KR20180037350A - Apparatus for diagnosing diseases using exhaled breath analysis - Google Patents

Abstract

The present invention provides an apparatus for diagnosing diseases using exhaled breath analysis, which diagnoses a disease by analyzing gas caused by the exhalation of a subject. The apparatus comprises: an exhalation inflow unit into which the exhalation of a subject flows; and a detection unit which detects mixed gas of VOCs in the exhalation that has passed through the exhalation inflow unit. The detection unit includes ion mobility spectroscopy (IMS).

Description

[0001] APPARATUS FOR DIAGNOSING DISEASES USING EXHALED BREATH ANALYSIS [0002]

The present invention relates to a disease diagnosis technique for diagnosing a human disease by analyzing human expiration.

The samples needed to diagnose the disease by expiration analysis are alveolar air containing VOCs and various gas components through gas exchange between the alveolar air and the blood in the capillary with the alveoli wall interposed. The alveolar air contains a biomarker, Which is the major component of the product.

Biomarker is a morphological, biochemical, and molecular biologic change characteristic of carcinogenesis, genetic disease, and obesity. It is possible to determine the risk of a substance by searching biomarkers. .

Figure 1 is a device for diagnosing disease through biomarker analysis in a conventional non-invasive human breath.

As shown in FIG. 1, in the disease diagnosis apparatus through the conventional breath analysis, a device configured based on a sensor array is used to detect a specific principal ingredient. In addition, a GC column was used to separate the components of the mixed analyte into individual components before reaching the detection sensor, and a 3-way solenoid valve was applied as a sampling device for collecting alveoli in the human breath.

First, the sensor array-based detection device has low sensitivity and low reproducibility when used over a long period of time. In order to analyze the pattern of the main component classified as the biomarker, it is necessary to fabricate a sensor capable of detecting a specific principal component material. If this process is not easy and a new substance is identified as a biomarker and needs to be detected, There is a problem in that a new sensor must be manufactured. In addition, it is necessary to show an electrical signal change only for the target substance, since an electrical signal due to interaction with not only the target substance but also similar substances may be generated, so that the generated signal is due to the main component classified as the biomarker, It is impossible to clearly distinguish whether or not it is caused by a defect.

Also, before the various VOCs present in the exhaled breath reach the sensor, a GC column of meter length was used to separate the components of the mixed analyte into their respective components Such a GC column has a low sample capacity, a small flowable flow range, and a long column length, which takes a long time to separate the mixed components, resulting in a long total analysis time And it takes a lot of time to check the diagnosis result through analysis results.

In order to diagnose diseases through exhalation analysis, the air of the alveoli from the exhalation process should be collected and measured. In order to collect the air of the alveoli, one unit should be spit long (about 350mL or more). In the past, there is only a 3-way solenoid valve for collecting the alveolar air in the sampling loop. There is a problem that it is difficult to confirm whether the air collected in the sampling loop is the air of the alveoli.

The inventor of the present invention has studied for a long time to solve the above problems, and after trial and error, has come to complete the present invention.

An object of the present invention is to provide a disease diagnosis apparatus by analyzing the breath of a person in a non-invasive manner to obtain a disease diagnosis result in a short time.

In addition, the present invention provides a disease diagnosis apparatus by means of breath analysis which can improve the reliability of diagnostic results by lowering the false positive rate.

On the other hand, other unspecified purposes of the present invention will be further considered within the scope of the following detailed description and easily deduced from the effects thereof.

In order to solve the above problems, a first aspect of the present invention is a disease diagnosis apparatus for analyzing a gas caused by an exhalation of a subject to diagnose a disease through exhalation analysis,

An exhale inflow portion into which the exhalation of the examinee flows; And

And a detection unit for detecting a mixed gas of VOCs in the exhalation unit that has passed through the exhalation inlet unit,

Characterized in that the detector comprises Ion Mobility Spectroscopy (IMS)

And provides a disease diagnosis device through exhalation analysis.

