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WO2025087536A1 - Système d'analyse de gaz - Google Patents

Système d'analyse de gaz Download PDF

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Publication number
WO2025087536A1
WO2025087536A1 PCT/EP2023/079991 EP2023079991W WO2025087536A1 WO 2025087536 A1 WO2025087536 A1 WO 2025087536A1 EP 2023079991 W EP2023079991 W EP 2023079991W WO 2025087536 A1 WO2025087536 A1 WO 2025087536A1
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WO
WIPO (PCT)
Prior art keywords
micro
analysis system
gas
gas analysis
plasma
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Pending
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PCT/EP2023/079991
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English (en)
Inventor
Vitalii VORKOV
Carolyn MOLL
Cristian Carlos D'ALESSANDRO
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Respiro BV
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Respiro BV
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Priority to PCT/EP2023/079991 priority Critical patent/WO2025087536A1/fr
Publication of WO2025087536A1 publication Critical patent/WO2025087536A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/66—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light electrically excited, e.g. electroluminescence
    • G01N21/67—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light electrically excited, e.g. electroluminescence using electric arcs or discharges
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/443—Emission spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • G01N33/4975—Physical analysis of biological material of gaseous biological material, e.g. breath other than oxygen, carbon dioxide or alcohol, e.g. organic vapours
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G01N2201/022—Casings
    • G01N2201/0221—Portable; cableless; compact; hand-held

Definitions

  • the present invention relates to a gas analysis system for detecting volatile organic compounds in a gas sample, such as a breath sample, and a method for analysing volatile organic compounds in a breath sample of a patient.
  • the present invention further relates to use of the gas analysis system for detecting volatile organic compounds in a gas sample.
  • COPD Chronic Obstructive Pulmonary Disease
  • exacerbation diagnosis is mainly determined by patient history and clinical symptombased criteria, such as increased dyspnoea, cough, sputum volume, and sputum purulence.
  • exacerbations are diagnosed at the clinic by means of generic lung function tests, since invasive diagnosis methods for obtaining direct proof of, e.g., bronchial infection are unpracticable for routine diagnosis. Furthermore, it is possible to detect and analyse breath biomarkers known as volatile organic compounds (VOCs), which are known to be indicative of exacerbation risks.
  • VOCs volatile organic compounds
  • Existing solutions for analysing gas include Gas Chromatography-Mass spectrometry (GC-MS), Field Asymmetric Ion Mobility Spectrometry (FAIMS), and plasma-based analytical methods like Inductively Coupled Plasma (ICPMS), Microwave-Induced Plasma (MIP-MS) and Capacitively Coupled Plasma Mass spectrometry (CCP-MS).
  • the detection limit and sensitivity of the measurement and detecting and analysing breath biomarkers vary greatly per technique employed.
  • a plasma is employed to dissociate and excite the molecules in the gas sample. This excitation of the molecules results in detectable emissions at specific spectral wavelengths, yielding information about the properties and constituents of the gas sample.
  • These solutions often involve large and expensive instruments.
  • the main drawbacks of these techniques include high costs, lack of portability, and the need for trained personnel to operate.
  • the complex preparation of the sample and of the instruments make these known techniques inefficient for diagnostics. That is, because these techniques are too complex, they are currently not being used for diagnostics.
  • so-called (electro)chemical sensors can be used to detect specific volatile compounds in gas samples. These sensors are based on a specific sensing mechanism that responds to the presence of a target chemical. For different types of chemical sensors, different principles for detection are used, such as chemical reactions, physical interactions, or changes in electrical properties. Gas analysers that are based on chemical sensors can be embodied as portable devices and can therefore provide an on-site and real-time gas analysis. However, a major disadvantage is that these gas analysers have limited specificity and can detect only specific chemical compounds.
  • exacerbations are thus diagnosed by symptomatic assessment and lung function tests. Furthermore, conventional approaches to gas analysis thus suffer either from bulkiness, complexity and time-consuming procedures, or from a lack of universality, sensitivity and accuracy. Therefore, exacerbations are often diagnosed too late, causing them to increase in duration and to increase the risk of future hospitalisation. Early detection of severe exacerbations is a top priority for COPD management because of the dramatic impact on quality of life, healthcare costs, and mortality. However, there is currently no user-friendly biomarker-based monitoring solution for rapid and early detection of COPD exacerbations at home. Furthermore, besides COPD, other respiratory diseases, such as certain types of cancer, could also be detectable based on VOCs.
