric field off and after the time t by a video image motion of cells and changes their size, the data in digital form is introduced and treated in a computer having a data
  • / o / is the lower frequency at which the polarizability aoj is measured
  • / / is the upper frequency at which the polarizability ⁇ / is measured.
  • is the electrical conductivity of the solution in which the measurements are made.
  • Ax is the magnitude of the deformation of the cell after turning off the electric field;
  • c - t Xl Lr cell viscosity, where: c 6 - ⁇ - R - In (Ax / A)
  • N d is the number of adherent cells in the field of observation of the microscope
  • N 0 is the total number of cells in the field of observation of the microscope
  • X J 0 1 is a statistically significant array for its subsequent use in the differential diagnosis of liver diseases, and then similar measurements of samples of red blood cells of patients with various types of pathologies are carried out with the characterization of red blood cells X ⁇ in real time, followed by comparison of these characteristics with the corresponding values of J J ° t , located in the computer database and the determination of the indicator ⁇ , the proximity of the measured characteristics of red blood cells to each of the seven types diagnosis:
  • K j normalizing diagnostic coefficients, which are calculated by the formula: the value of the y-th parameter from all x ° a parameters corresponding to all i-th diagnoses; MMH j (X J 0 1 ) - the minimum value of the y-th parameter of all
  • X j about 1 parameters corresponding to all the rth diagnoses, and the minimum value of ⁇ , measured parameters of human red blood cells corresponds to the / -th diagnosis, which is accepted as the final diagnosis.
  • the specified technical result is also achieved by the fact that in the device for measuring the viscoelastic characteristics of bioobject cells and for differential diagnosis of diffuse liver diseases, including a transparent measuring cell, in which electrodes are connected to a power source, as well as a measuring unit, according to the invention, the power source represents a variable voltage generator, and the measuring unit contains a microscope, optically coupled to a measuring cuvette and image analysis system for measuring the speed of red blood cells containing a video camera, optically coupled with a microscope, and a computer connected to the camera. Moreover, the electrodes in the measuring cell are installed with a gap sufficient for the formation of an average electric field in it in the range from 10 4 to 10 6 Volt / m.
  • red blood cells Under conditions of an inhomogeneous alternating electric field (NPEP), the mobility of red blood cells in suspension is tested. The experiments showed that red blood cells have significant mobility in an alternating inhomogeneous electric field. In a weakly conductive glucose solution, red blood cells normally progressively move to a region with a high electric field strength at a high frequency ("1-5 MHz) of the electric field. At a lower frequency of the electric field ("10-100 kHz), red blood cells move to the area with low electric field strength. In addition, it was found that red blood cells with liver pathology lose their ability to move in NPEP. The fundamental difference in the mobility of red blood cells in normal and pathological conditions and in NPEP is the basis of the invention.
  • FIG. 1 shows a block diagram of an automated installation for implementing the proposed method for measuring the visco-elastic characteristics of cells of biological objects and a method for differential diagnosis of diffuse liver diseases.
  • FIG. 2 shows a diagram of a measuring cell.
  • FIG. 3 shows the design of an existing automated installation for implementing the proposed method for measuring the visco-elastic characteristics of cells of biological objects and a method for differential diagnosis of diffuse liver diseases.
  • a device for measuring the viscoelastic characteristics of biological cells and for the differential diagnosis of diffuse liver diseases includes a collapsible optically transparent measuring cell 1 (Fig. 2), in which metal electrodes 2 and 3 are located, connected to an electric power source 4, as well as a measuring unit.
  • the power source 4 is an alternating voltage generator
  • the measuring unit (Fig. 1) contains a microscope 5, optically coupled to a measuring cell 1 and an image analysis system for measuring the speed of test cells, containing a video camera 6, optically connected to a microscope 5, and a computer 7 connected to the video camera 6.
  • Computer 7 contains a specialized image processing program.
  • Measuring cuvette 1 is placed on a movable table 5.
  • microscope electrodes 2 and 3 in the measuring cell 1 fitted with a clearance sufficient to form therein the average electric field in the range of from 10 4 to 10 b Volt / m.
  • the gap between the electrodes 2 and 3 in the experimental design of the cuvette 1 is set within 50-100 microns, and the thickness of these electrodes is 0.2-2 microns.
  • the design of the experimental operating installation (Fig. 3) additionally provides for an oscilloscope 8 connected to electrodes 2 and 3 of the measuring cell 1 for monitoring electrical parameters, as well as a monitor 9 connected to a digital video camera 6.
  • the device operates as follows.
  • the measuring cuvette 1 is mounted on a movable table of the microscope 5 and the indicated cuvette 1 is fixed on it.
  • a sample of a cell suspension with a known degree of dilution is introduced into the measuring cuvette 1.
  • the electrodes 2 and 3 of the measuring cuvette 1 supplied voltage (not more than 10 volts) from the source 4 (generator) AC voltage between which is formed an average electric field intensity in the range of from 10 4 to 10 b Volt / m.
