A tandem mass spectrometry ionization source for online detection of disease markers in end gases of human exhaled breath

Abstract

The application belongs to the technical field of mass spectrometry ionization source, and provides a tandem mass spectrometry ionization source for online detection of disease markers in end gas of human exhaled breath, aiming at solving the problems of complex exhaled breath sampling, insufficient detection sensitivity and difficult real-time monitoring in the prior art. The ionization source device can realize real-time online breath analysis of human exhaled breath, and can determine the end gas moment of the exhaled breath according to the change of the carbon dioxide concentration in the exhaled breath, so as to realize real-time analysis of the disease markers in the end gas of the exhaled breath. The technical scheme comprises a double-ionization source tandem design, the front end is a funnel-shaped chemical ionization source, which is specially used for high-sensitivity detection of volatile organic compounds in exhaled breath; the rear end is a photoelectron ionization source, which is used for real-time monitoring of carbon dioxide concentration and determination of end gas moment. The design considers the high sensitivity of organic matter detection and the accurate monitoring of carbon dioxide concentration through the way of partition ionization.

Description

Technical Field

[0001] This invention belongs to the field of mass spectrometry ionization source technology, and relates to a tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] In recent years, exhaled gas analysis, as a non-invasive method, has received widespread attention for assessing human physiological metabolism and diagnosing diseases. The theoretical basis of this method lies in the fact that volatile organic compounds (VOCs) produced during human metabolism can reach the lungs through blood circulation and are ultimately exhaled. In exhaled gas analysis, the collection of terminal gases is particularly important. These gases originate directly from the alveoli and can more accurately reflect the body's metabolic state.

[0004] Mass spectrometry, characterized by high throughput and high sensitivity, has been widely applied in the detection of human exhaled gases. One study used a self-developed vacuum ultraviolet photoionization VOCs mass spectrometer for early lung cancer screening. This method directly samples human exhaled gases and features real-time online analysis, enabling sensitive and rapid detection of multi-component VOCs. However, it cannot distinguish between the initial and final phases of exhaled gases. Another study proposed a device for analyzing various components in human exhaled gases. This device collects the final phase of exhaled gases and stores the collected gas in a sample collection and storage device before passing it through a mass spectrometer for analysis. However, this method does not adequately address the potential adsorption problem of gas components during storage in the design of the sample collection and storage device. This could lead to the loss or concentration changes of gas components, affecting the accuracy of the detection results.

[0005] In summary, the main problems currently faced by applying mass spectrometry technology to exhaled breath detection are:

[0006] (1) Limitations of sampling equipment. Existing sampling methods require exhaled air to be collected into a sample storage device, which is costly due to the high cost of steel cylinders. Gas bags, on the other hand, suffer from background residue and gas adsorption issues, affecting the accuracy of the test results.

[0007] (2) Collecting exhaled gas at the end of the breath is more difficult. The exhaled gas at the end of the breath can better reflect human metabolic products. How to collect it accurately and ensure the representativeness of the sample is still a technical challenge.

[0008] (3) Insufficient detection sensitivity. The concentration of disease markers in the exhaled gas terminal gas is usually in the range of ppbv (parts per billion) to pptv (parts per trillion), which places extremely high demands on the sensitivity of mass spectrometry detection. Summary of the Invention

[0009] To address the aforementioned issues, this invention provides a tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gases of human exhaled breath. This ionization source employs a modular design, integrating a funnel-shaped chemical ionization source 1 and a photoelectron ionization source 2, enabling efficient and accurate detection of different components in exhaled breath. Specifically, a detachable disposable mouthpiece 3 is installed at the front end of the funnel-shaped chemical ionization source 1 to ensure hygiene for each test and prevent cross-contamination. Volatile organic compounds (VOCs) in exhaled breath are efficiently ionized within the funnel-shaped chemical ionization source 1 through chemical or photoelectron ionization processes, achieving highly sensitive 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. Simultaneously, carbon dioxide in exhaled breath is ionized by a dedicated photoelectron ionization source 2. This ionization source can monitor changes in carbon dioxide concentration in real time and automatically distinguish between the front and rear gases of exhaled breath. This design enables the system to accurately identify and analyze VOCs in the exhaled breath, ensuring the accuracy and reliability of the detection results. This invention not only achieves real-time online mass spectrometry analysis of VOCs in the exhaled breath but also ensures high efficiency and accuracy in the detection process through modular structure and intelligent control. This invention provides strong technical support for the high-sensitivity detection of disease biomarkers and has broad application prospects.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] In a first aspect, the present invention provides a tandem mass spectrometry ionization source for online detection of disease markers in the terminal gas of human exhaled breath, comprising: a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and a gas collection device;

[0012] 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 behind.

