RU2787244C1 - Gas sensor cell for non-invasive analysis of human exhaled air - Google Patents

Abstract

FIELD: human condition research.

SUBSTANCE: invention relates to the field of research of the human condition by measuring the parameters of the composition of the inhaled air. Gas sensor cell for non-invasive analysis of the air exhaled by a person, including: an array of 1 to N semi-selective gas sensors with a different response mechanism selected in such a way as to give an uncorrelated response to disease markers contained in the exhaled air, an air temperature sensor, a relative air humidity; a measuring unit connected to the array of gas sensors, configured to apply a voltage of arbitrary amplitude to the electrodes of each gas sensor in the array and measure the time dependence of the value of the response parameter of each gas sensor in the array; a microprocessor to which a measuring unit, an air temperature sensor, a relative air humidity sensor are connected, while the microprocessor is configured to calculate the response value of each gas sensor in the array, average the obtained sensory response values, determine the probability of disease by analyzing the average sensory response values according to the classifier, previously stored in the memory of the microprocessor and obtained by measuring the sensory response for various samples of people with a particular disease or comparing average response values to compare the degree of a known disease.

EFFECT: improving the accuracy and reliability of measurement results.

2 cl, 5 dwg

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] The invention relates to the field of research and analysis of the human condition by measuring the parameters of the composition of the gas environment, which he exhales.

[0002] More specifically, the invention relates to gas analysis systems based on an array of semi-selective sensors with a different response mechanism and having cross-selectivity to nitrogen oxides, amines, sulfides, hydrocarbons, alcohols, aldehydes, terpenes, which are collectively known as marker volatile organic compounds (LOS) of various diseases.

[0003] The claimed invention can find application in the creation of devices and / or diagnostic complexes for primary non-invasive diagnostics and / or rapid testing for the presence of various diseases, for example, asthma, COPD, diabetes mellitus, acute respiratory diseases, which can be used to diagnose patients in medical facilities, in crowded places, as well as point-of-care devices for home use.

BACKGROUND OF THE INVENTION

[0004] A device for diagnosing human diseases by exhaled air is known [RU 51849U1, publication date 10.03.2006]. This device contains N gas sensors, each of which is designed to detect a specific gas in the exhaled air.

[0005] The main disadvantage of the device is its limited applications, since a person exhales about 750 compounds, and it is obvious that installing such a number of gas sensors is economically unprofitable and impossible, and, therefore, the device is capable of diagnosing a limited number of diseases.

[0006] A known method and system for rapid screening of pathogens in the breath using aptamers [CN 111381023A, publication date 07/07/2020]. The rapid screening system includes a mask with an adsorption membrane or a device for collecting pathogens in the breath by quick freezing, a device for irradiating the membrane with ultraviolet light or an oven for annealing the membrane to immobilize pathogens, an automatic liquid dispenser for adding a fluorescent reagent that can specifically bind to a protein of a pathogen or nucleic acid molecules on the membrane, a washer for washing the membrane of unreacted reagent, and a device for detecting fluorescence or color change.

[0007] The disadvantages of the method and system include the complexity of its execution, which makes the time to obtain data quite large, as well as the complexity of its restructuring for new compounds, because for each disease, the synthesis of a new reagent will be required, which, on the one hand, will have to join to the desired pathogen, and on the other hand, have a functional group that will provide a fluorescence signal in the required range.

[0008] An electronic nose system for detecting lung cancer in the early stages is known [CN 103018282B, publication date 07/15/2015]. This system contains: an array of sensors, which are monolayers of nanocrystals of various functional metals deposited on flat interdigital electrodes made of precious metals on a silicon substrate by thermal spraying; A sensitive metal nanocrystal monolayer was synthesized from metal nanoparticles using a specific organosulfidryl compound with various functional groups.

[0009] The disadvantage of this system may be its lack of sensitivity, since the resistive-type sensors used are usually less sensitive than FET-based devices. The disadvantages also include the use of one type of sensor elements in the array, while the use of sensors with a different response mechanism would make it possible to obtain less correlated responses, and thus detect not only lung cancer, but also other diseases.

