US20070062255A1 - Apparatus for collecting and analyzing human breath - Google Patents
Apparatus for collecting and analyzing human breath Download PDFInfo
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- US20070062255A1 US20070062255A1 US11/557,797 US55779706A US2007062255A1 US 20070062255 A1 US20070062255 A1 US 20070062255A1 US 55779706 A US55779706 A US 55779706A US 2007062255 A1 US2007062255 A1 US 2007062255A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/097—Devices for facilitating collection of breath or for directing breath into or through measuring devices
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/22—Devices for withdrawing samples in the gaseous state
- G01N1/2202—Devices for withdrawing samples in the gaseous state involving separation of sample components during sampling
- G01N1/2214—Devices for withdrawing samples in the gaseous state involving separation of sample components during sampling by sorption
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/02—Analysing fluids
- G01N29/022—Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/083—Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/22—Devices for withdrawing samples in the gaseous state
- G01N2001/2244—Exhaled gas, e.g. alcohol detecting
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/08—Preparation using an enricher
- G01N2030/085—Preparation using an enricher using absorbing precolumn
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/12—Preparation by evaporation
- G01N2030/126—Preparation by evaporation evaporating sample
- G01N2030/128—Thermal desorption analysis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/021—Gases
- G01N2291/0215—Mixtures of three or more gases, e.g. air
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/04—Wave modes and trajectories
- G01N2291/042—Wave modes
- G01N2291/0422—Shear waves, transverse waves, horizontally polarised waves
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/04—Wave modes and trajectories
- G01N2291/042—Wave modes
- G01N2291/0423—Surface waves, e.g. Rayleigh waves, Love waves
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/04—Wave modes and trajectories
- G01N2291/042—Wave modes
- G01N2291/0426—Bulk waves, e.g. quartz crystal microbalance, torsional waves
Definitions
- the invention relates to methods for collecting and analyzing exhaled breath samples for trace compounds, and devices, apparatuses, and systems for performing such methods.
- Exhaled breath of individuals with some diseases contains distinctive gases, or alveolar gradients compared to air, which differs markedly from the exhaled breath of healthy individuals, i.e. acetone in the breath of individuals with diabetes (Phillips 1992).
- ingested substances and/or therapeutic drugs are able to partition across the liquid/gas interface and exhaled proportional to systemic levels, i.e. alcohol.
- Detection of inflammatory markers in the diagnosis of several pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD) could substantially improve the understanding of the pathogenesis of these diseases, improve diagnosis, and identify the efficacy of different therapies.
- COPD chronic obstructive pulmonary disease
- Detection of compounds in the collected breath sample has been described using gas chromatography coupled with mass spectrometry (GC/MS), which are sensitive and selective but also bulky and complicated, as well as polymer-coated resistor arrays, which have low sensitivity and are not selective with complex mixtures such as the breath, have both been described (Phillips 1997; Lewis, Severin et al. 2001).
- a GC system for detection of volitile compounds in the breath has also been described with improved sensitivity and selectivity that utilizes breath collection on a absorbent sample tube and a second chromatography column for separation of compounds (Satoh, Yanagida et al. 2002).
- the present invention overcomes these and other inherent deficiencies in the prior art by providing novel breath sample collection and detection methods for use in health or disease diagnosis, as well as drug monitoring.
- the methods disclosed herein provide a means for detecting and quantifying one or more compounds of interest in the exhaled breath from a collected sample.
- the described processes have the advantages of producing reliable results from the described system while being portable and requiring minimal energy and space.
- the invention relates to the discovery that exhalation can be performed directly onto a sorbent phase, without the use of large collection tubes and heating equipment, and efficiently capture breath compounds for analysis.
- the use of desorbing captured breath compounds onto a first sorbent phase into a second thermal desorption column with detection using small, inexpensive vapor sensors has not previously been described.
- the sample must be collected onto a sorbent trap before analysis to extract compounds of interest over several breaths.
- a sample collector be portable, preferably a small handheld device similar to an asthma drug inhaler, that may be used to collect breath samples from patients and then processed on a central detection system.
- the SC collect several breaths only the alveolar breath from the alveoli of the lungs, which contains the volatile compounds of interest, which are present in the lung or have diffused from the blood, and not collect the ‘anatomical deadspace’ originating from the pharynx, trachea and bronchial tree where no gaseous interchange occurs.
- the content of the environmental air may contain low concentrations of the compounds of interest, it would also be desirable if a sample of the air that is inhaled may be collected onto a sorbent trap in a similar manner for comparison.
- a portable, robust detection system that extracts a gas sample from the concentrated breath and air samples as desired as an alternative to conventional GC/MS systems which are complicated and bulky.
- An ideal alternative would be a handheld chemical sensor, similar to an electronic nose, which are commercially-available for the detection of chemical spills and volatile organic compounds (VOC's).
- VOC's volatile organic compounds
- these sensor arrays alone may only be used to detect high concentrations of volatile compounds (milli-molar) with reduced sensitivity under high humidity conditions such as the exhaled breath.
- An improved sensor system with high sensitivity, coupled with a breath sample collector, which can be used to recognize simple and/or complex gas mixtures for a variety of exhaled compounds would be a great benefit to the medical field.
- the present invention provides methods of collecting and detecting compounds in a human breath sample, comprising: exhaling into a handheld sample collector to absorb at least one breath compound in an exhaled breath collector of said handheld sample collector; connecting the handheld sample collector to a breath analyzer; transferring the breath compounds from the exhaled breath collector of the sample collector into the breath analyzer; and detecting breath compounds using two or more sensors.
- the method may be performed to detect breath compounds for determining health or disease diagnosis, or for drug monitoring.
- the exhaling may comprise multiple exhaled breaths into the exhaled breath collector of the sample collector, and may contain at least one sorbent phase to absorb breath compounds.
- the sorbent phase is selected from, but not limited to, activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO 4 , alumina, polystyrene, and combinations thereof.
- the handheld sample collector may further comprise inhaling through an outside, or environmental, air collector, which may precede exhaling into the exhaled breath collector. The first portion of the exhaled breath may bypass the exhaled breath collector.
- the sample collector may be placed in fluid communication with a breath analyzer system, and the breath analyzer may separate the breath compounds using a thermal desorption column.
- Detection may be performed using mass spectroscopy, or electronic, optical, or acoustic vapor sensors.
- Sensors may include at least one sensor selected from the group consisting of surface acoustic wave sensors, shear horizontal wave sensors, flexural plate wave sensors, quartz microbalance sensors, conducting polymer sensors, dye-impregnated polymer film on fiber optic detectors, conductive composite sensors, chemiresistors, metal oxide gas sensors, electrochemical gas detectors, chemically sensitive field-effect transistors, and carbon black-polymer composite devices.
- the sensors are removable and/or replaceable.
- a breath sample may comprise multiple breath compounds, including, but not limited to, alcohols, ethers, ketones, amines, aldehydes, carbonyls, carbanions, alkanes, alkenes, alkynes, aromatic hydrocarbons, polynuclear aromatics, biomolecules, sugars, isoprenes, isoprenoids, VOCs, VOAs, indoles, pyridines, fatty acids, and off-gases of a microorganism.
- breath compounds including, but not limited to, alcohols, ethers, ketones, amines, aldehydes, carbonyls, carbanions, alkanes, alkenes, alkynes, aromatic hydrocarbons, polynuclear aromatics, biomolecules, sugars, isoprenes, isoprenoids, VOCs, VOAs, indoles, pyridines, fatty acids, and off-gases of a microorganism.
- the present invention also provides a profile that may be generated from the sensor response, which may be used to prepare a diagnostic profile of a patient. Further, a diagnosis based on the profile may be produced using the diagnostic method.
- the present invention includes methods of collecting and analyzing a human breath sample, comprising: exhaling into a handheld sample collector; placing the handheld sample collector in fluid communication with a breath analyzer; transferring compounds from the sample collector into the breath analyzer for separation on a thermal desorption column; detecting compounds using two or more polymer-coated surface acoustic wave sensors; and wherein the handheld sample collector is not in fluid communication with the breath analyzer during the exhaling.
- the present invention includes an apparatus for collecting and detecting compounds in a human breath sample comprising: a handheld sample collector; a connector for connecting the handheld sample collector in fluid communication with a breath analyzer; a flow controller for transferring the breath compounds from the sample collector into the breath analyzer; and two or more sensors for detection of breath compounds.
- the apparatus for collecting and detecting compounds in a human breath sample may be used to detect breath compounds for determining health or disease diagnosis, or for drug monitoring.
- the handheld sample collector of the apparatus may collect breath compounds from multiple breaths.
- the handheld sample collector may comprise an exhaled breath collector containing a sorbent phase to absorb breath compounds from an exhaled breath.
- the sorbent phase may be selected from activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO 4 , alumina, polystyrene, and combinations thereof.
- the handheld sample collector may further comprise an air collector, for compounds in environmental air, for collecting such compounds upon inhaling.
- the breath analyzer system of the apparatus may comprise a thermal desorption column.
- the breath analyzer system of the apparatus may contain a mass spectroscopy, or electronic, optical, or acoustic vapor sensors.
- Electronic, optical, or acoustic vapor sensors may include at least one sensor selected from the group consisting of surface acoustic wave sensors, shear horizontal wave sensors, flexural plate wave sensors, quartz microbalance sensors, conducting polymer sensors, dye-impregnated polymer film on fiber optic detectors, conductive composite sensors, chemiresistors, metal oxide gas sensors, electrochemical gas detectors, chemically sensitive field-effect transistors, and carbon black-polymer composite devices.
- FIG. 1 shows a top view of the breath sample collector with A) the related passages open upon inhalation, B) the related passages open upon initial exhalation, and C) the related passages open upon alveolar exhalation.
- FIG. 2 is an anatomical illustration depicting the human respiratory system and collection of alveloar breath into the sample collector.
- FIG. 3 is a general illustration of the design of the breath analyzer system.
- the invention is directed to improved methods for collecting human breath samples and analyzing collected exhaled samples for compounds and devices described herein.
- the invention is also directed to the application of such methods in health or disease diagnosis, as well as therapeutic drug monitoring.
- the present invention utilizes the discovery that breath samples may be concentrated efficiently onto a stable adsorbent particulate phase with low back-pressure, thereby avoiding discomfort for the patient.
- the present invention utilizes efficient detection of the breath sample using multiple sensors simultaneously, reducing the run-time and accuracy significantly.
- a handheld two-sided sample collector which may be used to concentrate compounds from the exhaled breath on one side and from the air on the other side.
- the SC is then placed into a breath analyzer (BAS) system which pumps the concentrated breath sample through a thermal desorption column for separation. Compounds are desorbed from the column, which provides time resolution, and detected using electronic, optical, or acoustic vapor sensors.
- BAS breath analyzer
- the invention includes several embodiments by which the SC and the BAS can be suitably modified for different applications or to offer sensitivity of each for different applications.
- the resulting sample collection and detection system may be used for detection for single breath compounds or multiple compounds for an overall diagnostic profile of a patient.
- the subject may be any breathing animal, preferably a human patient, of interest.
- a handheld sample collector having a body with an inhalation passage and exhalation passages, which bypasses sampling the first portion of breath from the anatomical dead-space, and only collects breath from the alveolar space.
- the exhalation passage is formed by a first exhalation channel having a proximal end and a distal end, and a restricting flap or vane disposed near the distal end. The restricting vane is hinged within the primary exhalation passage to selectively inhibit the flow of air through the first exhalation channel.
- the hinged vane moves into a position to occlude a substantial portion of the channel, thereby limiting flow through the channel and subsequently into the exhaled breath collector.
- the housing of the portable breath analyzer system includes a receptacle for the handheld sample collector, and the sensor module is removably mounted in the receptacle of the housing.
- the sensor module can include one or more sensors.
- the sensor module configured for use with a sensing apparatus.
- the sensor module is disposed within a housing that defines a receptacle.
- the sensor module includes a casing, an inlet and outlet connection for the handheld sample collector, a thermal desorption column, at least two sensors, and an electrical connector.
- the outlet port receives a test sample from the handheld sample collector and directs the test sample to the sample chamber.
- the sensors are located within or adjacent to the sample chamber and are configured to provide a distinct response when exposed to one or more analytes located within the handheld sample collector.
- the method of the present invention generally involves collecting and analyzing human breath.
- Techniques for collecting and analyzing gas samples are well-known in the art, and include such methods as environmental gas sampling on sorbent tubes, as well as headspace and trap and purge sampling for gas chromatography and GC/MS analysis.
- General air sampling systems include smoke detectors, volatile chemical detectors, and infrared gas sensors specific to a particular compound (such as C 0 2 ).
- detection of exhaled gases, such as oxygen, carbon dioxide, and nitric oxide are typically used in hospitals and emergency rooms to report important patient conditions, as well as breath alcohol detectors in law enforcement.
- detection of specific compounds in a breath sample requires reliable collection, processing, separation, and data interpretation to produce a reliable response.
- vapor sensing technologies including conducting polymers, electrochemical cells, gas chromatography/mass spectroscopy, infrared spectroscopy, ion mobility spectrometry, metal oxide semiconductor, photo-ionized detectors and surface acoustic wave sensors, have been evaluated for detection of compounds in the breath. Sensor sensitivity, selectivity, operating life, shelf-life, drift, linearity, initial cost, recurring costs, warm-up time, analysis time, power consumption, portability and calibration needs were evaluated. Although there is a large market opportunity to be able to diagnose medical conditions non-invasively by monitoring breath, one challenge is identifying the breath compounds, or analytes, that are present for each medical condition and determining if their concentrations are detectable.
- the sensor systems reviewed include: gas chromatography (GC), mass spectroscopy (MS), Fourier-transform infrared spectroscopy (FTIR), metal-oxide sensor (MOS), photo-ionization detection (PID), conducting polymers/electrochemical (CP/EC), fiber-optic fluorescent sensor (FOFI), surface acoustic wave (SAW), and pre-concentrator/thermal-desorption surface acoustic wave (PC/TD SAW).
- GC gas chromatography
- MS mass spectroscopy
- FTIR Fourier-transform infrared spectroscopy
- MOS metal-oxide sensor
- PID photo-ionization detection
- CP/EC conducting polymers/electrochemical
- FOFI fiber-optic fluorescent sensor
- SAW surface acoustic wave
- PC/TD SAW pre-concentrator/thermal-desorption surface acoustic wave
- GC/MS Gas chromatography/mass spectroscopy
- One technology separates the chemical components (GC) while the other one detects them (MS).
- MS gas chromatography/mass spectroscopy
- GC is the physical separation of two or more compounds based on their differential distribution between two phases, the mobile phase and stationary phase.
- the mobile phase is a carrier gas that moves a vaporized sample through a column coated with a stationary phase where separation takes place.
- a detector such as a Flame Ionization Detector (FID) or an Electrochemical Detector (ECD) converts the column eluent to an electrical signal that is measured and recorded. The signal is recorded as a peak in the chromatogram plot.
- FID Flame Ionization Detector
- ECD Electrochemical Detector
- Chromatograph peaks can be identified from their corresponding retention times.
- the retention time is measured from the time of sample injection to the time of the peak maximum, and is unaffected by the presence of other sample components.
- Retention times can range from seconds to hours, depending on the column selected the component, and the temperature gradient.
- the height of the peak relates to the concentration of a component in the sample mixture.
- Mass spectroscopy is a detection method, which can be coupled with GC or sample directly from the headspace of a sample, which ionizes, fragments, and rearranges a molecule under a given set of conditions and makes identification of the molecular weight/charge (m/z) of molecules possible.
- a mass spectrum is a plot showing the mass/charge ratio versus abundance data for ions from the sample molecule and its fragments.
- GC and the combination of GC/MS, are the most accurate, selective, and sensitive sensor technologies. They are also the most complex systems to use, the most expensive ($50,000 for a base instrument), the least portable with the slowest analysis time (minutes to hours). Even with significant development efforts, the GC/MS system is not a feasible commercial breath detection system, although components of GC can be miniaturized with improved detector technologies.
- a fluorescence molecule is immobilized in a polymer or sol-gel matrix, or onto a microsphere bead, and coated onto the end of optical fiber.
- the fluorescent compound such as ruthenium (McEvoy, McDonagh et al. 1997), or dye, such as Nile Red (Albert, Walt et al. 2001), undergoes an intensity or wavelength shift upon changes in the microenvironment due to interactions with a volatile compound.
- the sensor response is provided by producing an excitation light pulse through an optic fiber and measuring the emission spectra the returns using a spectrometer.
- SAW Surface Acoustic Wave
- SAW sensors are constructed with interdigital metal electrodes fabricated on piezoelectric substrates both to generate and to detect surface acoustic waves.
- Surface acoustic waves are waves that have their maximum amplitude at the surface and whose energy is nearly all contained within 15 to 20 wavelengths of the surface. Because the amplitude is a maximum at the surface such devices are very surface sensitive. Because of the popularity of cell phones, SAW devices, which act as electronic bandpass filters in hermetically sealed enclosures, have the highest sensor-to-sensor signal reproducibility of any of the systems described. In addition, they are small, require low-power, and are low-cost.
- SAW chemical sensors take advantage of this surface sensitivity to function as sensors. If a SAW device is coated with a thin polymer film it will affect the frequency and insertion loss of the device. If the device, with the chemo-selective polymer coating, is then subjected to chemical vapors that absorb onto the surface, then the frequency and insertion loss of the device will further change. It is this final change from baseline that allows the device to function as a chemical sensor.
- SAW devices are each coated with a different polymer material through spray-coat or spin-coat techniques, the response to a given chemical vapor will vary substantially from device to device based on the thickness and morphology of the final film, but alternative techniques of producing reproducible coatings are also available.