[0013] The funnel-shaped chemical ionization source includes: a funnel-shaped chemical ionization reaction chamber 5, with multiple ultraviolet light emitting devices arranged outside the funnel-shaped chemical ionization reaction chamber 5, and a heating device 6 and a first vacuum pump 7 arranged on the outer wall of the funnel-shaped chemical ionization reaction chamber 5.

[0014] The design of the funnel-shaped chemical ionization reaction chamber 5 in this invention results in less internal turbulence and mainly laminar flow, which enables efficient ion transport and improves ion aggregation efficiency. Secondly, the funnel-shaped design can effectively reduce the reaction between the sample and the funnel chemical reaction zone, reduce sample wall loss, and improve ionization efficiency.

[0015] A second aspect of the present invention provides an apparatus for online detection of disease biomarkers in the terminal gas of human exhaled breath, comprising: the aforementioned tandem mass spectrometry ionization source and mass spectrometer.

[0016] Beneficial effects of the present invention

[0017] (1) Convenient sampling and high fidelity: The present invention introduces human exhaled air directly into the ionization source through a disposable mouthpiece, eliminating the need for traditional sample collection and storage devices (such as steel cylinders or gas bags), avoiding problems such as sample residue, background pollution and gas adsorption, and significantly improving the fidelity of the sample and the reliability of the test results.

[0018] (2) Dual Ionization Source Synergistic Detection: This invention innovatively combines a funnel-shaped chemical ionization source with a photoelectron ionization source to achieve simultaneous detection of organic and inorganic substances in human exhaled breath. The funnel-shaped chemical ionization source utilizes nitrosyl cations / hydrated hydrogen ions to chemically react with organic matter or directly photoionize it, achieving efficient ionization of volatile organic compounds (VOCs). The funnel design improves the aggregation efficiency of gas molecules, enhances the ionization effect, and ensures high sensitivity detection of low-concentration VOCs. Through the combination of a vacuum ultraviolet lamp and reagent gas, it supports multiple ionization modes (such as chemical ionization and photoelectron ionization), suitable for detecting different types of VOCs. The photoelectron ionization source employs photogenerated electron ionization technology to achieve precise ionization of inorganic substances such as carbon dioxide. This design balances high sensitivity for organic matter detection with accuracy for inorganic matter detection.

[0019] (3) Real-time monitoring and precise analysis: This invention can monitor changes in carbon dioxide concentration in human exhaled air in real time, automatically identify and determine the timing of the exhaled gas, thereby enabling more precise analysis of disease biomarkers in the exhaled gas. This real-time online detection method not only simplifies the sampling process but also improves detection efficiency, providing reliable technical support for early disease diagnosis and health monitoring.

[0020] (4) The present invention has a simple structure, strong practicality, and is easy to promote. Attached Figure Description

[0021] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. Exemplary embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0022] Figure 1 The above is a schematic diagram of the structure of a tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath, provided in an embodiment of the present invention.

[0023] Figure 2 This is a schematic diagram of the installation of a vacuum ultraviolet lamp outside the funnel-shaped chemical ionization reaction chamber in a tandem mass spectrometry ionization source for online detection of disease markers in the terminal gas of human exhaled breath, provided by an embodiment of the present invention.

[0024] Figure 3 This is a mass spectrum of aldehydes in exhaled breath detected by a tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath, provided by an embodiment of the present invention.

[0025] Figure 4 This is a mass spectrum of CO2 at different concentrations obtained by an online detection tandem mass spectrometry ionization source for detecting disease markers in the terminal gas of human exhaled breath, provided by an embodiment of the present invention.

[0026] The components include: 1. Funnel-shaped chemical ionization source; 2. Photoelectron ionization source; 3. Disposable mouthpiece for exhaled breath sampling; 4. Vacuum ultraviolet lamp; 5. Funnel-shaped chemical ionization reaction chamber; 6. Heating device; 7. First vacuum pump; 8. Ion repulsion electrode; 9. Photoelectron emission electrode; 10. Segment quadrupole transport region; 11. Photoelectron ionization source cavity; 12. Ion extraction electrode; 13. Deuterium lamp; and 14. Second vacuum pump. Detailed Implementation

[0027] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or product instructions. Similarly, unless otherwise specified, the test methods of this invention are performed in accordance with conventional methods in the art or industry-standard methods or practices. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0029] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof.