[0010] An electronic nose system for early diagnosis and prediction of attacks of hereditary diseases associated with metabolism is known [WO 2020159464A3, publication date 09/24/2020]. The system consists of a set of metal oxide sensors, which are used to analyze the gas-air mixture.

[0011] The disadvantage of the system is a limited set of sensors, as well as the absence of any system for processing and interpreting information obtained using the sensors used.

[0012] A method is known for selective determination of the concentration of gaseous mercapto-containing and/or amine-containing compounds in a gaseous medium [RU 2675667C1, publication date 12/21/2018]. This result is achieved using a single gas sensor based on an organic field-effect transistor by measuring the amount of time change in the threshold voltage, which depends on the concentration of amine-containing compounds, while the amount of time change in the mobility of charge carriers depends on the concentration of mercapto-containing compounds.

[0013] The disadvantage of this method is the limited number of chemical compounds that can be selectively determined when using it.

[0014] A gas multisensor based on organic field-effect transistors and a device for analyzing a multicomponent gas mixture of the "electronic nose" type based on it are known [RU 2676860C1, publication date 01/11/2019]. The essence of the invention lies in the use of an array of organic field-effect transistors coated with different receptor layers based on various metalloporphyrins, which provide different selectivity of sensors in the array. Analysis of the responses of such an array using machine learning methods makes it possible to determine the type of gas and its concentration for compounds such as ammonia, hydrogen sulfide and nitrogen dioxide. Moreover, this technique also makes it possible to distinguish between these compounds in an unknown air mixture.

[0015] The disadvantage of this gas multisensor is the limited choice of sensors, which imposes a limitation on the number of analyzed chemical compounds, while the use of sensors with a different response mechanism (metal oxide sensors, electrochemical cells) can significantly expand the functionality of the detection system.

SUMMARY OF THE INVENTION

[0016] The technical problem to be solved by the claimed invention is to create a highly sensitive gas sensor cell for analyzing the composition of the gaseous medium exhaled by a person in order to non-invasively diagnose various diseases.

[0017] The technical result achieved in the implementation of the claimed invention is to create an embedded gas sensor cell containing an array of semi-selective sensors with different response mechanisms, which improves the accuracy and reliability of the measurement results due to the uncorrelated response from the individual sensors of the array. The ability to select different sensors ensures maximum analysis efficiency in the case of each specific disease characterized by different marker compounds in the composition of the exhaled gas mixture. The inventive gas cell can be a key element of medical devices that allow the analysis of exhaled air for the purpose of early diagnosis of various diseases, as well as for daily monitoring of the health of patients.

[0018] The claimed technical result is achieved due to the fact that the gas sensor cell for non-invasive analysis of air exhaled by a person includes:

an array of 1 to N gas sensors with a different response mechanism chosen to give an uncorrelated response to disease markers, an air temperature sensor, a relative air humidity sensor;

a measuring unit connected to the array of gas sensors, configured to apply a voltage of arbitrary amplitude to the electrodes of each gas sensor in the array and measure the dependence of the response parameter of each gas sensor in the array on time;

a microprocessor connected to a measuring unit, an air temperature sensor, a relative air humidity sensor, while the microprocessor is configured to calculate the response value of each gas sensor in the array, average the obtained values of sensory responses, determine the probability of disease or progression/remission of the disease by analyzing the averaged values sensory response according to a classifier previously stored in the memory of the microprocessor and obtained by measuring the sensory response for various samples of people with a particular disease, or comparing with previously obtained readings.

[0019] In addition, in a particular implementation, the gas array includes at least one sensor based on organic field-effect transistors, at least one electrochemical cell, and at least one metal oxide sensor.

[0020] An array of gas sensors with a different response mechanism has a significantly different selectivity and sensitivity range, which leads to the fact that the overall response to the mixture of compounds that make up the exhaled air of the patient will be significantly different and uncorrelated. This makes it possible to distinguish not only healthy people from sick people, which for a number of diseases is possible using a single sensor, in particular, monitoring the condition of asthma patients can be ensured by measuring only the level of nitric oxide II, which, for example, is implemented in the NOBreath device from Bedfont (https://www.bedfont.com/nobreath), but also distinguish different diseases from each other, including distinguishing in the early stages.