- the polymer is normally chosen so that each will have a different chemical affinity for a variety of organic chemical classes, i.e., hydrocarbon, alcohol, ketone, oxygenated, chlorinated, and nitrogenated. If the polymer films are properly chosen, each chemical vapor of interest will have a unique overall effect on the set of devices.
- SAW chemical sensors are useful in the range of organic compounds from hexane on the light, volatile extreme to semi-volatile compounds on the heavy, low volatility extreme.
- the breath sample must be concentrated onto a sorbent trap over several breaths to extract low concentration compounds-of-interest.
- a sample collector SC be portable, preferably a small handheld device similar to an asthma drug inhaler, that may be used to collect breath samples from patients and then processed on a central detection system that is also portable and user-friendly.
- the SC collect several breaths from the alveoli of the lungs, which contain the volatile compounds of interest present in the lung or have diffused from the blood. Air from the ‘anatomical deadspace’ originating from the pharynx, trachea, and bronchial tree where no gaseous interchange occurs should not be sampled.
- the content of the environmental air may contain low concentrations of the compounds of interest, it would also be desirable that a sample of the air that is inhaled be collected onto a sorbent trap in a similar manner for comparison.
- a SC with a sorbent tube which a patient exhales directly through has been shown to produce excellent absorption and desorption properties using common sorbent phase used in GC.
- the sorbent tube typically approximately 1 ⁇ 4 inch in diameter and 4 to 10 inches in length, produces low back-pressure from coarse particulates with minimal moisture absorption and high collection efficiency.
- the SC may also use an exhalation cavity, which is designed with one-way flaps to only capture certain portions of the exhaled breath, to obtain optimum sampling over multiple breaths.
- the SC is ideally fashioned with two sorbent tubes for collection of air upon inhalation and breath compounds upon inhalation, and can be used to flow the inhaled and exhaled gases simultaneously or in two separate sampling phases.
- the SC can be made of plastic, low weight and low cost, and may be used in a remote location and attached to the breath analyzer later for processing.
- the flow rate of the gas sample is regulated to control sampling variability, similar to GC, using a regulated gas supply. Interaction between the captured gas sample and gas flow system components, such as valves, pumps, and tubes, are minimized in the system design, i.e. non-adsorbing tubing, valves, etc.
- a mini-GC column is used to capture and separate compounds at 100-400 ml/min to optimize absorption onto the thermal desorption column. Furthermore, the temperature gradient is ramped from 60° C. to 240° C. over 40-80 seconds to desorb compounds for detection on, for example, a 4-SAW array. Optimization of these conditions for each sample is performed using a mathematical model to systematically investigate the effects of column packing, column temperature gradient, and gas flow to produce optimized sampling and analysis systems for a variety of diagnostic profiles.
- a miniature gas chromatography (GC) column, or thermal desorption (TD) column is used to capture vapors of interest from the SC and obtain time resolution detection.
- Molecules are absorbed onto the packed TD column as the gas sample flows through it and desorb in a temperature-dependant manner proportional to the vapor pressure of an analyte.
- Different molecules desorb at different temperatures, similar to GC, so time resolution of different compounds, proportional to the temperature gradient, is obtained.
- Time and the increase in column temperature yields a time resolution between the desorption of different molecules, as well as differences in the response of the 4 different sensors, resulting in a chromatogram for each sensor.
- the resulting data output is enhanced using the selectivity to the 4 different polymer-coated sensors and allows for recognition between multiple compounds in the breath or the presence of interferants (such as coffee or tobacco).
- interferants such as coffee or tobacco.
- the packing material in the TD column, sampling time, temperature range, and entire gas-flow system will be optimized for the analytes of interest, as well as for separation from interferring species.
- An example of the BAS is composed of 3 electronic subsystems include the following modules: (1) SAW oscillation circuits, (2) frequency counters, and (3) the controlling unit.
- the SAW oscillation circuits are responsible for generating a baseline resonant frequency based on the particular polymer coating applied to the SAW and a shifted resonant frequency based on the adsorption of the sample vapor to the individual polymer coated SAWs within the sensor array.
- the frequency counter determines the resonant frequency of the SAW resonator circuits and converts it to a voltage for analysis.
- the control module is responsible for sampling and conditioning input signals as well as multiplexing and timing communication with external devices.
- One configuration to measure SAW responses is to measure the frequency shifts based on a SAW resonator configuration.
- This delay line resonator configuration not only requires less circuitry but also gives responses with vastly superior precision than the pure delay line circuit, which measures amplitude variations compared to an external input signal.
- the resonator circuit is simply composed of the SAW sensor and a class A feedback amplifier with a gain greater than the signal attenuation that occurs in the SAW delay line, the SAW interdigital transducer electrodes (IDT), and supporting circuitry.
- the resonant frequency of the circuit is primarily determined by the SAW delay line characteristics such as delay line length and substrate material and IDT characteristics including finger amount and spacing.
- the frequency counter is multiplexed between the different sensors based upon the particular integrated circuit or device that is used.
- This analog output is then converted to digital data via an A/D converter normally on most common digital signal processor (DSP) or microcontroller chips.
- DSP digital signal processor
- the controlling unit is composed of common DSP and/or microcontrollers, which provide extremely precise timing abilities as well as on-board A/D conversion mechanisms, standard communication interfaces such as RS-232, and I/O ports for control mechanisms and memory interfacing.
- Feature extraction is the task of extracting relevant signal parameters, such as retention time through the thermal desorption column or sensor response ratios, from raw sensor signals.
- Standard measurements are made relative to a clean reference headspace sample, such as 1-bromo-4-fluoro-benzene.
- a typical measurement consists of exposing the sensor array to a reference, providing a baseline value, and comparing the reference to sample runs or adding the reference to the sample at a known concentration, referred to as an internal standard. Similar to a GC sample run, a compound is introduced onto the column and then a valve switches allowing flow of the carrier gas, in this case air, across the sensors.
- the various vapors are desorbed and exposed to the sensors for a given time (based on the association/dissociation of the vapor for the given polymer coating), which causes a change in the output/frequency of the 4 different sensors.
- Retention/desorption times and sensor responses may be referenced according to the internal standard to better test the model.
- the sensor response may span several seconds where the vapor desorbs from the column and the sensors have a rise time where the vapor associates with each sensor to a maximum and a decay time to return to the baseline value. From the response curve for each sensor features are extracted. The most common parameters extracted are the retention time of the peak and the individual sensor responses or ratios from a baseline level.
- FIG. 1A to 1 C The general design of the breath sample collection (SC) device is shown in FIG. 1A to 1 C and an anatomical description of a human exhaling through the breath sample collector in FIG. 2 .
- the mouth is placed in contact with the mouthpiece tube 11 that is an oriface with a grating that restricts flow to improve sample collection.
- an optional disposible cylinder 31 with a filter for reusing the SC without contamination is provided.
- FIG. 1A depicts the air-flow through the air collector 3 and collection of concentrations of environmental volatile compounds 7 upon inhalation.
- air is drawn through the mouthpiece orifice 11 which opens a vane 21 while vane 23 and 25 remain closed.
- Air is drawn through the rear orifice 13 and through air collector opening 15 and through the stationary collector phase.
- Environmental volatile compounds 7 are collected onto the stationary collector phase (shown as 4 ) and air exits air collector opening 16 , through vane 21 , and inhaled through mouthpiece orifice 11 .
- FIG. 1B depicts the initial air-flow through the bypass exhalation cavity 2 for avoiding collection of dead-space air upon exhalation.
- breath flows through the mouthpiece orifice 11 which closes vane 21 and opens vane 23 and 25 .
- the stationary collector phase of exhaled breath collector 5 restricts initial flow upon exhalation and the breath passes through the bypass exhalation passage 2 .
- Vane 27 which is designed to close at an assigned flow in conjunction with the mouthpiece oriface 11 , is initially open allowing the first portion of the exhaled breath to flow out rear oriface 13 . After the initial portion of the exhaled breath bypasses the exhaled breath collector 5 , vane 27 closes and the exhaled breath is diverted through vane 25 .
- FIG. 1C depicts the collection of volatile compounds of interest in the exhaled breath through the exhaled breath collector 5 .
- vane 27 closes, the exhaled breath is diverted through vane 25 and through exhaled breath collector opening 17 and through the stationary collector phase of the exhaled breath collector 5 .
- Exhaled volatile compounds 8 are collected onto the stationary collector phase (shown as 6 ) and breath exits through opening 18 and out rear orifice 13 .
- Suitable commercially available adsorbent materials for the collectors have been investigated (Groves, Zellers et al. 1998) and include, but are not limited to, activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO 4 , alumina, polystyrene, TENAX series, CARBOTRAP series, CARBOPACK series, CARBOXEN series, CARBOSEIVE series, PORAPAK series, SPHEROCARB series, Dow XUS series, and combinations thereof.
- Preferred low-pressure adsorbent combinations include, but are not limited to, TENAX TA and GR, CARBOTRAP, and Dow XUS565. Those skilled in the art will know of other suitable absorbent materials.
- FIG. 2 An anatomical description of a human exhaling through the breath sample collector is shown in FIG. 2 .
- the breath sample of interest for testing from the alveolar space can be separated from the dead-space air in the breath, which typically is the first 100-300 ml of the exhaled breath.
- FEV full expiratory volume
- EF expiratory flow
- the full expiratory volume (FEV) and the portion of exhaled breath sampled may be optimized to fit the general population, (B) the expiratory flow may be restricted through mouthpiece orifice and the type and density of the stationary phases, (C) the number of breaths can be controlled by inserting an optional counter that signals the user that the sampling is complete or bypasses all further exhaled breaths to flow through the bypass tube 2 shown in FIG. 1 .
- the number of breaths can be controlled by inserting an optional counter that signals the user that the sampling is complete or bypasses all further exhaled breaths to flow through the bypass tube 2 shown in FIG. 1 .
- the general apparatus shown in FIG. 3 of the breath analyzer system (BAS) 100 may be used to analyze the air and exhaled breath samples collected with the SA shown FIGS. 1A to 1 C.
- This design utilizing a (1) method of connecting the SC 105 to transfer volatile compounds to the (2) thermal desorption column 101 for further separation and then detection in the (3) sensor module 103 , offers several advantages including portability, sensitivity, and reproducibility not previously investigated. While previously described systems utilize less-sensitive online breath detection methods (RYBAK, THEKKADATH et al. 1999; Sunshine, Steinthal et al. 2001) and more cumbersome breath sampling techniques (Phillips 1995; Lewis, Severin et al. 2001) or collection bags (Kubo, Morisawa et al. 1999), the described technique takes advantage of highly efficient collection of compounds in the breath and detection using a highly sensitive portable detection system.
- the breath analyzer system (BAS) 100 is generally similar to a GC with motors, pumps, and valves required to bring the sample from the SC 105 into the thermal desorption column 101 for separation and then detection in the sensor module 103 .
- dry-air or an inert gas 111 which is temperature and humidity controlled, enters the SC 105 through connection 113 .
- Volatile compounds move out the SC 105 through connection 115 and through valve 107 to the thermal desorption column 101 .
- a dry-air purge that bypasses the thermal desorption column 101 may be performed by opening valve 119 .
- the gas sample enters the thermal desorption column 101 through connection 121 which then absorbs to the stationary phase in a similar manner to sample collection. Gas flow in this phase may be directed over the sensor module 103 or bypassed through valve 127 .
- the temperature of the thermal desorption column 101 controlled by a series of NiCr windings 123 around the column or other suitable heating setup, in this phase is generally below 100° C. for collection of most compounds on the stationary phase.
- the thermal desorption column 101 is heated to release the compounds for detection through valve 107 , connection 133 , and into the sensor module 103 and out passage 137 , over a much shorter time span than generally used for GC.
- the sensors 135 arrayed in a series of 2 to more than 32 in the sensor module 103 are monitored for electrical, acoustic, or optical changes relative to time during the run. Since the sensors 135 are designed to have chemoselectivity to different classes of compounds, selectivity of compounds may be performed through time resolution and sensor response.
- dry air may be used to purge the thermal desorption column 101 entering through valve 117 as well as the sensor module 103 entering through valve 131 .
- Example sensors for detection in the sensor module include, but are not limited to, polymer-coated SAW sensors and fiber-optic fluorescence sensors.
- SAW sensors are reasonably priced (less than $200) and have good sensitivity (tens of ppm) with very good selectivity. They are portable, robust and consume nominal power. They warm up in less than two minutes and require less than one minute for most analysis, and require no calibration. SAW sensors do not drift over time, have a long operating life (greater than five years) and have no known shelf life issues. They are sensitive to moisture, but this is eliminated with the use of the dry-air purge and thermal-desorption column.
- Fiber-optic fluorescent sensors also have similar properties to SAW sensors in general, but also are disposable since only the tip of the probe is replaced and no electronics like the SAW sensors. On board microprocessor electronics is required to control the sequences of the system and provide the computational power to interpret and analyze data from the array.
- Volatile organic compounds may be absorbed and/or metabolized from the inspired air (negative gradient) or added to alveolar breath as products of metabolism (positive gradient).
- Some features of this transformation have been well understood for many years: e.g., acetone exhaled in diabetic patients (Manolis 1983) and increased carbon dioxide by metabolism of glucose (Phillips 1992).
- alveolar breath may be used to diagnose several other disorders including lung cancer, liver disease, inflammatory bowel disease, rheumatoid arthritis and schizophrenia (Phillips, Erickson et al. 1995; Phillips, Gleeson et al. 1999; Phillips, Cataneo et al. 2000).
- the chemical analysis of breath therefore provides a non-invasive diagnostic test for the diagnosis of these and other diseases.
- the 13C-urea breath test is a well known accurate, noninvasive diagnosis of active Helicobacter pylori infection and can document post-therapy cure (Opekun, Abdalla et al. 2002).
- Results of several studies have shown that Pseudomonas, Klebsiella pneaumoniae, Proteus mirabolis, Staphylococcus aureus, Enterococcus, Clostrdium, E. coli , and M. tuberculosis emit volatile compounds into the headspace of cultures (Larsson, Mardh et al. 1978; Labows, McGinley et al. 1980; Pons, Rimbault et al.
- a rapid, non-invasive, and easy-to-use diagnostic system for detection of tuberculosis (TB), for example, using a patient's breath could substantially improve global control strategies.
- TB tuberculosis
- progress over the last decade has improved the speed and quality of TB diagnostic systems in industrialized countries, a cost effective system for use in third-world countries where TB is prevalent is still not available.
- the composition and concentration of volatile compounds emitted from TB-infected cells in the lung is largely unknown.
- detection of tuberculostearic acid (TSA) in TB cultures and sputum and serum samples of TB patients using gas chromatography/mass spectrometry (GC/MS) methods suggests the presence of characteristic metabolites that might be useful in diagnosing TB.
- TSA tuberculostearic acid
- GC/MS gas chromatography/mass spectrometry
- the degree of effects from an administered drug, as well as the side effects, is directly related to absorption, distribution, metabolism, and elimination (ADME) of the drug at the site-of-action.
- the concentration at the site-of-action determines the therapeutic effects, which for most drugs is related to the systemic levels of the drug in the blood after oral, injected, inhaled, or administered through other forms of drug delivery. Therefore, the “drug” will be taken to be any chemical agent that is administered to provide therapeutic effects, or alternatively administered as a diagnostic aid.
- drugs are administered to provide beneficial therapeutic effect, often drugs can also cause mild to severe side effects, which are directly related to the concentration of the drug in the body.
- concentration of the drug in the body is regulated both by the amount of drug ingested by the subject over a given time period, or the dosing regimen, and the rate at which the drug is eliminated from the body.
- Therapeutic drug monitoring for improving therapies normally requires the collection and analysis of a blood sample. Such tests are invasive, complex, and require extended time for analysis. While most drugs are eliminated renally or hepatically, many drugs and metabolites are also eliminated through the breath by crossing the liquid:gas barrier in the lung.
- exhaled metabolites or markers of side effects may also be monitored using the described system, as well as simply detecting the presence of a drug or marker to monitor patient compliance to drug regimens.
- the erythromycin and 13C-urea H. pylon breath tests are such examples where specific metabolic pathways lead to exhaled products which may provide important markers (Lee, Gwee et al. 1998; Rivory, Slaviero et al. 2001).
- Monitoring of drug levels or flavoring agents may also be performed to monitor adherence to drug regimens after dosing to improve patient outcomes.
- Menthol is a common agent in chewing gum and cigarettes.
- a sample of menthol crystals 200 mg, Spectrum Chemical
- Breathing was simulated using a Pulmosim (Blease) set for 1000 ml breaths and a one-way valve connected at the output to produce an exhaled breath every 10 seconds.
- the vial was connected to the bottom of a 1 ⁇ 2′′ T-connection and allowed flow to travel over the headspace of the menthol, liquid at 37° C.
- a stopper was fixed to the other side of the T-connector and a 1 liter Tedlar bag (1 breath) and sorbent tubes (12 inches long, 1 ⁇ 4′′ diameter) with 2 g of Tenax GC (20/35, Alltech) and Carbotrap (20/40, Supelco) were connected for sampling.
- the detection system currently utilizes a PC/TD 4-SAW setup as shown in FIG. 3 .
- Three of the four SAW sensors were coated with ethyl-cellulose (A), polyisobutylene (B), and polyepichlorohydrin (C) with acceptable thicknesses (10-50 nm) while one remained uncoated as a control (D).
- the SAW resonator frequencies were simultaneously monitored after desorption from the thermal desorption column producing 4 individual profiles with time of menthol.
- the thermal desorption/pre-concentrator column (1 inch long, 1/16′′ diameter) was packed with Tenax GC packing and a 40 second flow was used (at 130 ml/min) for the LOAD phase and an 80 second flow (at 400 ml/min) was used for the RUN phase with a thermal ramp of 2° C./second.