  • a gas analysis system for detecting volatile organic compounds in a gas sample, such as a breath sample, wherein the gas analysis system comprises: a fluid system for gas to flow therethrough; a gas sample inlet arranged for receiving the gas sample in the fluid system; a substrate body; an array of micro-plasma generator units arranged on the substrate body, wherein each of the micro-plasma generator units comprises a discharge chamber arranged for receiving a portion of the gas sample from the fluid system, wherein each of the micro-plasma generator units is arranged for ionising molecular entities of the gas sample in the discharge chamber to generate a micro-plasma discharge in the discharge chamber; and a detector module arranged to detect photons emitted by the micro-plasma discharge and to provide a detection signal representative of wavelengths of the detected photons, the wavelengths being indicative of volatile organic compounds in the gas sample.
  • the gas analysis system comprising the array of microplasma generator units offers several advantages.
  • An advantage of plasma-based gas analysis is the ability to dissociate chemical species of a gas sample such that a number of photons with characteristic wavelengths is emitted, generating a distinctive spectrum for spectral analysis to be measured, which enables detection of a broad range of molecules and enables the molecular origin and concentration of the species to be determined.
  • the photon count is proportional to the concentration of the molecular entity in the gas sample, the range of concentrations that can be measured with plasma-based gas analysis is broad, ranging from parts-per-billion to saturation.
  • Micro-plasma generators are plasma generators that are often sized between a few micrometres and multiple millimetres. They generate non-thermal plasmas that interact with gas samples, producing characteristic emission spectra for a spectral analysis. In comparison to the existing solutions that require laboratory-scale equipment or are based on (electro)chemical sensors, micro-plasma generators are compact and have low power requirements, while enabling the analysis of a wide range of compounds in a breath sample with low power consumption. In contrast, many conventional gas analysis systems use considerable amounts of power, which limits their use in resource-constrained environments or in portable devices.
  • micro-plasma generators The small size of the micro-plasma generators and their low power consumption make them suitable for microfabrication and enable them to be arranged in parallel or series to thereby create an array of micro-plasma generators.
  • Arranging the micro-plasma generator units in an array can enhance the photon emission efficiency and the sensitivity and accuracy of the gas analysis.
  • the larger the number of micro-plasma generator units in the array the higher the detection accuracy, as signal noise and crosstalk can be reduced. That is, the signal noise is inversely proportional to the number of plasma sources.
  • the number of micro-plasma generator units in the array is for instance in the range of 2 to 10,000 units, preferably 10 to 1,000 units, more preferably 50 to 200 units.
  • the mutual distance of the micro-plasma generator units in the array is preferably in the range of 0.01 to 10 millimetres, preferably 0.1 to 5 millimetres, more preferably 1 to 2 millimetres. At smaller mutual distances, it may become more difficult to accurately measure the spectra with the detector module.
  • miniaturisation of the system into, e.g., a chip of 1 to 25 square centimetres can be enabled such that the integration of the gas analysis system into compact and portable devices is facilitated.
  • the size of the chip is related to the number and size of micro-plasma generators.
  • the present gas analysis system allows non-invasive diagnosis by analysing exhaled breath, which makes the process more user-friendly and more suitable for repeated measurements for acquiring historical data.
  • the gas sample inlet may be connected to, or may itself be, e.g., a mouthpiece or tube for receiving a breath sample exhaled by a patient thereinto.
  • a portable universal gas analyser enables patients to self-monitor at home in an unobtrusive manner and thus facilitates monitoring more frequently, whereas conventional breath analysis techniques may involve time-consuming processes that can delay the acquisition of critical information.
  • the present solution can rapidly provide patients and clinicians with warning signs of symptom worsening, which can enable the clinicians to make timely, objective decisions and early treatment adjustments.
  • the present solution can thus support the decisionmaking of the clinician beyond what current physiological, symptom-based assessment methods offer such that, ultimately, hospitalisations can be prevented.
  • the morbidity and mortality associated with exacerbations can be reduced and patient health and quality of life can be improved.
  • the present solution thus enables a shift towards preventive COPD patient management.
  • each of the micro-plasma generator units may further comprise a pair of electrodes, wherein the micro-plasma generator unit is arranged for applying a voltage between the electrodes for ionising said molecular entities of the gas sample in the discharge chamber.
  • the voltage is preferably in the range of 0.01 to 10 kilovolts, preferably 0.05 to 3 kilovolts, more preferably 0.1 to 1 kilovolt. A minimum voltage is required for the plasma generation to happen, while, at excessively high voltages, the plasma may become less stable and the electrode lifetime is reduced.
  • Electrodes serve as the contact points through which electrical currents are applied to create the micro-plasma discharges that ionise and excite the surrounding gaseous molecules, whereby characteristic spectral emissions are produced that can be analysed for the presence of specific gases or biomarkers.
  • Electrodes are typically made of conductive materials, such as metals, which are chosen for their stability and compatibility with the plasma generation process.
