Tandem mass spectrum ionization source for online detection of disease markers in tail end gas of expired gas of human body

Abstract

The invention belongs to the technical field of mass spectrum ionization sources, provides a tandem mass spectrum ionization source for online detection of disease markers in tail end gas of expired gas of a human body, and aims to solve the problems of complex expired gas sampling, insufficient detection sensitivity and difficult real-time monitoring in the prior art. According to the ionization source device, real-time online expiration analysis of expired gas of a human body can be achieved, the expired gas end gas moment can be determined according to the change of the concentration of carbon dioxide in the expired gas, and therefore real-time analysis of disease markers in the expired gas end gas is achieved. According to the technical scheme, the design that double ionization sources are connected in series is adopted, and a funnel-shaped chemical ionization source is arranged at the front end and specially used for high-sensitivity detection of volatile organic compounds in exhaled air; the photoelectron ionization source is arranged at the rear end and used for monitoring the carbon dioxide concentration in real time and determining the end gas moment. According to the design, high sensitivity of organic matter detection and accurate monitoring of carbon dioxide concentration are both considered in a partitioned ionization mode. The efficient, sensitive and reliable mass spectrum ionization source device is provided for exhaled gas detection, automatic distinguishing of the front end and the tail end of exhaled gas and high-sensitivity analysis of disease markers in tail end gas can be achieved, the sampling process can be simplified, the detection efficiency can be improved, and the mass spectrum ionization source device has wide application prospects, can be suitable for various scenes and has wide application prospects. The method includes clinical disease early diagnosis, health monitoring and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of mass spectrometry ionization source, and relates to a tandem mass spectrometry ionization source for online detection of disease markers in end gas of human exhaled breath. BACKGROUND

[0002] The information disclosed in this BACKGROUND section is only for the purpose of increasing the understanding of the general background of the present application, and should not be taken as an acknowledgement or any form of suggestion that this information forms prior art that is publicly known.

[0003] In recent years, exhaled breath detection as a non-invasive method has attracted widespread attention in assessing human physiological metabolism and disease diagnosis. The theoretical basis of this detection method is that volatile organic compounds (VOCs) produced in the human metabolic process can reach the lungs through blood circulation and eventually be excreted out of the body with exhalation. In exhaled breath detection, the collection of end gas is particularly important. This part of gas is directly derived from alveoli and can more accurately reflect the metabolic state of the body.

[0004] Mass spectrometry technology has the characteristics of high throughput and high sensitivity, and has been widely used in human exhaled breath detection. Some studies have used self-developed vacuum ultraviolet photoionization VOCs mass spectrometry to screen early lung cancer, which can directly sample human exhaled breath and has the characteristics of real-time online analysis, and can sensitively and rapidly detect multiple components of VOCs, but cannot distinguish the front and end gas of exhaled breath. Some studies have proposed a device for analyzing and detecting each component in human exhaled breath, which collects the end gas of human exhaled breath and stores the collected gas in a sample collection and storage device, and then introduces it into a mass spectrometer for detection and analysis. However, this method does not fully solve the problem of adsorption of gas components that may occur during storage in the design of the sample collection and storage device, which may cause loss or concentration change of gas components, affecting the accuracy of the detection results.

[0005] In summary, the current problems faced by mass spectrometry technology applied to exhaled breath detection are mainly as follows: (1) Limitations of sampling equipment. In existing sampling methods, exhaled breath needs to be collected into a sample storage device, and the cost of a steel cylinder is relatively high, while a gas bag has background residue and gas adsorption problems, which affect the accuracy of the detection results.

[0006] (2) Difficulty in collecting end gas of exhaled breath. The end gas of exhaled breath can better reflect the metabolic products of the human body, and how to accurately collect and ensure the representativeness of the sample is still a technical difficulty.

[0007] (3) Insufficient detection sensitivity. The concentration of disease markers in the end gas of exhaled breath is usually in the ppbv (parts per billion) to pptv (parts per trillion) range, which puts extremely high requirements on the sensitivity of mass spectrometric detection. SUMMARY

[0008] To solve the above problems, the present application provides a tandem mass spectrometry ionization source for online detection of disease markers in the end gas of human exhaled breath. The ionization source adopts a modular design, integrating a funnel-shaped chemical ionization source 1 and a photoelectron ionization source 2, and can achieve efficient and accurate detection of different components in exhaled breath. Specifically, the front end of the funnel-shaped chemical ionization source 1 is equipped with a detachable disposable mouthpiece 3 to ensure the hygiene of each detection and avoid cross contamination. Volatile organic compounds (VOCs) in exhaled breath are efficiently ionized by chemical ionization or photoionization in the funnel-shaped chemical ionization source 1, thereby achieving high sensitivity detection. The funnel-shaped design not only improves the aggregation efficiency of gas molecules, but also enhances the ionization effect, ensuring the capture and detection of low concentration VOCs. At the same time, carbon dioxide in exhaled breath is ionized by a special photoelectron ionization source 2. This ionization source can monitor the changes in carbon dioxide concentration in real time and automatically distinguish between the front gas and the end gas of exhaled breath. Through this design, the system can accurately identify and analyze VOCs in the end gas of exhaled breath, ensuring the accuracy and reliability of the detection results. The design of the present application not only realizes real-time online mass spectrometric analysis of VOCs in the end gas of exhaled breath, but also ensures the efficiency and accuracy of the detection process through modular structure and intelligent control. The present application provides strong technical support for high-sensitivity detection of disease markers and has wide application prospects.