- the sensor response from the Tedlar bag sample showed two peaks at 15 and 25 seconds with a sensor affinity of D>C>B>A, and similar (but lower) sensor responses following desorption from Tenax and Carbotrap after desorption at 70-80° C.
- breath samples could be collected following oral dosing of a menthol-containing formulation (i.e., a tablet or inhaler), or other flavoring agents, and communicated to a doctor or pharmacist to confirm that a patient is adhering to a drug regimen at home.
- a menthol-containing formulation i.e., a tablet or inhaler
- Example 2 Analysis of a gas sample of pentane was produced similar to Example 1 in accordance with the present invention.
- Polyunsaturated fatty acids are found in the cellular and subcellular membranes and are prone to lipid peroxidation as a result of the extremely weak binding of the hydrogen atoms to the carbon chain.
- Increased breath alkanes, particularly ethane and pentane have demonstrated increased oxidative stress in breast cancer, rheumatoid arthritis, heart transplant rejection, acute myocardial infarction, schizophrenia, and bronchial asthma (Phillips 1992).
- a sample of n-pentane (1 ml, Fisher, HPLC grade) was similarly placed into a 20 ml glass vial placed into a water bath at 37° C.
- Samples were collected in a Tedlar bag and onto Tenax GC and Carbotrap sorbent tubes and analyzed using the 4-SAW sensor array.
- the SAW resonator frequencies were simultaneously monitored after desorption from the thermal desorption column again producing 4 individual profiles with time of pentane.
- Example 1 Analysis of a gas sample of ethanol production from E. coli culture was produced similar to Example 1 in accordance with the present invention.
- Ethanol has been previously observed in E. coli fermentation, as well as Clostridium , using headspace sampling and GC analysis.
- One milliliter samples of ethanol, 1-isopropanol (internal standard), and acetic acid standards, as well as E. coli culture, were similarly placed into a 20 ml glass vial placed into a water bath at 37° C.
- GC chromatograms with 1-propanol internal standard were also identified using a Varian 3600 GC with an HP 19395A of Lowry broth and E. coli showed peaks corresponding to ethanol, which is produced by E. coli during the fermentation process, 1-propanol, and acetic acid, which is a component of Lowry broth, at 2.3, 2.8, and 6.5 minutes, respectively, on a fused silica column with a temperature ramp of 20 degrees/minute.
- the 4-SAW sensor responses and time resolution for ethanol, 1-propanol, and acetic acid standards, as well as E. coli culture showed varying sensor responses to the polymer coated SAWs for each low molecular weight compound.
- the compounds were desorbed quickly into the sensor array, with resolution times of 8, 20, and 4 seconds for ethanol, 1-propanol, and acetic acid, respectively.
- Using control of the pre-concentrator thermal profile a stable baseline, short retention times, and affinity for water can be controlled.
- Tenax-GC thermal desorption column phase is selective for high boiling compounds such as alcohols, phenols, and monoamines, but other packings such as Carbowax, Porapak, and Chromosorb (Alltech) may be used depending on separation of the desired compounds.
- breath samples may be analyzed for detection/diagnosis of various bacterial infections from emitted gases, or indirectly from emitted gases such as ammonia from metabolism of urease activity of H. pylori after ingestion of urea.
- sampling and storage of breath samples onto sorbent tubes for alcohol level determination by law enforcement may be performed more accurately than before using the described invention.
- Propofol is an anesthetic agent that is infused during surgery and subject to high patient-to-patient variability in distribution and clearance (Favetta, Degoute et al. 2002).
- Current multi-gas anesthesia monitors SAM® Monitor, GE Medical Systems
- vital sign monitoring provide less sensitive and incomplete monitoring during surgery and deaths from over-anesthetizing patients has been reported (Sear and Higham 2002).
- a sample of propofol (1 ml, Sigma) was similarly placed into a 20 ml glass vial placed into a water bath at 37° C.
Abstract
The present invention provides methods of collecting and detecting compounds in a human breath sample, comprising: exhaling into a handheld sample collector to absorb at least one breath compound in an exhaled breath collector of said collector; connecting the handheld sample collector to a breath analyzer; transferring the breath compounds from the exhaled breath collector of the sample collector into the breath analyzer; and detecting breath compounds using two or more sensors. The method may be performed to detect breath compounds for determining health or disease diagnosis, or for drug monitoring.
Description
- The present application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 60/352,322, filed Jan. 29, 2002. The entire content of the aforementioned application is specifically incorporated herein by reference.
- 1. Field of the Invention
- The invention relates to methods for collecting and analyzing exhaled breath samples for trace compounds, and devices, apparatuses, and systems for performing such methods.
- 2. Description of Related Art
- Exhaled breath of individuals with some diseases contains distinctive gases, or alveolar gradients compared to air, which differs markedly from the exhaled breath of healthy individuals, i.e. acetone in the breath of individuals with diabetes (Phillips 1992). In addition, because of the high systemic blood flow to the lungs, ingested substances and/or therapeutic drugs are able to partition across the liquid/gas interface and exhaled proportional to systemic levels, i.e. alcohol. Detection of inflammatory markers in the diagnosis of several pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), could substantially improve the understanding of the pathogenesis of these diseases, improve diagnosis, and identify the efficacy of different therapies. Although progress over the last decade has improved monitoring of forced expiratory volume (FEV) and spirometry, as well as exhaled carbon dioxide and nitric oxide (Montuschi, Kharitonov et al. 2001), these markers tend to vary greatly from patient to patient. Preliminary studies measuring levels of recently identified inflammatory markers in the exhaled breath such as ethane and 8-isoprostane using gas chromatography/mass spectrometry (GC/MS) has shown higher magnitude differences in exhaled levels of COPD patients (ethane 2.77+/−0.25 ppb and 8-isoprostane 40+/−3.1 pg/ml in breath condensate) compared to healthy patients (ethane 0.88+/−0.09 ppb and 8-isoprostane 10.8+/−0.8 pg/ml in breath condensate), suggesting exhaled volatile organic compounds (VOCs) may provide improved markers of COPD and other conditions compared to exhaled NO, CO2, and H2O2 (Montuschi, Collins et al. 2000; Paredi, Kharitonov et al. 2000). Exhaled VOC profiles have provided a link to other diseases where high levels of oxidative stress markers are present, including lung cancer, liver disease, inflammatory bowel disease, rheumatoid arthritis, and schizophrenia (Phillips, Erickson et al. 1995; Phillips, Herrera et al. 1999; Phillips, Cataneo et al. 2000). Results of several studies have also shown that Pseudomonas, Klebsiella pneaumoniae, Proteus mirabolis, Staphylococcus aureus, Enterococcus, Clostrdium, and E. coli emit volatile compounds into the headspace of cultures, also suggesting that diagnosis of patients with these diseases could be performed from monitoring compounds in the breath (Larsson, Mardh et al. 1978; Labows, McGinley et al. 1980; Pons, Rimbault et al. 1985; Zechman, Aldinger et al. Yu, Hamilton-Kemp et al. 2000; Aathithan, Plant et al. 2001).
- Unfortunately, progress in breath testing for various diseases and drug monitoring is hindered by the technical difficulty of detecting very low concentrations of exhaled compounds in the breath (nanomolar or picomolar concentrations). Research has been reported using breath sampling using large heated tubes (Phillips 1995) and cylindrical (Lewis, Severin et al. 2001) containers to collect desired portions of the breath for sampling. Unfortunately, these systems require power for pumping and temperature control limiting their widespread use. Detection of compounds in the collected breath sample has been described using gas chromatography coupled with mass spectrometry (GC/MS), which are sensitive and selective but also bulky and complicated, as well as polymer-coated resistor arrays, which have low sensitivity and are not selective with complex mixtures such as the breath, have both been described (Phillips 1997; Lewis, Severin et al. 2001). In addition, a GC system for detection of volitile compounds in the breath has also been described with improved sensitivity and selectivity that utilizes breath collection on a absorbent sample tube and a second chromatography column for separation of compounds (Satoh, Yanagida et al. 2002). Unfortunately, though, there are no currently available portable vapor or gas sensor systems that can collect and detect mixtures of volatile compounds at low levels in breath, as well as separate compounds from the large exhaled water content. What is desired is an optimized sample collection system and superior detection capabilities. In addition, it would be beneficial if sample collection system and the detection system were small in size, ideally hand-held or portable, without compromising sensitivity and selectivity of the compound of interest for detection.
- The present invention overcomes these and other inherent deficiencies in the prior art by providing novel breath sample collection and detection methods for use in health or disease diagnosis, as well as drug monitoring. In general, the methods disclosed herein provide a means for detecting and quantifying one or more compounds of interest in the exhaled breath from a collected sample.
- The described processes have the advantages of producing reliable results from the described system while being portable and requiring minimal energy and space. The invention relates to the discovery that exhalation can be performed directly onto a sorbent phase, without the use of large collection tubes and heating equipment, and efficiently capture breath compounds for analysis. In addition, the use of desorbing captured breath compounds onto a first sorbent phase into a second thermal desorption column with detection using small, inexpensive vapor sensors has not previously been described. First, the sample must be collected onto a sorbent trap before analysis to extract compounds of interest over several breaths. It is desirable that a sample collector (SC) be portable, preferably a small handheld device similar to an asthma drug inhaler, that may be used to collect breath samples from patients and then processed on a central detection system. It is also desirable that the SC collect several breaths only the alveolar breath from the alveoli of the lungs, which contains the volatile compounds of interest, which are present in the lung or have diffused from the blood, and not collect the ‘anatomical deadspace’ originating from the pharynx, trachea and bronchial tree where no gaseous interchange occurs. Finally, since the content of the environmental air may contain low concentrations of the compounds of interest, it would also be desirable if a sample of the air that is inhaled may be collected onto a sorbent trap in a similar manner for comparison.
- For detection, a portable, robust detection system that extracts a gas sample from the concentrated breath and air samples as desired as an alternative to conventional GC/MS systems which are complicated and bulky. An ideal alternative would be a handheld chemical sensor, similar to an electronic nose, which are commercially-available for the detection of chemical spills and volatile organic compounds (VOC's). Unfortunately, these sensor arrays alone may only be used to detect high concentrations of volatile compounds (milli-molar) with reduced sensitivity under high humidity conditions such as the exhaled breath. An improved sensor system with high sensitivity, coupled with a breath sample collector, which can be used to recognize simple and/or complex gas mixtures for a variety of exhaled compounds would be a great benefit to the medical field.
- The process also has several advantages over previously described breath collection and analysis techniques including:
- 1. Portable: the breath collection apparatus allows for collection of the breath sample in any environment, i.e., on the battlefield or in an emergency room.
- 2. User-friendly: the breath collection apparatus is easy to operate and presents no significant resistance to sampling via inhalation and exhalation. In addition, the detection system processes the sample and provides the desired response in an easy-to-operate interface.
- 3. Disposible: the breath collection apparatus provides no possible exposure to cross-contamination or exposure to infectious pathogens from another patient.
- 4. Efficient sampling: The breath collection apparatus can control the breath sampling by collecting only the alveolar breath component, not the dead space.
- 5. Concentration of sample: The breath collection apparatus may allow for the alveolar breath to be sampled over multiple breaths, thus improving the possibility of detecting compounds of interest that are present at extremely low concentrations in the breath.
- The present invention provides methods of collecting and detecting compounds in a human breath sample, comprising: exhaling into a handheld sample collector to absorb at least one breath compound in an exhaled breath collector of said handheld sample collector; connecting the handheld sample collector to a breath analyzer; transferring the breath compounds from the exhaled breath collector of the sample collector into the breath analyzer; and detecting breath compounds using two or more sensors. The method may be performed to detect breath compounds for determining health or disease diagnosis, or for drug monitoring.
- The exhaling may comprise multiple exhaled breaths into the exhaled breath collector of the sample collector, and may contain at least one sorbent phase to absorb breath compounds. The sorbent phase is selected from, but not limited to, activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO4, alumina, polystyrene, and combinations thereof. The handheld sample collector may further comprise inhaling through an outside, or environmental, air collector, which may precede exhaling into the exhaled breath collector. The first portion of the exhaled breath may bypass the exhaled breath collector.
- The sample collector may be placed in fluid communication with a breath analyzer system, and the breath analyzer may separate the breath compounds using a thermal desorption column.
- Detection may be performed using mass spectroscopy, or electronic, optical, or acoustic vapor sensors. Sensors may include at least one sensor selected from the group consisting of surface acoustic wave sensors, shear horizontal wave sensors, flexural plate wave sensors, quartz microbalance sensors, conducting polymer sensors, dye-impregnated polymer film on fiber optic detectors, conductive composite sensors, chemiresistors, metal oxide gas sensors, electrochemical gas detectors, chemically sensitive field-effect transistors, and carbon black-polymer composite devices. The sensors are removable and/or replaceable.
- A breath sample may comprise multiple breath compounds, including, but not limited to, alcohols, ethers, ketones, amines, aldehydes, carbonyls, carbanions, alkanes, alkenes, alkynes, aromatic hydrocarbons, polynuclear aromatics, biomolecules, sugars, isoprenes, isoprenoids, VOCs, VOAs, indoles, pyridines, fatty acids, and off-gases of a microorganism.
- The present invention also provides a profile that may be generated from the sensor response, which may be used to prepare a diagnostic profile of a patient. Further, a diagnosis based on the profile may be produced using the diagnostic method.
- In other embodiments, the present invention includes methods of collecting and analyzing a human breath sample, comprising: exhaling into a handheld sample collector; placing the handheld sample collector in fluid communication with a breath analyzer; transferring compounds from the sample collector into the breath analyzer for separation on a thermal desorption column; detecting compounds using two or more polymer-coated surface acoustic wave sensors; and wherein the handheld sample collector is not in fluid communication with the breath analyzer during the exhaling.
- In other embodiments, the present invention includes an apparatus for collecting and detecting compounds in a human breath sample comprising: a handheld sample collector; a connector for connecting the handheld sample collector in fluid communication with a breath analyzer; a flow controller for transferring the breath compounds from the sample collector into the breath analyzer; and two or more sensors for detection of breath compounds.
- The apparatus for collecting and detecting compounds in a human breath sample may be used to detect breath compounds for determining health or disease diagnosis, or for drug monitoring.
- The handheld sample collector of the apparatus may collect breath compounds from multiple breaths. The handheld sample collector may comprise an exhaled breath collector containing a sorbent phase to absorb breath compounds from an exhaled breath. The sorbent phase may be selected from activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO4, alumina, polystyrene, and combinations thereof. The handheld sample collector may further comprise an air collector, for compounds in environmental air, for collecting such compounds upon inhaling.
- The breath analyzer system of the apparatus may comprise a thermal desorption column. In addition, the breath analyzer system of the apparatus may contain a mass spectroscopy, or electronic, optical, or acoustic vapor sensors. Electronic, optical, or acoustic vapor sensors may include at least one sensor selected from the group consisting of surface acoustic wave sensors, shear horizontal wave sensors, flexural plate wave sensors, quartz microbalance sensors, conducting polymer sensors, dye-impregnated polymer film on fiber optic detectors, conductive composite sensors, chemiresistors, metal oxide gas sensors, electrochemical gas detectors, chemically sensitive field-effect transistors, and carbon black-polymer composite devices.
- The drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
-
FIG. 1 shows a top view of the breath sample collector with A) the related passages open upon inhalation, B) the related passages open upon initial exhalation, and C) the related passages open upon alveolar exhalation. -
FIG. 2 is an anatomical illustration depicting the human respiratory system and collection of alveloar breath into the sample collector. -
FIG. 3 is a general illustration of the design of the breath analyzer system. - The invention is directed to improved methods for collecting human breath samples and analyzing collected exhaled samples for compounds and devices described herein. The invention is also directed to the application of such methods in health or disease diagnosis, as well as therapeutic drug monitoring. The present invention utilizes the discovery that breath samples may be concentrated efficiently onto a stable adsorbent particulate phase with low back-pressure, thereby avoiding discomfort for the patient. In addition, the present invention utilizes efficient detection of the breath sample using multiple sensors simultaneously, reducing the run-time and accuracy significantly.
- In one embodiment, a handheld two-sided sample collector (SC) is described which may be used to concentrate compounds from the exhaled breath on one side and from the air on the other side. The SC is then placed into a breath analyzer (BAS) system which pumps the concentrated breath sample through a thermal desorption column for separation. Compounds are desorbed from the column, which provides time resolution, and detected using electronic, optical, or acoustic vapor sensors. This combination of sample collection and analysis using portable, user-friendly devices provides an excellent alternative to conventional diagnostic techniques that are costly, time-consuming, and often unpredictable.
- The invention includes several embodiments by which the SC and the BAS can be suitably modified for different applications or to offer sensitivity of each for different applications. The resulting sample collection and detection system may be used for detection for single breath compounds or multiple compounds for an overall diagnostic profile of a patient.
- Thus, it is an object of the present invention to provide a method for collecting breath samples using a handheld sample collector with a sorbent phase to concentrate compounds from the exhaled breath.
- It is a further object of the present invention to provide a method for collecting breath samples using a handheld sample collector with two sorbent phase compartments to concentrate compounds from the exhaled breath on one side and from the air on the other side.
- It is a further object of the present invention to provide a method for collecting breath samples using a handheld sample collector that selectively samples the exhaled breath specifically from the alveolar space using flow divertor so that the first portion of the breath from the anatomical deadspace bypasses the sample collector.
- In addition, it is an object of the present invention to provide such a handheld sample collector that controls sampling of the inhaled and exhaled breath when placed in contact with the mouth, thereby maximizing collection of compounds in the breath and environmental air. The subject may be any breathing animal, preferably a human patient, of interest.
