WO1999061895A1 - Systeme et procede de detection d'un compose d'haleine a l'aide d'une diode laser - Google Patents

Systeme et procede de detection d'un compose d'haleine a l'aide d'une diode laser Download PDF

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Publication number
WO1999061895A1
WO1999061895A1 PCT/US1999/012044 US9912044W WO9961895A1 WO 1999061895 A1 WO1999061895 A1 WO 1999061895A1 US 9912044 W US9912044 W US 9912044W WO 9961895 A1 WO9961895 A1 WO 9961895A1
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Prior art keywords
molecular
sample
light beam
åtion
abso
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PCT/US1999/012044
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English (en)
Inventor
Yizhong Yu
Ramon U. Martinelli
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Sarnoff Corporation
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Priority to AU42242/99A priority Critical patent/AU4224299A/en
Publication of WO1999061895A1 publication Critical patent/WO1999061895A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • 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
    • A61B5/0836—Measuring rate of CO2 production

Definitions

  • the present invention is directed to measuring molecular content, and, more particularly, to a system measuring molecular content employing a diode laser.
  • a factory may monitor content of toxic gases such as HC1 or H S in emissions.
  • measuring molecular content is gaining increased importance in the medical field, where monitoring molecular content of gases in the breath may be used to diagnose and treat certain diseases. Ulcer diagnosis and treatment is an example of an appUcation for monitoring and determining molecular content of a gas-sample.
  • ulcers may be a result of Helicobacter Pylori bacterium infection.
  • the bacteria live in the mucus layer lining of the stomach.
  • the organisms secrete proteins that interact with the stomach's epithelial cells and attract macrophages and neutrophils, cells that cause inflammation.
  • the bacteria further produce urease, an enzyme that helps to break down urea into ammonia and carbon dioxide.
  • the bacteria also secrete toxins that contribute to the formation of stomach ulcers. If such infection is present in an individual, the infection may be diagnosed by measuring elevated CO 2 content of a breath sample of the individual after ingesting 13 C-labeled urea.
  • the first column lists commonly measured molecules including water vapor and the atmospheric gases such as methane (CHt), and carbon dioxide (CO 2 ).
  • CHt methane
  • CO 2 carbon dioxide
  • the second column gives the wavelength, ⁇ , of one of the many absorption Unes arising from overtone transitions among the vibrational, rotational or combination abso ⁇ tion bands of the respective molecule.
  • the third and fourth columns list strengths, S, of the abso ⁇ tion Unes and the atmospheric pressures- broadened half-widths, ⁇ , of the abso ⁇ tion lines, respectively.
  • Trace-gas monitoring systems may detect a molecular abso ⁇ tion on the order of 10 "6 , so sensitivity may be given as in equation (3):
  • a trace-gas monitoring system may include a sample-gas collection system and a laser which emits light through the gas sample.
  • a detector may measure the received power of light passing through the sample, and then abso ⁇ tion may be determined.
  • Sensitivity is proportional to the abso ⁇ tion pathlength. Extending the abso ⁇ tion pathlength from 1 m to 10 m, which may be accomplished by using multipass gas-sampling cells, improves sensitivity by a factor of 10. However, a long pathlength, even if multipass gas-sampling cells are employed, produces a larger, more expensive monitoring system. Sensitivity is proportional to ⁇ p , implying choosing the strongest molecular abso ⁇ tion lines possible; therefore, a wavelength of the diode laser is desirably matched to the abso ⁇ tion line.
  • the present invention relates to a trace-gas monitoring system and method for determining a content of a first molecular type in a gas sample.
  • the trace-gas monitoring system collects the gas sample in a sample cell and emits a light beam through the sample cell with a diode laser coupled to the sample cell.
  • the light beam has a first wavelength and a first spectral width on the order of a wavelength and a spectral width of an abso ⁇ tion line of the first molecular type.
  • the light beam When the light beam is passed from the diode laser through the gas sample of the sample cell to the detector, the light beam experiences a molecular abso ⁇ tion by the molecular type as the light beam passes through the gas sample.
  • Molecular abso ⁇ tion of the light beam by the first molecular type is detected with a detector coupled to the sample cell, and the detected molecular abso ⁇ tion is related to the content of the first molecular type in the sample cell.
  • FIG. 1 is a block diagram of a breath detection system in accordance with an exemplary embodiment of the present invention
  • FIG. 2 illustrates a structure of a diode laser of the system of FIG. 1 operating in the near-infrared range.