[0009] To achieve the above-mentioned purpose, the present application adopts the following technical solutions: In a first aspect of the present application, a tandem mass spectrometry ionization source for online detection of disease markers in the end gas of human exhaled breath is provided, comprising: a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and a gas collection device. The gas collection device is connected to the funnel-shaped chemical ionization source 1, and the funnel-shaped chemical ionization source 1 is connected to the photoelectron ionization source 2 in front and back. The funnel-shaped chemical ionization source includes a funnel-shaped chemical ionization reaction chamber 5, a plurality of ultraviolet light emitting devices are provided outside the funnel-shaped chemical ionization reaction chamber 5, and a heating device 6 and a first vacuum pump 7 are provided on the outer wall of the funnel-shaped chemical ionization reaction chamber 5.

[0010] The funnel-shaped chemical ionization reaction cavity 5 of the application has less internal turbulence, mainly laminar flow, so that the ions can be effectively transported, and the ion aggregation efficiency is improved; secondly, the funnel-shaped design can effectively reduce the reaction of the sample and the funnel chemical reaction area, reduce the wall loss of the sample, and improve the ionization efficiency.

[0011] In a second aspect, the application provides a device for online detection of disease markers in the end gas of human exhaled breath, comprising: the tandem mass spectrometry ionization source and the mass spectrometer.

[0012] Advantages of the application (1) Convenient sampling and high fidelity: the application directly introduces the human exhaled breath into the ionization source through a disposable mouthpiece, without the need for traditional sample collection and storage devices (such as steel cylinders or gas bags), avoiding problems such as sample residue, background contamination, and gas adsorption, significantly improving the fidelity of the sample and the reliability of the detection results.

[0013] (2) Dual ionization source cooperative detection: the application innovatively combines the funnel-shaped chemical ionization source with the photoelectron ionization source, realizing the simultaneous detection of organic and inorganic substances in human exhaled breath. The funnel-shaped chemical ionization source utilizes nitrosyl cation / hydronium ion to chemically react with organic substances or directly photoionize, achieving efficient ionization of volatile organic compounds (VOCs); the funnel-shaped design improves the aggregation efficiency of gas molecules, enhances the ionization effect, and ensures high sensitivity detection of low-concentration VOCs; through the cooperation of vacuum ultraviolet lamps and reagent gases, multiple ionization modes (such as chemical ionization and photoionization) are supported, suitable for the detection of different types of VOCs. The photoelectron ionization source uses photoelectron ionization technology to achieve accurate ionization of inorganic substances such as carbon dioxide. This design takes into account the high sensitivity of organic substance detection and the accuracy of inorganic substance detection.

[0014] (3) Real-time monitoring and accurate analysis: the application can monitor the change of carbon dioxide concentration in human exhaled breath in real time, automatically identify and determine the time of the end gas of exhaled breath, and thus more accurately analyze the disease markers in the end gas. This real-time online detection method not only simplifies the sampling process, but also improves the detection efficiency, providing reliable technical support for early disease diagnosis and health monitoring.

[0015] (4) The application has simple structure, strong practicability, and is easy to popularize. BRIEF DESCRIPTION OF DRAWINGS

[0016] The drawings accompanying the specification of the application form part of the application and serve to provide further understanding of the application. The exemplary embodiments of the application and their descriptions serve to explain the application and do not constitute an improper limitation of the application.

[0017] Figure 1is a tandem mass spectrometry ionization source provided by an embodiment of the present application for online detection of disease markers in the end gas of human exhaled breath; Figure 2 is a schematic diagram of installation of an external vacuum ultraviolet lamp in a funnel-shaped chemical ionization reaction cavity of a tandem mass spectrometry ionization source provided by an embodiment of the present application for online detection of disease markers in the end gas of human exhaled breath; Figure 3 is a mass spectrum of detection of aldehydes in exhaled breath by a tandem mass spectrometry ionization source provided by an embodiment of the present application for online detection of disease markers in the end gas of human exhaled breath; Figure 4 is a mass spectrum of detection of different concentrations of CO2 by a tandem mass spectrometry ionization source provided by an embodiment of the present application for online detection of disease markers in the end gas of human exhaled breath; wherein 1, funnel-shaped chemical ionization source; 2, photoelectron ionization source; 3, exhaled breath sampling disposable mouthpiece; 4, vacuum ultraviolet lamp; 5, funnel-shaped chemical ionization reaction cavity; 6, heating device; 7, first vacuum pump; 8, ion repulsion electrode; 9, photoelectron emission electrode; 10, fragment quadrupole transmission zone; 11, photoelectron ionization source cavity; 12, ion extraction electrode; 13, deuterium lamp; 14, second vacuum pump. DETAILED DESCRIPTION

[0018] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the present application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The reagents or materials used in the present application can be purchased through conventional routes, and unless otherwise specified, the reagents or materials used in the present application are used according to conventional methods in the art or according to the product instructions. Similarly, unless otherwise specified, the test methods of the present application are also tested according to conventional methods in the art or general methods or standards in the industry. In addition, any method and material similar or equivalent to those described can be applied to the method of the present application. The preferred implementation methods and materials described herein are only for demonstration.