In addition, the present invention is characterized in that when the flow rate of the exhalation unit that is formed between the exhalation unit and the IMS and flows through the exhalation unit has been set to a predetermined fixed amount, the exhalation unit is directly discharged and the flow rate of the exhalation unit passing through the exhalation unit is And an expiration supply regulator for supplying the expiration date to the IMS when the expiration amount is equal to or larger than the predetermined amount.

Wherein the exhalation supply regulator comprises:

A flow rate measuring unit for measuring a flow rate of the exhalation unit passing through the exhalation unit;

A sample loop temporarily accommodating the patient to adjust the supply of the patient to the IMS according to the flow rate of the patient measured by the flow measuring unit;

A 6-way valve for controlling a movement line of the ox unit to the sample loop and a movement line of a carrier gas to move the ox unit through the sample loop to the IMS; And

And a control unit for controlling the 6-way valve according to the flow rate of the exhalation measured by the flow rate measuring unit to control supply of the exhalation unit accommodated in the sample loop to the IMS.

The present invention may further comprise an MCC column (Multi-Capillary Column) formed between the exhalation supply regulating unit and the IMS and separating various mixed gas components in the exhalation before the exhalation unit is supplied to the IMS.

Further, the present invention may further include a first temperature controller for maintaining the temperature of the sample loop and the inside of the 6-way valve at a predetermined temperature.

Further, the present invention may further include a second temperature controller for maintaining the temperature inside the MCC column at a preset temperature.

The present invention may further include a third temperature controller for maintaining the temperature of the IMS at a preset temperature.

The present invention may further comprise a gas supply unit for supplying a carrier gas for moving the ox unit to the IMS and a drift gas for guiding a magnetic field while moving in a direction opposite to the moving direction of the ox unit within the IMS.

Wherein the carrier gas and the drift gas are the same gas and include nitrogen gas or air,

The gas-

A gas tank for containing the nitrogen gas or air;

And a Y-fitting that is connected to the gas tank and divides the nitrogen gas or air contained in the gas tank into a carrier gas and a drift gas.

In addition, the gas tank may be replaced with an external air suction pump and a filter.

The present invention may further comprise a moisture removing filter formed between the expiratory volume inlet and the flow volume measuring unit to remove moisture from the expired volume passed through the expiratory volume inlet.

By using the present invention, an IMS sensor having excellent sensitivity and reproducibility can be applied to detect VOCs or the like, which is a main component classified as a biomarker, thereby reducing the false-positive rate and improving the reliability of the diagnosis result.

In addition, since the MCC is used for pre-separation faster than the conventional method, the total analysis time is shortened, and the diagnosis result can be confirmed within a short time.

Since IMS outputs detection signals for various VOCs, each data can be constructed for diagnosis of various diseases based on the topographic plot.

On the other hand, even if the effects are not explicitly mentioned here, the effect described in the following specification, which is expected by the technical features of the present invention, and its potential effects are treated as described in the specification of the present invention.

FIG. 1 is a diagram showing an apparatus for diagnosing a disease through biomarker analysis in a conventional non-invasive human breath.
FIG. 2 is a diagram illustrating a disease diagnosis apparatus using breath analysis according to an embodiment of the present invention. Referring to FIG.
FIG. 3 is a diagram illustrating an IMS of a disease diagnosis apparatus using breath analysis according to an embodiment of the present invention. Referring to FIG.
4 is a diagram illustrating an analysis of a signal obtained from an IMS according to an embodiment of the present invention into an output signal based on a topographic plot.
FIG. 5 is a view showing a connection state of a 6-way valve and a flow of an exhalation when the exhalation flow rate according to an embodiment of the present invention has not reached a preset value.
FIG. 6 is a view showing a connection state of a 6-way valve and a flow of an exhalation flow when an exhalation flow rate according to an embodiment of the present invention has reached a preset value.
7 is a view illustrating the separation of mixed gas components by an MCC column according to an embodiment of the present invention.
FIG. 8 is a view showing a configuration using outside air as a drift gas and a carrier gas according to an embodiment of the present invention.
FIG. 9 is a view showing a moisture removing filter for removing moisture of the breathing unit between a breathing unit and a flow measuring unit according to an embodiment of the present invention.
It is to be understood that the invention is not 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.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the like elements throughout.