  • the electrodes may be comprised of one or more selected from the group consisting of copper, nickel, stainless steel, gold, platinum, chromium, molybdenum and tungsten.
  • the detector can capture and measure the emitted photons and may convert this received optical signal, formed by the captured photons, into an electrical signal which can then be processed and analysed.
  • detectors and imaging systems may be used, such as photodiodes or charge-coupled devices (CCDs).
  • CCDs charge-coupled devices
  • the spectral acquisition may be done by means of, e.g., a photodiode, a spectrometer, a hyperspectral camera, or a CMOS detector. The output of these devices is then a signal proportional to the concentration of the chemical in the gas sample.
  • the detector module preferably comprises at least one of a plurality of photodiodes, a spectrometer, and an imaging sensor, such as a CCD, hyperspectral camera, photodiodes with optical filters, or complementary metal-oxide-semiconductor (CMOS) sensor.
  • CMOS complementary metal-oxide-semiconductor
  • the detector module preferably comprises a plurality of such detectors, wherein it is further preferred if each detector is associated with a respective micro-plasma generator unit or subset of micro-plasma generator units.
  • the detector module may for instance only detect light with wavelengths in the range of 0.1 to 2 micrometres, preferably 0.2 to 1 micrometre.
  • the gas analysis system may further comprise a processor module, arranged to receive the detection signal and to determine volatile organic compound data representing at least one property of volatile organic compounds in the gas sample and to provide a gas analysis output signal representing the volatile organic compound data. More specifically, the presence, type and/or quantity of one or more biomarkers in the gas sample may be determined, preferably of one or more VOCs linked to, or indicative or predictive of, COPD exacerbations or other diseases.
  • a processor module in the system, the detected photons can be analysed and interpreted in real-time.
  • the processor module is preferably arranged to conduct, based on the detection signal, spectral analysis of the detected photons.
  • the processor module is preferably arranged to determine the volatile organic compound data using a classification algorithm. The volatile organic compound data may be determined on the basis of one or more spectral lines resulting from the detected photons, in particular the spectral lines associated with the biomarkers to be identified.
  • the gas analysis system may further comprise a signal transmitter module arranged for transferring, preferably wirelessly, the detection signal or the gas analysis output signal to a signal receiver such as a remote signal receiver.
  • the data may be transferred to, e.g., a cloud-based data portal or a remote monitoring portal in the form of a software application running on a mobile device such as a smartphone.
  • the detection signal may thus be processed remotely, it can still be processed in real-time.
  • the data may be transferred via, e.g., a 4G or 5G cellular network, Bluetooth, WiFi, ZigBee, Near Field Communication (NFC), Radio-Frequency Identification (RFID), Long-Range Wide Area Network (LoRaWAN), ANT+, Z-Wave, or Thread.
  • a 4G or 5G cellular network Bluetooth, WiFi, ZigBee, Near Field Communication (NFC), Radio-Frequency Identification (RFID), Long-Range Wide Area Network (LoRaWAN), ANT+, Z-W
  • the gas analysis system may further comprise a power supply module arranged for powering the gas analysis system, in particular the micro-plasma generator units and the detector module, and preferably also the processing module and/or the signal transmitter module.
  • the power supply module preferably comprises a battery.
  • the micro-plasma generator units may be of the type of one of glow discharge (GD), dielectric barrier discharge (DBD) and micro-hollow cathode discharge (MHCD), such as dielectric barrier micro-hollow cathode discharge (DB-MHCD).
  • GD glow discharge
  • DMD dielectric barrier discharge
  • MHCD micro-hollow cathode discharge
  • DB-MHCD dielectric barrier micro-hollow cathode discharge
  • the electrodes are usually arranged horizontally on mutually opposite sides and are separated by a small gap therebetween with a size in the range from a few micrometres to a few millimetres.
  • the behaviour and characteristics of plasma are related to the surface attributes of the materials involved, the pressure conditions, and the spatial separation of the electrodes.
  • the surface characteristics dictate the propensity for ionisation and photon emission across diverse materials.
  • Pressure and voltage modulate the particle density and collision frequencies of the plasma, thereby influencing ionisation kinetics.
  • the separation distance governs the electric field, influencing the interparticle energy transfer mechanisms.
  • a microchip based on glow discharge is compact and easy to fabricate and requires simple electronics to operate.
  • the small size of the GD micro-plasma sources enables parallel operation of multiple micro-plasma sources. Furthermore, glow discharge plasma is normally generated at low pressures between 0.1 and 15 millibar. However, at the microlevel of the micro-plasma generator units, plasma generation can take place at pressures up to atmospheric pressure or at pressures as high as 0.9 bar, such that there is no need for high or ultra-high vacuum. The pressure is, inter alia, related to the distance between the two electrodes.