[0020] The present application will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are an explanation of the present application rather than a limitation.

[0021] As introduced in the background, volatile organic compounds (VOCs) in human exhaled breath can represent the disease of human body, but only the end gas can more accurately reflect the metabolic state of the body. For accurate measurement of low concentration VOCs, it is of great significance to develop new measurement technology. The invention patent (application number: 201510153472.5) uses self-developed vacuum ultraviolet photoionization VOCs mass spectrometry to screen early lung cancer, which can directly sample human exhaled breath and has the characteristics of real-time online analysis, and can sensitively and quickly detect multi-component VOCs to analyze the relationship between VOCs component content and cancer. However, this technology cannot distinguish the front-end and end gas of exhaled breath, which may interfere with the detection results of low concentration VOCs in the front-end gas, reducing the accuracy of the analysis. The invention patent (application number: 202011410877.X) proposes a device for analyzing and detecting each component in human exhaled gas, which collects the end gas of human exhaled breath and stores the collected gas in a sample collection and storage device, and then introduces it into a mass spectrometer for detection and analysis. However, the invention does not fully solve the problem of adsorption of gas components that may occur during storage in the design of the sample collection and storage device, which may cause loss or concentration change of the gas components, affecting the accuracy of the detection results. In order to solve the above technical problems, the invention proposes a tandem mass spectrometry ionization source for online detection of disease markers in the end gas of human exhaled breath, which includes a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and an exhaled gas sampling disposable mouthpiece 3. The funnel-shaped chemical ionization source 1 can generate hydronium ions and nitrosyl cations by introducing reagent gas or directly use a vacuum ultraviolet lamp 4 for photoionization, achieving efficient ionization of VOCs; the funnel-shaped design improves the aggregation efficiency of gas molecules, enhances the ionization effect, and ensures high sensitivity detection of low concentration VOCs. The photoelectron ionization source 2 uses vacuum ultraviolet light generated by a deuterium lamp 13, generates photoelectrons through a photoelectron emission electrode 9, achieves efficient ionization of carbon dioxide, and realizes efficient transmission of ions through a fragment quadrupole rod; the invention can monitor the change of carbon dioxide concentration in real time, automatically identify and determine the time of the end gas of exhaled breath, ensure that the analysis object is the high concentration disease marker in the end gas, and avoid the interference of low concentration VOCs in the front-end gas.

[0022] As Figure 1 shown, the embodiment provides a tandem mass spectrometry ionization source for online detection of disease markers in the end gas of human exhaled breath, which includes a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and a gas collection device; The gas collection device is connected to the funnel-shaped chemical ionization source 1, and the funnel-shaped chemical ionization source 1 is connected to the photoelectron ionization source 2 in front and back; The funnel-shaped chemical ionization source comprises a funnel-shaped chemical ionization reaction cavity 5, a plurality of ultraviolet light emitting devices are arranged outside the funnel-shaped chemical ionization reaction cavity 5, and a heating device 6 and a first vacuum pump 7 are arranged on the outer wall of the funnel-shaped chemical ionization reaction cavity 5.

[0023] The present application improves the detection method of human exhaled breath by online mass spectrometry from the traditional gas bag or steel cylinder sampling detection to the use of disposable mouthpiece 3 for direct sampling, which significantly reduces the sample loss and pollution problems caused by the gas storage device. The volatile organic compounds (VOCs) in the exhaled breath are efficiently ionized by chemical ionization (such as hydronium or nitrosyl cation reaction) or photoionization process in the funnel-shaped chemical ionization source 1, ensuring high sensitivity detection of low concentration VOCs. At the same time, the photoelectron ionization source 2 can monitor the change of carbon dioxide concentration in real time, automatically distinguish the front-end gas and the end gas of the exhaled breath, and ensure that the analysis object is the high concentration disease marker in the end gas. The fragment quadrupole transmission zone can focus and transmit ions, ensuring efficient transmission of ions. Through this dual-ionization source cooperative design, the system not only realizes efficient ionization and accurate detection of VOCs, but also avoids the interference of low concentration VOCs in the front-end gas by real-time monitoring of carbon dioxide concentration, significantly improving the accuracy and reliability of the detection results. In addition, the use of disposable mouthpiece 3 avoids cross contamination, further ensuring the originality of the sample and the hygiene of the detection.