The terminology used in this application is used only to describe a specific embodiment and is not intended to limit the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present application, the terms "comprises" or "having" and the like are used to specify that there is a feature, a number, a step, an operation, an element, a component or a combination thereof described in the specification, But do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or combinations thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Hereinafter, an embodiment of a disease diagnosis apparatus based on breath analysis according to the present invention will be described in detail with reference to the accompanying drawings, wherein like reference numerals refer to like or corresponding components A duplicate description thereof will be omitted.

FIG. 2 is a diagram illustrating a disease diagnosis apparatus using breath analysis according to an embodiment of the present invention. Referring to FIG. The apparatus for diagnosing disease through exhalation analysis according to the present invention includes a breath input unit 100 and a detection unit.

The expiratory inflow section 100 may include a mouthpiece, where the subject blows expiration by exhalation. The subject can hold the mouthpiece in his mouth and give a long breath to deliver the breath. At this time, the mouthpiece is preferably made of a material excellent in heat resistance and chemical resistance.

The detection unit has a function of detecting a mixed gas of VOCs in the exhalation unit 100 that has passed through the breath input unit 100. In the present invention, the IMS 200 is used as the detection unit. The IMS 200 can detect a biomarker by identifying a component through a difference in ion mobility according to size, shape, mass, charge, etc. of ionized molecules or ions in the subject's breath.

FIG. 3 is a diagram illustrating an IMS 200 of a disease diagnosis apparatus through exhalation analysis according to an embodiment of the present invention.

The IMS 200 basically comprises a sample suction unit, an ionization unit, an ion molecular reaction zone, an ion movement tube, a collector, a signal amplification unit, and an electronic control unit. When the VOCs mixed gas components reach the IMS 200, they are ionized by a chemical reaction with a reactive ion formed from an ionization source such as a Ni63 isotope in the ionization source region or a corona discharge, to have a charge of + or - , A certain amount of the ionized gas flows into the ion moving tube through the on / off control of the shutter between the reaction region and the ion moving tube.

At this time, a strong magnetic field is formed inside the ion moving tube, and molecules or ions ionized by the electric field induction move toward the collector. The collector outputs a signal whenever an ionized molecule or ion arrives.

The drift gas moves in the direction opposite to the moving direction of the ions in the ion moving tube. Since the ion crosses the drift gas several times and receives resistance, the impact surface area varies depending on the size and shape of the ion and the degree of influence of the magnetic field varies depending on the surface charge. The time required to fly the aircraft will be different.

By separating and detecting ions using the IMS 200, it is possible to easily construct a database for the main component material that is excellent in sensitivity, excellent in reproducibility even for long-term use, and classified as a biomarker do.

4 is a diagram illustrating an analysis of a signal obtained from the IMS 200 according to an embodiment of the present invention into an output signal based on a topographic plot.

It is possible to show a topographic plot expressed by a drift time, a retention time, and a signal intensity based on the signal detected at the collector of the IMS 200. It is possible to construct a database for each disease through analysis of the output signal pattern based on the table graphic plane.

4A is a UI program developed for analyzing the pattern of the output signal of the IMS 200 through the topographical plot. The y axis of the drift time (ms) to the right of the x axis represents the y axis of the left side of the retention time (min) Amplitude (mV). It is possible to diagnose the disease by checking the biomarker main component for each disease and constructing the output signal pattern for it.

FIG. 4 (b) shows a graph of the signal output for the drift time accumulated during the retention time, which is actually displayed in the UI program.

Since database construction of main ingredient materials classified as biomarkers is easy, it is possible to diagnose various diseases through pattern analysis algorithm.

In order to diagnose diseases through exhalation analysis, the alveolar air should be collected and measured. In order to collect the air of the alveoli, one unit should be spit long (about 350ml or more).

Therefore, the present invention may further include an exhalation supply regulator 300 for analyzing the components of the exhalation gas only when the exhalation is discharged through a long breath.