  • FIG. 3A is a graph showing a current-tuning characteristic vs. wavelength of a laser as may be employed in the present invention.
  • FIG. 3B is a graph showing a current-tuning characteristic vs. output power of a laser as may be employed in the present invention.
  • FIG. 4 is a graph showing a ramp signal employed to sweep a wavelength of an optical signal provided by a diode laser
  • FIG. 5 is a graph showing power of a detected ramp signal from an optical path illustrating the effects of wavelength abso ⁇ tion on a diode laser optical signal by 13 CO 2 and
  • FIG. 6 is a block diagram of a synchronous detection system as employed by detectors of the signal and reference optical paths of the exemplary system as shown in FIG. 1;
  • FIG. 7 is a graph of a spectrometer signal of a detected signal power of a second harmonic signal versus wavelength for two abso ⁇ tion lines as measured by the exemplary system of FIG. 1;
  • FIG. 8 shows an exploded view of spectrometer signal versus wavelength for the abso ⁇ tion line for 13 CO 2 as shown in FIG. 7;
  • FIG. 9 illustrates a breath analysis for 13 C0 2 and 12 CO 2 content of breath samples for two subjects, one subject a control subject and the other subject having ingested 200mg of 13 C- doped sodium bicarbonate.
  • the present invention relates to a diode laser-based, trace-gas monitoring system and method that accurately measures a ratio of molecular concentration.
  • a laser of the trace-gas monitor system emits a relatively high power Ught output beam having a narrow spectral width on the order of one-tenth or less the spectral width of each abso ⁇ tion line of the molecules for which the ratio of molecular concentration is measured.
  • Preferred embodiments of the present invention include a distributed feedback, (DFB), single-frequency diode laser emitting with a relatively long wavelength, between 2-3 ⁇ m, for example, in order to increase a sensitivity of the trace-gas monitor system for a given path of light through a gas sample.
  • DFB distributed feedback
  • a preferred embodiment of the present invention relates to a laser-based trace-gas monitoring system and method that accurately measures a ratio of C0 2 and CO 2 concentration, and hence, a relative rise in the 13 C0 2 concentration, in a breath sample.
  • Such monitor desirably has a precision or accuracy of less than approximately one hundred parts per billion.
  • the monitoring system desirably employs a DFB, single-frequency, diode laser emitting at. for example, between 2 to 3 micrometer ( ⁇ m) and probing molecular abso ⁇ tion Unes of 1 C0 2 and 13 CO 2 .
  • a pair of 12 CO 2 and 13 C0 2 abso ⁇ tion Unes is selected and compared to determine relative compound concentrations of 12 CO and 13 CO 2 in the breath sample.
  • diode lasers may serve as Ught output beam sources in trace-gas monitoring based on laser-abso ⁇ tion spectroscopy in accordance with the present invention.
  • Monitoring systems employing longer wavelength lasers of 2-3 ⁇ m have increased sensitivity, and so allow for a reduction of size and/or complexity of the monitoring system.
  • the laser may be employed to probe gas-samples in hostile environments, such as high- temperature furnaces, corrosive atmospheres, and areas having volumes containing toxic gases, in which chemically-based monitors may not function well.
  • the laser may be employed to probe volumes of highly purified gases in which chemically-based monitoring systems may contaminate the volume.
  • a medical application of trace-gas monitoring in accordance with the present invention employs near-infrared diode lasers to monitor molecular content of trace-gases in a human breath sample in which over 400 trace gases may be found, and in particular 13 C0 2 and 12 CO 2 trace-gases.
  • the human breath contains about 4% CO 2 , and about 1% of the C0 2 is the stable, non-radioactive isotope ' CO 2 .
  • C0 2 to 12 C0 2 ratio may be measured in the breath sample.
  • Liver and pancreatic functions, glucose uptake, and Helicobacter Pylori infections of the digestive tract may be analyzed by this technique. Consequently, the preferred embodiment of the present invention is described herein with reference to this exemplary application.
  • FIG. 1 is a block diagram of a breath detection system 100 in accordance with an exemplary embodiment of the present invention.
  • the system 100 includes a sample acquisition section, a cell section, a laser section and a detector section.
  • the sample acquisition section of system 100 includes filter 102, flow meter 104, check valve (C/V) 106, valves VI and V2, pressure sensors PI and P2, pump 128, and heaters 108 and 110.
  • the cell section includes sample cell 124 which contains the sample of breath to be measured for concentrations of 12 CO 2 and 13 CO , and reference cell 122, which contains a reference sample of gas having a
  • the sample cell 124 may be a 3.4-m, multi-pass abso ⁇ tion gas sample cell and the reference cell 122 may be a 5- cm reference cell.