[0024] In some embodiments, the funnel-shaped chemical ionization reaction cavity 5 is a first vacuum zone, and the photoelectron ionization source cavity 11 is a second vacuum zone; the first vacuum zone and the second vacuum zone are separated by ion repulsion electrodes 8 for differential gas pressure. The first vacuum pump 7 is responsible for maintaining the vacuum degree of the first vacuum zone, and the second vacuum pump 14 is responsible for maintaining the vacuum degree of the second vacuum zone. Through the multi-stage vacuum system design, the vacuum degrees of different regions are ensured to meet the needs of ionization and ion transmission.

[0025] Preferably, the vacuum degree of the first vacuum zone is 6000 Pa to 7000 Pa, and the vacuum degree of the second vacuum zone is 50 Pa to 100 Pa.

[0026] Preferably, the pumping speed of the first vacuum pump 7 is 3.5 L / s, and the pumping speed of the second vacuum pump 14 is 3.5 L / s.

[0027] The funnel-shaped chemical ionization source 1 is installed behind the photoelectron ionization source 2, and by optimizing the photoelectron generation and regulation mechanism, more photoelectrons can be generated by irradiating the metal electrode with vacuum ultraviolet light at low pressure (50-100 Pa), the collision loss of photoelectrons with gas molecules is reduced, and more photoelectrons can effectively act on target molecules. At the same time, adjusting the voltage of the photoelectron emission electrode can regulate the energy of the photoelectron, and realize efficient ionization of high ionization energy substances such as CO2.

[0028] In some embodiments, the inner diameter of the cavity of the funnel-shaped chemical ionization reaction cavity 5 gradually increases from the neck of the funnel, the angle of the funnel is 70-80°, the outer part of the cavity is grounded, and the internal gas pressure is 6000-7000 Pa.

[0029] In some embodiments, the ultraviolet light emitting device is a vacuum ultraviolet lamp 4, three of which are arranged on the same circle with the axis of the funnel-shaped chemical ionization reaction cavity 5 as the center, and the angle between them and the center line of the funnel-shaped chemical ionization reaction cavity 5 is 80-85°. In some embodiments, the heating device 6 is a ceramic heating sheet, a polytetrafluoroethylene heat insulation plate, a heating belt, and a temperature control box. The ceramic heating sheet and the heating belt are powered and heated by the temperature control box, and the heating temperature is preferably 50-500℃. In some embodiments, there is no electric field in the funnel-shaped chemical ionization reaction cavity 5, and the product ions and the unspent reagent ions are pushed into the mass spectrometer for detection by the gas flow.

[0030] As shown in Figure 2 The funnel-shaped chemical ionization reaction cavity 5 is installed with the vacuum ultraviolet lamp 4, different reagent gases can be introduced according to the experimental requirements, so as to generate specific reagent ions. Through this design, the reaction cavity can realize multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, and direct photoionization.

[0031] The funnel-shaped chemical ionization source 1 is used to ionize volatile organic compounds in exhaled air, and three vacuum ultraviolet lamps 4 are installed outside the funnel-shaped chemical ionization reaction cavity 5, which can realize multiple ionization modes at the same time, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, and direct photoionization, which improves the detection sensitivity and selectivity of different VOCs, and is suitable for the detection of various disease markers; the heating device 6 is used to maintain the temperature stability in the reaction cavity, to ensure that the volatile organic compounds (VOCs) remain gaseous during the ionization process, and to avoid condensation. The photoelectron ionization source 2 inside is irradiated by a deuterium lamp 13 to generate high-energy photoelectrons on the photoelectron emission electrode 9, and the photoelectron energy is controlled by the voltage of the photoelectron emission electrode 9, so as to ensure efficient ionization of carbon dioxide.

[0032] In some embodiments, the gas collection device is an exhaled breath sampling disposable mouthpiece 3, which is sealingly connected to the funnel neck of the funnel-shaped chemical ionization reaction cavity 5 to ensure that more exhaled gas can enter the funnel-shaped chemical ionization reaction cavity 5.

[0033] In some embodiments, the photoelectron ionization source 2 comprises a photoelectron ionization source cavity 11, in which an ion repulsion electrode 8, a photoelectron emission electrode 9, a fragment quadrupole transmission zone electrode 10, and an ion extraction electrode 12 are sequentially arranged along the axial direction; the photoelectron ionization source cavity 11 is externally provided with a deuterium lamp 13 and a second vacuum pump 14.

[0034] In some embodiments, the ion repulsion electrode 8, the photoelectron emission electrode 9, the fragment quadrupole transmission zone electrode 10, and the ion extraction electrode 12 are coaxially arranged with central through holes and are parallel to each other. In some embodiments, the funnel-shaped chemical ionization reaction cavity 5 is also coaxially arranged with the above-mentioned electrodes to ensure the detection effect.