INFORMATION CONFIRMING THE IMPLEMENTATION OF THE INVENTION

[0021] The implementation of the invention is confirmed by the drawings, which show:

Figure 1 shows a diagram of the analysis of exhaled air with the collection of exhalation directly into the device.

Figure 2 shows a diagram of the analysis of exhaled air with pre-collection in a sampling bag, from which air is supplied to the sensor cell using a membrane pump.

Figure 3 shows a diagram of the analysis of exhaled air with pre-collection in a sampling bag, from which air is supplied to the sensor cell by creating a rarefied environment in the latter by vacuum.

Figure 4 shows the response of an array of sensors, consisting of 6 (six) sensors (graphs are numbered from (a) to (e) in order to demonstrate the response of each individual sensor in the array) when analyzing the exhaled air of a healthy person for 10 (ten) days . The horizontal line corresponds to the median value of healthy people.

Figure 5 shows the response of a sensor array consisting of 6 (six) sensors (graphs are numbered from (a) to (e) in order to demonstrate the response of each individual sensor in the sensor array). Under the same letters in figure 4 and figure 5, the same sensors are presented in the array when analyzing the exhaled air of a person who was initially in remission, but after 2 (two) days his condition worsened, and after another 5 (five) days began to return to normal. The horizontal line corresponds to the median remission.

In the drawings, positions have the following meanings:

1 - an array of sensors with a different response mechanism, located inside the sensor cell;

2 - air temperature sensor inside the sensor cell;

3 - relative air humidity sensor inside the sensor cell;

4 - sensor cell;

5 - measuring block;

6 - microprocessor with memory;

7 - electronic part;

8 - device for non-invasive analysis of air exhaled by a person;

9 - output device, PC, monitor, or built-in memory card;

10 - outlet valve;

11 - removable mouthpiece with filter;

12 - sampling bag;

13 - membrane pump with inlet filter;

14 - vacuum pump;

15 - inlet valve;

[0022] The device 8 for non-invasive analysis of air exhaled by a person, presented in figure 1, includes:

a sensor cell 4 including an array of gas sensors 1, an air temperature sensor 2 and a relative air humidity sensor 3;

measuring unit 5 containing a voltage source (not shown in the drawings) capable of applying a voltage of arbitrary amplitude to the electrodes (drain-source and gate-source in the case of organic field-effect transistors; a pair of electrodes in the case of metal oxide sensors and between the reference, measuring and counter electrode in the case of electrochemical cells) (not shown in the drawings) of each gas sensor 1 in the array, as well as a unit for measuring the response parameter (current, resistance, voltage) (not shown in the drawings), capable of simultaneously measuring the response parameter of each gas sensor 1 in the array, depending on time;

a microprocessor 6 connected to the voltage source and the response parameter measurement unit of the measuring unit 5, capable of supplying control voltages to the voltage source according to the measurement program;

device 9 for outputting measurement results.

removable mouthpiece with filter 11 for collecting exhaled air;

Microprocessor 6 is equipped with software that provides:

calculating an average response value for each gas sensor 1 in the array;

transforming an array of measured response values to determine the probability of a particular disease, for example, using machine learning methods;

storage in memory of data on calibration measurements with different samples of healthy and sick people with various diseases;

[0023] The microprocessor 6 is connected to the means 9 for outputting information to the user (for example, a monitor, a display, etc.).

[0024] Also connected to the microprocessor 6 is an air temperature sensor 2 and a relative air humidity sensor 3, which provide additional information about the exhaled air atmosphere, as well as heaters (not shown in the drawings) of the gas sensors of the array 1, which provide controlled heating of the gas array element. 1 sensors to control the speed of touch response and recovery.