  • the laser section includes laser 116. lens 118, mirror 130, and beam splitter 132, and the detector section includes detectors 112 and 126 each having respective lens 114 and 120.
  • the gas-sample cell 124 shown in FIG. 1 may not necessarily be a self-contained single or multi-pass abso ⁇ tion gas sample cell.
  • the emitted light beam of the laser 116 may traverse a distance in the atmosphere to monitor pollutants, or the Ught beam may traverse a perimeter of a chemical installation to sense the escape of toxic-gases.
  • An optical waveguide surrounded by the gas sample to be detected in accordance with the present invention may be an alternative embodiment of gas-sample cell 124 of the present invention. Since a multi-pass cell is bulky, relatively expensive and, in some cases, has a low throughput, the multi-pass cell may not be preferred for some applications.
  • the total optical throughput after 100 passes may be only 13 %.
  • evanescent wave penetration from the optical waveguide into the surrounding gas sample may be used to sense gas abso ⁇ tion.
  • Evanescent wave penetration from the optical waveguide into the surrounding gas sample may occur when a light beam emitted by laser 116 travels in a medium having higher refractive index than that of the surrounding medium.
  • fused single-mode fiber optic couplers may be very sensitive to the refractive index of the surrounding medium.
  • Single-mode optical fibers may have a core size of approximately 10 ⁇ m when stretched during a fusing process.
  • a fused region then becomes a composite waveguide, formed by cladding and the surrounding medium, with coupling occurring due to mode beating in the fused region.
  • Refractive index and abso ⁇ tion coefficient are related by the Kramers-Kronig dispersion relationship.
  • An optical fiber sensor with a spool of such a waveguide in a container filled with gases (or breath) to be measured may be constructed. If the optical fiber is packed into a relatively small volume, such a sensor may be very efficient and sensitive, and have better performance when compared to a multi-pass abso ⁇ tion gas sample cell.
  • system 100 acquires a breath sample in the following manner.
  • a controller not shown, is employed to coordinate the functions of each device of system 100. Initially, the system is off, and when turned on, pump 128 is initially enabled. First, the system 100 desirably purges the sample cell 124, pipes and other volumes which may contribute to possible contamination of a new breath sample. Once pump 128 is enabled, the controller closes valve VI and opens valve V2, thereby allowing operation of pump 128 to empty the sample cell 124. Once the system 100 is purged, the controller closes V2. The individual breaths into an input orifice 132 to provide a breath-input stream, and valve VI is opened after an initial part of the breath-input stream is discarded through C/N 106.
  • An amount of the initial part is determined by flow meter 104.
  • This initial part of the breath-input stream is desirably discarded to provide a sample having a rich CO content previously resident deep in the patient's lung cavity, known as the alviolar portion of the breath.
  • Opening valve VI causes sample cell 124 to fill with breath sample gas.
  • An individual may take several breaths, and so provide several breath-input streams, for the required amount of breath sample to be collected in sample cell 124. Such additional samples may increase accuracy of the measurement process.
  • valve V2 desirably opens after venting the first portion of each breath to provide a sample having a rich CO content.
  • Filter 102 removes particulates from a breath-input steam, and this filter 102 may be a disposable biological filter.
  • the C/V 106 also prevents back-flow of air into the system since, for any breath-input stream, a portion of the stream during sample collection will pass through the C/V 106.
  • the entire system 100 may be flushed with air or N 2 to eUminate any possible contamination.
  • the system 100 preferably employs a relatively small, commercially available pump that may maintain a vacuum of 50 Torr or less.
  • a pump may be a DAL-5D available from ULVAC Technologies.
  • the valves V2 and VI controlling sample cell pressure and breath flow, respectively, may also be commercially available.
  • the laser section of system 100 includes a semiconductor diode laser for laser 116 desirably operating in the 1.6-3 ⁇ m range. Lasers operating with longer wavelengths may be preferred to increase sensitivity and shorten pathlength of Ught through a sample cell.
  • the laser 116 may be tuned by either changing its operating temperature or electric current to probe 12 CO and l3 C0 2 molecular abso ⁇ tion lines, as described subsequently, and laser 116 may be a distributed feedback (DFB) single-frequency diode laser.