- It is another object of the present invention to provide such a handheld sample collector which is easy to use and which has either multiple breath sampling capabilities, or the ability to be conveniently reloaded.
- It is still another object of the present invention to provide such a handheld sample collector that is mechanically simple, does not require depletable power sources, and which is relatively inexpensive.
- The above and other objects of the invention are realized in specific illustrated embodiments of a handheld sample collector having a body with an inhalation passage and exhalation passages, which bypasses sampling the first portion of breath from the anatomical dead-space, and only collects breath from the alveolar space. The exhalation passage is formed by a first exhalation channel having a proximal end and a distal end, and a restricting flap or vane disposed near the distal end. The restricting vane is hinged within the primary exhalation passage to selectively inhibit the flow of air through the first exhalation channel. Thus, as the user exhales, forcing air from the proximal end to the distal end of the first exhalation channel, the hinged vane moves into a position to occlude a substantial portion of the channel, thereby limiting flow through the channel and subsequently into the exhaled breath collector.
- It is a further object of the present invention to provide a method of analyzing the concentrated breath and air sample from the sample collector by using a portable breath analyzer system composed which thermally desorbs compounds from the sample collector using detection by either gas chromatography/mass spectroscopy, fiber-optic fluorescent sensors, or surface acoustic wave sensors.
- In a variation of the above embodiment, the housing of the portable breath analyzer system includes a receptacle for the handheld sample collector, and the sensor module is removably mounted in the receptacle of the housing. In this embodiment, the sensor module can include one or more sensors.
- Another specific embodiment of the invention provides a sensor module configured for use with a sensing apparatus. The sensor module is disposed within a housing that defines a receptacle. The sensor module includes a casing, an inlet and outlet connection for the handheld sample collector, a thermal desorption column, at least two sensors, and an electrical connector. The outlet port receives a test sample from the handheld sample collector and directs the test sample to the sample chamber. The sensors are located within or adjacent to the sample chamber and are configured to provide a distinct response when exposed to one or more analytes located within the handheld sample collector.
- The method of the present invention generally involves collecting and analyzing human breath. Techniques for collecting and analyzing gas samples are well-known in the art, and include such methods as environmental gas sampling on sorbent tubes, as well as headspace and trap and purge sampling for gas chromatography and GC/MS analysis. General air sampling systems include smoke detectors, volatile chemical detectors, and infrared gas sensors specific to a particular compound (such as C0 2). In addition, detection of exhaled gases, such as oxygen, carbon dioxide, and nitric oxide, are typically used in hospitals and emergency rooms to report important patient conditions, as well as breath alcohol detectors in law enforcement. Specifically, though, detection of specific compounds in a breath sample requires reliable collection, processing, separation, and data interpretation to produce a reliable response.
- Several vapor sensing technologies, including conducting polymers, electrochemical cells, gas chromatography/mass spectroscopy, infrared spectroscopy, ion mobility spectrometry, metal oxide semiconductor, photo-ionized detectors and surface acoustic wave sensors, have been evaluated for detection of compounds in the breath. Sensor sensitivity, selectivity, operating life, shelf-life, drift, linearity, initial cost, recurring costs, warm-up time, analysis time, power consumption, portability and calibration needs were evaluated. Although there is a large market opportunity to be able to diagnose medical conditions non-invasively by monitoring breath, one challenge is identifying the breath compounds, or analytes, that are present for each medical condition and determining if their concentrations are detectable. In addition, each person will have different concentrations and compositions of analytes (inter-patient variability), making analysis of diverse populations difficult. Typically, there will also exist chemically similar analytes that interfere with the analysis making selectivity of trace concentrations another important factor. Thus, a sensitive and specific sensor platform is needed that is portable and cost effective. The relevant gas sensor technologies are reviewed below (Table 1) comparing the selectivity, sensitivity to humidity, overall sensitivity, drift, size/portability, reproducibility on large scale, energy consumption, and initial and annual costs. The sensor systems reviewed include: gas chromatography (GC), mass spectroscopy (MS), Fourier-transform infrared spectroscopy (FTIR), metal-oxide sensor (MOS), photo-ionization detection (PID), conducting polymers/electrochemical (CP/EC), fiber-optic fluorescent sensor (FOFI), surface acoustic wave (SAW), and pre-concentrator/thermal-desorption surface acoustic wave (PC/TD SAW). In particular, the FOFI and PC/TD SAW sensors are discussed as particularly strong platforms, compared to GC/MS, for a sensitive commercial product.
TABLE 1 Comparison of different sensor platforms and requirements for a diagnostic system. PC/ GC/ CP/ TD MS FTIR MOS PID EC FOFI SAW SAW Compound ++ + − −− − + − ++ Selectivity Interferants/ ++ + − − −− + −− ++ Humidity Sens. Sensitivity ++ − ++ + + + + ++ Drift − − − − + − + Size/Portable −− −− + + + ++ ++ ++ Re- − + − ++ + ++ producibility/ Mass Manufact. Power/Energy −− −− − + + ++ ++ ++ Consumption Initial Cost −− −− ++ + + ++ ++ ++ (<$1,000) Annual Cost −− −− ++ − − ++ ++ ++ - Gas chromatography/mass spectroscopy (GC/MS) is actually a combination of two technologies. One technology separates the chemical components (GC) while the other one detects them (MS). Technically, GC is the physical separation of two or more compounds based on their differential distribution between two phases, the mobile phase and stationary phase. The mobile phase is a carrier gas that moves a vaporized sample through a column coated with a stationary phase where separation takes place. When a separated sample component elutes from the column, a detector, such as a Flame Ionization Detector (FID) or an Electrochemical Detector (ECD), converts the column eluent to an electrical signal that is measured and recorded. The signal is recorded as a peak in the chromatogram plot. Chromatograph peaks can be identified from their corresponding retention times. The retention time is measured from the time of sample injection to the time of the peak maximum, and is unaffected by the presence of other sample components. Retention times can range from seconds to hours, depending on the column selected the component, and the temperature gradient. The height of the peak relates to the concentration of a component in the sample mixture.
- Mass spectroscopy is a detection method, which can be coupled with GC or sample directly from the headspace of a sample, which ionizes, fragments, and rearranges a molecule under a given set of conditions and makes identification of the molecular weight/charge (m/z) of molecules possible. A mass spectrum is a plot showing the mass/charge ratio versus abundance data for ions from the sample molecule and its fragments. The disadvantage of using MS independently from GC is that complex mixtures, such as breath, would provide an assembly of mass peaks that would be nearly impossible to interpret.
- GC, and the combination of GC/MS, are the most accurate, selective, and sensitive sensor technologies. They are also the most complex systems to use, the most expensive ($50,000 for a base instrument), the least portable with the slowest analysis time (minutes to hours). Even with significant development efforts, the GC/MS system is not a feasible commercial breath detection system, although components of GC can be miniaturized with improved detector technologies.
- In a photoluminescent, or fluorescent, type optical sensor, a fluorescence molecule is immobilized in a polymer or sol-gel matrix, or onto a microsphere bead, and coated onto the end of optical fiber. The fluorescent compound, such as ruthenium (McEvoy, McDonagh et al. 1997), or dye, such as Nile Red (Albert, Walt et al. 2001), undergoes an intensity or wavelength shift upon changes in the microenvironment due to interactions with a volatile compound. The sensor response is provided by producing an excitation light pulse through an optic fiber and measuring the emission spectra the returns using a spectrometer. Some of the advantages of optical sensor over electrodes include reproducibility, small and light weight, large dynamic range, ease of multiplexing, ease of calibration, and low power (LED light source) requirement.
- Surface Acoustic Wave (SAW) sensors are constructed with interdigital metal electrodes fabricated on piezoelectric substrates both to generate and to detect surface acoustic waves. Surface acoustic waves are waves that have their maximum amplitude at the surface and whose energy is nearly all contained within 15 to 20 wavelengths of the surface. Because the amplitude is a maximum at the surface such devices are very surface sensitive. Because of the popularity of cell phones, SAW devices, which act as electronic bandpass filters in hermetically sealed enclosures, have the highest sensor-to-sensor signal reproducibility of any of the systems described. In addition, they are small, require low-power, and are low-cost.
- SAW chemical sensors take advantage of this surface sensitivity to function as sensors. If a SAW device is coated with a thin polymer film it will affect the frequency and insertion loss of the device. If the device, with the chemo-selective polymer coating, is then subjected to chemical vapors that absorb onto the surface, then the frequency and insertion loss of the device will further change. It is this final change from baseline that allows the device to function as a chemical sensor.
- If several SAW devices are each coated with a different polymer material through spray-coat or spin-coat techniques, the response to a given chemical vapor will vary substantially from device to device based on the thickness and morphology of the final film, but alternative techniques of producing reproducible coatings are also available. The polymer is normally chosen so that each will have a different chemical affinity for a variety of organic chemical classes, i.e., hydrocarbon, alcohol, ketone, oxygenated, chlorinated, and nitrogenated. If the polymer films are properly chosen, each chemical vapor of interest will have a unique overall effect on the set of devices. SAW chemical sensors are useful in the range of organic compounds from hexane on the light, volatile extreme to semi-volatile compounds on the heavy, low volatility extreme.
- In general, the breath sample must be concentrated onto a sorbent trap over several breaths to extract low concentration compounds-of-interest. It is desirable that a sample collector (SC) be portable, preferably a small handheld device similar to an asthma drug inhaler, that may be used to collect breath samples from patients and then processed on a central detection system that is also portable and user-friendly. It is also desirable that the SC collect several breaths from the alveoli of the lungs, which contain the volatile compounds of interest present in the lung or have diffused from the blood. Air from the ‘anatomical deadspace’ originating from the pharynx, trachea, and bronchial tree where no gaseous interchange occurs should not be sampled. Finally, since the content of the environmental air may contain low concentrations of the compounds of interest, it would also be desirable that a sample of the air that is inhaled be collected onto a sorbent trap in a similar manner for comparison.
- A SC with a sorbent tube which a patient exhales directly through has been shown to produce excellent absorption and desorption properties using common sorbent phase used in GC. The sorbent tube, typically approximately ¼ inch in diameter and 4 to 10 inches in length, produces low back-pressure from coarse particulates with minimal moisture absorption and high collection efficiency. The SC may also use an exhalation cavity, which is designed with one-way flaps to only capture certain portions of the exhaled breath, to obtain optimum sampling over multiple breaths. The SC is ideally fashioned with two sorbent tubes for collection of air upon inhalation and breath compounds upon inhalation, and can be used to flow the inhaled and exhaled gases simultaneously or in two separate sampling phases. The SC can be made of plastic, low weight and low cost, and may be used in a remote location and attached to the breath analyzer later for processing.
- The gas sample that is introduced into the sensor system, using a headspace analyzer or a sorbent column, needs to be delivered without loss of signal by absorption to tubing and connections. The flow rate of the gas sample is regulated to control sampling variability, similar to GC, using a regulated gas supply. Interaction between the captured gas sample and gas flow system components, such as valves, pumps, and tubes, are minimized in the system design, i.e. non-adsorbing tubing, valves, etc. We recently observed in an animal study significant losses of an exhaled medication were detected from adsorption to certain types of porous tubing (unpublished results). For a 4-SAW BAS system, a mini-GC column is used to capture and separate compounds at 100-400 ml/min to optimize absorption onto the thermal desorption column. Furthermore, the temperature gradient is ramped from 60° C. to 240° C. over 40-80 seconds to desorb compounds for detection on, for example, a 4-SAW array. Optimization of these conditions for each sample is performed using a mathematical model to systematically investigate the effects of column packing, column temperature gradient, and gas flow to produce optimized sampling and analysis systems for a variety of diagnostic profiles.
- A miniature gas chromatography (GC) column, or thermal desorption (TD) column, is used to capture vapors of interest from the SC and obtain time resolution detection. Molecules are absorbed onto the packed TD column as the gas sample flows through it and desorb in a temperature-dependant manner proportional to the vapor pressure of an analyte. Different molecules desorb at different temperatures, similar to GC, so time resolution of different compounds, proportional to the temperature gradient, is obtained. Time and the increase in column temperature yields a time resolution between the desorption of different molecules, as well as differences in the response of the 4 different sensors, resulting in a chromatogram for each sensor. The resulting data output is enhanced using the selectivity to the 4 different polymer-coated sensors and allows for recognition between multiple compounds in the breath or the presence of interferants (such as coffee or tobacco). In general, the packing material in the TD column, sampling time, temperature range, and entire gas-flow system will be optimized for the analytes of interest, as well as for separation from interferring species.
- An example of the BAS is composed of 3 electronic subsystems include the following modules: (1) SAW oscillation circuits, (2) frequency counters, and (3) the controlling unit. The SAW oscillation circuits are responsible for generating a baseline resonant frequency based on the particular polymer coating applied to the SAW and a shifted resonant frequency based on the adsorption of the sample vapor to the individual polymer coated SAWs within the sensor array. The frequency counter determines the resonant frequency of the SAW resonator circuits and converts it to a voltage for analysis. The control module is responsible for sampling and conditioning input signals as well as multiplexing and timing communication with external devices.
- One configuration to measure SAW responses is to measure the frequency shifts based on a SAW resonator configuration. This delay line resonator configuration not only requires less circuitry but also gives responses with vastly superior precision than the pure delay line circuit, which measures amplitude variations compared to an external input signal. The resonator circuit is simply composed of the SAW sensor and a class A feedback amplifier with a gain greater than the signal attenuation that occurs in the SAW delay line, the SAW interdigital transducer electrodes (IDT), and supporting circuitry. The resonant frequency of the circuit is primarily determined by the SAW delay line characteristics such as delay line length and substrate material and IDT characteristics including finger amount and spacing. Sensitivity has been shown to be proportional to resonant frequency, however noise also increases with frequency. Previous studies with SAW devices in the hundreds of megahertz range have shown sensitivities into the ppb (parts per billion) range with comparable sensitivities to GC.
- The frequency counter outputs an analog voltage of the form v(t)=G(t)f(t) where v(t) is a real time voltage, f(t) is the resonant frequency, and G(t) is a device dependent function. The frequency counter is multiplexed between the different sensors based upon the particular integrated circuit or device that is used. This analog output is then converted to digital data via an A/D converter normally on most common digital signal processor (DSP) or microcontroller chips. The controlling unit is composed of common DSP and/or microcontrollers, which provide extremely precise timing abilities as well as on-board A/D conversion mechanisms, standard communication interfaces such as RS-232, and I/O ports for control mechanisms and memory interfacing.
- Feature extraction is the task of extracting relevant signal parameters, such as retention time through the thermal desorption column or sensor response ratios, from raw sensor signals. Standard measurements are made relative to a clean reference headspace sample, such as 1-bromo-4-fluoro-benzene. A typical measurement consists of exposing the sensor array to a reference, providing a baseline value, and comparing the reference to sample runs or adding the reference to the sample at a known concentration, referred to as an internal standard. Similar to a GC sample run, a compound is introduced onto the column and then a valve switches allowing flow of the carrier gas, in this case air, across the sensors. As the thermal desorption column ramps to higher temperatures the various vapors are desorbed and exposed to the sensors for a given time (based on the association/dissociation of the vapor for the given polymer coating), which causes a change in the output/frequency of the 4 different sensors. Retention/desorption times and sensor responses may be referenced according to the internal standard to better test the model. The sensor response may span several seconds where the vapor desorbs from the column and the sensors have a rise time where the vapor associates with each sensor to a maximum and a decay time to return to the baseline value. From the response curve for each sensor features are extracted. The most common parameters extracted are the retention time of the peak and the individual sensor responses or ratios from a baseline level.
- Reference will now be made to the drawings in which the various elements of the present invention will be given numeral designations and in which the invention will be discussed so as to enable one skilled in the art to make and use the invention. It is to be understood that the following description is only exemplary of the principles of the present invention, and should not be viewed as narrowing the pending claims.
- The general design of the breath sample collection (SC) device is shown in
FIG. 1A to 1C and an anatomical description of a human exhaling through the breath sample collector inFIG. 2 . The apparatus shown inFIG. 1A to 1C of themain housing 1 of the handheld sample collector withoutside air collector 3 and a exhaledbreath collector 5. The mouth is placed in contact with themouthpiece tube 11 that is an oriface with a grating that restricts flow to improve sample collection. Inserted on the mouthpiece anoptional disposible cylinder 31 with a filter for reusing the SC without contamination is provided. -
FIG. 1A depicts the air-flow through theair collector 3 and collection of concentrations of environmentalvolatile compounds 7 upon inhalation. Upon inhalation air is drawn through themouthpiece orifice 11 which opens avane 21 whilevane rear orifice 13 and throughair collector opening 15 and through the stationary collector phase. Environmentalvolatile compounds 7 are collected onto the stationary collector phase (shown as 4) and air exitsair collector opening 16, throughvane 21, and inhaled throughmouthpiece orifice 11. -
FIG. 1B depicts the initial air-flow through thebypass exhalation cavity 2 for avoiding collection of dead-space air upon exhalation. Upon the initial exhalation, breath flows through themouthpiece orifice 11 which closesvane 21 and opensvane breath collector 5 restricts initial flow upon exhalation and the breath passes through thebypass exhalation passage 2.Vane 27, which is designed to close at an assigned flow in conjunction with themouthpiece oriface 11, is initially open allowing the first portion of the exhaled breath to flow outrear oriface 13. After the initial portion of the exhaled breath bypasses the exhaledbreath collector 5,vane 27 closes and the exhaled breath is diverted throughvane 25. -
FIG. 1C depicts the collection of volatile compounds of interest in the exhaled breath through the exhaledbreath collector 5. Aftervane 27 closes, the exhaled breath is diverted throughvane 25 and through exhaledbreath collector opening 17 and through the stationary collector phase of the exhaledbreath collector 5. Exhaledvolatile compounds 8 are collected onto the stationary collector phase (shown as 6) and breath exits throughopening 18 and outrear orifice 13. - Suitable commercially available adsorbent materials for the collectors have been investigated (Groves, Zellers et al. 1998) and include, but are not limited to, activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO4, alumina, polystyrene, TENAX series, CARBOTRAP series, CARBOPACK series, CARBOXEN series, CARBOSEIVE series, PORAPAK series, SPHEROCARB series, Dow XUS series, and combinations thereof. Preferred low-pressure adsorbent combinations include, but are not limited to, TENAX TA and GR, CARBOTRAP, and Dow XUS565. Those skilled in the art will know of other suitable absorbent materials.