[0035] In some embodiments, the diameter of the through hole of the funnel neck of the funnel-shaped chemical ionization reaction cavity 5 is 0.3-0.8 mm, the diameter of the through hole of the ion repulsion electrode 8 is 0.8-1.5 mm, and the diameter of the through hole of the ion extraction electrode 12 is 0.5-1.2 mm.

[0036] In some embodiments, the ion repulsion electrode 8, the photoelectron emission electrode 9, the fragment quadrupole transmission zone electrode 10, and the ion extraction electrode 12 are sequentially loaded with different voltages in the order of decreasing absolute value of voltage, thereby forming an ion transmission channel in the axial direction.

[0037] In some embodiments, the ion repulsion electrode 8 and the ion extraction electrode 12 are both plate electrodes with a conical protrusion at the center, and the conical tip is laterally machined with an ion transmission through hole. In some embodiments, the fragment quadrupole transmission zone is mounted at the rear of the photoelectron emission electrode 9, and the fragment quadrupole transmission zone is composed of a plurality of fragment electrode rings, which are plate structures with a central hole. The electrode rings are fixed on four insulating rods placed at equal distances, and each electrode ring is isolated by an insulating ring of the same size. The electrode rings of each rod are applied with a direct current voltage through a voltage dividing resistor, thereby forming a direct current electric field along the axial direction, and are connected to a capacitor with the same capacitance value to apply a radio frequency voltage. The fragment quadrupole transmission zone can effectively focus the ions generated from the funnel-shaped chemical ionization source 1 and the photoelectron ionization zone through its unique quadrupole electric field design. The quadrupole electric field regulates the motion trajectory of the ions, thereby concentrating the dispersed ion beam near the central axis of the transmission zone, reducing the loss of ions in the transmission process, and improving the ion transmission efficiency.

[0038] Preferably, the insulating rod is made of polyether ether ketone or ceramic.

[0039] Preferably, the size of the quadrupole ring is: inner diameter 5 mm, outer diameter 9 mm, height 4 mm, and the size of the polyether ether ketone ring is: inner diameter 5 mm, outer diameter 9 mm, height 0.5 mm.

[0040] Preferably, the resistance of the voltage dividing resistor is 10 MΩ; the capacitance is 100 nF, the radio frequency voltage frequency is 1.8 MHz, and the peak-peak value is 300 V.

[0041] In some embodiments, the photoelectron emission electrode is a cylindrical structure with a through hole in the center; the deuterium lamp is connected to the photoelectron emission electrode, and the vacuum ultraviolet light is irradiated onto the ring surface in the cylinder through the small hole on the side of the cylinder to generate photoelectrons; In some embodiments, the ion exit is provided on the ion extraction electrode 12, and the ion exit is connected to the mass spectrometer; specifically, the ion exit is connected to the mass spectrometer, that is, the ions obtained by ionizing the gas sample in the ionization source cavity are directly introduced into the mass spectrometer through the ion exit on the ion extraction electrode 12.

[0042] In this embodiment, the mass spectrometer is a time-of-flight mass spectrometer, and the single detection is in the order of microseconds, so that the changes of the volatile organic matter content in the front-end gas and the end gas of the human exhaled air can be observed.

[0043] There are many disease markers in the end gas of human exhaled air, which can reveal the health condition of the human body. For example, benzene series (such as styrene, toluene), aldehydes (such as hexanal, pentanal) and alkanes (such as n-decane) are often detected in the exhaled air of lung cancer patients; the concentration of acetone in the exhaled air of diabetic patients is increased, indicating poor blood glucose control or ketoacidosis; liver disease patients may contain mercaptans (such as dimethyl sulfide) and pentane in their exhaled air, indicating liver failure or lipid peroxidation; the concentration of ammonia and dimethylamine in the exhaled air of patients with kidney disease is increased, indicating abnormal kidney function; the concentration of pentane and hydrogen sulfide in the exhaled air of patients with gastrointestinal diseases is increased, which may be related to Helicobacter pylori infection or intestinal flora disorder. In addition, methylbenzene, nonanal, and aldehyde and ketone substances can be detected in the exhaled air of patients with infectious diseases such as tuberculosis and COVID-19. For the aldehydes in the above disease markers, standard gas analysis is performed, Figure 3 The mass spectrum of the aldehyde standard gas (acetaldehyde, propenal, propyl aldehyde, butenal, n-butyl aldehyde, benzaldehyde, pentanal, m-methyl benzaldehyde, hexanal) obtained by the tandem mass spectrometry ionization source described in this embodiment. For the CO2 gas in the human exhaled air, CO2 standard gas is used for analysis, Figure 4 The CO2 signal response fold line graph of different concentrations obtained by the tandem mass spectrometry ionization source described in this embodiment.