  • DFB distributed feedback
  • laser 116 probes molecular abso ⁇ tion lines of 13 C0 2 and 12 C0 2 at 5000.8570 cm “1 for 1 C0 2 and 5000.4808 cm “1 for 12 CO 2 , since this pair of abso ⁇ tion lines has large spectrum separation of 11.2 GHz, and there is no, or low, interference in the wavevelengths of interest from H 2 0 abso ⁇ tion lines.
  • InGaAs/InP DFB diode lasers have been highly developed for telecommunications, these devices typically operate at wavelengths of 1.3 and 1.55 ⁇ m. which correspond to the spectral locations of minimum loss in siUca fibers. These devices provide Ught power on the order of tens of milliwatts, and their linewidths are generally less than 100 MHz.
  • DFB diode lasers may be constructed that operate at room-temperature in the wavelength interval of 1.2 to 2.0 ⁇ m. However, lasers emitting at longer wavelength are desirable to decrease a pathlength of light passing through a gas sample, which may be required to achieve sufficient sensitivity to monitor H 2 O, CO and C0 2 and CKU.
  • FIG. 2 shows the physical structure of an InGaAs/InGaAsP/InP DFB laser 200 as may be employed in the present invention operating in the near-infrared range at, for example, wavelengths of 1.39, 1.6, and 1.65 ⁇ m. These devices may be formed using metalorganic vapor-phase expitaxy. For these diode lasers, a linewidth of the emitted wavelength may be less than or equal to approximately 10 MHz.
  • n + InP substrate 202 For example, on a 5-cm-diameter n + InP substrate 202, a 1- ⁇ m thick n + InP buffer layer and 1.5- ⁇ m thick n InP cladding layer 204 are grown.
  • the guiding and active layers 208 of the structure are formed with a thickness of approximately 1 ⁇ m on the cladding layer, the guiding and active layers 208 comprising separate-confinement-heterostructure (SCH) having multiple quantum wells (MQW).
  • SCH-MQW structure comprises layers of InGaAsP along with four compressively strained InGaAs or InGaAsP QWs, each QW separated by InGaAsP barrier layers.
  • the compressively-strained InGaAs QWs are employed in 1.6- and 1.65- ⁇ m lasers and InGaAsP QWs are employed in the 1.39- ⁇ m devices.
  • the SCH and barrier layers are of the same composition, having a bandgap of 1 eV for 1.6- and 1.65- ⁇ m lasers and 1.1 eV for 1.39- ⁇ m lasers.
  • 100-nm InP spacer and 100-nm InGaAsP grating layers 210 are grown on top of the guide layers.
  • the wafer is then removed from the growth system and a first-order Bragg grating is fabricated as a grating layer employing, for example, holographic and reactive-ion-beam etching techniques as known in the art.
  • the grating thickness may be about 75 nm, and the grating period, ⁇ , of such laser is determined by the free-space wavelength ⁇ o and the modal refractive index, n e of the laser structure, as in equation (4).
  • the wafer is placed into the growth system, and the InP p cladding layer and InGaAs p+ cap layers 212 are grown.
  • the cladding layers 202 and 212 and the MQW-SCH layers 208 form a dielectric waveguide pe ⁇ endicular to the growth plane. Ridge waveguides 3 to 5 ⁇ m wide may be etched into the wafer as shown in FIG. 2 to provide index-guiding of the optical mode parallel to the growth plane and assure single-spatial-mode output.
  • the optical phase shift upon reflection at the rear facet breaks the symmetry between the two degenerate DFB modes, thereby producing single-mode output.
  • the laser is mounted junction-side (p-side) down on a metal contact.
  • SCH-MQW lasers may also be fabricated in a similar manner using compressively strained, quaternary compounds, such as GalnAsSb, for quantum wells. Such SCH-MQW lasers may be desirable for applications for laser 116 operating with a wavelength between 2- 3 ⁇ m.
  • operation of the laser may be provided through three signals, a temperature control (TEC) signal, low frequency, ramp modulation signal with DC bias (DC & RAMP), and a radio frequency (RF) modulation signal.
  • the TEC signal may be used to tune the diode laser to a certain operating wavelength, as well as to control any variations in operation using calibration information.
  • the DC & RAMP signals are used to scan, or sweep, the operating wavelength of the diode laser about a predefined wavelength range that encompasses the pair of 13 CO 2 and 12 CO 2 abso ⁇ tion Unes.
  • a RF carrier for synchronous detection modulates the laser frequency.
  • a power monitor photodiode (not shown) on the backside of laser 116 may also be included to detect and correct for any long-term laser output power fluctuations.
  • Current-tuning may be employed to scan the output wavelength through the spectroscopic features of the gas. Therefore, it is desirable to increase the current-tuning rate for scanning a large frequency interval with a minimal current change.