- An anatomical description of a human exhaling through the breath sample collector is shown in
FIG. 2 . As shown, the breath sample of interest for testing from the alveolar space can be separated from the dead-space air in the breath, which typically is the first 100-300 ml of the exhaled breath. For collecting the highest concentration of volatile compounds of interest present in the breath, several collection factors must be optimized including the full expiratory volume (FEV) and expiratory flow (EF) of the patient, the portion of exhaled breath sampled, type and amount of stationary phase, and the number of breaths collected. Through the optimized design of the SC, (A) the full expiratory volume (FEV) and the portion of exhaled breath sampled may be optimized to fit the general population, (B) the expiratory flow may be restricted through mouthpiece orifice and the type and density of the stationary phases, (C) the number of breaths can be controlled by inserting an optional counter that signals the user that the sampling is complete or bypasses all further exhaled breaths to flow through thebypass tube 2 shown inFIG. 1 . In addition, it may be of interest to sample the air and the exhaled breath in separate breaths through modification of the SC so the alveolar gradient of exhaled volatile compounds is not reduced through collection after passing through the air collector. - The general apparatus shown in
FIG. 3 of the breath analyzer system (BAS) 100 may be used to analyze the air and exhaled breath samples collected with the SA shownFIGS. 1A to 1C. This design, utilizing a (1) method of connecting theSC 105 to transfer volatile compounds to the (2)thermal desorption column 101 for further separation and then detection in the (3)sensor module 103, offers several advantages including portability, sensitivity, and reproducibility not previously investigated. While previously described systems utilize less-sensitive online breath detection methods (RYBAK, THEKKADATH et al. 1999; Sunshine, Steinthal et al. 2001) and more cumbersome breath sampling techniques (Phillips 1995; Lewis, Severin et al. 2001) or collection bags (Kubo, Morisawa et al. 1999), the described technique takes advantage of highly efficient collection of compounds in the breath and detection using a highly sensitive portable detection system. - As depicted in
FIG. 3 , the breath analyzer system (BAS) 100 is generally similar to a GC with motors, pumps, and valves required to bring the sample from theSC 105 into thethermal desorption column 101 for separation and then detection in thesensor module 103. In the sample LOAD phase, dry-air or aninert gas 111, which is temperature and humidity controlled, enters theSC 105 throughconnection 113. Volatile compounds move out theSC 105 throughconnection 115 and throughvalve 107 to thethermal desorption column 101. In a preliminary step a dry-air purge that bypasses thethermal desorption column 101 may be performed by openingvalve 119. The gas sample enters thethermal desorption column 101 throughconnection 121 which then absorbs to the stationary phase in a similar manner to sample collection. Gas flow in this phase may be directed over thesensor module 103 or bypassed throughvalve 127. The temperature of thethermal desorption column 101, controlled by a series ofNiCr windings 123 around the column or other suitable heating setup, in this phase is generally below 100° C. for collection of most compounds on the stationary phase. - During the RUN phase, dry-air or an inert gas sample enters
valve 117, bypassing theSC 105, and thethermal desorption column 101 is heated to release the compounds for detection throughvalve 107,connection 133, and into thesensor module 103 and outpassage 137, over a much shorter time span than generally used for GC. Thesensors 135 arrayed in a series of 2 to more than 32 in thesensor module 103, are monitored for electrical, acoustic, or optical changes relative to time during the run. Since thesensors 135 are designed to have chemoselectivity to different classes of compounds, selectivity of compounds may be performed through time resolution and sensor response. During the PURGE phase, dry air may be used to purge thethermal desorption column 101 entering throughvalve 117 as well as thesensor module 103 entering throughvalve 131. - Example sensors for detection in the sensor module include, but are not limited to, polymer-coated SAW sensors and fiber-optic fluorescence sensors. SAW sensors are reasonably priced (less than $200) and have good sensitivity (tens of ppm) with very good selectivity. They are portable, robust and consume nominal power. They warm up in less than two minutes and require less than one minute for most analysis, and require no calibration. SAW sensors do not drift over time, have a long operating life (greater than five years) and have no known shelf life issues. They are sensitive to moisture, but this is eliminated with the use of the dry-air purge and thermal-desorption column. Fiber-optic fluorescent sensors also have similar properties to SAW sensors in general, but also are disposable since only the tip of the probe is replaced and no electronics like the SAW sensors. On board microprocessor electronics is required to control the sequences of the system and provide the computational power to interpret and analyze data from the array. An advantage of this technique, though, is that improved sensitivity through control of analyte desorption and gas flow, as well as direct comparison and validation using GC, is possible.
- The analysis of exhaled breath provides an excellent means of assessing VOC's present in the body from a variety of conditions. The rapid equilibration between concentrations in the pulmonary blood supply and in alveolar air is known. The diagnostic potential of breath analysis has been recognized for many years, and links have been established between specific volatile organic vapor metabolites in the breath and several medical conditions (Manolis 1983). In 1971, Pauling found that normal human breath contained several hundred different VOCs in low concentrations (Pauling, Robinson et al. 1971). Since then, more than a thousand different VOCs have been observed employing progressively more sophisticated and sensitive assays in low concentrations in normal human breath (Phillips 1997).
- In general, normal human alveolar breath contains a large number of volatile organic compounds in low concentrations (nanomolar or picomolar) present from local and systemic cellular biological processing and metabolism. Therefore, the analysis of breath offers an excellent platform for the monitoring of various biological states. Another application is the evaluation of exposures to industrial solvents such as benzene, toluene, styrene (Droz and Guillemin 1986). The non-invasive nature of monitoring exposure of these volitile compounds by sampling the breath makes it potentially more rapid and convenient than blood or urine analysis. However, high background concentrations of water vapor and the presence of certain endogenous organic vapors make the collection of accurate measurements more difficult using standard techniques (Groves and Zellers 1996).
- Volatile organic compounds (VOCs) may be absorbed and/or metabolized from the inspired air (negative gradient) or added to alveolar breath as products of metabolism (positive gradient). Some features of this transformation have been well understood for many years: e.g., acetone exhaled in diabetic patients (Manolis 1983) and increased carbon dioxide by metabolism of glucose (Phillips 1992). In addition, there is evidence alveolar breath may be used to diagnose several other disorders including lung cancer, liver disease, inflammatory bowel disease, rheumatoid arthritis and schizophrenia (Phillips, Erickson et al. 1995; Phillips, Gleeson et al. 1999; Phillips, Cataneo et al. 2000). Thus, the chemical analysis of breath therefore provides a non-invasive diagnostic test for the diagnosis of these and other diseases.
- The 13C-urea breath test is a well known accurate, noninvasive diagnosis of active Helicobacter pylori infection and can document post-therapy cure (Opekun, Abdalla et al. 2002). Results of several studies have shown that Pseudomonas, Klebsiella pneaumoniae, Proteus mirabolis, Staphylococcus aureus, Enterococcus, Clostrdium, E. coli, and M. tuberculosis emit volatile compounds into the headspace of cultures (Larsson, Mardh et al. 1978; Labows, McGinley et al. 1980; Pons, Rimbault et al. 1985; Rimbault, Niel et al. 1986; Zechman, Aldinger et al. 1986; Cundy, Willard et al. 1991; Jenkins, Morris et al. 2000; Yu, Hamilton-Kemp et al. 2000; Aathithan, Plant et al. 2001). The volatile profiles of cultures of several bacterial strains reveal various acids, alcohols, aldehydes, ketones, and amines using gas chromatography (GC). While direct sampling of the bacteria culture media and swab culture samples from patients mouths provide more direct ways to detect strain and concentration, breath sampling offers many advantages including speed and reproducibility.
- First, different strains of bacteria, such as E. coli and Clostridium, are so different biochemically that they emit very characteristic compounds, which provide a fingerprint for each genus and species. Using GC techniques, chemical groups or specific compounds have been identified as typical volatile metabolites for certain bacteria (Labows, McGinley et al. 1980; Cundy, Willard et al. 1991). For example, Pseudomonas aeruginosa produced a characteristic profile of methyl ketones (excluding 2-tridecanone) and 1-undecene as a major component; however, no indole was found in this organism (Zechman and Labows 1985; Zechman, Aldinger et al. 1986). Recently, as part of the development of digital aroma technology, studied headspace compounds from several bacteria including P. aeruginosa and E. coli, alcohols including ethanol were identified as the primary products isolated (Arnold and Senter 1998). Second, sampling of the breath offers a non-invasive sampling route for identification of specific compounds for detection of bacteria and other organisms, especially for infection in the throat and lungs.
- A rapid, non-invasive, and easy-to-use diagnostic system for detection of tuberculosis (TB), for example, using a patient's breath could substantially improve global control strategies. Although progress over the last decade has improved the speed and quality of TB diagnostic systems in industrialized countries, a cost effective system for use in third-world countries where TB is prevalent is still not available. The composition and concentration of volatile compounds emitted from TB-infected cells in the lung is largely unknown. However, detection of tuberculostearic acid (TSA) in TB cultures and sputum and serum samples of TB patients using gas chromatography/mass spectrometry (GC/MS) methods suggests the presence of characteristic metabolites that might be useful in diagnosing TB. While direct sampling of a large volume of exhaled breath of infected patients could be sampled using Tedlar bags and analyzed with methods such as GC/MS, low bacillary load, patient-to-patient variability, as well as intra-day to inter-day sampling, would most likely not lead to a strong signal to identify a characteristic profile. Unfortunately, similar to the other exhaled compounds reviewed for detection, there is the concern that dilution with dead-space air and that the lung and throat tissue may absorb and metabolize a fraction of the emitted volatile compounds. Thus, a breath analysis system with very low limits of detection (LOD) is described to help rapidly diagnose patients in the active disease stage, as well as test response to anti-tuberculosis therapies and vaccines pre and post-exposure.
- The degree of effects from an administered drug, as well as the side effects, is directly related to absorption, distribution, metabolism, and elimination (ADME) of the drug at the site-of-action. The concentration at the site-of-action determines the therapeutic effects, which for most drugs is related to the systemic levels of the drug in the blood after oral, injected, inhaled, or administered through other forms of drug delivery. Therefore, the “drug” will be taken to be any chemical agent that is administered to provide therapeutic effects, or alternatively administered as a diagnostic aid.
- Although drugs are administered to provide beneficial therapeutic effect, often drugs can also cause mild to severe side effects, which are directly related to the concentration of the drug in the body. The concentration of the drug in the body, in turn, is regulated both by the amount of drug ingested by the subject over a given time period, or the dosing regimen, and the rate at which the drug is eliminated from the body. Therapeutic drug monitoring for improving therapies normally requires the collection and analysis of a blood sample. Such tests are invasive, complex, and require extended time for analysis. While most drugs are eliminated renally or hepatically, many drugs and metabolites are also eliminated through the breath by crossing the liquid:gas barrier in the lung. Although different levels of a drug would be present in the exhaled breath depending on partitioning, breath rate, and physical state of the person and lungs, after factoring losses for collection and detection variations in the detected breath concentration versus time should be proportional to the systemic concentrations. This invention provides an excellent, non-invasive means of providing information on the systemic drug profile for tailoring drug dose or dosing regimens. Examples of “narrow therapeutic window” drugs or drugs with harmful side effects for which therapeutic drug monitoring is used include bupivacaine, coumadin, cyclosporine, insulin, and anesthetic agents such as propofol. In addition, exhaled metabolites or markers of side effects may also be monitored using the described system, as well as simply detecting the presence of a drug or marker to monitor patient compliance to drug regimens. The erythromycin and 13C-urea H. pylon breath tests are such examples where specific metabolic pathways lead to exhaled products which may provide important markers (Lee, Gwee et al. 1998; Rivory, Slaviero et al. 2001). Monitoring of drug levels or flavoring agents may also be performed to monitor adherence to drug regimens after dosing to improve patient outcomes.
- The following examples are included to demonstrate example embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute relevant examples for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
- Menthol Detection
- Analysis of a gas sample of menthol was produced in accordance with the present invention. Menthol is a common agent in chewing gum and cigarettes. A sample of menthol crystals (200 mg, Spectrum Chemical) was placed into a 20 ml glass vial placed into a water bath at 37° C. Breathing was simulated using a Pulmosim (Blease) set for 1000 ml breaths and a one-way valve connected at the output to produce an exhaled breath every 10 seconds. The vial was connected to the bottom of a ½″ T-connection and allowed flow to travel over the headspace of the menthol, liquid at 37° C. A stopper was fixed to the other side of the T-connector and a 1 liter Tedlar bag (1 breath) and sorbent tubes (12 inches long, ¼″ diameter) with 2 g of Tenax GC (20/35, Alltech) and Carbotrap (20/40, Supelco) were connected for sampling.
- The detection system currently utilizes a PC/TD 4-SAW setup as shown in
FIG. 3 . Three of the four SAW sensors were coated with ethyl-cellulose (A), polyisobutylene (B), and polyepichlorohydrin (C) with acceptable thicknesses (10-50 nm) while one remained uncoated as a control (D). The SAW resonator frequencies were simultaneously monitored after desorption from the thermal desorption column producing 4 individual profiles with time of menthol. The thermal desorption/pre-concentrator column (1 inch long, 1/16″ diameter) was packed with Tenax GC packing and a 40 second flow was used (at 130 ml/min) for the LOAD phase and an 80 second flow (at 400 ml/min) was used for the RUN phase with a thermal ramp of 2° C./second. The sensor response from the Tedlar bag sample showed two peaks at 15 and 25 seconds with a sensor affinity of D>C>B>A, and similar (but lower) sensor responses following desorption from Tenax and Carbotrap after desorption at 70-80° C. In this fashion, breath samples could be collected following oral dosing of a menthol-containing formulation (i.e., a tablet or inhaler), or other flavoring agents, and communicated to a doctor or pharmacist to confirm that a patient is adhering to a drug regimen at home. - Pentane Detection
- Analysis of a gas sample of pentane was produced similar to Example 1 in accordance with the present invention. Polyunsaturated fatty acids are found in the cellular and subcellular membranes and are prone to lipid peroxidation as a result of the extremely weak binding of the hydrogen atoms to the carbon chain. Increased breath alkanes, particularly ethane and pentane, have demonstrated increased oxidative stress in breast cancer, rheumatoid arthritis, heart transplant rejection, acute myocardial infarction, schizophrenia, and bronchial asthma (Phillips 1992). A sample of n-pentane (1 ml, Fisher, HPLC grade) was similarly placed into a 20 ml glass vial placed into a water bath at 37° C. Samples were collected in a Tedlar bag and onto Tenax GC and Carbotrap sorbent tubes and analyzed using the 4-SAW sensor array. The SAW resonator frequencies were simultaneously monitored after desorption from the thermal desorption column again producing 4 individual profiles with time of pentane. The sensor response from the Tedlar bag and the sorbent tubes showed a single peak at 42 seconds with a sensor affinity of A>C>B=D, and similar (but lower) sensor responses following desorption from Tenax and Carbotrap after desorption at 70-80° C. In this fashion, breath samples may be analyzed for detection/diagnosis of various disease of oxidative stress.
- Ethanol Detection
- Analysis of a gas sample of ethanol production from E. coli culture was produced similar to Example 1 in accordance with the present invention. Ethanol has been previously observed in E. coli fermentation, as well as Clostridium, using headspace sampling and GC analysis. One milliliter samples of ethanol, 1-isopropanol (internal standard), and acetic acid standards, as well as E. coli culture, were similarly placed into a 20 ml glass vial placed into a water bath at 37° C. Direct headspace sampling, as well as samples collected in a Tedlar bag and onto Tenax GC and Carbotrap sorbent tubes similar to Example 1, were analyzed using the 4-SAW sensor array. GC chromatograms with 1-propanol internal standard were also identified using a Varian 3600 GC with an HP 19395A of Lowry broth and E. coli showed peaks corresponding to ethanol, which is produced by E. coli during the fermentation process, 1-propanol, and acetic acid, which is a component of Lowry broth, at 2.3, 2.8, and 6.5 minutes, respectively, on a fused silica column with a temperature ramp of 20 degrees/minute. The 4-SAW sensor responses and time resolution for ethanol, 1-propanol, and acetic acid standards, as well as E. coli culture, showed varying sensor responses to the polymer coated SAWs for each low molecular weight compound. The compounds were desorbed quickly into the sensor array, with resolution times of 8, 20, and 4 seconds for ethanol, 1-propanol, and acetic acid, respectively. Using control of the pre-concentrator thermal profile a stable baseline, short retention times, and affinity for water can be controlled. Also, Tenax-GC thermal desorption column phase is selective for high boiling compounds such as alcohols, phenols, and monoamines, but other packings such as Carbowax, Porapak, and Chromosorb (Alltech) may be used depending on separation of the desired compounds. In this fashion, breath samples may be analyzed for detection/diagnosis of various bacterial infections from emitted gases, or indirectly from emitted gases such as ammonia from metabolism of urease activity of H. pylori after ingestion of urea. In addition, sampling and storage of breath samples onto sorbent tubes for alcohol level determination by law enforcement may be performed more accurately than before using the described invention.