  • Dielectric barrier discharge also known as silent discharge
  • DBD Dielectric barrier discharge
  • An AC high voltage with a frequency in the range of a few hertz to 100 megahertz or 20 megahertz, preferably up to 100 kilohertz, more preferably 10 to 50 kilohertz, is applied across the dielectric layer, resulting in periodic micro discharges between electrodes.
  • the durability of the electrodes can be enhanced,
  • the complexity of the electronics may increase and, for the system to be suitable for use in for instance a medical device, increased protective measures such as electromagnetic shielding are generally to be considered.
  • DBD digital versatile disk
  • the gas can be kept at a low temperature, such that thermal resilience is ensured, and such that additional cooling is generally not required.
  • sputtering which may be encountered in DC-type discharges, is minimal in DBD, such that the lifetime of the DBD-type microchip can be enhanced.
  • DBDs can be easily manufactured in various configurations.
  • Micro-hollow cathode discharges also referred to as microstructure electrode discharges (MSED) are configurations comprising metal-insulator-metal structures provided with a hole through them. These discharges are capable of functioning within the low-to-atmospheric pressure range.
  • MHCD devices are conventionally operated using DC and generally are a stable plasma source with a high plasma density.
  • the ions that bombard the electrodes form the main cause of sputtering.
  • Sputtering can be decreased by operating the MHCD with an AC radio frequency (RF) voltage, especially at high frequencies of, e.g., ten megahertz.
  • RF radio frequency
  • DB-MHCD dielectric barrier micro-hollow cathode discharge
  • the DB-MCHD may be operated with an alternating square, sine or triangular wave voltage with steep slopes to generate homogeneous plasma, which results in a more robust plasma source with a high plasma density and a long durability, relative to the conventional MHCD.
  • the dielectric material in, e.g., the DBD or DB-MHCD may be for example glass, quartz glass, mica, poly(4,4'-oxydiphenylene-pyromellitimide), also known as Kapton, or polytetrafluoroethylene (PTFE), also known as Teflon. It is preferred if the dielectric material is nonconducting, does not react with the gas sample, does not contaminate the gas sample, and does not outgas.
  • the thickness of the dielectric layer is for instance in the range of 0.1 micrometre to 1 millimetre, preferably 1 micrometre to 0.5 millimetre, more preferably, 0.01 to 0.2 millimetre. At thicker layers, a higher voltage is required to generate the discharge.
  • each of the micro-plasma generator units comprises a layered structure, which comprises the electrodes and an insulator layer arranged therebetween, wherein the layered structure is provided with a through-hole, extending from one electrode through the insulator layer to the other electrode, wherein the through-hole defines the discharge chamber.
  • the diameter of the hole is for instance in the range of 0.1 micrometre to 1 millimetre, preferably 1 micrometre to 0.5 millimetre, more preferably, 0.01 to 0.2 millimetre.
  • gas can pass through at higher flow rates, which could enhance the plasma density.
  • more power is then required to sustain the plasma. If the hole is too big in diameter, the stability of the plasma may decrease.
  • the electrode layer thickness may be in the range of 0.1 micrometre to 1 millimetre, preferably 1 micrometre to 0.5 millimetre, more preferably, 0.01 to 0.2 millimetre. If the electrode is too thin, there is an increased risk of damage which can affect the plasma generation. In addition, the manufacture of a narrow electrode may be more complicated.
  • the fluid system comprises a plurality of microfluidic channels in fluid communication with the gas sample inlet, wherein the microfluidic channels arranged for directing the gas sample to the discharge chambers for ionising said molecular entities of the gas sample.
  • the microfluidic channels for directing the gas sample flow enable controlled dosage and delivery of gas sample portions to the micro-plasma generator units, such that the microfluidic channels enable precise sample introduction and thereby contribute to the overall reliability and performance of the micro-plasma array.
  • the gas sample portions may be directed to the sectors for simultaneous or sequential analysis.
  • the microfluidic channels may be formed on, or integrated into, the substrate body.
  • the system further comprises a control system arranged to control the flow of the gas sample through the fluid system.
  • a control system arranged to control the flow of the gas sample through the fluid system.
  • control system may comprise a sampler arranged to manage the introduction of gas samples into the fluid system, and/or a flow controller arranged to control flow rates inside the fluid system.
  • a control system enhances the accuracy and reproducibility of the measurements.
  • the control system comprises a plurality of flow control components such as pumps and valves, preferably microfluidic flow control components such as micropumps and microvalves, wherein the flow control components are arranged to control the rates of flow of the gas sample to the discharge chambers.
  • flow control components such as pumps and valves, preferably microfluidic flow control components such as micropumps and microvalves, wherein the flow control components are arranged to control the rates of flow of the gas sample to the discharge chambers.