[0025] In a preferred embodiment of the invention, the array of gas sensors 1 consists of sensors in an amount from 1 to N, including at least one sensor based on an organic field-effect transistor, consisting of two electrodes (“drain” and “source”), separated by a layer of an organic semiconductor, a gate electrode and a dielectric layer described, for example, in patent RU 2675667C1, at least one metal oxide sensor, consisting of two electrodes ("drain" and "source"), separated by a semiconductor layer, as well as a heater, which provides heating of the semiconductor to the operating temperature (the choice of temperature is determined by the required level of sensitivity [Metal Oxide Gas Sensors: Sensitivity and Influencing Factors // Sensors (Basel). - 2010. - V. 10, No. 3. - P. 2088-106.]) and at least one electrochemical cell consisting of three electrodes (reference, measurement and counter electrode) placed in the electrolyte.

[0026] The active layer of the organic semiconductor of an organic field-effect transistor can be obtained by any known method, including solution or printing technologies, and more specifically methods such as the rotating substrate method, the pouring method, the Langmuir-Blodgett and Langmuir-Schaeffer methods, thermal and magnetron sputtering in vacuum , the method of physical steam transport and others. Methods for obtaining by the Langmuir-Blodgett and Langmuir-Schaeffer methods, as well as by the rotating substrate method are described in the article [Operationally Stable Ultrathin Organic Field Effect Transistors Based on Siloxane Dimers of Benzothieno[3,2-B][1]Benzothiophene Suitable for Ethanethiol Detection // advanced electronic materials. - 2022. - P. 2101039. DOI: 10.1002/aelm.202101039.].

[0027] In a preferred embodiment of the invention, different response selectivity of gas sensors 1 based on organic field-effect transistors in an array is achieved by coating the semiconductor layer of the transistor with an additional receptor layer. Such gas sensors are described, for example, in patent RU 2676860C1, where thin films of metalloporphyrins with various metals in the coordination center were used as receptor layers. Also, different selectivity of sensors in the array is provided by the use of metal oxide sensors and electrochemical cells with various semiconductors or selective membranes [Online Breath Analysis Using Metal Oxide Semiconductor Sensors (Electronic Nose) for Diagnosis of Lung Cancer // J Breath Res. - 2019. - V. 14, No. 1. - P. 016004.].

[0028] The need to use an array of gas sensors 1 sensors with a different response mechanism is due to the fact that the recognition efficiency of healthy and sick people decreases when using sensors of the same type that give a correlated response, since the use of the latter does not allow obtaining additional information and distinguishing diseases from each other.

[0029] The inventive gas sensor cell can be used to create a device for non-invasive analysis of air exhaled by a person, which contains a removable mouthpiece 11 with a filter, while the sensor cell 4 (Fig. 1) is connected by tubes to the mouthpiece 11, which ensures the collection of exhalation directly into the sensory cell, whose outlet is connected to valve 10, which ensures the discharge of the test sample. At the same time, a clean air supply system can be connected to the input of the sensor cell 4 to purge the cell before the next diagnostic cycle (not shown in the drawings).

[0030] In a particular case of the implementation of a device for non-invasive analysis of the air exhaled by a person, the sensor cell 4 (Fig. 2) is connected to the membrane pump 13, which acts as a forced sampling system from the sampling bag 12, in which the analyzed exhaled air is preliminarily collected.

[0031] In a particular case of the implementation of a device for non-invasive analysis of air exhaled by a person, the sensor cell 4 (Fig. 3) is connected to a vacuum pump 14, which acts as a forced sampling system from a sampling bag 12 connected to the inlet of the sensor cell 4 through a valve 15. For sampling, valve 15 closes in this way, valve 10 opens, a rarefied atmosphere is created in cell 4 with the help of a vacuum pump 14, valve 10 closes, valve 15 opens, and due to the pressure difference in the sampling bag 12 and sensor cell 4, a portion of the exhaled air enters the latter.