[0044] In this embodiment, the funnel-shaped chemical ionization source 1 comprises a funnel-shaped chemical ionization reaction chamber 5, a first vacuum pump 7, a heating device 6, a first vacuum ultraviolet lamp 4-1, a second vacuum ultraviolet lamp 4-2, and a third vacuum ultraviolet lamp 4-3. The photoelectron ionization source 2 comprises an ion repulsion electrode 8, a deuterium lamp 13, a photoelectron emission electrode 9, a fragment quadrupole transmission zone, an ion extraction electrode 12, a second vacuum pump 14, and a photoelectron ionization source chamber 11. The ionization source chamber is sequentially provided with the funnel-shaped chemical ionization reaction chamber 5, the ion repulsion electrode 8, the photoelectron emission electrode 9, the fragment quadrupole transmission zone, and the ion extraction electrode 12 along the axial direction, and the multiple electrodes are coaxially arranged in parallel with the central through hole. The exhaled gas sampling disposable mouthpiece 3 is sealingly connected to the funnel neck of the funnel-shaped chemical ionization reaction chamber 5.

[0045] The diameter of the through hole of the funnel neck of the funnel-shaped chemical ionization reaction chamber 5 is 0.3-0.8mm, the diameter of the through hole of the ion repulsion electrode 8 is 0.8-1.5mm, and the diameter of the through hole of the ion extraction electrode 12 is 0.5-1.2mm.

[0046] The ion repulsion electrode 8, the photoelectron emission electrode 9, the fragment quadrupole transmission zone electrode 10, and the ion extraction electrode 12 are sequentially loaded with different voltages in the order of the absolute value of the voltage from high to low, forming an ion transmission channel in the axial direction.

[0047] The present application improves the detection method of human exhaled gas online mass spectrometry from the traditional gas bag or steel cylinder sampling detection to the use of disposable mouthpiece 3 for direct sampling, significantly reducing the sample loss and pollution problems caused by the gas storage device. The volatile organic compounds (VOCs) in the exhaled gas are efficiently ionized by chemical ionization (such as hydrated hydrogen ion or nitrosyl cation reaction) or photoionization process in the funnel-shaped chemical ionization source 1, ensuring high sensitivity detection of low concentration VOCs. At the same time, the photoelectron ionization source 2 can monitor the change of carbon dioxide concentration in real time, automatically distinguish the front-end gas and the end gas of the exhaled gas, and ensure that the analysis object is the high concentration disease marker in the end gas. The fragment quadrupole transmission zone can focus and transmit ions, ensuring efficient transmission of ions. Through the cooperative design of the double ionization source, the system not only realizes efficient ionization and accurate detection of VOCs, but also avoids the interference of low concentration VOCs in the front-end gas by real-time monitoring of carbon dioxide concentration, significantly improving the accuracy and reliability of the detection results. In addition, the use of disposable mouthpiece 3 avoids cross contamination, further ensuring the originality of the sample and the hygiene of the detection.

[0048] In this embodiment, the ion repulsion electrode 8 and the ion extraction electrode 12 are both plate electrodes with a conical protrusion at the center, and the conical tip is machined with a through hole for ion transmission in the transverse direction.

[0049] Further, the inner diameter of the cavity of the funnel-shaped chemical ionization reaction chamber 5 gradually increases from the neck of the funnel, the angle of the funnel is 70-80°, and the outside of the cavity is grounded; the three vacuum ultraviolet lamps 4 are on the same circle with the axis of the funnel-shaped chemical ionization reaction chamber 5 as the center, and the angle between them and the center line of the reaction chamber is 80°.

[0050] The heating device 6 is a ceramic heating sheet, a polytetrafluoroethylene heat insulation plate, a heating belt, and a temperature control box. The ceramic heating sheet and the heating belt are powered and heated by the temperature control box and monitored. The heating temperature is preferably 50℃-500℃.

[0051] There is no electric field in the funnel-shaped chemical ionization reaction chamber 5, and the product ions and the unspent reagent ions are pushed into the mass spectrometer for detection by the gas flow.

[0052] As shown in Figure 2 The vacuum ultraviolet lamp 4 is installed on the cavity wall of the funnel-shaped chemical ionization reaction chamber 5, and different reagent gases can be introduced according to experimental requirements to generate specific reagent ions. Through this design, the reaction chamber can realize multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization.

[0053] The funnel-shaped chemical ionization source 1 is used to ionize volatile organic compounds in exhaled breath, and three vacuum ultraviolet lamps 4 are installed outside the funnel-shaped chemical ionization reaction chamber 5. Multiple ionization modes can be realized simultaneously, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization, which improves the detection sensitivity and selectivity of different VOCs and is suitable for the detection of various disease markers; the heating device 6 is used to maintain the temperature stability in the reaction chamber, ensuring that the volatile organic compounds (VOCs) remain gaseous during the ionization process and avoid condensation. The high-energy photoelectrons are generated by irradiating the photoelectron emission electrode 9 with a deuterium lamp 13 inside the photoelectron ionization source 2, and the photoelectron energy is controlled by the voltage of the photoelectron emission electrode 9, so the efficient ionization of carbon dioxide can be ensured.