- Propofol Detection
- Analysis of a gas sample of propofol was produced similar to Example 1 in accordance with the present invention. Propofol is an anesthetic agent that is infused during surgery and subject to high patient-to-patient variability in distribution and clearance (Favetta, Degoute et al. 2002). Current multi-gas anesthesia monitors (SAM® Monitor, GE Medical Systems), as well as vital sign monitoring, provide less sensitive and incomplete monitoring during surgery and deaths from over-anesthetizing patients has been reported (Sear and Higham 2002). A sample of propofol (1 ml, Sigma) was similarly placed into a 20 ml glass vial placed into a water bath at 37° C. Samples were collected in a Tedlar bag and onto Tenax GC and Carbotrap sorbent tubes and analyzed using the 4-SAW sensor array. The SAW resonator frequencies were simultaneously monitored after desorption from the thermal desorption column again producing 4 individual profiles with time of propofol. The sensor response from the Tedlar bag was not present, but sensor responses direct headspace sampling and from the sorbent tubes showed two peaks at 15 and 35 seconds with a sensor affinity of D>A>C>B. In this fashion, drug levels may be analyzed from sampling a patients breath during anesthesia for monitoring. In addition, other drugs may be detected directly or metabolic products, such as in 14CO2 with erythromycin, from analysis of the exhaled breath.
- The following literature citations as well as those cited above are incorporated in pertinent part by reference herein for the reasons cited in the above text:
- Aathithan, S., J. C. Plant, et al. (2001). “Diagnosis of Bacteriuria by Detection of Volatile Organic Compounds in Urine Using an Automated Headspace Analyzer with Multiple Conducting Polymer Sensors.” J Clin Microbiol 39(7): 2590-3.
- Albert, K. J., D. R. Walt, et al. (2001). “Optical multibead arrays for simple and complex odor discrimination.” Anal Chem 73(11): 2501-8.
- Arnold, J. and S. Senter (1998). “Use of digital aroma technology and SPME to compare volatile compounds produced by bacteria isolated from processed poultry.” J. Sci. Food Agric 78: 343-348.
- Cundy, K. V., K. E. Willard, et al. (1991). “Comparison of traditional gas chromatography (GC), headspace GC, and the microbial identification library GC system for the identification of Clostridium difficile.” J Clin Microbiol 29(2): 260-3.
- Droz, P. O. and M. P. Guillemin (1986). “Occupational exposure monitoring using breath analysis.” J Occup Med 28(8): 593-602.
- Favetta, P., C. S. Degoute, et al. (2002). “Propofol metabolites in man following propofol induction and maintenance.” Br J Anaesth 88(5): 653-8.
- Groves, W., E. Zellers, et al. (1998). “Analyzing organic vapors in exhaled breath using a surface acoustic wave sensor array with preconcentrator: Selection and characterization of the preconcentrator adsorbent.” Anal Chim Acta 371: 131-143.
- Groves, W. A. and E. T. Zellers (1996). “Investigation of organic vapor losses to condensed water vapor in Tedlar bags used for exhaled-breath sampling.” Am Ind Hvq Assoc J 57(3): 257-63.
- Jenkins, R. O., T. A. Morris, et al. (2000). “Phosphine generation by mixed- and monoseptic-cultures of anaerobic bacteria.” Sci Total Environ 250(1-3): 73-81.
- Kubo, Y., K. Morisawa, et al. (1999). Apparatus and breathing bag for spectrometrically measuring isotopic gas. USPTO. US, Otsuka Pharmaceutical Co., Ltd.
- Labows, J. N., K. J. McGinley, et al. (1980). “Headspace analysis of volatile metabolites of Pseudomonas aeruginosa and related species by gas chromatography-mass spectrometry.” J Clin Microbiol 12(4): 521-6.
- Larsson, L., P. A. Mardh, et al. (1978). “Detection of alcohols and volatile fatty acids by head-space gas chromatography in identification of anaerobic bacteria.” J Clin Microbiol 7(1): 23-7.
- Lee, H. S., K. A. Gwee, et al. (1998). “Validation of [13C]urea breath test for Helicobacter pylori using a simple gas chromatograph-mass selective detector.” Eur J Gastroenterol Hepatol 10(7): 569-72.
- Lewis, N., E. Severin, et al. (2001). Trace level detection of analytes using artificial olfactometry. USA, Cyrano Sciences, Inc. (Pasadena, Calif.); California Institute of Technology (Pasadena, Calif.).
- Lewis, N., E. Severin, et al. (2001). Trace level detection of analytes using artificial olfactometry. USPTO. US, Cyrano Sciences California Institute of Technology.
- Manolis, A. (1983). “The diagnostic potential of breath analysis.” Clin Chem 29(1): 5-15.
- McEvoy, A., C. McDonagh, et al. (1997). “Optimisation of sol-gel-derived silica films for optical oxygen sensing.” Journal of Sol-Gel Science and Technology 8(1-3): 1121-1125.
- Montuschi, P., J. V. Collins, et al. (2000). “Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers.” Am J Respir Crit Care Med 162(3 Pt 1): 1175-7.
- Montuschi, P., S. A. Kharitonov, et al. (2001). “Exhaled carbon monoxide and nitric oxide in COPD.” Chest 120(2): 496-501.
- Opekun, A. R., N. Abdalla, et al. (2002). “Urea breath testing and analysis in the primary care office.” J Fam Pract 51(12): 1030-2.
- Paredi, P., S. A. Kharitonov, et al. (2000). “Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease.” Am J Respir Crit Care Med 162(2 Pt 1): 369-73.
- Pauling, L., A. B. Robinson, et al. (1971). “Quantitative analysis of urine vapor and breath by gas-liquid partition chromatography.” Proc Natl Acad Sci USA 68(10): 2374-6.
- Phillips, M. (1992). “Breath tests in medicine.” Sci Am 267(1): 74-9.
- Phillips, M. (1995). Breath collection. USPTO. US.
- Phillips, M. (1997). “Method for the collection and assay of volatile organic compounds in breath.” Anal Biochem 247(2): 272-8.
- Phillips, M., R. N. Cataneo, et al. (2000). “Effect of age on the breath methylated alkane contour, a display of apparent new markers of oxidative stress.” J Lab Clin Med 136(3): 243-9.
- Phillips, M., G. A. Erickson, et al. (1995). “Volatile organic compounds in the breath of patients with schizophrenia.” J Clin Pathol 48(5): 466-9.
- Phillips, M., K. Gleeson, et al. (1999). “Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study.” Lancet 353(9168): 1930-3.
- Phillips, M., J. Herrera, et al. (1999). “Variation in volatile organic compounds in the breath of normal humans.” J Chromatoqr B Biomed Sci Appl 729(1-2): 75-88.
- Pons, J. L., A. Rimbault, et al. (1985). “Gas chromatographic-mass spectrometric analysis of volatile amines produced by several strains of Clostridium.” J Chromatogr 337(2): 213-21.
- Rimbault, A., P. Niel, et al. (1986). “Headspace gas chromatographic-mass spectrometric analysis of light hydrocarbons and volatile organosulphur compounds in reduced-pressure cultures of Clostridium.” J Chromatogr 375(1): 11-25.
- Rivory, L. P., K. A. Slaviero, et al. (2001). “The erythromycin breath test for the prediction of drug clearance.” Clin Pharmacokinet 40(3): 151-8.
- RYBAK, I., G. THEKKADATH, et al. (1999). A SAMPLE COLLECTION AND DETECTION SYSTEM USED FOR BREATH ANALYSIS. PCT. Canada, IDS INTELLIGENT DETECTION SYSTEMS, INC.
- Satoh, K., A. Yanagida, et al. (2002). Method and apparatus for analyzing breath sample. USA, Suzuki Motor Corporation (Shizuoka, JP); Takenaka; Akira (Kyoto-fu, JP).
- Sear, J. W. and H. Higham (2002). “Issues in the perioperative management of the elderly patient with cardiovascular disease.” Drugs Aging 19(6): 429-51.
- Sunshine, S., M. Steinthal, et al. (2001). Handheld Sensing Apparatus. USPTO. US, Cyrano Sciences, Inc.
- Yu, K., T. R. Hamilton-Kemp, et al. (2000). “Volatile compounds from Escherichia coli 01 57:H7 and their absorption by strawberry fruit.” J Agric Food Chem 48(2): 413-7.
- Zechman, J. M., S. Aldinger, et al. (1986). “Characterization of pathogenic bacteria by automated headspace concentration-gas chromatography.” J Chromatoqr 377: 49-57.
- Zechman, J. M. and J. N. Labows, Jr. (1985). “Volatiles of Pseudomonas aeruginosa and related species by automated headspace concentration—gas chromatography.” Can J Microbiol 31(3): 232-7.
Claims (16)
1-26. (canceled)
27. An apparatus for collecting and detecting compounds in a human breath sample comprising:
a handheld sample collector comprising a sorbent phase;
a breath analyzer comprising a thermal desorption column;
two or more sensors for detection of breath compounds; and
a flow controller for controlling the transfer of breath compounds from the sample collector into the breath analyzer,
wherein the handheld sample collector and breath analyzer are configured for fluid communication with each other so that breath compounds from the sample collector can pass into the breath analyzer for detection.
28. The apparatus of claim 27 , wherein the apparatus is configured to detect at least one breath compound chosen from alcohols, ethers, ketones, amines, aldehydes, carbonyls, carbanions, alkanes, alkenes, alkynes, aromatic hydrocarbons, polynuclear aromatics, biomolecules, sugars, isoprenes, isoprenoids, VOCs, VOAs, indoles, pyridines, fatty acids, and off-gases of a microorganism
29. The apparatus of claim 27 , wherein the apparatus is configured to detect breath compounds for health or disease diagnosis.
30. The apparatus of claim 29 , wherein the disease is chosen from acute myocardial infarction, asthma, bacterial infection, breast cancer, chronic obstructive pulmonary disease, diabetes, heart transplant rejection, inflammatory bowel disease, liver disease, lung cancer, rheumatoid arthritis, or schizophrenia.
31. The apparatus of claim 30 , wherein the bacterial infection is chosen from Helicobacter pylori, Pseudomonas, Klebsiella pneumoniae, Proteus mirabolis, Staphylococcus aureus, Enterococcus, Clostridium, E. col, and M. tuberculosis infections.
32. The apparatus of claim 27 , wherein the apparatus is configured to detect breath compounds for drug monitoring.
33. The apparatus of claim 27 , wherein the apparatus is configured to detect breath compounds for determination of exposure to industrial solvents.
34. The apparatus of claim 27 , wherein the apparatus is configured such that the handheld sample collector is not in fluid communication with the breath analyzer during sample collection.
35. The apparatus of claim 27 , wherein the handheld sample collector comprises an inhalation passage and an exhalation passage.
36. The apparatus of claim 27 , wherein the handheld sample collector is configured to collect breath compounds from multiple breaths.
37. The apparatus of claim 27 , wherein the sorbent phase is selected from activated carbon, silica gel, activated alumina, molecular sieve carbon, molecular sieve zeolites, silicalite, AlPO4, alumina, polystyrene, and combinations thereof.
38. The apparatus of claim 27 , wherein the apparatus further comprises an air collector for collecting compounds in environmental air upon inhaling.
39. The apparatus of claim 38 , wherein the air collector comprises a sorbent phase.
40. The apparatus of claim 27 , wherein the sensors comprise at least one sensor selected from the group consisting of mass spectrometers, surface acoustic wave sensors, quartz microbalance sensors, conducting polymer sensors, dye-impregnated polymer film on fiber optic detectors, conductive composite sensors, chemiresistors, metal oxide gas sensors, electrochemical gas detectors, chemically sensitive field-effect transistors, and carbon black-polymer composite devices.
41. The apparatus of claim 27 , wherein the sensors are polymer-coated surface acoustic wave sensors.
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US20070167853A1 (en) * | 2002-01-22 | 2007-07-19 | Melker Richard J | System and method for monitoring health using exhaled breath |
US20080092629A1 (en) * | 2006-10-20 | 2008-04-24 | Masao Suga | Gas component collector, gas component collecting device, filter producing method, and gas component analyzing apparatus |
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US20110005300A1 (en) * | 2009-07-07 | 2011-01-13 | Tricorntech Corporation | CASCADED GAS CHROMATOGRAPHS (CGCs) WITH INDIVIDUAL TEMPERATURE CONTROL AND GAS ANALYSIS SYSTEMS USING SAME |
US20110023581A1 (en) * | 2009-07-31 | 2011-02-03 | Tricorntech Corporation | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
US20110247396A1 (en) * | 2008-10-17 | 2011-10-13 | Smiths Detection Inc. | Sensor system with close-loop-adsorption circulation |
US20110283770A1 (en) * | 2009-02-10 | 2011-11-24 | Hok Instrument Ab | Breath analysis |
US20140014098A1 (en) * | 2012-07-11 | 2014-01-16 | Be Aerospace, Inc. | Aircraft crew member protective breathing apparatus |
US20140366126A1 (en) * | 2011-04-29 | 2014-12-11 | Theodosios Kountotsis | Breath actuation of electronic and non-electronic devices for preventing unauthorized access |
US8978444B2 (en) | 2010-04-23 | 2015-03-17 | Tricorn Tech Corporation | Gas analyte spectrum sharpening and separation with multi-dimensional micro-GC for gas chromatography analysis |
US9228997B2 (en) | 2009-10-02 | 2016-01-05 | Soberlink, Inc. | Sobriety monitoring system |
WO2016007817A1 (en) * | 2014-07-11 | 2016-01-14 | Inspired Technologies, Inc. | Improved devices, systems and methods for detecting a bilateral differential in olfactory detection threshold for pure odorants |
US9239323B2 (en) | 2009-10-02 | 2016-01-19 | Soberlink, Inc. | Sobriety monitoring system |
US9404836B2 (en) | 2014-06-27 | 2016-08-02 | Pulse Health Llc | Method and device for carbonyl detection and quantitation |
US9417232B2 (en) | 2009-10-02 | 2016-08-16 | Bi Mobile Breath, Inc. | Sobriety monitoring system |
US9480461B2 (en) | 2008-03-10 | 2016-11-01 | Volatile Analysis Corporation | Methods for extracting chemicals from nasal cavities and breath |
US9766215B2 (en) | 2011-09-07 | 2017-09-19 | Parker-Hannifin Corporation | Analytical system and method for detecting volatile organic compounds in water |
US9922508B2 (en) | 2015-10-09 | 2018-03-20 | Soberlink Healthcare, Llc | Bioresistive-fingerprint based sobriety monitoring system |
WO2018126119A1 (en) * | 2016-12-30 | 2018-07-05 | Lee Luke P | Aerosol capture and processing device |
US10168315B2 (en) | 2012-10-29 | 2019-01-01 | Technion Research & Development Foundation Ltd. | Sensor technology for diagnosing tuberculosis |
WO2019023246A1 (en) * | 2017-07-25 | 2019-01-31 | Pulmostics Limited | Temperature variation for sensor array based detection technology |
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WO2020011450A1 (en) * | 2018-07-09 | 2020-01-16 | Fresenius Vial Sas | System and method for identifying and/or measuring a substance concentration in the exhaled breath of a patient |
US10557844B2 (en) | 2016-04-08 | 2020-02-11 | Soberlink Healthcare, Llc | Bioresistive-fingerprint based sobriety monitoring system |
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US11033203B2 (en) * | 2016-04-25 | 2021-06-15 | Owlstone Medical Limited | Systems and device for capturing breath samples |
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Families Citing this family (113)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034024A1 (en) | 1999-11-08 | 2001-05-17 | University Of Florida Research Foundation, Inc. | Marker detection method and apparatus to monitor drug compliance |
US20050233459A1 (en) * | 2003-11-26 | 2005-10-20 | Melker Richard J | Marker detection method and apparatus to monitor drug compliance |
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US7220387B2 (en) * | 2002-07-23 | 2007-05-22 | Apieron Biosystems Corp. | Disposable sensor for use in measuring an analyte in a gaseous sample |
US20060160134A1 (en) * | 2002-10-21 | 2006-07-20 | Melker Richard J | Novel application of biosensors for diagnosis and treatment of disease |
AU2003299850A1 (en) | 2002-12-20 | 2004-07-22 | Amidex, Inc. | Breath aerosol collection system and method |
US20050191757A1 (en) * | 2004-01-20 | 2005-09-01 | Melker Richard J. | Method and apparatus for detecting humans and human remains |
JP4634720B2 (en) * | 2004-01-20 | 2011-02-16 | サントリーホールディングス株式会社 | Gas detection method and detection apparatus |
US20080220984A1 (en) * | 2004-03-10 | 2008-09-11 | Bright Frank V | Method for diagnosis of physiological states by detecting patterns of volatile analytes |