The exhalation supply regulator 300 may be located between the exhalation inlet 100 and the IMS 200. When the flow rate of the expired air passing through the expiratory air inflow part 100 is less than the predetermined fixed amount, the expired air supply control part 300 discharges the expired air to the outside as it is, and when the flow rate of the expired air passing through the expiratory air inflow part 100 is equal to or larger than the predetermined fixed amount (IMS) 200 to the IMS 200 only.

The configuration of the exhalation supply controller 300 will be described with reference to FIG.

The exhalation supply regulator 300 includes a flow measuring unit 310, a sample loop 320, a 6-way valve 330, and a controller 340.

The flow rate measuring unit 310 is a device for measuring the flow rate of the exhalation unit 100 through the exhalation unit 100. The flow measuring unit 310 includes a flow meter, and the flow meter is a device for measuring the flow rate of the gas. The flow meter can measure the flow rate of the expired gas in real time.

The sample loop 320 is a space for collecting only the air of the alveoli of the exhalation gas, and temporarily accommodates the exhalation before the exhalation is supplied to the IMS 200. By adjusting the 6-way valve 330 described below, the exhalation of the sample loop 320 is transferred to the IMS 200 or externally. That is, when the flow rate measuring unit 310 measures the aerosol having a constant flow rate or more, that is, about 350 mL or more, the aerosol of the sample loop 320 is moved to the IMS 200 through on / off control of the 6-way valve 330. When the aerobic part of the sample loop 320 is measured by the flow measuring part 310, the aerobic part of the sample loop 320 is discharged to the outside. Detailed operation control of the 6-way valve 330 will be described later. The sample loop 320 is preferably made of a material having excellent heat resistance and chemical resistance.

The control unit 340 controls the 6-way valve 330 according to the flow rate of the exhalation measured by the flow measuring unit 310 to control the supply of the exhalation unit accommodated in the sample loop 320 to the IMS 200 .

The 6-way valve 330 is a valve for controlling the flow line of the exhalation gas and the flow line of the carrier gas. The 6-way valve 330 is composed of a total of six ports. And is controlled through the operation control signal of the controller 340 according to the flow rate of the exhalation.

5 is a view showing the connection state of the 6-way valve 330 and the flow of the exhalation unit when the exhalation flow rate according to the embodiment of the present invention has not reached the preset value.

When the exhalation flow rate does not reach the preset value, the port 2 and the port 6 are connected to allow the carrier gas to be delivered to the MCC column 400, and the exhalation gas introduced from the mouthpiece of the exhalation inlet 100 The port 1 and the port 3 are connected to the sample loop 320 and the port 4 and the port 6 are connected to allow the exhalation of the sample loop 320 to be discharged to the outside. Therefore, the carrier gas is delivered to the MCC column 400 without passing through the sample loop 320, and the patient's breath is discharged through the sample loop 320. [

6 is a view showing the connection state of the 6-way valve 330 and the flow of the exhalation when the exhalation flow rate according to an embodiment of the present invention has reached a preset value.

When the exhalation flow rate reaches the preset value, the connection state of the port is explained. At this time, the sample loop 320 is full.

Port 2 and port 3 are connected so that carrier gas can be delivered to the sample loop 320 and port 4 is connected to the sample loop 320 to deliver a full expiration air And the port 6 are connected to each other so that the exhalation gas introduced from the mouthpiece is directly connected to the port 1 and the port 6 so as to be discharged without passing through the sample loop 320.

Therefore, the carrier gas is led to the MCC column 400 through the air of the alveoli filled with the sample loop 320, and the flow rate of the exhalation of the subject is discharged outside without passing through the sample loop 320. The air of the alveoli passing through the MCC column 400 is separated and transferred to the IMS 200 sensor for analysis.

7 is a view illustrating separation of a mixed gas component by the MCC column 400 according to an embodiment of the present invention.

It is possible to separate various mixed gas components in the exhalation before moving the introduced exhalation to the IMS 200 and analyzing it. That is, the present invention uses a multi-capillary column (MCC) column as a pre-separation apparatus before the IMS 200. Since the MCC column 400 has a very high capacity, consisting of a bundle of about 1,000 thin parallel capillaries, a wide range of flow rates and a short total column length in centimeters (Cm) It is possible to separate the mixed components with excellent resolution.

