RU38568U1 - DEVICE FOR NON-INVASIVE DIAGNOSIS OF HELICOBACTER PYLORI INFECTION - Google Patents

Abstract

The invention relates to devices for non-invasive atraumatic diagnosis of gastroduodenal diseases caused by bacteria Helicobacter pylori (hereinafter referred to as H. pylori), in particular, to a device that allows the determination and recording of urea hydrolysis products of urea H. pylori, namely ammonia with associated organic amines (hereinafter ammonia). The device contains a means of sampling air from the oral cavity, connected to the input of a specially designed chamber in which the ammonia electrochemical sensor is located, as well as signal measuring, processing, and signal indicators that can repeatedly receive signal values from the ammonia electrochemical sensor characterizing the ammonia content in the oral cavity patient, and accumulate these values. The device can significantly increase the specificity of determining H. pylori infection, reduce the likelihood of a false positive diagnosis and determine the presence of infection in poorly infected patients.

Description

The invention relates to devices for non-invasive atraumatic diagnosis of gastroduodenal diseases caused by bacteria Helicobacter pylori (hereinafter referred to as H. pylori), in particular, to a device that allows the determination and recording of urea hydrolysis products of urea H. pylori, namely ammonia with associated organic amines, in expired air (hereinafter ammonia).

Known indicator tubes [patent RU No. 2100010 "Method for the non-invasive diagnosis of Helicobacteriosis in vivo", Kornienko EA, Mileiko V.E., publ. 12/27/97 Bull. No. 36], commonly used in gas analytical practice for analyzing air for ammonia content, using which they control the ammonia content in the air of the oral cavity. These tubes are filled with selective chemisorbent, quantitatively adsorbing ammonia. When passing through the tube samples of the analyzed air in the sorption zone, the sorbent changes color. The linear dimensions of the colored column are proportional to the ammonia content in the sample.

The use of glass tubes is unsafe for both the doctor and the patient. Their use leads to a long duration of the survey due to the need for two measurements and their relatively low sensitivity. Also, the tubes do not allow a clear conclusion about the infection of the patient due to the small difference in the levels of the linear dimensions of the stained chemisorbent, corresponding to the initial and load contents of ammonia.

Closest to the claimed device is [US Patent No. 6509169, IPC C 12 Q 1/04 Detection of Helicobacter pylori I Ratcliff N. et at. - Publ. 01/21/2003], containing two chambers, each of which has an inlet for receiving the analyzed air and each of them contains an electronic or electrochemical ammonia sensor that changes its resistance when exposed to an air sensor from the patient's lungs and / or stomach. In one of these chambers, ammonia absorption means is disposed between the inlet and the sensor. The sensors are connected to a means for measuring their electrical resistance. The device also has a means for comparing the resistances of both sensors and means for producing a visible output signal.

The device operates as follows: a gas sample is obtained from the patient’s stomach and / or lungs and injected into two chambers with sensors, and one of them has a means for absorbing ammonia. Thus, when air passes through the sensors, one of them receives a signal in the form of a resistance corresponding to the content of ammonia in the air, and on the other, a signal corresponding to this sample of air with the exception of ammonia from it on an ammonia-absorbing agent. These signals are compared electronically and the result of the comparison is a visible signal corresponding to a positive or negative diagnosis.

The disadvantage of this device is that it involves a single determination of the ammonia content, i.e. only the initial content, and the diagnosis based on this definition. This can lead to an inaccurate diagnosis, as this value is affected not only by the patient’s presence of H. pylori infection, but also by the functioning of his liver and kidneys.

The sensitivity of the device is small, as it is designed to work with small air samples. Due to the low sensitivity, the device does not allow to reliably diagnose a slightly infected patient whose ammonia content is slightly higher than that of an uninfected patient.

In addition, the loss of the detected component at the stage of sampling and air transfer to the sensor due to the use of an intermediate tank is possible. In this case, both in this intermediate tank and on all the connecting elements of the device, ammonia sorption is possible, leading to a distortion of the measurement result.