US20060062734A1 (en) * | 2004-09-20 | 2006-03-23 | Melker Richard J | Methods and systems for preventing diversion of prescription drugs |
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EP1926990A2 (en) * | 2005-09-06 | 2008-06-04 | Koninklijke Philips Electronics N.V. | Nitric oxide detection |
US7736903B2 (en) * | 2005-10-05 | 2010-06-15 | Delphi Technologies, Inc. | Tracer to compensate for environmental variations that influence a chemical vapor sensor measurement |
US8348853B2 (en) * | 2006-02-06 | 2013-01-08 | Deka Products Limited Partnership | System, method and device for aiding in the diagnosis of respiratory dysfunction |
EP3279329A1 (en) | 2006-07-21 | 2018-02-07 | Xyleco, Inc. | Conversion systems for biomass |
US7914460B2 (en) | 2006-08-15 | 2011-03-29 | University Of Florida Research Foundation, Inc. | Condensate glucose analyzer |
US7788963B2 (en) * | 2006-10-31 | 2010-09-07 | Ric Investments, Llc | System and method for calibrating a determination of partial pressure of one or more gaseous analytes |
WO2008121183A2 (en) * | 2007-02-09 | 2008-10-09 | The Research Foundation Of State University Of New York | Method for diagnosis of physiological states by detecting patterns of volatile analytes |
AU2008222632A1 (en) * | 2007-03-08 | 2008-09-12 | Fsp Instruments, Inc. | Gas analyzer |
US20110009762A1 (en) * | 2007-03-08 | 2011-01-13 | FILT Lungen-und Thoraxdiagnostik GmbH | Portable pneumotachograph for measuring components of an expiration volume and method therefor |
WO2008137749A1 (en) * | 2007-05-04 | 2008-11-13 | Upspring Ltd. | Diagnostic device and method for testing hydration and other conditions |
AU2008284273A1 (en) * | 2007-08-08 | 2009-02-12 | Kemeta, Llc | Biosensor system with a multifunctional portable electronic device |
GB0717433D0 (en) * | 2007-09-07 | 2007-10-17 | Bedfont Scient Ltd | Apparatus and method |
KR100894800B1 (en) | 2008-01-31 | 2009-04-22 | 전북대학교산학협력단 | A surface acoustic wave sensor for detecting a lung cancer |
US9164073B1 (en) | 2008-02-11 | 2015-10-20 | Pavel Nosovitskiy | Multi-functional, discrete determination of concentrations of gases in a gaseous mixture |
US8185325B2 (en) * | 2008-02-11 | 2012-05-22 | Pavel Nosovitskiy | Multi-functional, discrete and mutually exclusive method for determining concentrations of gases in a gaseous mixture |
PT104077A (en) * | 2008-05-28 | 2009-11-30 | Univ Nova De Lisboa | PROFILES OF VOLATILE HIBROCARBONATE COMPOUNDS, CELLULOSIC MATERIAL DEGRADATION / AGING MARKERS AND PATALOGIA MARKERS |
US8366630B2 (en) * | 2008-05-29 | 2013-02-05 | Technion Research And Development Foundation Ltd. | Carbon nanotube structures in sensor apparatuses for analyzing biomarkers in breath samples |
DE102008027630A1 (en) * | 2008-06-05 | 2009-12-10 | Filt Lungen- Und Thoraxdiagnostik Gmbh | Portable pneumotachograph for measuring components of the expiratory volume |
US20090317916A1 (en) * | 2008-06-23 | 2009-12-24 | Ewing Kenneth J | Chemical sample collection and detection device using atmospheric pressure ionization |
AT14763U1 (en) * | 2008-10-16 | 2016-05-15 | Darwin Gmbh | Set and method for obtaining a breathing air sample |
CN104856679B (en) * | 2008-12-01 | 2019-02-22 | 创控科技股份有限公司 | The breast rail system and method managed for asthma, pulmonary tuberculosis and pulmonary cancer diagnosis and disease |
US8481324B2 (en) | 2008-12-04 | 2013-07-09 | Technion Research And Development Foundation Ltd. | Apparatus and methods for diagnosing renal disorders |
EP2379128A4 (en) * | 2008-12-23 | 2014-02-05 | Us Gov Health & Human Serv | Lung aerosol collection device |
US8529462B2 (en) * | 2009-02-06 | 2013-09-10 | Justice Ez Trac, Llc | Apparatus and method for passive testing of alcohol and drug abuse |
US20100228141A1 (en) * | 2009-03-05 | 2010-09-09 | Theodosios Kountotsis | Tamper resistant receptacle where access is actuated by breath samples and method of manufacturing the same |
WO2011029888A1 (en) | 2009-09-09 | 2011-03-17 | Sensa Bues Ab | Surface-enhanced raman scattering for drug detection in exhaled breath |
US20110098590A1 (en) * | 2009-10-26 | 2011-04-28 | Pulse Health Llc | Methods and apparatuses for detecting analytes |
EP2591331A4 (en) | 2010-07-06 | 2017-06-07 | Deton Corp. | System for airborne bacterial sample collection and analysis |
US8403861B2 (en) * | 2010-09-02 | 2013-03-26 | Anaxsys Technology Limited | Detection of respiratory system lesions |
CN104939831B (en) * | 2010-09-09 | 2018-11-09 | 森撒部伊斯公司 | The system and method and application thereof of sample are collected from the expiratory air of subject |
US20120168024A1 (en) * | 2010-12-29 | 2012-07-05 | Robin Beck | Breath Containment Keepsake Item and Method |
EP2518499B1 (en) * | 2011-03-09 | 2015-06-10 | Sensa Bues AB | A portable sampling device and method for drug detection from exhaled breath |
WO2013028770A1 (en) * | 2011-08-22 | 2013-02-28 | Booth Eric Jason | System and method for trapping and collecting volatile compounds |
US9089279B2 (en) * | 2011-12-29 | 2015-07-28 | General Electric Company | Ion-based breath analysis system |
US9600001B2 (en) * | 2012-01-13 | 2017-03-21 | Perkinelmer Health Sciences, Inc. | Devices, systems and methods for purging and loading sorbent tubes |
WO2013132085A1 (en) | 2012-03-08 | 2013-09-12 | Sensa Bues Ab | A portable sampling device and method for detection of biomarkers in exhaled breath |
US9689826B2 (en) | 2012-03-11 | 2017-06-27 | Technion Research And Development Foundation Ltd. | Detection of chronic kidney disease and disease progression |
US9770192B2 (en) * | 2012-03-19 | 2017-09-26 | Richard C. Fuisz | Method and system to amplify and measure breath analytes |
TWI456198B (en) * | 2012-05-18 | 2014-10-11 | Univ Nat Sun Yat Sen | Portable detection system for allergic diseases |
WO2014008323A1 (en) * | 2012-07-03 | 2014-01-09 | Chevron U.S.A. Inc. | Detection of hydrocarbons in aqueous environments |
US9617582B2 (en) | 2012-09-04 | 2017-04-11 | University Of Maryland College Park | Human exhaled aerosol droplet biomarker system and method |
EP2706355A1 (en) | 2012-09-11 | 2014-03-12 | Sensa Bues AB | System and method for eluting and testing substance from exhaled aerosol sample |
CN105339486B (en) | 2013-03-12 | 2018-12-21 | 德汤公司 | The system collected and analyzed for breath sample |
WO2014165732A1 (en) * | 2013-04-04 | 2014-10-09 | The Regents Of The University Of California | System and method for utilizing exhaled breath for monitoring inflammatory states |
CH707875B1 (en) * | 2013-04-11 | 2017-10-31 | Sunstar Suisse Sa | Apparatus and method for the analysis of a respiratory gas mixture, especially for the detection of halitosis. |
WO2015017354A1 (en) * | 2013-07-29 | 2015-02-05 | University Of Houston System | Volatile organic gases as bioindicators for transplant rejection |
DE102013112921A1 (en) * | 2013-11-22 | 2015-05-28 | IMSPEX DIAGNOSTICS Ltd. | Method for measuring human exhaled air by gas chromatography ion mobility spectrometry |
US20150301019A1 (en) * | 2014-04-16 | 2015-10-22 | James R. Smith | Hand Held Breath Analyzer |
CN106796217A (en) * | 2014-07-21 | 2017-05-31 | 泰克年研究发展基金会公司 | For the composition of directly breathing sampling |
US9733225B2 (en) * | 2015-03-07 | 2017-08-15 | Matthew David Armstrong | Spectroscopic breath detector |
WO2017031303A1 (en) | 2015-08-18 | 2017-02-23 | University Of Cincinnati | Analyte sensor and method of use |
WO2017042716A1 (en) * | 2015-09-11 | 2017-03-16 | Koninklijke Philips N.V. | Multi-bed sorbent tubes and use thereof |
US10386351B2 (en) | 2015-12-07 | 2019-08-20 | Nanohmics, Inc. | Methods for detecting and quantifying analytes using gas species diffusion |
US10386365B2 (en) | 2015-12-07 | 2019-08-20 | Nanohmics, Inc. | Methods for detecting and quantifying analytes using ionic species diffusion |
WO2017123582A1 (en) * | 2016-01-11 | 2017-07-20 | Avisa Pharma Inc. | Methods for detecting bacterial lung infections |
US10502665B2 (en) | 2016-04-18 | 2019-12-10 | University Of Maryland, College Park | Aerosol collection system and method |
US20170336389A1 (en) * | 2016-05-23 | 2017-11-23 | Zansors Llc | Sensor assemblies and methods of use |
US10178963B1 (en) * | 2016-06-09 | 2019-01-15 | Dynosense, Corp. | Gas collection apparatus and method to analyze a human breath sample |
EP3518762B1 (en) | 2016-09-28 | 2024-01-10 | Indian Institute of Technology, Guwahati | A lung condition monitoring device |
US10524726B2 (en) | 2016-11-17 | 2020-01-07 | Biointellisense, Inc. | Medication adherence and/or counterfeit detection wearable electronic device |
CN108245757A (en) * | 2017-12-20 | 2018-07-06 | 浙江大学 | Breathed air acquisition device based on breathing circuit |
GB2571938B (en) * | 2018-03-12 | 2022-04-13 | Owlstone Inc | Mobile device |
WO2019178247A1 (en) * | 2018-03-15 | 2019-09-19 | Biolum Sciences Llc | Sensor devices and systems for monitoring markers in breath |
AU201815511S (en) | 2018-05-07 | 2018-12-17 | Sensa Bues Ab | Breath sampling device |
US11131615B2 (en) | 2018-06-07 | 2021-09-28 | Nanohmics, Inc. | Sensor and methods for detecting and quantifying ions and molecules |
CN112771376A (en) * | 2018-07-09 | 2021-05-07 | 费森尤斯维尔公司 | System and method for identifying and/or measuring substance concentration in exhaled breath of a patient |
JP7050248B2 (en) * | 2018-07-24 | 2022-04-08 | 曽田香料株式会社 | Retronasal aroma analysis method or evaluation method and equipment used for it |
KR20210041006A (en) * | 2018-07-31 | 2021-04-14 | 유니버시티 오브 노스 텍사스 | Rapid detection and quantification technology of volatile organic compounds (VOCS) using breathing samples |
US11841372B1 (en) | 2018-07-31 | 2023-12-12 | Inspectir Systems, Llc | Techniques for rapid detection and quantitation of volatile organic compounds (VOCs) using breath samples |
US11874270B1 (en) | 2018-07-31 | 2024-01-16 | Inspectir Systems, Llc | Techniques for rapid detection and quantitation of volatile organic compounds (VOCs) using breath samples |
US11662340B1 (en) | 2018-07-31 | 2023-05-30 | InspectIR Systems, Inc. | Techniques for rapid detection and quantitation of volatile organic compounds (VOCS) using breath samples |
US11721533B1 (en) | 2018-07-31 | 2023-08-08 | Inspectir Systems, Llc | Techniques for rapid detection and quantitation of volatile organic compounds (VOCS) using breath samples |
US11879890B1 (en) | 2018-07-31 | 2024-01-23 | Inspectir Systems, Llc | Techniques for rapid detection and quantitation of volatile organic compounds (VOCS) using breath samples |
US11841359B1 (en) | 2018-07-31 | 2023-12-12 | Inspectir Systems, Llc | Techniques for portable rapid detection and quantitation of volatile organic compounds (VOCS) using breath samples |
WO2020123565A1 (en) * | 2018-12-10 | 2020-06-18 | Anastasia Rigas | Breath analyzer devices and breath test methods |
WO2020145896A1 (en) * | 2019-01-11 | 2020-07-16 | National University Of Singapore | Sample collection device |
AU2020252109A1 (en) * | 2019-03-31 | 2021-10-28 | Resmed Inc. | Methods and apparatuses for analyzing one or more analytes from a user |
WO2020263125A1 (en) * | 2019-06-24 | 2020-12-30 | Общество с ограниченной ответственностью "Научно-техническое предприятие "ТКА" | Device for diagnosing helicobacter pylori bacteria infection |
RU194744U1 (en) * | 2019-06-24 | 2019-12-23 | Общество с ограниченной ответственностью "Научно-техническое предприятие "ТКА" | Device for the diagnosis of infection with the bacterium Helicobacter pylori |
US20210137413A1 (en) | 2019-11-07 | 2021-05-13 | Vitalii Vorkov | Method of Exhaled Gas Analysis and a Universal Portable Breath Content Analyzer for Carrying out the Method |
CN110763785A (en) * | 2019-11-13 | 2020-02-07 | 中国科学院声学研究所 | Drug determination method |
US11193926B2 (en) * | 2020-03-13 | 2021-12-07 | Quintron Instrument Company, Inc. | Breath testing apparatus |
WO2021252696A1 (en) * | 2020-06-09 | 2021-12-16 | Graham Biosciences Llc | Device and methods for collecting and processing analytes in air/breath |
CN112180002A (en) * | 2020-08-31 | 2021-01-05 | 四川省中医药科学院 | Method for identifying low-volatility traditional Chinese medicinal materials on site by using surface acoustic wave gas chromatograph |
CN112180004A (en) * | 2020-08-31 | 2021-01-05 | 四川省中医药科学院 | Method for identifying high-volatility traditional Chinese medicinal materials on site by using surface acoustic wave gas chromatograph |
WO2022140045A1 (en) * | 2020-12-23 | 2022-06-30 | Vaon, Llc | Breathalyzer |
EP4275042A1 (en) * | 2021-01-07 | 2023-11-15 | Nanose Medical Ltd | Detection of respiratory tract infections (rtis) |
WO2022212620A1 (en) * | 2021-04-01 | 2022-10-06 | Janssen Biotech, Inc. | Drug material interactions using quartz crystal microbalance sensors |
CA3221298A1 (en) * | 2021-06-03 | 2022-12-08 | Ricardo Daniel DE SIMONE | A device for detecting health disorders from biological samples and a detection process |
WO2023102638A2 (en) * | 2021-12-06 | 2023-06-15 | The University Of British Columbia | Apparatus for gas sample collection |
CN116840379A (en) * | 2023-07-13 | 2023-10-03 | 中国科学院西北生态环境资源研究院 | Method for measuring difference of carbon dioxide in atmosphere and human body expiration by using carbon dioxide family |
Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4759210A (en) * | 1986-06-06 | 1988-07-26 | Microsensor Systems, Inc. | Apparatus for gas-monitoring and method of conducting same |
US5081871A (en) * | 1989-02-02 | 1992-01-21 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Breath sampler |
US5465728A (en) * | 1994-01-11 | 1995-11-14 | Phillips; Michael | Breath collection |
US5469369A (en) * | 1992-11-02 | 1995-11-21 | The United States Of America As Represented By The Secretary Of The Navy | Smart sensor system and method using a surface acoustic wave vapor sensor array and pattern recognition for selective trace organic vapor detection |
US5479815A (en) * | 1994-02-24 | 1996-01-02 | Kraft Foods, Inc. | Method and apparatus for measuring volatiles released from food products |
US5705735A (en) * | 1996-08-09 | 1998-01-06 | Medical Graphics Corporation | Breath by breath nutritional requirements analyzing system |
US5826577A (en) * | 1996-01-30 | 1998-10-27 | Bacharach, Inc. | Breath gas analysis module |
US5964712A (en) * | 1995-10-09 | 1999-10-12 | Otsuka Pharmaceutical Co., Ltd. | Apparatus and breathing bag for spectrometrically measuring isotopic gas |
US6148657A (en) * | 1996-08-13 | 2000-11-21 | Suzuki Motor Corporation | Method and apparatus for analyzing a breath sample |
US6234006B1 (en) * | 1998-03-20 | 2001-05-22 | Cyrano Sciences Inc. | Handheld sensing apparatus |
US6244096B1 (en) * | 1998-06-19 | 2001-06-12 | California Institute Of Technology | Trace level detection of analytes using artificial olfactometry |
US20010037070A1 (en) * | 2000-02-22 | 2001-11-01 | Cranley Paul E. | Personal computer breath analyzer for health-related behavior modification and method |
US6428483B1 (en) * | 1999-05-08 | 2002-08-06 | Oridion Medical 1987, Ltd. | Waveform interpreter for respiratory analysis |
US6609068B2 (en) * | 2000-02-22 | 2003-08-19 | Dow Global Technologies Inc. | Personal computer breath analyzer for health-related behavior modification and method |
US6726637B2 (en) * | 2001-12-06 | 2004-04-27 | Michael Phillips | Breath collection apparatus |
US7153272B2 (en) * | 2002-01-29 | 2006-12-26 | Nanotherapeutics, Inc. | Methods of collecting and analyzing human breath |
-
2003
- 2003-01-29 WO PCT/US2003/001065 patent/WO2003064994A2/en not_active Application Discontinuation
- 2003-01-29 US US10/502,950 patent/US7153272B2/en not_active Expired - Fee Related
- 2003-01-29 AU AU2003207552A patent/AU2003207552A1/en not_active Abandoned
-
2006
- 2006-11-08 US US11/557,797 patent/US20070062255A1/en not_active Abandoned
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4759210A (en) * | 1986-06-06 | 1988-07-26 | Microsensor Systems, Inc. | Apparatus for gas-monitoring and method of conducting same |
US5081871A (en) * | 1989-02-02 | 1992-01-21 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Breath sampler |