[0030] As described in the background section, human exhaled breath contains volatile organic compounds (VOCs) that characterize human diseases. However, only the end-stage gases can more accurately reflect the body's metabolic state. Therefore, developing novel measurement technologies is crucial for accurately measuring low concentrations of VOCs. The invention patent (application number: 201510153472.5) uses a self-developed vacuum ultraviolet photoionization VOCs mass spectrometry to screen for early-stage lung cancer. It can directly sample human exhaled breath and features real-time online analysis, enabling sensitive and rapid detection of multi-component VOCs and analysis of the relationship between VOC component content and cancer. However, this technology cannot distinguish between the beginning and end stages of exhaled breath, which may lead to interference from low concentrations of VOCs in the beginning-stage gases, reducing the accuracy of the analysis. An invention patent (application number: 202011410877.X) proposes a device for analyzing and detecting various components in human exhaled gas. This device collects the gas at the end of human exhalation and stores the collected gas in a sample collection and storage device, which is then passed into a mass spectrometer for analysis. However, the design of the sample collection and storage device in this invention does not adequately address the adsorption problem that may occur during the storage of gas components, which may lead to the loss or concentration change of gas components and affect the accuracy of the detection results. To solve the above technical problems, this invention proposes a tandem mass spectrometry ionization source for online detection of disease biomarkers in human exhaled gas, including a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and a disposable exhaled gas sampling nozzle 3. The funnel-shaped chemical ionization source 1 can generate hydrated hydrogen ions and nitrosyl cations by introducing reagent gas or directly perform photoionization using a vacuum ultraviolet lamp 4, 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 concentrations of VOCs. The photoelectron ionization source 2 uses vacuum ultraviolet light generated by the deuterium lamp 13 to generate photoelectrons through the photoelectron emission electrode 9, thereby achieving efficient ionization of carbon dioxide and efficient ion transport through a segmented quadrupole. This invention can monitor changes in carbon dioxide concentration in real time, automatically identify and determine the timing of the exhaled gas at the end of the breath, and ensure that the analysis target is a high concentration of disease markers in the end gas, avoiding interference from low concentrations of VOCs in the front gas.

[0031] like Figure 1 As shown, this embodiment provides a tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath, including: a funnel-shaped chemical ionization source 1, a photoelectron ionization source 2, and a gas collection device;

[0032] 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 behind.

[0033] The funnel-shaped chemical ionization source includes: a funnel-shaped chemical ionization reaction chamber 5, with multiple ultraviolet light emitting devices arranged outside the funnel-shaped chemical ionization reaction chamber 5, and a heating device 6 and a first vacuum pump 7 arranged on the outer wall of the funnel-shaped chemical ionization reaction chamber 5.

[0034] This invention, through innovative design, improves the online mass spectrometry detection method for human exhaled breath from traditional gas bag or cylinder sampling to direct sample injection using a disposable mouthpiece 3, significantly reducing sample loss and contamination problems that may be caused by gas storage devices. Volatile organic compounds (VOCs) in exhaled breath are efficiently ionized within the funnel-shaped chemical ionization source 1 through chemical ionization (such as the reaction of hydrated hydrogen ions or nitrosyl cations) or photoionization processes, ensuring high sensitivity detection of low-concentration VOCs. Simultaneously, the photoelectron ionization source 2 can monitor changes in carbon dioxide concentration in real time, automatically distinguishing between the initial and final gases of exhaled breath, ensuring that the analysis targets are high-concentration disease biomarkers in the final gas. The segmental quadrupole transmission region can focus and transport ions, guaranteeing efficient ion transport. Through this dual ionization source collaborative design, the system not only achieves efficient ionization and accurate detection of VOCs, but also avoids interference from low-concentration VOCs in the initial 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 mouthpieces avoids cross-contamination, further ensuring the originality of the samples and the hygiene of the testing.

[0035] In some embodiments, the funnel-shaped chemical ionization reaction chamber 5 is the first vacuum region, and the photoelectron ionization source chamber 11 is the second vacuum region; the first and second vacuum regions are separated by an ion repulsion electrode 8 to provide a pressure difference. The first vacuum pump 7 is responsible for maintaining the vacuum level in the first vacuum region, and the second vacuum pump 14 is responsible for maintaining the vacuum level in the second vacuum region. This multi-stage vacuum system design ensures that the vacuum levels in different regions meet the requirements for ionization and ion transport.

[0036] Preferably, the vacuum degree of the first vacuum zone is 6000Pa~7000Pa, and the vacuum degree of the second vacuum zone is 50Pa~100Pa.