The task to which the invention is directed is the development of a device for non-invasive diagnosis of H. pylori infection, which is more sensitive and allows you to more reliably determine the presence of infection in patients, especially weakly infected

The essence of the claimed invention lies in the fact that in a device for non-invasive diagnosis of H. pylori infection in vivo, containing a means of sampling air from the oral cavity, connected to the input of the chamber, in which the ammonia electrochemical sensor is located, as well as measuring, processing and signal indication , the chamber is made integral, its lid and base, when connected, form a channel for the passage of an air sample, while the ammonia electrochemical sensor is fixed at the base of the chamber so that its sensitive the part is located in the cavity of the channel for the passage of the air sample, in front of it in the direction of the air in the cavity of the channel for the passage of the air sample

an air heating unit is installed, the camera output is connected to an aspiration device, an additional unit for protection of the electrochemical ammonia sensor, an amplification and filtering unit for the channel of the electrochemical ammonia sensor are introduced into the device, and the signal measuring, processing and indication devices include a measuring unit, a processing and control unit, a memory unit and an indication unit, wherein the first output of the electrochemical ammonia sensor is connected to the input of the protection unit of the electrochemical ammonia sensor, the first output of which is connected to the input the electrochemical ammonia sensor, and the second output with an amplification and filtering unit channel of the electrochemical ammonia sensor, the output of which is connected to the first input of the measurement unit, and the output of which is connected to the first input of the processing and control unit, the third output of which is connected to the input of the memory unit, the fourth output the processing and control unit is connected to the input of the display unit, and the second input of the processing and control unit is connected to the output of the memory unit.

A temperature sensor can be installed in the chamber next to the electrochemical ammonia sensor, and a temperature sensor channel amplification and filtering unit is added to the device, the input of which is connected to the temperature sensor output, and the output of the temperature sensor channel amplification and filtering unit is connected to the second input of the measurement unit.

The input of the air heating unit can be connected to the first output of the processing and control unit.

The input of the suction device can be connected to the second output of the processing and control unit.

A means of sampling air from the oral cavity is placed in front of the camera, connected to it by a hose and may be a mouthpiece, the design of which allows it to be fixed in the patient’s mouth and serves as a barrier for saliva to enter the sample of taken air [Baraldi E. et al. Measurement of exhaled nitric oxide in children, 2001 // Eur. Respir. J. - 2002. - Vol. 20. - P.223-237].

The chamber in which the electrochemical sensor is located is made integral, its lid and base, when connected, form a channel for the passage of an air sample.

The camera can be made of chemically resistant plastic, its shape and dimensions are determined by the dimensions of the sensor and other elements of the device placed in it.

The electrochemical ammonia sensor, is, for example, a two-electrode sensor [Technical description of the ammonia sensor E-2 0-200 ppm NH ₃ . National Technical University of Ukraine "Kiev Polytechnic Institute"], or three-electrode ZAM sensor manufactured by City Technology.

The electrochemical sensor is fixed at the base of the chamber in such a way that its sensitive part is located in the cavity of the channel for the passage of the air sample.

In the direction of the air in front of the electrochemical sensor, an air heating unit is installed on the base of the camera, which can be made in the form of an MLT resistor, located in the channel of the camera, and is fixed, for example, on the base of the camera.

An air heating unit is installed in front of the electrochemical ammonia sensor in order to prevent condensation of water vapor on the sensitive surface of the sensor by heating the analyzed air.

For example, a temperature sensor can be installed on the base of the camera next to the electrochemical ammonia sensor, which, for example, is made in the form of an AD 22100 chip. A temperature sensor is installed, for example, next to the electrochemical ammonia sensor due to the fact that this arrangement allows you to quickly track a change in the temperature of the air in the chamber in the sensor region, converting the air temperature in the chamber channel into an electrical signal to enable monitoring of the temperature.

The outlet of the chamber is connected to an aspiration device providing forced air supply from the oral cavity through the chamber. The device is installed behind the camera, connected to it via a hose, and can be made in the form, for example, of an aspirator or microcompressor [Zolotov Yu.A., Ivanov V.M., Amelin V.G. Chemical test methods of analysis. - M .: Editorial URSS, 2002. - S.240-241].

In the electronic part of the device are additionally introduced:

- ammonia sensor protection unit, the circuit of which allows both in the case of using a two-electrode sensor and a three-electrode:

- convert the signal from the electrochemical ammonia sensor in the form of an electric current to voltage.

- protect the sensor from overloads at high levels of ammonia in the sample of analyzed air

- prevent the polarization of the sensor when the device is in the off state, which ensures its immediate availability for operation immediately after turning on the device.

During operation of the device, in the case of using a three-electrode sensor, this unit allows you to compensate for the polarization of the sensor, which leads to a narrowing of the measuring range of the sensor.