[0054] Further, the photoelectron emission electrode 9 is provided with a segmental quadrupole transmission zone at the rear part, which is composed of a plurality of segmental electrode rings in the form of a plate with a central hole; the electrode rings are fixed on four insulating rods placed at equal distances, and each electrode ring is isolated by an insulating ring of the same size; the electrode rings of each rod are applied with a direct current voltage by a voltage dividing resistor, thereby forming a direct current electric field along the axial direction, and at the same time, a radio frequency voltage is applied by connecting capacitors of the same capacitance.

[0055] Preferably, the insulating rod is made of polyether ether ketone or ceramic.

[0056] Preferably, the segmental quadrupole ring has a size of 5mm in inner diameter, 9mm in outer diameter and 4mm in height, and the polyether ether ketone ring has a size of 5mm in inner diameter, 9mm in outer diameter and 0.5mm in height.

[0057] Preferably, the voltage dividing resistor has a resistance of 10MΩ, the capacitor has a capacitance of 100nF, the radio frequency voltage has a frequency of 1.8MHz and a peak-to-peak value of 300V.

[0058] In the embodiment, the photoelectron emission electrode 9 is in the form of a cylinder with a through hole in the center; the deuterium lamp 13 is connected to the photoelectron emission electrode 9, and the vacuum ultraviolet light is irradiated onto the ring surface in the cylinder through the small hole in the side of the cylinder to generate photoelectrons.

[0059] The ion exit is provided on the ion extraction electrode 12 and connected to the mass spectrometer. Specifically, the ion exit is connected to the mass spectrometer, and the ions generated by the ionization of the gas sample in the ion source cavity are directly introduced into the mass spectrometer through the ion exit on the ion extraction electrode 12.

[0060] In the embodiment, the funnel-shaped chemical ionization reaction cavity 5 is the first vacuum zone, and the photoelectron ionization source cavity 11 is the second vacuum zone; the pressure difference between the first vacuum zone and the second vacuum zone is divided by the ion repulsion electrode 8.

[0061] The first vacuum pump 7 is responsible for maintaining the vacuum degree of the first vacuum zone, and the second vacuum pump 14 is responsible for maintaining the vacuum degree of the second vacuum zone. Through the multi-stage vacuum system design, the vacuum degrees of different regions are ensured to meet the needs of ionization and ion transmission.

[0062] Preferably, the vacuum degree of the first vacuum zone is 6000Pa~7000Pa, and the vacuum degree of the second vacuum zone is 50Pa~100Pa.

[0063] Preferably, the first vacuum pump 7 has a pumping speed of 3.5 L / s, and the second vacuum pump 14 has a pumping speed of 3.5 L / s.

[0064] The present application installs a photoelectron ionization source 2 behind the funnel-shaped chemical ionization source 1, and by optimizing the photoelectron generation and regulation mechanism, more photoelectrons can be generated when the vacuum ultraviolet light irradiates the metal electrode at low pressure (50-100 Pa), the collision loss of photoelectrons with gas molecules is reduced, and more photoelectrons can effectively act on target molecules. At the same time, adjusting the voltage of the photoelectron emission electrode can regulate the energy of the photoelectrons, and realize efficient ionization of high ionization energy substances such as CO2.

[0065] In this embodiment, the mass spectrometer is a time-of-flight mass spectrometer, and a single detection is in the order of microseconds, so that the change of the content of volatile organic compounds in the front-end gas and the end gas of the human exhaled gas can be observed.

[0066] There are many disease markers in the end gas of human exhaled gas, which can reveal the health condition of the human body. For example, benzene series (such as styrene, toluene), aldehydes (such as hexanal, pentanal) and alkanes (such as n-decane) are often detected in the exhaled gas of lung cancer patients; the concentration of acetone in the exhaled gas of diabetic patients is increased, indicating poor blood glucose control or ketoacidosis; liver disease patients may contain mercaptans (such as dimethyl sulfide) and pentane in their exhaled gas, indicating liver failure or lipid peroxidation; the concentration of ammonia and dimethylamine in the exhaled gas of patients with kidney disease is increased, indicating abnormal kidney function; the concentration of pentane and hydrogen sulfide in the exhaled gas of patients with gastrointestinal diseases is increased, which may be related to Helicobacter pylori infection or intestinal flora disorder. In addition, methylbenzene, nonanal, and aldehyde and ketone substances can be detected in the exhaled gas of patients with infectious diseases such as tuberculosis and COVID-19. For the aldehydes in the above disease markers, standard gas analysis is performed, Figure 3 The mass spectrum of the aldehyde standard gas (acetaldehyde, propenal, propyl aldehyde, butenal, n-butyl aldehyde, benzaldehyde, pentanal, m-methyl benzaldehyde, hexanal) obtained by the tandem mass spectrometry ionization source described in this embodiment. For the CO2 gas in the human exhaled gas, CO2 standard gas is used for analysis, Figure 4 The CO2 signal response fold line graph of different concentrations obtained by the tandem mass spectrometry ionization source described in this embodiment.