[0037] 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.

[0038] This invention installs a photoelectron ionization source 2 after a funnel-shaped chemical ionization source 1. By optimizing the photoelectron generation and control mechanism, more photoelectrons are generated when vacuum ultraviolet light irradiates the metal electrode under low pressure (50-100 Pa), reducing collision losses of photoelectrons by gas molecules and ensuring that more photoelectrons can effectively act on the target molecules. Simultaneously, adjusting the voltage of the photoelectron emitting electrode can control the energy of the photoelectrons, achieving efficient ionization of high-ionization-energy substances such as CO2.

[0039] In some embodiments, the inner diameter of the funnel-shaped chemical ionization reaction chamber 5 gradually increases from the neck of the funnel, the funnel angle is 70-80°, the outside of the chamber is grounded, and the internal air pressure is 6000~7000 Pa.

[0040] In some embodiments, the ultraviolet light emitting device is a vacuum ultraviolet lamp 4, and three of them are arranged on the same circle with the axis of the funnel-shaped chemical ionization reaction chamber 5 as the center, and the angle between them is 80-85° with the center line of the funnel-shaped chemical ionization reaction chamber 5.

[0041] In some embodiments, the heating device 6 is a ceramic heating element, a polytetrafluoroethylene heat insulation plate, a heating belt, and a temperature control box. The ceramic heating element and the heating belt are powered, heated, and monitored through the temperature control box. The heating temperature is preferably 50°C to 500°C.

[0042] In some embodiments, the funnel-shaped chemical ionization reaction chamber 5 has no electric field, and relies on airflow to propel product ions and unconsumed reagent ions into the mass spectrometer for detection.

[0043] like Figure 2 As shown, the vacuum ultraviolet lamp 4 is installed on the wall of the funnel-shaped chemical ionization reaction chamber 5, which can introduce different reagent gases according to experimental requirements to generate specific reagent ions. Through this design, the reaction chamber can achieve multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization.

[0044] This invention utilizes a funnel-shaped chemical ionization source 1 to ionize volatile organic compounds (VOCs) in exhaled breath. Three vacuum ultraviolet lamps 4 are installed externally in the funnel-shaped chemical ionization reaction chamber 5, enabling simultaneous implementation of multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization. This improves the detection sensitivity and selectivity for different VOCs and is suitable for detecting various disease biomarkers. A heating device 6 maintains a stable temperature within the reaction chamber, ensuring that VOCs remain gaseous during ionization and preventing condensation. Inside the photoelectron ionization source 2, a deuterium lamp 13 irradiates a photoelectron emission electrode 9 to generate high-energy photoelectrons. The photoelectron energy is controlled by the voltage of the photoelectron emission electrode 9, thus ensuring efficient ionization of carbon dioxide.

[0045] In some embodiments, the gas collection device is a disposable exhaled gas sampling nozzle 3, which is sealed to the funnel neck of the funnel-shaped chemical ionization reaction chamber 5 to ensure that more exhaled gas can enter the funnel-shaped chemical ionization reaction chamber 5.

[0046] In some embodiments, the photoelectron ionization source 2 includes: a photoelectron ionization source cavity 11, wherein an ion repulsion electrode 8, a photoelectron emission electrode 9, a segment quadrupole transport region electrode 10, and an ion extraction electrode 12 are sequentially arranged along the axial direction inside the photoelectron ionization source cavity 11; and a deuterium lamp 13 and a second vacuum pump 14 are arranged outside the photoelectron ionization source cavity 11.

[0047] In some embodiments, the ion repulsion electrode 8, photoelectron emission electrode 9, segment quadrupole transport region electrode 10, and ion extraction electrode 12 are parallel to each other and coaxially placed with a central through hole.

[0048] The funnel-shaped chemical ionization reaction chamber 5 is also coaxially arranged with the aforementioned electrodes to ensure detection effectiveness.

[0049] In some embodiments, the diameter of the funnel neck through-hole of the funnel-shaped chemical ionization reaction chamber 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.

[0050] In some embodiments, the ion repulsion electrode 8, photoelectron emission electrode 9, segment quadrupole transport region electrode 10, and ion extraction electrode 12 are sequentially loaded with different voltages in descending order of absolute voltage value, forming an ion transport channel in the axial direction.

[0051] In some embodiments, the ion repulsion electrode 8 and the ion extraction electrode 12 are both plate electrodes with a conical protrusion in the center, and the tip of the cone is machined with a through hole for ion transmission in the transverse direction.