Saving the electrochemical sensor in the operating mode significantly speeds up the operation of the device and increases the reliability of the diagnosis. At

when the device is operated with several patients in a row in the event of a severe infection of one of them, and, consequently, a high concentration of ammonia in the air exhaled by them, the ammonia sensor can enter saturation mode and, leaving it, affect the diagnosis of the next patient, since In this case, nonlinear distortions occur and the electric current at the output of the sensor is not proportional to the actual concentration of ammonia in the air.

The amplification and filtering unit of the channel of the electrochemical ammonia sensor can be made, for example, based on the AD 8542 microcircuit and contains a two-stage amplifier. The first cascade is a differential amplifier circuit, and the second cascade is a non-inverting amplifier circuit. This unit is used to amplify and filter the signal in the channel of the electrochemical ammonia sensor, which prepare the signal for further processing.

The amplification and filtering unit of the temperature sensor channel can be performed, for example, based on the AD 8541 microcircuit and contains, for example, a non-inverting amplifier. This unit also serves to amplify and filter the signal in the channel of the temperature sensor, if necessary for further signal processing.

Means for measuring, processing and indicating the signal of the device contain:

- measurement unit,

- processing and control unit,

- memory block

- display unit,

The functions of the measurement unit, the processing and control unit, and the memory unit in the inventive device are performed by a microcontroller, for example, an ATMeda 163-8-A1 type manufactured by ATMEL.

The display unit can be made in the form of an LCD WH WH220A-NGG-CP from WINSTAR, it displays the processing results and operating modes of the device.

Using a computer interface unit, which can be made in the form of FTDI232 or ADM202 microcircuits, depending on the type of interface, the processing results and operating modes of the device can be transferred to a personal computer via a standard USB or RS-232 interface. Through the same unit and interface, a program embedded in a personal computer allows you to control the operation of the device.

The inventive device is organized and designed to analyze samples of a larger volume of air (total volume of 1-10 l). The device can significantly increase the specificity of determining the infection, reduce the likelihood

making a false positive diagnosis and determining the presence of infection in poorly infected patients due to the possibility of repeatedly receiving signal values from an electrochemical ammonia sensor characterizing the ammonia content in the patient's oral cavity, accumulating these measurements and processing in a certain way. The device is easy to use, which facilitates the work of medical staff. The device is structurally solved in such a way that the path length of the air sample from the oral cavity to the sensor is minimized due to the absence of intermediate containers for collecting or transporting air samples. This allows you to reduce the loss of the determined component due to its sorption on the walls of these containers and connecting elements.

The patient’s infection is determined by comparing the signal values corresponding to the initial ammonia content in the air of the oral cavity with the signal values corresponding to the loading ammonia content. Infection can be determined once, or continuously, or periodically.

In this case, the comparison is carried out both by the maximum values of the signals and by the average values of the signals. The rates of increase in signal values over a specific time interval can also be compared, which allows the kinetics of enzymatic hydrolysis to be estimated.

The essence of the claimed device is illustrated by graphic materials, which depict:

Figure 1 - block diagram of a device for non-invasive diagnosis of Helicobacter pylori infection;

Figure 2 - connection diagram of the protection unit of the electrochemical sensor for a two-electrode sensor

Figure 3. - wiring diagram for the protection block of an electrochemical sensor for a three-electrode sensor.

Figure 4 - camera design.

The device contains (figure 1): a sampling device 1 connected by a hose to the inlet of the chamber 2, composed of a cover 3 and a base 4 with the formation of a channel between them for the passage of an air sample (figure 4). In this chamber 2, on the base 4, an air heating unit 5 is installed, followed by an electrochemical ammonia sensor 6, so that its sensitive part is located in the cavity of the channel of the chamber 2. Next to the electrochemical ammonia sensor 6 on the base 4 of the chamber 2 is a temperature sensor 7. The outlet of the chamber 2 is connected by a hose to the suction device 8. The device also contains

the protection unit of the electrochemical ammonia sensor 9, the amplification and filtering channel of the electrochemical ammonia sensor 10, the amplification and filtering channel of the temperature sensor 11, and the means for measuring, processing and indicating the signal comprise a measurement unit 12, a processing and control unit 13, a memory unit 14 and a unit indication 15, and can also be used in conjunction with a computer 16.