[0067] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Those skilled in the art can make various modifications and changes to the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A tandem mass spectrometry ionization source for online detection of disease markers in end-tidal breath gases of a human subject, characterized in that, The application relates to a funnel-shaped chemical ionization source (1), a photoelectron ionization source (2) and a gas collecting device. The gas collecting device is connected with the funnel-shaped chemical ionization source (1), and the funnel-shaped chemical ionization source (1) is connected with the photoelectron ionization source (2) in front and back. The funnel-shaped chemical ionization source comprises a funnel-shaped chemical ionization reaction cavity (5), a plurality of ultraviolet light emitting devices are arranged outside the funnel-shaped chemical ionization reaction cavity (5), and a heating device (6) and a first vacuum pump (7) are arranged on the outer wall of the funnel-shaped chemical ionization reaction cavity (5). The funnel-shaped chemical ionization reaction cavity (5) is a first vacuum area, and a photoelectron ionization source cavity (11) is a second vacuum area; the first vacuum area and the second vacuum area are connected through an ion repulsion electrode (8) for gas pressure difference division.

2. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 1, characterized in that, The inner diameter of the cavity of the funnel-shaped chemical ionization reaction cavity (5) gradually increases from the funnel neck, the funnel angle is 70-80 DEG, the cavity is externally grounded, and the internal gas pressure is 6000-7000 Pa.

3. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 1, characterized in that, The funnel-shaped chemical ionization reaction cavity (5) is free of electric field, and product ions and unspent reagent ions are pushed into a mass spectrometer for detection through gas flow.

4. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 1, wherein, The ultraviolet light emitting devices are vacuum ultraviolet lamps (4), three of which are arranged on the same circle with the axis of the funnel-shaped chemical ionization reaction cavity (5) as the center, and the angle between the three is 80-85 DEG with the center line of the funnel-shaped chemical ionization reaction cavity (5).

5. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 1, wherein, Alternatively, the heating device (6) is a ceramic heating sheet, a polytetrafluoroethylene heat insulation plate, a heating belt or a temperature control box; the ceramic heating sheet and the heating belt are powered and heated and monitored through the temperature control box, and the heating temperature is 50 DEG C-500 DEG C. Alternatively, the gas collecting device is an exhaled gas sampling disposable mouthpiece (3) which is sealingly connected with the funnel neck of the funnel-shaped chemical ionization reaction cavity (5). The photoelectron ionization source (2) comprises a photoelectron ionization source cavity (11), the photoelectron ionization source cavity (11) is sequentially provided with an ion repulsion electrode (8), a photoelectron emitting electrode (9), a fragment quadrupole rod transmission area electrode (10) and an ion extraction electrode (12) along the axial direction; and the photoelectron ionization source cavity (11) is externally provided with a deuterium lamp (13) and a second vacuum pump (14).

6. The tandem mass spectrometry ionization source for online detection of disease markers in end- tidal gases of human exhaled breath of claim 1, wherein, The ion repulsion electrode (8), the photoelectron emitting electrode (9), the fragment quadrupole rod transmission area electrode (10) and the ion extraction electrode (12) are coaxially arranged in parallel and have central through holes.

7. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 6, characterized in that, Alternatively, the ion repulsion electrode (8) and the ion extraction electrode (12) are both plate electrodes with conical protrusions at the central parts, and the conical tips are horizontally machined to have ion transmission through holes. Alternatively, the ion repulsion electrode (8), the photoelectron emitting electrode (9), the fragment quadrupole rod transmission area electrode (10) and the ion extraction electrode (12) are sequentially loaded with different voltages in the order of the absolute values of the voltages from high to low, so as to form an ion transmission channel in the axial direction. ​ 8. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 6, characterized in that, The fragment quadrupole transmission zone is composed of a plurality of fragment electrode rings, which are plate structures with a central opening; the electrode rings are fixed on four insulating rods placed at equal distances, and each electrode ring is isolated by an insulating ring of the same size; the electrode rings of each pole rod are applied with a direct current voltage through a voltage dividing resistor, and a capacitor with the same capacitance value is connected to apply a radio frequency voltage.

9. The tandem mass spectrometry ionization source for online detection of disease markers in the end gases of human exhaled breath according to claim 6, characterized in that, The photoelectron emission electrode is a cylindrical structure with a through hole in the center; the deuterium lamp is connected to the photoelectron emission electrode, and the vacuum ultraviolet light is irradiated onto the ring surface in the cylinder through the small holes on the side of the cylinder to generate photoelectrons; Or, an ion outlet is arranged on the ion extraction electrode, and the ion outlet is connected to the mass spectrometer. Or, the funnel neck through hole diameter of the funnel-shaped chemical ionization reaction chamber (5) is 0.3-0.8mm, the through hole diameter of the ion repulsion electrode (8) is 0.8-1.5mm, and the through hole diameter of the ion extraction electrode (12) is 0.5-1.2mm.

10. A device for online detection of a disease marker in the end gas of human exhaled breath, comprising: The tandem mass spectrometry ionization source and mass spectrometer of any one of claims 1-9.

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