[0052] In some embodiments, a segmented quadrupole transmission region is installed at the rear of the photoelectron emitting electrode 9. This segmented quadrupole transmission region consists of multiple segmented electrode rings, each a plate structure with a central opening. The electrode rings are fixed to four equidistant insulating rods, and each electrode ring is isolated by an insulating ring of the same size. A DC voltage is applied to each electrode ring via a voltage-dividing resistor, forming a DC electric field along the axial direction. Simultaneously, a capacitor of the same capacitance is connected to apply a radio frequency voltage. Through its unique quadrupole electric field design, the segmented quadrupole transmission region can effectively focus ions generated from the funnel-shaped chemical ionization source 1 and ions generated from the photoelectron ionization region. By controlling the ion trajectory, the quadrupole electric field concentrates the dispersed ion beam near the central axis of the transmission region, reducing ion loss during transmission and improving ion transmission efficiency.

[0053] Preferably, the insulating rod is made of polyetheretherketone or ceramic.

[0054] Preferably, the dimensions of the segmental quadrupole ring are: inner diameter of 5 mm, outer diameter of 9 mm, and height of 4 mm, and the dimensions of the polyetheretherketone ring are: inner diameter of 5 mm, outer diameter of 9 mm, and height of 0.5 mm.

[0055] Preferably, the voltage divider resistor has a resistance of 10MΩ; the capacitor has a capacitance of 100nF; the radio frequency voltage is 1.8MHz; and the peak-to-peak value is 300V.

[0056] In some embodiments, the photoelectron emitting electrode is a cylindrical structure with a through hole at the center; the deuterium lamp is connected to the photoelectron emitting electrode, and vacuum ultraviolet light irradiates the inner ring surface of the cylinder through a small hole on the side of the cylinder to generate photoelectrons;

[0057] In some embodiments, the ion extraction electrode 12 is provided with an ion outlet, which is connected to a mass spectrometer; specifically, the ion outlet is connected to the mass spectrometer, that is, the ions obtained by ionization of the gas sample in the ionization source cavity are directly introduced into the mass spectrometer through the ion outlet on the ion extraction electrode 12.

[0058] In this embodiment, the mass spectrometer is a time-of-flight mass spectrometer, with a single detection time in the microsecond range, thus allowing observation of changes in the content of volatile organic compounds in the front and rear gases of human exhaled breath.

[0059] The exhaled breath contains various disease biomarkers that can reveal a person's health status. For example, benzene compounds (such as styrene and toluene), aldehydes (such as hexanal and pentanal), and alkanes (such as n-decane) are often detected in the exhaled breath of lung cancer patients; elevated acetone concentrations in the exhaled breath of diabetic patients indicate poor blood sugar control or ketoacidosis; the exhaled breath of liver disease patients may contain thiols (such as dimethyl sulfide) and pentane, suggesting liver failure or lipid peroxidation; elevated ammonia and dimethylamine concentrations in the exhaled breath of kidney disease patients indicate abnormal kidney function; and elevated pentane and hydrogen sulfide concentrations in the exhaled breath of gastrointestinal disease patients may be related to Helicobacter pylori infection or intestinal flora imbalance. Furthermore, methylbenzene, nonanal, and aldehydes and ketones can be detected in the exhaled breath of patients with infectious diseases such as tuberculosis and COVID-19. Standard gas analysis was performed on aldehydes among these disease biomarkers. Figure 3 This is the mass spectrum of aldehyde standard gases (acetaldehyde, acrolein, propionaldehyde, butenal, n-butyraldehyde, benzaldehyde, pentanal, m-methylbenzaldehyde, and hexanal) obtained from the tandem mass spectrometry ionization source described in this embodiment. For CO2 gas in human exhaled breath, CO2 standard gas was used for analysis. Figure 4 This is a line graph showing the CO2 signal response at different concentrations obtained from the tandem mass spectrometry ionization source described in this embodiment.

[0060] In this embodiment, the funnel-shaped chemical ionization source 1 includes 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.

[0061] The photoelectron ionization source 2 includes an ion repulsion electrode 8, a deuterium lamp 13, a photoelectron emission electrode 9, a segment quadrupole transport region, an ion extraction electrode 12, a second vacuum pump 14, and a photoelectron ionization source cavity 11.

[0062] The ionization source cavity is arranged in sequence along the axial direction as follows: a funnel-shaped chemical ionization reaction chamber 5, an ion repulsion electrode 8, a photoelectron emission electrode 9, a segment quadrupole transport region, and an ion extraction electrode 12. The multiple electrodes are parallel to each other and are placed coaxially with the central through hole.