  • the dynamics of individual cells in the measuring cell 1 is recorded.
  • a video signal of the dynamics of cell movement is fed to a computer 7 (with a specialized image processing program), where data are processed and cell characteristics of biological objects, including their viscoelastic, are calculated characteristics used, for example, for the differential diagnosis of diffuse liver diseases.
  • the advantage of the device for measuring the viscoelastic characteristics of a cell of biological objects using a high-frequency electric field compared to existing analogues is that it provides an increase in the accuracy of measuring the viscoelastic characteristics of a cell at the same time both by changing the amplitude and by the frequency of the alternating voltage on the electrodes in the cell for measurements, and reduction of time for one measurement.
  • a method for measuring the visco-elastic characteristics of cells of biological objects and a method for differential diagnosis of diffuse diseases of the liver are implemented as follows.
  • 1st stage of measurements and calculations It relates both to a method for measuring the characteristics of cells of biological objects, including viscoelastic characteristics, for example red blood cells, and to a method for differential diagnosis of diffuse liver diseases.
  • samples are diluted with a given coefficient k, and the mixture of the studied material samples with a given cell concentration C k is transferred to measuring cell 1.
  • an inhomogeneous alternating electric field is formed with a frequency of 10 kHz to 5 MHz and an average electric field strength in the gap between the electrodes in in the range from 10 4 to 10 6 Volt / m by applying voltage (not more than 10 Volts) to the electrodes 2 and 3 from the source 4 (generator) of power supply.
  • the obtained data are digitally input and processed in a computer having a computer program for data storage and processing, as a result of which average values of characteristics of X j cells are determined biological objects, including the elastic-elastic characteristics of red blood cells, for a given sample (where j is the serial number of the characteristic from 1 to 8).
  • a c is the polarizability of the cell
  • EO is the intensity of the external electric field
  • ⁇ 0 is the dielectric constant of the vacuum.
  • the equilibrium frequency is calculated by the formula:
  • is the electrical conductivity of the solution in which the measurements are made.
  • Cell stiffness (c) is the fifth diagnostic parameter of the cell (viscoelastic characteristic of the cell) and is calculated depending on the amount of deformation Ax according to the formula:
  • Ax A - exp (- ⁇ • t). (9) where is the t-time after turning off the electric field,, 4 is the strain value Ax at the moment the electric field is turned off.
  • the rate of change of the strain ⁇ depends on the stiffness and viscosity of the cell ⁇ c :
  • the cell destruction coefficient is determined, which is the eighth diagnostic parameter:
  • K 1 - r-, (15), where: MAKC 1 (X 0 ,,) -
  • Normalizing diagnostic coefficients K j allow one to compare in dimensionless form the measured parameters having different dimensions, as well as bring the values of these parameters to values close to unity.
  • the cuvette 1 is made in the form of two glass plates on which electrodes 2 and 3 are parallel formed by photolithography. To increase the life of the electrodes, they are coated with a dielectric layer. The distance between the plates is 50 microns.
  • a sample of human red blood cells is diluted in a 5% glucose solution in a ratio of 1: 1000 to obtain a suspension of red blood cells until a concentration is reached erythrocytes, for example, 1 million / ml with a dynamic viscosity of the suspension ⁇ w> equal to 1.2-10 "3 groin.
  • the flow rate is 50 5 ⁇ m / s.
  • the optimal frequency of the electric field is 1 MHz, at which the deformation of human red blood cells is most pronounced, and the amplitude of the electric signal is 10 V.
  • the experiments showed that for each of the studied cell types there is an optimal The values of frequency and amplitude of the electric field at which the maximum th degree of deformation.
  • Example 2 The formation of a statistical data array for the differential diagnosis of diffuse liver diseases
  • Example 1 The method of preparing red blood cell samples and the measurement process in cuvette 1 during the period of exposure to the electric field and after it is turned off after a time t by recording the image of the movement of cells and changing their size is described in Example 1. After measuring the characteristics x ° _.
  • a statistically reliable data array is formed from them, which are digitally input and processed in a computer having a computer program for data storage and processing, as a result of which average values of the characteristics x °, erythrocyte cells are determined.
  • a computer fragment of the averaged characteristics of x °, erythrocytes of patients in this statistical array is presented in table 2 for clarity.
  • the obtained statistically reliable data array is used later in the differential diagnosis of diffuse liver diseases.
  • Example 3 Differential diagnosis of diffuse liver disease in real time
  • Example 3.1 Patient B., as a result of measurements of red blood cell characteristics, received the following analysis results
  • Example 3.2 Patient C, as a result of measurements of the characteristics of his red blood cells, received the following analysis results
  • the proposed device can be manufactured in a small enterprise and industrial production using standard equipment, modern materials and technology, which implements a method for measuring the visco-elastic characteristics of red blood cells and a method for differential diagnosis of diffuse liver diseases.