As a result, the time required for the total analysis is shortened, and the results of the diagnosis can be confirmed in a short time.

The present invention may include a first temperature regulator 500 for maintaining the temperature in the sample loop 320 and the 6-way valve 330 at a predetermined temperature.

The first temperature regulator 500 maintains a predetermined temperature by heating to prevent gas from being adsorbed in the sample loop 320. For this, a temperature sensor for measuring a real-time temperature and a heater for supplying heat may be included. Preferably, the temperature inside the sample loop 320 and the 6-way valve 330 can be maintained at a uniform temperature (about 40 to 60). The region where the uniform temperature is maintained may include a region through which the gas is introduced into the sample loop 320 through the expiratory inlet and a region into which the carrier gas flows.

In addition, the present invention may further include a second temperature controller 600 for maintaining the temperature inside the MCC column 400 at a preset temperature.

The second temperature regulator 600 supplies heat to the MCC column 400 to maintain the MCC column 400 at a constant temperature for a proper separation of the mixed gas. By measuring the real time temperature through the temperature sensor and adjusting the heat supply accordingly, the inside of the MCC column 400 can always maintain the set value (about 40 to 80).

More precisely, it is intended to prevent the gas such as VOCs from being adsorbed while passing through the inside of the MCC column 400 and to allow smooth separation. The region heated to a uniform temperature is a region where the gas is MCC A region to be introduced into the column 400 and an area to be transported to the IMS 200 in the MCC column 400 may be included.

In addition, the present invention may further include a third temperature controller 700 for maintaining the temperature inside the IMS 200 at a preset temperature.

The IMS 200 is heated to measure the real time temperature through the temperature sensor and the supply of heat is controlled according to the measured temperature so that the IMS 200 is always kept at a uniform temperature To 250).

(IOC) 200 is a region that is heated to a uniform temperature. The IMS 200 is a region in which a carrier gas is introduced into the IMS 200, A gas injection port region, a drift gas injection port region, and an area externally discharged from the IMS 200 may be included.

The present invention may further include a gas supply unit 800 for supplying a drift gas and a carrier gas. The gas supply unit 800 includes a gas tank 810, and a Y-fitting 820.

Nitrogen gas or air may be used for the drift gas and the carrier gas. Such gas may be accommodated in the gas tank 810 and classified by the Y-fitting 820 so as to be suitably used for each use of the drift gas and the carrier gas.

The carrier gas carries the full alveolar air in the sample loop 320 to the MCC column 400, pre-separates it, and then transports it to the ionization region of the IMS 200. The drift gas flows in the direction opposite to the flow direction of the ions in the IMS 200, and functions to induce a resistance to ions moving by induction in the magnetic field. The drift gas has a difference in ion mobility .

The Y-fitting 820 is a structure for bifurcating the flow of the flow rate. The Y-Fitting 820 uses a flow rate from the high-purity gas tanks 810 and 810 filled with nitrogen gas or air at the same time for the use of the carrier gas and the drift gas To flow in two directions.

An MFC (Mass Flow Controller) is installed in the drift gas and carrier gas movement lines after the Y-fitting 820 to control the flow rates of the drift gas and the carrier gas, respectively.

FIG. 8 is a view showing a configuration using outside air as a drift gas and a carrier gas according to an embodiment of the present invention.

As the drift gas and the carrier gas, a certain amount of nitrogen gas contained in the gas tank 810 or outside air other than air may be used as it is. External air may be sucked through the suction pump 830 and then transferred to the Y-fitting 820 via the filter 840 so that the external air may be used as the drift gas and the carrier gas.

9 is a view showing a moisture removing filter 110 for removing moisture of the breathing unit between the breathing unit 100 and the flow measuring unit 310 according to an embodiment of the present invention.

Since the analysis of the expiration can be greatly affected by moisture, a filter for removing the moisture of the expiration can be added between the expiration opening 100 and the flow rate measuring unit 310.