[0063] The exhaled breath sampling disposable mouthpiece 3 is sealed to the funnel neck of the funnel-shaped chemical ionization reaction chamber 5.

[0064] The funnel-shaped chemical ionization reaction chamber 5 has a funnel neck through-hole diameter of 0.3-0.8 mm, the ion repulsion electrode 8 has a through-hole diameter of 0.8-1.5 mm, and the ion extraction electrode 12 has a through-hole diameter of 0.5-1.2 mm.

[0065] The ion repulsion electrode 8, photoelectron emission electrode 9, segment quadrupole transport region electrode 10, and ion extraction electrode 12 are sequentially loaded with different voltages in descending order of absolute voltage value, forming an ion transport channel in the axial direction.

[0066] This invention, through innovative design, improves the online mass spectrometry detection method for human exhaled breath from traditional gas bag or cylinder sampling to direct sample injection using a disposable mouthpiece 3, significantly reducing sample loss and contamination problems that may be caused by gas storage devices. Volatile organic compounds (VOCs) in exhaled breath are efficiently ionized within the funnel-shaped chemical ionization source 1 through chemical ionization (such as the reaction of hydrated hydrogen ions or nitrosyl cations) or photoionization processes, ensuring high sensitivity detection of low-concentration VOCs. Simultaneously, the photoelectron ionization source 2 can monitor changes in carbon dioxide concentration in real time, automatically distinguishing between the initial and final gases of exhaled breath, ensuring that the analysis targets are high-concentration disease biomarkers in the final gas. The segmental quadrupole transmission region can focus and transport ions, guaranteeing efficient ion transport. Through this dual ionization source collaborative design, the system not only achieves efficient ionization and accurate detection of VOCs, but also avoids interference from low-concentration VOCs in the initial 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 mouthpieces avoids cross-contamination, further ensuring the originality of the samples and the hygiene of the testing.

[0067] In this embodiment, the ion repulsion electrode 8 and the ion extraction electrode 12 are both plate electrodes with a conical protrusion in the center, and the tip of the cone is machined with a through hole for ion transmission in the transverse direction.

[0068] Furthermore, the inner diameter 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 chamber 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 angles between them form an 80° angle with the center line of the reaction chamber.

[0069] The heating device 6 consists of a ceramic heating element, a polytetrafluoroethylene heat insulation plate, a heating belt, and a temperature control box. The ceramic heating element and the heating belt are powered and heated and monitored through the temperature control box. The preferred heating temperature is 50℃~500℃.

[0070] There is no electric field inside the funnel-shaped chemical ionization reaction chamber 5. The product ions and unconsumed reagent ions are propelled into the mass spectrometer for detection by airflow.

[0071] like Figure 2As shown, the vacuum ultraviolet lamp 4 is installed on the wall of the funnel-shaped chemical ionization reaction chamber 5, which can introduce different reagent gases according to experimental requirements to generate specific reagent ions. Through this design, the reaction chamber can achieve multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization.

[0072] This invention utilizes a funnel-shaped chemical ionization source 1 to ionize volatile organic compounds (VOCs) in exhaled breath. Three vacuum ultraviolet lamps 4 are installed externally in the funnel-shaped chemical ionization reaction chamber 5, enabling simultaneous implementation of multiple ionization modes, including chemical ionization of hydrated hydrogen ions and nitrosyl cations, as well as direct photoionization. This improves the detection sensitivity and selectivity for different VOCs and is suitable for detecting various disease biomarkers. A heating device 6 maintains a stable temperature within the reaction chamber, ensuring that VOCs remain gaseous during ionization and preventing condensation. Inside the photoelectron ionization source 2, a deuterium lamp 13 irradiates a photoelectron emission electrode 9 to generate high-energy photoelectrons. The photoelectron energy is controlled by the voltage of the photoelectron emission electrode 9, thus ensuring efficient ionization of carbon dioxide.

[0073] Furthermore, a segmented quadrupole transmission region is installed at the rear of the photoelectron emitting electrode 9. This segmented quadrupole transmission region consists of multiple segmented electrode rings, each a plate structure with a central opening. The electrode rings are fixed to four equidistant insulating rods, and each electrode ring is isolated by an insulating ring of the same size. A DC voltage is applied to the electrode rings of each rod through a voltage-dividing resistor, forming a DC electric field along the axial direction. Simultaneously, a capacitor of the same capacitance is connected to apply a radio frequency voltage. Through its unique quadrupole electric field design, the segmented quadrupole transmission region can effectively focus ions generated from the funnel-shaped chemical ionization source 1 and ions generated from the photoelectron ionization region. By controlling the trajectory of the ions, the quadrupole electric field concentrates the dispersed ion beam near the central axis of the transmission region, reducing ion loss during transmission and improving ion transmission efficiency.