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Abstract

L'invention appartient au domaine de la médecine. Les procédés et dispositifs de l'invention peuvent s'employer à des fins d'analyse de l'état physiologique des cellules dans le sang de l'homme ou des animaux et à des fins de détermination du stade d'une maladie du foie. Les procédés comprennent la sélection des échantillons du foie, avec un coefficient k préalablement réglé, la détermination de la viscosité dynamique θw d'une suspension de globules rouges dans la solution isotonique indiquée et le transfert du mélange de globules rouges examiné possédant la concentration de cellules prédéterminée dans une cuvette de mesure (1) dans laquelle on forme un champ électrique alternatif non homogène possédant une fréquence entre 10 kHz et 5 mHz et une tension moyenne du champ électrique E0 comprise entre 104 et 106 volt / m dans l'entrefer entre les électrodes, reliées avec une source d'alimentation électrique (4). On mesure les vitesses moyennes ξc du mouvement de chaque cellule dans la suspension et leur rayon moyen R dans les intervalles de temps déterminés pendant la période de l'action du champ électrique et après son extinction après un temps t par l'enregistrement vidéo du mouvement des cellules et de la modification de ses dimensions au moyen d'une caméra vidéo (6), relié optiquement à un microscope (5). Les données obtenues sont introduites et traitées sous forme numérique dans un ordinateur (7) contenant un programme de calcul d'accumulation et de traitement des données, ce qui permet de déterminer les caractéristiques de viscosité et d'élasticité des cellules.
PCT/RU2004/000336 2004-08-30 2004-08-30 Procede de mesure des caracteristiques de viscosite et d'elasticite des cellules d'objets biologiques, procede de diagnostic differentiel de maladies diffuses du foie d'origine virale ou alcoolique et dispositif pour mettre en oeuvre ces procedes WO2006036079A1 (fr)

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RU2004126112/15A RU2296327C2 (ru) 2004-08-30 2004-08-30 Способ дифференциальной диагностики заболеваний печени
RU2004126112 2004-08-30

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CN109142452A (zh) * 2018-10-26 2019-01-04 浙江师范大学 基于压阻式微悬桥传感器的血液粘弹力测量装置与方法
CN109142452B (zh) * 2018-10-26 2021-03-26 浙江师范大学 基于压阻式微悬桥传感器的血液粘弹力测量装置与方法

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