  • the microvalves, or other microfluidic flow control components are preferably arranged in the microfluidic channels to control the rates of flow of the gas sample or portions thereof to the discharge chambers via the micro fluidic channels.
  • the system further comprises at least one optical element for transmitting a beam of the emitted photons therethrough to the detector module, wherein the at least one optical element is arranged between the array and the detector module.
  • the optical elements can be used to improve the sensitivity and specificity of the system by enhancing the photon collection across the whole spectral range of interest, using for instance spectral filters and optical lenses. This can avoid the saturation and interference of specific spectral lines and can therefore enhance the sensitivity and the spectral range of detection.
  • the emissions associated with different gases or biomarkers can be selectively detected, wherein the risk of false positives and crosstalk between detectors of the detector module can be minimised.
  • the at least one optical element is at least one of a collimator, a spectral filter and a focusing lens.
  • the spectral filter may be arranged to selectively transmit or block photons of at least one predefined spectral band.
  • the filter can selectively transmit or block specific spectral bands of light emitted by the plasma discharges to filter out unwanted emission bands and can thereby isolate the emissions corresponding to different target gases, like specific VOCs, from background emissions also referred to as noise.
  • the filter may be integrated in the chip.
  • the filter may for instance only transmit light with wavelengths in the range of 0.1 to 2 micrometres, preferably 0.2 to 1 micrometre. It is preferred if the range of transmitted wavelengths corresponds to the range of wavelengths detected by the detector module.
  • the collimator such as a collimating lens
  • the collimator may be arranged to narrow the beam of emitted photons along a direction from the array to the detector module.
  • collimating optics can increase the number of photons collected by the detector module and therefore enhance the sensitivity of the measurement.
  • the focusing lens may be arranged to focus the beam of emitted photons along a direction from the array to the detector module.
  • the optical elements are preferably stacked in layers.
  • a further preferred embodiment of the gas analysis system comprises an optical stack arranged between the array and the detector module, wherein the optical stack comprises at least one, preferably each, of the collimator, the spectral filter and the focusing lens. It is then preferred if the collimator is arranged between the array and the spectral filter, and the focusing lens is arranged between the spectral filter and the detector module.
  • the optical stack preferably consists of only the collimator, the spectral filter and the focusing lens.
  • the miniaturisation and integration of multiple plasma sources onto a single chip, and optionally the microfluidic flow control components and the filtering optics enable economies of scale in manufacturing such that, relative to conventional systems, production costs can be significantly reduced.
  • the characteristics of the photon emission may partially depend on the geometry and mutual distance of the electrodes and may be adjusted by changing the voltage or current through the electrodes and/or by changing the flow rate of the gas sample through the system.
  • the sensitivity of the system can be conveniently increased by increasing the photon emissions by increasing the plasma densities by modifying the power or geometric configuration of the micro-plasma generator units.
  • the total plasma volume can be considerably reduced, such that the plasma density increases, with the use of micro-plasma sources as opposed to conventional plasma sources.
  • the array of micro-plasma generator units is preferably subdivided into sectors. That is, according to a preferred embodiment of the gas analysis system, the system comprises a plurality of subsets of micro-plasma generator units of the array, wherein a first subset and at least one further subset thereof are arranged in distinct sectors of the substrate body.
  • the micro-plasma generator units of the first subset are then preferably configured to generate a micro-plasma discharge with a first emission spectrum, wherein the micro-plasma generator units of the at least one further subset are, relative to at least the micro-plasma generator units of the first subset, differently configured to generate a micro-plasma discharge with a further emission spectrum.
  • the subsets are configured to optimally ionise molecular entities of respective types. More specifically, different power configurations, in terms of for instance voltage and current, may be used for each subset of micro-plasma generator units such that the subsets within the array are each optimally configured to produce unique spectral emissions characteristic of specific analytes.
  • different power configurations in terms of for instance voltage and current, may be used for each subset of micro-plasma generator units such that the subsets within the array are each optimally configured to produce unique spectral emissions characteristic of specific analytes.
  • the ionisation and excitation of specific molecules like biomarkers can be optimised such that the subsets are respectively tuned for different analytes to customise the sensitivity of the system to the different target analytes.
  • This adaptability ensures that a wide range of substances can be detected with high accuracy, even at low concentrations such as parts per billion, whereby false negatives can be effectively mitigated, and the reliability of the analysis can be improved.
  • the plurality of subsets preferably comprises at least three or at least four subsets, more preferably at least five or at least six subsets, wherein the micro-plasma generator units of each subset respectively are then, relative to the micro-plasma generator units of the other subsets, differently configured to generate a micro-plasma discharge with a respective emission spectrum.