[0032] The use of a device for non-invasive analysis of air exhaled by a person containing the inventive gas sensor cell is carried out as follows:

, одновременно измеряя величины параметров отклика (ток, сопротивление, напряжение)

, представляющие собой сигналы газовых сенсоров 1 в зависимости от времени. Длительность и период подачи напряжения выбирается так, чтобы минимизировать дрейф базовой линии при этом получая максимально высокую сенсорную чувствительность каждого газового сенсора 1 в массиве. Во время процедуры первичной калибровки значения параметров отклика для каждого из газовых сенсоров 1 измеряются

в 95% влажном воздухе, сохраняются в памяти микропроцессора 6 и далее используются как параметр для расчета сенсорного отклика

по формуле

. [0033] An exhalation sample of a person being diagnosed, containing various metabolites, whose composition and concentration change during illness, is sent to a sensor cell 4, which includes an array of N gas sensors 1, consisting of organic field-effect transistors, metal oxide sensors and electrochemical cells using one of sampling method: directly using a removable mouthpiece 11 with a filter (figure 1) or forcibly using a membrane pump 13 or a vacuum pump 14, while the sample of exhaled air is collected in advance in the sampling bag 12 (figure 2,3). The electrodes (not shown in the drawings) of each of N gas sensors 1 in the array using a multi-channel voltage source (not shown in the drawings) of the measuring unit 5 are supplied with a rectangular voltage with a duration t and a period T of the amplitude

while simultaneously measuring the magnitude of the response parameters (current, resistance, voltage)

, representing the signals of gas sensors 1 depending on time. The duration and period of the voltage application is chosen to minimize baseline drift while maximizing the sensory sensitivity of each gas sensor 1 in the array. During the initial calibration procedure, the response parameter values for each of the gas sensors 1 are measured

in 95% humid air, stored in the memory of the microprocessor 6 and then used as a parameter for calculating the sensory response

according to the formula

.

с заданной периодичностью T, которые усредняются в микропроцессоре 6 для каждого газового сенсора 1 по времени для получения средних откликов R на выдыхаемый воздух. Средние значения откликов R сравниваются либо с предыдущими данными диагностируемого, чтобы понять степень прогрессии/ремиссии его болезни либо сравниваются с классификатором болезней, измеренным, рассчитанным, например, методами машинного обучения и занесенным предварительно в память микропроцессора 6. [0034] Thus, with each measurement, an array of N gas sensors 1 generates a series of values

with a given periodicity T, which are averaged in the microprocessor 6 for each gas sensor 1 over time to obtain average responses R to the exhaled air. The average response values R are compared either with the previous data of the diagnosed person in order to understand the degree of progression / remission of his disease, or compared with the disease classifier, measured, calculated, for example, by machine learning methods and previously entered into the memory of the microprocessor 6.

[0035] Figure 4 (a)-(e) shows the dynamics of responses from an array of various sensors 1 to the exhaled air of a healthy person. The figure shows the middle line, which takes into account the spread of responses R, which occurs because the fence was made at different times of the day. Figure 5 (a)-(e) shows the dynamics of the disease, which is reflected in the change in the response R of the gas sensors 1, as well as the subsequent remission after the disease, in which the response R of the gas sensors 1 returns to the remission level.

Claims (5)

1. Gas sensor cell for non-invasive analysis of air exhaled by a person, including: an array of 1 to N semi-selective gas sensors with a different response mechanism chosen to give an uncorrelated response to disease markers contained in the exhaled air, an air temperature sensor, a relative air humidity sensor; a measuring unit connected to the array of gas sensors, configured to apply a voltage of arbitrary amplitude to the electrodes of each gas sensor in the array and measure the time dependence of the value of the response parameter of each gas sensor in the array; a microprocessor connected to a measuring unit, an air temperature sensor, a relative air humidity sensor, wherein the microprocessor is configured to calculate the response value of each gas sensor in the array, average the obtained sensory response values, determine the probability of disease by analyzing the averaged sensory response values according to the classifier, pre-stored in the memory of the microprocessor and obtained by measuring the sensory response for different samples of people with a particular disease or comparing average response values to compare the degree of a known disease. 2. Gas sensor cell according to claim 1, characterized in that the array of gas sensors includes at least one sensor based on organic field-effect transistors, at least one electrochemical cell and at least one metal oxide sensor.

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