The present invention may further include a sieve & carbon filter. The sieve & carbon filter removes moisture in the gas passing through the IMS 200, purifies the polluted air with a substance such as VOCs, To be discharged into the atmosphere.

The scope of protection of the present invention is not limited to the description and the expression of the embodiments explicitly described in the foregoing. It is again to be understood that the present invention is not limited by the modifications or substitutions that are obvious to those skilled in the art.

100:
110: Moisture removal filter
200: IMS
300:
310: Flow measuring unit
320: Sample Loop
330: 6-way valve
340:
400: MCC column
500: first temperature regulator
600: second temperature regulator
700: third temperature regulator
800: gas supply part
810: Gas tank
820: Y-Fitting
830: Suction pump
840: Filter

Claims (11)

An apparatus for diagnosing a disease through expiration analysis for diagnosing a disease by analyzing a gas caused by an exhalation of a subject,
An exhale inflow portion into which the exhalation of the examinee flows; And
And a detection unit for detecting a mixed gas of VOCs in the exhalation unit that has passed through the exhalation inlet unit,
Characterized in that the detector comprises Ion Mobility Spectroscopy (IMS)
Disease diagnosis device through exhalation analysis. The method according to claim 1,
Wherein when the flow rate of the exhalation unit that is formed between the exhalation unit and the IMS and flows through the exhalation unit has been set to a predetermined fixed amount, Further comprising an expiration supply regulator for supplying the exhalation unit to the IMS.
Disease diagnosis device through exhalation analysis. 3. The method of claim 2,
Wherein the exhalation supply regulator comprises:
A flow rate measuring unit for measuring a flow rate of the exhalation unit passing through the exhalation unit;
A sample loop temporarily accommodating the patient to adjust the supply of the patient to the IMS according to the flow rate of the patient measured by the flow measuring unit;
A 6-way valve for controlling a movement line of the ox unit to the sample loop and a movement line of a carrier gas to move the ox unit through the sample loop to the IMS; And
And a control unit for controlling the 6-way valve according to the flow rate of the exhalation measured by the flow rate measuring unit to control supply of the exhalation unit accommodated in the sample loop to the IMS.
Disease diagnosis device through exhalation analysis. 3. The method of claim 2,
Further comprising an MCC column (Multi-Capillary Column) formed between the exhalation supply regulating unit and the IMS and separating various mixed gas components in the exhalation before the exhalation unit is supplied to the IMS.
Disease diagnosis device through exhalation analysis. The method of claim 3,
Further comprising a first temperature controller for maintaining the temperature of the sample loop and the inside of the 6-way valve at a preset temperature.
Disease diagnosis device through exhalation analysis. 5. The method of claim 4,
And a second temperature controller for maintaining the temperature inside the MCC column at a preset temperature.
Disease diagnosis device through exhalation analysis. The method according to claim 1,
Further comprising a third temperature regulator for maintaining the temperature inside the IMS at a predetermined temperature.
Disease diagnosis device through exhalation analysis. The method of claim 3,
Further comprising a gas supply unit for supplying a carrier gas for moving the ox unit to the IMS and a drift gas for guiding a magnetic field while moving in a direction opposite to the moving direction of the ox unit within the IMS.
Disease diagnosis device through exhalation analysis. 9. The method of claim 8,
Wherein the carrier gas and the drift gas are the same gas and include nitrogen gas or air,
The gas-
A gas tank for containing the nitrogen gas or air;
And a Y-fitting which is connected to the gas tank and divides the nitrogen gas or air contained in the gas tank into a carrier gas and a drift gas.
Disease diagnosis device through exhalation analysis. 10. The method of claim 9,
Characterized by comprising an external air suction pump and a filter in place of the gas tank.
Disease diagnosis device through exhalation analysis. The method of claim 3,
Further comprising a moisture removing filter formed between the expiratory volume inflow section and the flow volume measurement section for removing water from the breathing section that has passed through the expiration volume inflow section,
Disease diagnosis device through exhalation analysis.

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