  • the detector module may be arranged to detect photons with a first photon energy that are emitted by the micro-plasma discharges generated by the micro-plasma generator units of the first subset and, distinctively therefrom, photons with a further photon energy that are emitted by the micro-plasma discharges generated by the micro-plasma generator units of the at least one further subset.
  • the detectors of the detector module may be, relative to each other, differently configured to detect photons of different wavelengths or wavebands.
  • different regions of the chip may be dedicated to a certain waveband by increasing the sensitivity of the detector to that waveband. This way, multiple perspectives of the emitted photons, in particular their spectrum, are provided. As such, the overall selectivity of the chip can be improved, such that a more robust signal processing and more accurate results can be obtained.
  • micro-plasma generator units in an array, specific sections can be dedicated to specific molecular entities, such that it is enabled to differentiate between different molecular entities to improve the specificity of the analysis. Consequently, more reliable results can be provided, especially in complex environments where multiple substances may be present, like in exhaled breath containing multiple volatile compounds. Moreover, concurrent or successive analyses of multiple analytes within the same sample can be enabled. Hence, sectorisation of the micro-plasma generator units, as described above, can be advantageous for enhancing the detection of different chemical elements or compounds.
  • a portable gas analysis device comprising a portable housing and a gas analysis system, wherein the gas analysis system is arranged in the portable housing, wherein the portable housing encloses the gas analysis system, wherein the gas analysis system comprises a fluid system for gas to flow therethrough, a gas sample inlet arranged for receiving the gas sample in the fluid system, and a plasma generator comprising a discharge chamber arranged for receiving at least a portion of the gas sample from the fluid system, wherein the plasma generator is arranged for ionising molecular entities of the gas sample in the discharge chamber to generate a plasma discharge in the discharge chamber, wherein the system further comprises a detector module arranged to detect photons emitted by the plasma discharge and to provide a detection signal representative of wavelengths of the detected photons, the wavelengths being indicative of volatile organic compounds in the gas sample.
  • the gas analysis system is a gas analysis system according to any of the embodiments described above.
  • the gas analysis system of the portable gas analysis device may comprise a plasma generator without the array of micro-plasma generator units.
  • the plasma generator may comprise a pair of electrodes, wherein the microplasma generator unit is arranged for applying a voltage between the electrodes for ionising molecular entities of the gas sample in the discharge chamber.
  • the portable gas analyser can perform accurate, universal on-site gas analysis in real-time, such that at-home monitoring, in addition to hospital monitoring, can be enabled.
  • the device is preferably a handheld device.
  • a method for analysing volatile organic compounds in a breath sample of a patient comprises: providing a gas analysis system according to any of the preceding claims; receiving the breath sample, exhaled by the patient into the gas sample inlet of the gas analysis system, in the fluid system of the gas analysis system; receiving, in the discharge chambers of the array of micro-plasma generator units of the gas analysis system, portions of the breath sample from the fluid system; generating micro-plasma discharges in the discharge chambers by ionising molecular entities of the breath sample in the discharge chamber; detecting, using the detector module of the gas analysis system, photons emitted by the micro-plasma discharges; determining, based on the detected photons, volatile organic compound data representing at least one property of volatile organic compounds in the breath sample.
  • the breath sample can be exhaled by the patient into the gas sample inlet or into a container that allows the collected breath sample to be transferred into the gas sample inlet, such that the method is a non-invasive breath analysis method.
  • the step of generating the micro-plasma discharges comprises generating the microplasma discharges at a pressure of at least 0.1 millibar, preferably in the range of 1 millibar to 1 atm, more preferably 0.5 to 1 bar.
  • the method may thus further comprise the step of controlling the pressure to remain in said range of at least 0.1 millibar, preferably 1 millibar to 1 atm, more preferably 0.5 to 1 bar. That is, the system may be conveniently operated at, e.g., 1 bar or 1 atm.
  • VOCs of interest may include for example phenol, hydrogen, 2-pentanone, acetaldehyde, cyclohexane, isobutane, hexanal, methane and ethylene, and especially acetone, 1,2-pentadiene, toluene, butyrolactone, ethylbenzene, (Z)-2-decenal, limonene, 4,7-dimethyl-undecane, eicosane, and 1 -undecanol.
  • the present invention is however not limited to the monitoring of COPD patients.
  • the gas analysis system can be applied to indicate any disease associated with detectable biomarkers, in particular respiratory and gastrointestinal diseases such as asthma, lung cancer and irritable bowel syndrome (IBS).
  • the compact micro-plasma-based gas analysis system can also be advantageously deployed outside of the medical context, for instance in environmental studies, space applications, forensics and food quality control.