US5469369A (en) * | 1992-11-02 | 1995-11-21 | The United States Of America As Represented By The Secretary Of The Navy | Smart sensor system and method using a surface acoustic wave vapor sensor array and pattern recognition for selective trace organic vapor detection |
US5465728A (en) * | 1994-01-11 | 1995-11-14 | Phillips; Michael | Breath collection |
US5479815A (en) * | 1994-02-24 | 1996-01-02 | Kraft Foods, Inc. | Method and apparatus for measuring volatiles released from food products |
US5964712A (en) * | 1995-10-09 | 1999-10-12 | Otsuka Pharmaceutical Co., Ltd. | Apparatus and breathing bag for spectrometrically measuring isotopic gas |
US5826577A (en) * | 1996-01-30 | 1998-10-27 | Bacharach, Inc. | Breath gas analysis module |
US5705735A (en) * | 1996-08-09 | 1998-01-06 | Medical Graphics Corporation | Breath by breath nutritional requirements analyzing system |
US6148657A (en) * | 1996-08-13 | 2000-11-21 | Suzuki Motor Corporation | Method and apparatus for analyzing a breath sample |
US6341520B1 (en) * | 1996-08-13 | 2002-01-29 | Suzuki Motor Corporation | Method and apparatus for analyzing breath sample |
US6234006B1 (en) * | 1998-03-20 | 2001-05-22 | Cyrano Sciences Inc. | Handheld sensing apparatus |
US6244096B1 (en) * | 1998-06-19 | 2001-06-12 | California Institute Of Technology | Trace level detection of analytes using artificial olfactometry |
US6319724B1 (en) * | 1998-06-19 | 2001-11-20 | Cyrano Sciences, Inc. | Trace level detection of analytes using artificial olfactometry |
US6428483B1 (en) * | 1999-05-08 | 2002-08-06 | Oridion Medical 1987, Ltd. | Waveform interpreter for respiratory analysis |
US20010037070A1 (en) * | 2000-02-22 | 2001-11-01 | Cranley Paul E. | Personal computer breath analyzer for health-related behavior modification and method |
US6609068B2 (en) * | 2000-02-22 | 2003-08-19 | Dow Global Technologies Inc. | Personal computer breath analyzer for health-related behavior modification and method |
US6726637B2 (en) * | 2001-12-06 | 2004-04-27 | Michael Phillips | Breath collection apparatus |
US7153272B2 (en) * | 2002-01-29 | 2006-12-26 | Nanotherapeutics, Inc. | Methods of collecting and analyzing human breath |
Cited By (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070167853A1 (en) * | 2002-01-22 | 2007-07-19 | Melker Richard J | System and method for monitoring health using exhaled breath |
US20080092629A1 (en) * | 2006-10-20 | 2008-04-24 | Masao Suga | Gas component collector, gas component collecting device, filter producing method, and gas component analyzing apparatus |
US7882754B2 (en) * | 2006-10-20 | 2011-02-08 | Hitachi, Ltd. | Gas component collector, gas component collecting device, filter producing method, and gas component analyzing apparatus |
US20080289397A1 (en) * | 2007-04-20 | 2008-11-27 | Kazi Zulfiqur Ali Hassan | Portable analytical system for detecting organic chemicals in water |
US8302458B2 (en) | 2007-04-20 | 2012-11-06 | Parker-Hannifin Corporation | Portable analytical system for detecting organic chemicals in water |
USRE44533E1 (en) | 2007-04-25 | 2013-10-08 | Stc.Unm | Diagnosis of infection in the lungs of patients |
US20080305050A1 (en) * | 2007-04-25 | 2008-12-11 | Graham Timmins | Analysis of P. aeruginosa infection in patients |
US7717857B2 (en) * | 2007-04-25 | 2010-05-18 | Stc.Unm | Diagnosis of P. aeruginosa infection in the lungs of patients |
KR100983827B1 (en) | 2007-08-20 | 2010-09-27 | 동양물산기업 주식회사 | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
US9144396B2 (en) | 2007-08-20 | 2015-09-29 | Yong Sahm Choe | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
WO2009025488A3 (en) * | 2007-08-20 | 2009-04-16 | Dongyang Moolsan Co Ltd | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
US20110021942A1 (en) * | 2007-08-20 | 2011-01-27 | Tongyang Moolsan Co., Ltd. | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
WO2009025488A2 (en) * | 2007-08-20 | 2009-02-26 | Tongyang Moolsan Co., Ltd. | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
US20100191474A1 (en) * | 2007-10-23 | 2010-07-29 | Technion Research And Development Foundation Ltd. | Electronic nose device with sensors composed of nanowires of columnar discotic liquid crystals with low sensititive to humidity |
US20090124865A1 (en) * | 2007-11-14 | 2009-05-14 | Kiernan James E | System and methods for stress release and associated nitric oxide release for treatment of pain in specific parts of the body |
US8418523B2 (en) * | 2008-03-03 | 2013-04-16 | Keith Lueck | Calibration and accuracy check system for a breath tester |
US20100223975A1 (en) * | 2008-03-03 | 2010-09-09 | Keith Lueck | Calibration and Accuracy Check System for a Breath Tester |
US8713985B2 (en) | 2008-03-03 | 2014-05-06 | Alcotek, Inc. | Calibration and accuracy check system |
US9480461B2 (en) | 2008-03-10 | 2016-11-01 | Volatile Analysis Corporation | Methods for extracting chemicals from nasal cavities and breath |
US20090247890A1 (en) * | 2008-03-26 | 2009-10-01 | Nellcor Puritan Bennett Llc | Solid state myocardial infarction detector |
US8087283B2 (en) | 2008-06-17 | 2012-01-03 | Tricorntech Corporation | Handheld gas analysis systems for point-of-care medical applications |
US20090308136A1 (en) * | 2008-06-17 | 2009-12-17 | Tricorntech Corporation | Handheld gas analysis systems for point-of-care medical applications |
US8695401B2 (en) | 2008-06-17 | 2014-04-15 | Tricorntech Corporation | Handheld gas analysis systems for point-of-care medical applications |
JP2010008374A (en) * | 2008-06-30 | 2010-01-14 | Nippon Koden Corp | Method and apparatus for analyzing gas component derived from living body, and disease determination supporting apparatus |
US20090326338A1 (en) * | 2008-06-30 | 2009-12-31 | Nihon Kohden Corporation | Method and apparatus for analyzing gas component derived from living body and disease determination supporting apparatus |
US20100012124A1 (en) * | 2008-07-08 | 2010-01-21 | Alexander Roger Deas | Rebreather respiratory loop failure detector |
US20110247396A1 (en) * | 2008-10-17 | 2011-10-13 | Smiths Detection Inc. | Sensor system with close-loop-adsorption circulation |
US8650932B2 (en) * | 2008-10-17 | 2014-02-18 | Smiths Detection Inc. | Sensor system with close-loop-adsorption circulation |
US20110283770A1 (en) * | 2009-02-10 | 2011-11-24 | Hok Instrument Ab | Breath analysis |
WO2010127309A1 (en) * | 2009-04-30 | 2010-11-04 | Volatile Analysis Corporation | Apparatuses and methods for extracting chemicals from bodily cavities and breath |
US9683974B2 (en) | 2009-07-07 | 2017-06-20 | Tricorntech Corporation | Cascaded gas chromatographs (CGCs) with individual temperature control and gas analysis systems using same |
US20110005300A1 (en) * | 2009-07-07 | 2011-01-13 | Tricorntech Corporation | CASCADED GAS CHROMATOGRAPHS (CGCs) WITH INDIVIDUAL TEMPERATURE CONTROL AND GAS ANALYSIS SYSTEMS USING SAME |
US8999245B2 (en) | 2009-07-07 | 2015-04-07 | Tricorn Tech Corporation | Cascaded gas chromatographs (CGCs) with individual temperature control and gas analysis systems using same |
US9658196B2 (en) | 2009-07-31 | 2017-05-23 | Tricorntech Corporation | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
US8707760B2 (en) | 2009-07-31 | 2014-04-29 | Tricorntech Corporation | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
US20110023581A1 (en) * | 2009-07-31 | 2011-02-03 | Tricorntech Corporation | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
WO2011014886A3 (en) * | 2009-07-31 | 2011-06-30 | Tricorntech Corporation | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
CN102498381A (en) * | 2009-07-31 | 2012-06-13 | 创控生技股份有限公司 | Gas collection and analysis system with front-end and back-end pre-concentrators and moisture removal |
US9417232B2 (en) | 2009-10-02 | 2016-08-16 | Bi Mobile Breath, Inc. | Sobriety monitoring system |
US9746456B2 (en) | 2009-10-02 | 2017-08-29 | Bi Mobile Breath, Inc. | Sobriety monitoring system |
US9228997B2 (en) | 2009-10-02 | 2016-01-05 | Soberlink, Inc. | Sobriety monitoring system |
US9239323B2 (en) | 2009-10-02 | 2016-01-19 | Soberlink, Inc. | Sobriety monitoring system |
US9921192B2 (en) | 2010-04-23 | 2018-03-20 | Tricorntech Corporation | Gas analyte spectrum sharpening and separation with multi-dimensional micro-GC for gas chromatography analysis |
US8978444B2 (en) | 2010-04-23 | 2015-03-17 | Tricorn Tech Corporation | Gas analyte spectrum sharpening and separation with multi-dimensional micro-GC for gas chromatography analysis |
US11796515B2 (en) | 2010-04-23 | 2023-10-24 | Tricorntech Corporation | Gas analyte spectrum sharpening and separation with multi-dimensional micro-GC for gas chromatography analysis |
US11035834B2 (en) | 2010-04-23 | 2021-06-15 | TricornTech Taiwan | Gas analyte spectrum sharpening and separation with multi-dimensional micro-GC for gas chromatography analysis |
US20140366126A1 (en) * | 2011-04-29 | 2014-12-11 | Theodosios Kountotsis | Breath actuation of electronic and non-electronic devices for preventing unauthorized access |
US9830441B2 (en) * | 2011-04-29 | 2017-11-28 | Theodosios Kountotsis | Breath actuation of electronic and non-electronic devices for preventing unauthorized access |
US10161920B2 (en) | 2011-09-07 | 2018-12-25 | Parker-Hannifin Corporation | Analytical system and method for detecting volatile organic compounds in water |
US9766215B2 (en) | 2011-09-07 | 2017-09-19 | Parker-Hannifin Corporation | Analytical system and method for detecting volatile organic compounds in water |
US10413215B2 (en) | 2012-04-12 | 2019-09-17 | Enose Holding B.V. | Mobile device and method for analysing breath samples |
US20140014098A1 (en) * | 2012-07-11 | 2014-01-16 | Be Aerospace, Inc. | Aircraft crew member protective breathing apparatus |
US10046184B2 (en) | 2012-07-11 | 2018-08-14 | B/E Aerospace, Inc. | Aircraft crew member protective breathing apparatus |
US9498656B2 (en) * | 2012-07-11 | 2016-11-22 | B/E Aerospace, Inc. | Aircraft crew member protective breathing apparatus |
US10837956B2 (en) | 2012-10-29 | 2020-11-17 | Technion Research & Development Foundation Ltd | Sensor technology for diagnosing tuberculosis |
US10168315B2 (en) | 2012-10-29 | 2019-01-01 | Technion Research & Development Foundation Ltd. | Sensor technology for diagnosing tuberculosis |
US10925515B2 (en) | 2014-05-22 | 2021-02-23 | Picomole Inc. | Alveolar breath collection apparatus |
US9797815B2 (en) | 2014-06-27 | 2017-10-24 | Pulse Health Llc | Breath analysis system |
US10495552B2 (en) | 2014-06-27 | 2019-12-03 | Pulse Health Llc | Breath analysis system |
US9404836B2 (en) | 2014-06-27 | 2016-08-02 | Pulse Health Llc | Method and device for carbonyl detection and quantitation |
US9594005B2 (en) | 2014-06-27 | 2017-03-14 | Pulse Health Llc | Fluorescence detection assembly |
US9546930B2 (en) | 2014-06-27 | 2017-01-17 | Pulse Heath Llc | Analysis cartridge |
US9494495B2 (en) | 2014-06-27 | 2016-11-15 | Pulse Health Llc | Breath analysis system |
US10197477B2 (en) | 2014-06-27 | 2019-02-05 | Pulse Health Llc | Analysis cartridge and method for using same |
US10426395B2 (en) | 2014-07-11 | 2019-10-01 | Inspired Technologies, Inc. | Method for screening a patient for alzheimer's disease |
WO2016007817A1 (en) * | 2014-07-11 | 2016-01-14 | Inspired Technologies, Inc. | Improved devices, systems and methods for detecting a bilateral differential in olfactory detection threshold for pure odorants |
US9936913B2 (en) | 2014-07-11 | 2018-04-10 | Inspired Technologies, Inc. | Methods for cascading pure odorants to the nostrils of patients |
US9717454B2 (en) | 2014-07-11 | 2017-08-01 | Inspired Technologies, Inc. | Method of ruling out Alzheimer's disease |
US10895565B2 (en) | 2015-06-05 | 2021-01-19 | Parker-Hannifin Corporation | Analysis system and method for detecting volatile organic compounds in liquid |
US9922508B2 (en) | 2015-10-09 | 2018-03-20 | Soberlink Healthcare, Llc | Bioresistive-fingerprint based sobriety monitoring system |
US10557844B2 (en) | 2016-04-08 | 2020-02-11 | Soberlink Healthcare, Llc | Bioresistive-fingerprint based sobriety monitoring system |
US11033203B2 (en) * | 2016-04-25 | 2021-06-15 | Owlstone Medical Limited | Systems and device for capturing breath samples |
US11181519B2 (en) | 2016-06-16 | 2021-11-23 | Technion Research & Development Foundation Limited | System and method for differential diagnosis of diseases |
WO2018126119A1 (en) * | 2016-12-30 | 2018-07-05 | Lee Luke P | Aerosol capture and processing device |
US11018470B2 (en) | 2017-03-13 | 2021-05-25 | Picomole Inc. | System for optimizing laser beam |
WO2019023246A1 (en) * | 2017-07-25 | 2019-01-31 | Pulmostics Limited | Temperature variation for sensor array based detection technology |
EP3713657A4 (en) * | 2017-12-21 | 2021-09-01 | Oridion Medical 1987 Ltd. | Bypass filter |
US11964106B2 (en) | 2017-12-21 | 2024-04-23 | Oridion Medical 1987 Ltd. | Bypass filter |
WO2020011450A1 (en) * | 2018-07-09 | 2020-01-16 | Fresenius Vial Sas | System and method for identifying and/or measuring a substance concentration in the exhaled breath of a patient |
US11029295B2 (en) | 2018-10-11 | 2021-06-08 | Tintoria Piana Us, Inc. | Voctron: a low weight portable air sampling device |
US11499916B2 (en) | 2019-04-03 | 2022-11-15 | Picomole Inc. | Spectroscopy system and method of performing spectroscopy |
US11105739B2 (en) | 2019-04-03 | 2021-08-31 | Picomole Inc. | Method and system for analyzing a sample using cavity ring-down spectroscopy, and a method for generating a predictive model |
WO2020198841A1 (en) | 2019-04-03 | 2020-10-08 | Picomole Inc. | Spectroscopy system and method of performing spectroscopy |
CN114008441A (en) * | 2019-04-03 | 2022-02-01 | 皮可摩尔公司 | Spectroscopic system and method of performing spectroscopy |
US10921246B2 (en) | 2019-04-03 | 2021-02-16 | Picomole Inc. | Method of tuning a resonant cavity, and cavity ring-down spectroscopy system |
EP3948227A4 (en) * | 2019-04-03 | 2022-12-28 | Picomole Inc. | Method and system for analyzing a sample using cavity ring-down spectroscopy, and a method for generating a predictive model |
US11035789B2 (en) | 2019-04-03 | 2021-06-15 | Picomole Inc. | Cavity ring-down spectroscopy system and method of modulating a light beam therein |
CN112345654A (en) * | 2019-08-06 | 2021-02-09 | 红塔烟草(集团)有限责任公司 | Method for identifying oil stain smoke pollution source based on chromatographic fingerprint spectrum |
US11921096B2 (en) * | 2019-09-10 | 2024-03-05 | Regents Of The University Of Minnesota | Fluid analysis system |
US20210072208A1 (en) * | 2019-09-10 | 2021-03-11 | Boston Scientific Scimed, Inc. | Fluid analysis system |
US11957450B2 (en) | 2020-02-28 | 2024-04-16 | Picomole Inc. | Apparatus and method for collecting a breath sample using an air circulation system |
US11782049B2 (en) | 2020-02-28 | 2023-10-10 | Picomole Inc. | Apparatus and method for collecting a breath sample using a container with controllable volume |
US11045111B1 (en) * | 2020-05-18 | 2021-06-29 | Canary Health Technologies Inc. | Real time breath analyzer for detecting volatile organic compounds and identifying diseases or disorders |
US11846574B2 (en) | 2020-10-29 | 2023-12-19 | Hand Held Products, Inc. | Apparatuses, systems, and methods for sample capture and extraction |
US11852567B2 (en) | 2020-10-29 | 2023-12-26 | Hand Held Products, Inc. | Apparatuses, systems, and methods for sample capture and extraction |
US11852568B2 (en) | 2020-10-29 | 2023-12-26 | Hand Held Products, Inc. | Apparatuses, systems, and methods for sample capture and extraction |
US11828689B2 (en) | 2020-10-29 | 2023-11-28 | Hand Held Products, Inc. | Apparatuses, systems, and methods for sample capture and extraction |
WO2023002215A1 (en) * | 2021-07-22 | 2023-01-26 | Owlstone Medical Limited | Breath sampling device |
EP4166924A3 (en) * | 2021-09-24 | 2023-06-07 | Hand Held Products, Inc. | Apparatuses, systems, and methods for sample capture and extraction |
Also Published As
Publication number | Publication date |
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US7153272B2 (en) | 2006-12-26 |
WO2003064994A3 (en) | 2003-12-18 |
WO2003064994A2 (en) | 2003-08-07 |
US20050065446A1 (en) | 2005-03-24 |
AU2003207552A1 (en) | 2003-09-02 |
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