[0074] Preferably, the insulating rod is made of polyetheretherketone or ceramic.

[0075] Preferably, the dimensions of the segmental quadrupole ring are: inner diameter of 5 mm, outer diameter of 9 mm, and height of 4 mm, and the dimensions of the polyetheretherketone ring are: inner diameter of 5 mm, outer diameter of 9 mm, and height of 0.5 mm.

[0076] Preferably, the voltage divider resistor has a resistance of 10MΩ; the capacitor has a capacitance of 100nF; the radio frequency voltage is 1.8MHz; and the peak-to-peak value is 300V.

[0077] In this embodiment, the photoelectron emitting electrode 9 is a cylindrical structure with a through hole in the center; the deuterium lamp 13 is connected to the photoelectron emitting electrode 9, and vacuum ultraviolet light irradiates the inner ring surface of the cylinder through the small hole on the side of the cylinder to generate photoelectrons.

[0078] The ion extraction electrode 12 is provided with an ion outlet, which is connected to the mass spectrometer. Specifically, the ion outlet is connected to the mass spectrometer, meaning that ions obtained from the ionization of the gas sample in the ionization source chamber are directly introduced into the mass spectrometer through the ion outlet on the ion extraction electrode 12.

[0079] In this embodiment, the funnel-shaped chemical ionization reaction chamber 5 is the first vacuum region, and the photoelectron ionization source chamber 11 is the second vacuum region; the first vacuum region and the second vacuum region are separated by the ion repulsion electrode 8.

[0080] The first vacuum pump 7 is responsible for maintaining the vacuum level in the first vacuum zone, and the second vacuum pump 14 is responsible for maintaining the vacuum level in the second vacuum zone. Through the multi-stage vacuum system design, it is ensured that the vacuum level in different zones meets the requirements for ionization and ion transport.

[0081] Preferably, the vacuum degree of the first vacuum zone is 6000Pa~7000Pa, and the vacuum degree of the second vacuum zone is 50Pa~100Pa.

[0082] 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.

[0083] This invention installs a photoelectron ionization source 2 after a funnel-shaped chemical ionization source 1. By optimizing the photoelectron generation and control mechanism, more photoelectrons are generated when vacuum ultraviolet light irradiates the metal electrode under low pressure (50-100 Pa), reducing collision losses of photoelectrons by gas molecules and ensuring that more photoelectrons can effectively act on the target molecules. Simultaneously, adjusting the voltage of the photoelectron emitting electrode can control the energy of the photoelectrons, achieving efficient ionization of high-ionization-energy substances such as CO2.

[0084] In this embodiment, the mass spectrometer is a time-of-flight mass spectrometer, with a single detection time in the microsecond range, thus allowing observation of changes in the content of volatile organic compounds in the front and rear gases of human exhaled breath.

[0085] The exhaled breath contains various disease biomarkers that can reveal a person's health status. For example, benzene compounds (such as styrene and toluene), aldehydes (such as hexanal and pentanal), and alkanes (such as n-decane) are often detected in the exhaled breath of lung cancer patients; elevated acetone concentrations in the exhaled breath of diabetic patients indicate poor blood sugar control or ketoacidosis; the exhaled breath of liver disease patients may contain thiols (such as dimethyl sulfide) and pentane, suggesting liver failure or lipid peroxidation; elevated ammonia and dimethylamine concentrations in the exhaled breath of kidney disease patients indicate abnormal kidney function; and elevated pentane and hydrogen sulfide concentrations in the exhaled breath of gastrointestinal disease patients may be related to Helicobacter pylori infection or intestinal flora imbalance. Furthermore, methylbenzene, nonanal, and aldehydes and ketones can be detected in the exhaled breath of patients with infectious diseases such as tuberculosis and COVID-19. Standard gas analysis was performed on aldehydes among these disease biomarkers. Figure 3 This is the mass spectrum of aldehyde standard gases (acetaldehyde, acrolein, propionaldehyde, butenal, n-butyraldehyde, benzaldehyde, pentanal, m-methylbenzaldehyde, and hexanal) obtained from the tandem mass spectrometry ionization source described in this embodiment. For CO2 gas in human exhaled breath, CO2 standard gas was used for analysis. Figure 4 This is a line graph showing the CO2 signal response at different concentrations obtained from the tandem mass spectrometry ionization source described in this embodiment.