  • Possible applications include: medical diagnostics by analysing breath or metabolic gas samples (from, e.g., a laboratory culture blood sample) to detect and quantify biomarkers associated with various health conditions, in order to aid in the early diagnosis of respiratory diseases, types of cancer, metabolic disorders, and infections, thereby providing healthcare professionals with valuable information for timely intervention and personalised treatment plans; environmental monitoring such as real-time air quality monitoring, wherein pollutants such as nitrogen oxides (NO X ), sulphur dioxide (SO2), ozone (O3), volatile organic compounds (VOCs) and particulate matter can be detected and quantified, wherein the portability of the system enables deployment in large-area monitoring networks; industrial emissions control by providing accurate and rapid analysis of emissions to ensure compliance with regulations and to minimise environmental impact; air quality assessment, in particular for indoor environments such as residential and commercial buildings or healthcare settings, wherein harmful pollutants and VOCs that may affect the health and well-being of people can be identified; personal health and wellbeing, wherein individuals can monitor their own breath biomarkers to track their metabolism, hydration levels, and overall
  • illegal drug detection wherein drug residues or volatile compounds associated with illegal drugs can be rapidly detected by analysing air samples in proximity to individuals, objects or vehicles such that the presence of drug particles or vapours can be indicated
  • air quality mapping wherein the gas analysis system may be integrated into unmanned aerial vehicles (UAVs) or weather stations to perform aerial air quality mapping such that large- scale and rapid surveys of air pollution in vast or inaccessible regions is enabled to aid in environmental research and emergency response.
  • UAVs unmanned aerial vehicles
  • weather stations to perform aerial air quality mapping such that large- scale and rapid surveys of air pollution in vast or inaccessible regions is enabled to aid in environmental research and emergency response.
  • Figure 1 represents a portable gas analysis device for analysing VOCs in a breath sample
  • Figure 2 represents an exploded view of the layered structure of a gas analysis system
  • Figure 3 is a schematic representation of the gas analysis system
  • Figure 4A shows a substrate provided with a micro-plasma array of a first type
  • Figure 4B is a cutaway drawing of the substrate shown in Figure 4A;
  • Figure 5A shows a substrate provided with a micro-plasma array of a second type
  • Figure 5B is a cutaway drawing of the substrate shown in Figure 5A;
  • Figure 6 is a diagrammatic representation of the operation of the gas analysis system.
  • FIG. 1 a schematic representation of a handheld breath analyser 1 is shown.
  • the breath analyser 1 also referred to as breathalyser, comprises a portable housing 2 and a gas analysis system 10 enclosed by the housing 2.
  • the breathalyser 1 is provided with a mouthpiece 3 for receiving a breath sample 4 exhaled by a person thereinto. From the inlet 3, the breath sample 4 is directed into the gas analysis system 10 via a fluid channel.
  • the gas analysis system 10 is schematically represented by a pair of electrodes Ila, 1 lb arranged at a mutual distance to receive the breath sample 4 in a chamber 12 therebetween.
  • a sufficient voltage is applied between the electrodes 1 la, 1 lb, molecular entities of the breath sample 4 in the chamber 12 are ionised such that a plasma discharge is generated which emits photons 5 of various wavelengths which are indicative of volatile organic compounds (VOCs) in the breath sample 4.
  • VOCs volatile organic compounds
  • the gas analysis system 10 further comprises, in addition to the electrodes I la, 1 lb, a detection and processing module 13 which, based on the wavelengths of the photons 5, in particular by spectral analysis, determines VOC data representing the presence, type and quantity of VOCs predictive of COPD exacerbations and provides an output signal 6 representing the VOC data.
  • the spectral analysis can enable an accurate differentiation of specific breath biomarkers like VOCs that are predictive of COPD exacerbations. As such, an accurate biomarker-based prediction of COPD exacerbation risks can be provided in real-time.
  • the signal 6 may be transmitted to a healthcare professional for further analysis of the VOC data.
  • the data may be processed using a classification algorithm before or after the signal 6 representing the data is transmitted, to determine the presence and quantity of specific biomarkers, diseases, or medical conditions based on their unique spectral signatures.
  • the result is, e.g., a diagnosis of the exacerbation risk.
  • the process steps are diagrammatically illustrated in Figure 6.
  • the gas analysis system 10 is schematically shown in more detail in exploded view.
  • the gas analysis system 10 comprises a layered structure including a substrate 14 onto which an array of micro-plasma generator units 11 is microfabricated, an optical collimator 15, a spectral filter 16, a focusing lens 17, and a spectrometer 131 or detector plate provided with an array of photodiodes.
  • a beam of photons emitted by the micro-plasma discharges generated by the array of micro-plasma units 11 is then transmitted through the optical elements 15, 16, 17 to the detector 131.