The first output of the electrochemical ammonia sensor 6 is connected to the first input of the protection unit of the electrochemical ammonia sensor 9, the second output of the electrochemical ammonia sensor is connected to the second input of the protection unit of the electrochemical ammonia sensor 9, the first output of which is connected to the input of the electrochemical ammonia sensor 6, and the second output the input of the amplification and filtering unit of the channel of the electrochemical ammonia sensor 10, the output of which is connected to the first input of the measurement unit 12, the second input of which is connected to the output of the unit filtering and filtering the channel of the temperature sensor 11, the input of which is connected to the output of the temperature sensor 7, and the output of the measuring unit 12 is connected to the first input of the processing and control unit 13, the first output of which is connected to the input of the air heating unit 5, the second output is connected to the input of the suction device 8, the third output with the input of the memory unit 14, the fourth output with the input of the display unit 15, and the second input of the processing and control unit 13 is connected to the output of the memory unit 14, in addition, the fifth output of the processing and control unit 13 can be connected with an input unit for interfacing with the computer 16, the output of which in this case is linked to the third input of the processing and control unit 13.

A diagram of the protection block of the electrochemical ammonia sensor 9 and its connection to the electrochemical ammonia sensor 6 is shown in FIG. 2 for a two-electrode electrochemical ammonia sensor, and in FIG. 3 for a three-electrode electrochemical ammonia sensor.

For a two-electrode sensor, the protection unit of the electrochemical ammonia sensor 9 contains a current-voltage converter 17, a bias source 18, a voltage limiter 19, a key 20, a load resistance 21, while the output of the current-voltage converter 17 is connected to the input of the limiter 19, and is the second output of the block protect the electrochemical ammonia sensor 9, the output of the limiter 19 is connected to the first input of the current-voltage converter 17, and to the first output of the load resistance 21, the second output of which is connected to the second output m of the key 20 and is the input of the protection unit of the electrochemical sensor 6, the first output of the key 20 is connected to the output of the bias source 18, with the second input of the current-voltage converter and is the first output of the protection unit of the electrochemical sensor 6.

For a three-electrode sensor, the protection unit of the electrochemical ammonia sensor 9 further comprises a device for compensating the polarization voltage of the electrochemical sensor 6.

The device operates as follows:

In the oral cavity of the patient is placed a means of sampling air 1 in the form of a mouthpiece. Air through the connecting hose enters the chamber 2 and is forced through the chamber due to the operation of the suction device 8. The air in the chamber is heated due to the operation of the unit 5 installed in the channel of the chamber 2 in front of the electrochemical ammonia sensor 6. Then, heated air passes through the channel of the chamber 2 above the sensitive surface the electrochemical sensor of ammonia 6 and enters the temperature sensor 7. The electrochemical sensor of ammonia 6 produces signals in the form of an electric current proportional to holding the ammonia in the air sample, which was supplied to the sensor.

Further, this signal in the form of an electric current is supplied to the first input of the protection unit of the electrochemical ammonia sensor 9, and converted to voltage when passing through the current-voltage converter 17, it is fed to the input of the amplification and filtering unit of the channel of the electrochemical sensor 10. In case of high infection of the patient, and accordingly high concentration of ammonia in the analyzed air, the value of the output current of the electrochemical ammonia sensor 6 exceeds the permissible value. In this case, the voltage limiter 19 eliminates the saturation of the current-voltage converter 17, providing its low input resistance and the required load of the electrochemical ammonia sensor 6, equal to the value of the load resistance 21. The load resistance linearizes the conversion characteristic of the electrochemical ammonia sensor 6.

In the case of polarization of the sensor after examination of a highly infected patient, the sensor remains polarized, which may affect the result of the analysis of the next patient. In this case, the polarity of the current coming from the electrochemical sensor of ammonia 6 is changed. The bias source 18 allows the reverse current to pass through the current-voltage converter 17.

In the operating mode of the device, the conclusions of the key 20 are open and do not affect the operation of the device circuit. In the absence of a supply voltage, the current flowing from the electrochemical ammonia sensor 6 cannot pass through the current-voltage converter 17. In this case, the current passes through a key 20, the terminals of which close the input and output of the electrochemical ammonia sensor 6, ensuring its protection from polarization.

The current-voltage converter 17 is made, for example, on the basis of an op amp type AD 8606, the bias source 18 is based on a silicon diode BAV99, the voltage limiter 19 is based on a Zener diode type KC133A, the key 20 is a field-effect transistor KP103, the load resistance 21 is an SMD resistor .

In the case of using a three-electrode sensor, a polarization compensation unit 22 should be introduced into the circuit of the protection unit of the electrochemical sensor 9.