[0086] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath, characterized in that, include: Funnel-shaped chemical ionization source (1), photoelectron ionization source (2), and 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 behind. 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). The funnel-shaped chemical ionization reaction chamber (5) is the first vacuum zone, and the photoelectron ionization source chamber (11) is the second vacuum zone; the first vacuum zone and the second vacuum zone are separated by an ion repulsion electrode (8) to achieve a pressure difference. The inner diameter 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°, the outside of the chamber is grounded, and the internal air pressure is 6000~7000 Pa. There is no electric field inside the funnel-shaped chemical ionization reaction chamber (5). The product ions and unconsumed reagent ions are driven into the mass spectrometer for detection by airflow. The ultraviolet light emitting device is a vacuum ultraviolet lamp (4), and three of them are set on the same circle with the axis of the funnel-shaped chemical ionization reaction chamber (5) as the center, and the angle between them is 80-85° with the center line of the funnel-shaped chemical ionization reaction chamber (5); The funnel-shaped chemical ionization source generates hydrated hydrogen ions and nitrosyl cations by introducing reagent gas or directly uses a vacuum ultraviolet lamp for photoionization. The photoelectron ionization source (2) includes: a photoelectron ionization source cavity (11), wherein an ion repulsion electrode (8), a photoelectron emission electrode (9), a segment quadrupole transport region electrode (10), and an ion extraction electrode (12) are arranged sequentially along the axial direction inside the photoelectron ionization source cavity (11); a deuterium lamp (13) and a second vacuum pump (14) are arranged outside the photoelectron ionization source cavity (11); Volatile organic compounds in exhaled air are ionized in a funnel-shaped chemical ionization source (1) through chemical ionization or photoionization. At the same time, carbon dioxide in exhaled air is ionized by a photoelectron ionization source (2). This ionization source can monitor the change in carbon dioxide concentration in real time and automatically distinguish between the front gas and the end gas of exhaled air.

2. The tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath as described in claim 1, characterized in that, The heating device (6) consists of a ceramic heating element, a polytetrafluoroethylene heat insulation plate, a heating belt, and a temperature control box. The ceramic heating element and the heating belt are powered and heated and monitored through the temperature control box. The heating temperature is 50℃~500℃. Alternatively, the gas collection device is a disposable exhaled air sampling nozzle (3), which is sealed to the neck of the funnel-shaped chemical ionization reaction chamber (5).

3. The tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath as described in claim 1, characterized in that, The ion repulsion electrode (8), photoelectron emission electrode (9), segment quadrupole transport region electrode (10), and ion extraction electrode (12) are parallel to each other and coaxially placed with a central through hole. Alternatively, the ion repulsion electrode (8) and the ion extraction electrode (12) are both plate electrodes with a conical protrusion in the center, and the tip of the cone is machined with a through hole for ion transmission in the transverse direction. Alternatively, the ion repulsion electrode (8), photoelectron emission electrode (9), segment quadrupole transport region electrode (10), and ion extraction electrode (12) are sequentially loaded with different voltages in descending order of absolute voltage value to form an ion transport channel in the axial direction.

4. The tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath as described in claim 1, characterized in that, The segment quadrupole transmission area is composed of multiple segment electrode rings, each of which is a plate structure with a central opening. The electrode rings are fixed on four equally spaced insulating rods, and each electrode ring is isolated by an insulating ring of the same size. A DC voltage is applied to the electrode rings of each pole through a voltage divider resistor, forming a DC electric field along the axial direction. At the same time, a capacitor of the same capacitance value is connected to apply a radio frequency voltage.

5. The tandem mass spectrometry ionization source for online detection of disease biomarkers in the terminal gas of human exhaled breath as described in claim 1, characterized in that, The photoelectron emitting electrode is a cylindrical structure with a through hole in the center; the deuterium lamp is connected to the photoelectron emitting electrode, and vacuum ultraviolet light shines through the small hole on the side of the cylinder onto the inner ring surface of the cylinder to generate photoelectrons. Alternatively, an ion outlet may be provided on the ion extraction electrode, and the ion outlet may be connected to a mass spectrometer; Alternatively, the diameter of the funnel neck through hole of the funnel-shaped chemical ionization reaction chamber (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.

6. A device for online detection of disease biomarkers in the terminal gas of human exhaled breath, comprising: The tandem mass spectrometry ionization source and mass spectrometer according to any one of claims 1-5.

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