  • Such a stack of optical elements 15, 16, 17 can improve the sensitivity and specificity of the photon measurements.
  • FIG 3 is another schematic representation of the gas analysis system 10, wherein a micro-plasma source 11 is schematically represented in more detail.
  • the micro-plasma generator unit 11 is shown here as a layered structure, which comprises a pair of electrodes I la, 11b and a dielectric insulator layer 111 therebetween, and is provided with a through-hole 12 defining the chamber in which the micro-plasma discharge is generated that emits a beam of photons 5 to be transmitted through the optical elements 15, 16 to the detector 131.
  • Figure 4A represents a substrate body 14 provided with a 9-by-9 array of micro-plasma generator units 11 for generating micro-plasma through glow discharge (GD).
  • GD micro-plasma through glow discharge
  • Six distinct detection zones 101, 102, 103, 104, 105, 106 within the array are indicated by dashed rectangles.
  • the microplasma sources 11 in five of these zones are respectively configured to identify five specific VOCs by detecting five different distinctive spectral lines, such that the sensitivity for each of these VOCs can be optimised.
  • the micro-plasma sources 11 of the sixth subset 106 are configured for system calibration, using for instance ambient air or another predetermined calibration gas.
  • each micro-plasma source 11 is provided with a 0.2- millimetre diameter through-hole 12 through the substrate 14 for a portion of the breath sample 4 to enter the area between the electrodes 1 la, 1 lb.
  • Figure 5 A represents a substrate body 14 provided with a 9-by-9 array of micro-plasma generator units 11 for generating micro-plasma through micro-hollow cathode discharge (MHCD).
  • the micro-plasma generator units 11 are mutually spaced at a distance d of about 2 millimetres.
  • Five distinct detection zones 101, 102, 103, 104, 105 within the array are indicated by dashed rectangles.
  • the micro-plasma sources 11 in four of these zones are respectively configured to identify four specific VOCs by detecting four different distinctive spectral regions, such that the sensitivity for each of these VOCs can be optimised.
  • the micro-plasma sources 11 of a first subset 101 may be operated at 600 volts to generate a micro-plasma discharge for optimally detecting a first type of VOC
  • the micro-plasma sources 11 of a second subset 102 may be operated at 800 volts to generate a micro-plasma discharge for optimally detecting a second type of VOC
  • the micro-plasma sources 11 of the fifth subset 105 are configured for system calibration, using for instance ambient air or another predetermined calibration gas.
  • each micro-plasma source 11 comprises a layered structure wherein an insulator layer 19 with a thickness of 0.5 millimetre is sandwiched between the electrodes Ila, 11b.
  • the layered structure is provided with a 0.2-millimetre diameter through-hole 12 through the substrate 14 for a portion of the breath sample 4 to enter the area between the electrodes Ila, 11b.
  • Each micro-plasma source 11 may further comprise outer dielectric layers 18 arranged to insulate the electrodes Ila, 11b to reduce the deterioration rate thereof.
  • the type of micro-plasma sources 11 in the array can be for example DBD or DB-MHCD.
  • different sectors of the substrate 14 may be provided with different types of micro-plasma sources.
  • the micro-plasma sources 11 of different subsets may be differently configured due to a different distance between the electrodes.

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Abstract

L'invention concerne un système d'analyse de gaz pour détecter des composés organiques volatils dans un échantillon de gaz, tel qu'un échantillon d'haleine. Le système d'analyse de gaz comprend : - un système de fluide permettant au gaz de s'écouler à travers celui-ci ; - une entrée d'échantillon de gaz agencée pour recevoir l'échantillon de gaz dans le système de fluide ; - un corps de substrat ; - un réseau d'unités de générateur de microplasma agencées sur le corps de substrat, chacune des unités de générateur de microplasma comprenant une chambre de décharge agencée pour recevoir une partie de l'échantillon de gaz provenant du système de fluide, chacune des unités de générateur de microplasma étant agencée pour ioniser des entités moléculaires de l'échantillon de gaz dans la chambre de décharge pour générer une décharge de microplasma dans la chambre de décharge ; et - un module de détecteur agencé pour détecter des photons émis par la décharge de microplasma et pour fournir un signal de détection représentatif de longueurs d'onde des photons détectés, les longueurs d'onde indiquant la présence de composés organiques volatils dans l'échantillon de gaz.
PCT/EP2023/079991 2023-10-26 2023-10-26 Système d'analyse de gaz Pending WO2025087536A1 (fr)

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DE19821244A1 (de) * 1998-05-12 1999-12-02 Bosch Gmbh Robert Verfahren und Vorrichtung zur unmittelbaren optischen Diagnose von atmosphärennahen Plasmen und Plasmen bei Atmosphörendruckin Mikroplasmazellen
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