A voltage proportional to its polarization is removed from the second (additional) output of the electrochemical ammonia sensor 6, which is fed to the second input of the polarization compensation unit 22, where it is compared with the bias voltage. The comparison result from the output of the polarization compensation unit 22 is fed to the input of the electrochemical ammonia sensor 6 in the form of a voltage compensating for the internal voltage of its polarization.

Otherwise, the operation of the protection unit of the electrochemical ammonia sensor 9 with a three-electrode sensor is similar to the operation of the protection unit for a two-electrode sensor.

Next, the electrical signal from the output of the protection unit of the electrochemical ammonia sensor 9 is fed to the input of the amplification and filtering unit of the channel of the electrochemical ammonia sensor 10, where it is amplified and filtered for further processing. The same function is performed by the amplification and filtering unit of the channel of the temperature sensor 11, which amplifies the electrical signal from the output of the temperature sensor 7. The measurement unit 12, implemented as a 10-bit analog-to-digital converter integrated in the microcontroller, converts the analogue electrical signals received at its inputs into digital form. The processing and control unit 13, using the program for the microcontroller, collects digital data from the measurement unit 12, processes it and stores it together with the processing results using the memory unit 14, implemented as a built-in static memory of the microcontroller. Another function of the processing and control unit 13 is to maintain the temperature at the sensor within specified limits. In this case, the processing and control unit 13 analyzes the data of the temperature sensor 7 and, depending on their value, controls the air heating unit 5. The processing results and operating modes of the device are displayed using the display unit 15, implemented, for example, in the form of a standard liquid crystal display. The same results can be sent using the interface unit with computer 16 to a personal computer via a standard USB or RS-232 interface. Through the same unit and interface, a personal computer program can control the operation of the device.

The device is “protected” by the survey methodology, namely, the program implemented by the microcontroller. Thus, the possibility of disrupting the order of actions during the survey is eliminated, gross blunders are excluded, and the measurement error is reduced by accurately measuring time intervals and eliminating the influence of the human factor.

The specific procedure and conditions for the diagnosis implemented using this device has the form of a program that operates, for example, according to the following algorithm:

1. The measurement period is divided into two sections:

"Basal" - lasting 1.5 minutes.

"Load" - lasting 7.5 minutes.

2. The measurement cycle begins immediately after the patient has taken urea.

3. Measurement is made 1 time per second.

4. The arithmetic average of all measurements in each of the sections is calculated.

5. The arithmetic mean values for the “basal” and “load” sections are compared.

6. These average values are displayed on the display device in the form of two columns whose heights are proportional to the arithmetic mean values.

7. Based on the ratio of the heights of the columns, a conclusion is made about the infection of the patient.

Claims (4)

1. Device for non-invasive diagnosis of Helicobacter pylori infection, containing means for sampling air from the oral cavity, connected to the input of the chamber, in which the electrochemical ammonia sensor is located, as well as means for measuring, processing and indicating the signal, characterized in that the camera is made integral the lid and the base, when connected, form a channel for the passage of an air sample, while the ammonia electrochemical sensor is fixed in the base of the chamber so that its sensitive part is located in the cavity of the channel I pass the air sample, in front of it in the direction of the air flow in the cavity of the channel for the passage of the air sample, an air heating unit is installed, the camera output is connected to an aspiration device, the protection unit of the electrochemical ammonia sensor, the amplification and filtering unit of the channel of the electrochemical ammonia sensor are introduced into the device, and means for measuring, processing and indicating a signal comprise a measuring unit, a processing and control unit, a memory unit and an indicating unit, wherein the first output of the electrochemical ammonia sensor is connected is connected to the input of the protection unit of the electrochemical ammonia sensor, the first output of which is connected to the input of the electrochemical ammonia sensor, and the second output to the input of the amplification and filtering unit of the channel of the electrochemical ammonia sensor, the output of which is connected to the first input of the measurement unit, the output of which is connected to the first input of the processing unit and control, the third output of which is connected to the input of the memory unit, the fourth output of the processing and control unit is connected to the input of the display unit, and the second input of the processing and control unit is connected nen yield of the storage unit. 2. The device according to claim 1, characterized in that a temperature sensor is installed in the camera next to the electrochemical ammonia sensor, an amplification and filtering unit for the temperature sensor channel is added to the device, the input of which is connected to the output of the temperature sensor, and the output of the channel amplification and filtering unit a temperature sensor is connected to the second input of the measurement unit. 3. The device according to claim 1, characterized in that the input of the air heating unit is connected to the first output of the processing and control unit. 4. The device according to claim 1, characterized in that the input of the suction device is connected to the second output of the processing and control unit.