  • Increasing the thermal resistance of the heatsink may be employed since a given ramp-current amplitude produces a larger change in junction temperature, and thus a larger increase in the output wavelength. This may be accomplished by mounting the laser p-side up.
  • an increased tuning rate may be effected by adding an amount of alumina of 125 ⁇ m thickness inte ⁇ osed between the diode laser and the copper heatsink of the package.
  • the current-tuning characteristic of a diode laser constructed as shown in FIG. 2 is shown in FIG. 3A.
  • the increase in output wavelength with increased diode laser current indicates a dominant thermal tuning mechanism: increased diode current increases the junction temperature, which increases the modal refractive index and shifts a Bragg resonance condition of the laser to longer wavelengths. Linear thermal expansion of the grating also contributes to the increase in wavelength. This effect is one-tenth that of refractive index changes. However, increased current injects more charge into the SCH- MQW region of the device, reducing the refractive index, and decreasing wavelength with increasing current. Under normal operating conditions, the thermal effect dominates, and the wavelength increases with increasing current and temperature.
  • FIG. 3B shows an output power characteristic of a 1.6- ⁇ m laser used to detect CO and CO 2 .
  • the data were taken at 7.8°C, at which temperature the laser was used to detect CO .
  • the threshold current is 90 mA, and the external quantum efficiency is 23% near threshold. At slightly less than 12mW output the output power saturates and begins to decrease.
  • a diode laser may exhibit both types of current-tuning effects.
  • a negative slope for the curve indicates a predominantly thermal tuning effect, in which the refractive index is increasing current, owing to an increase in the junction temperature.
  • a positive slope indicates that the injected-charge effect predominates. In this case it is the increasing amount of injected charge, which lowers the refractive index, that dominates the current tuning. From these data the temperature-tuning rate at a constant current for an embodiment of the laser shown in FIG. 2 is about 0.13 nm/K.
  • FIG. 4 is a graph showing a ramp signal for current tuning of laser 116 employed to sweep a wavelength of an optical signal provided by the laser 116.
  • the ramp signal applied to the laser 116 may be an asymmetric saw-tooth waveform having peak level P T , and a return pass slope 202 much steeper than that of a forward pass slope 201.
  • This ramp signal allows scanning by the diode laser 116 for spectrum measurement, and for exemplary embodiments of the present invention, Doppler molecular abso ⁇ tion linewidths of CO 2 are in the order of 300 MHz full width/half-maximum, while the separation between 13 C0 2 and I2 C0 2 molecular abso ⁇ tion lines may be greater than 10 GHz.
  • laser 116 may emit having a line width of 10 MHz or less.
  • a modified saw-tooth wave may be employed to improve sensitivity of SNR.
  • Such modified saw-tooth waveform in conjunction with the ramp signal of FIG. 4, may boost either laser DC current or operating temperature in the middle of the scan period. Synchronized with the unmodified saw-tooth waveform as applied to laser 116, laser 116 may change emitting wavelength abruptly after scanning through a first abso ⁇ tion peak.
  • laser 116 begins operating at the starting edge of a second abso ⁇ tion peak while also shrinking a time span between the two abso ⁇ tion peaks.
  • Such modified sweep effectively eliminates the spectrum region between two abso ⁇ tion lines, which has little or no contribution to the determination of the 13 CO 2 to 12 CO 2 ratio.
  • this modification of laser operation of the preferred embodiment may increase observed SNR.
  • lens 118 collimates light emission of the laser 116.
  • Laser colUmating lens 118 may either be provided on an X-Y-Z translation stage or may be attached directly to the mounting of laser 116 to minimize possible instabilities due to pump vibration. Fiber coupUng of the laser 116 may also be employed. Such embodiment may not require mirror 130 or colUmating lens 118.
  • ColUmated light of laser 116 is directed by, for example, optional mirror 130 to beam splitter 132. Beam spUtter 132 provides sample and reference beam signal. The path of the reference beam signal passes through the reference cell 122 filled with a known molecular concentration which may be a known concentration ratio of CO 2 to l2 C0 2 .
  • a controller may calculate calibration information and then adjust operation of the diode laser 116 through, for example, the TEC signal.
  • the path of the sample beam signal passes through the sample cell 124 filled with the breath sample for measuring the molecular concentration ratio directly.
  • all optics may be anti-reflection coated and wedged optical windows to reduce etalon effects that increase noise and reduce stability.
  • all optical paths and optics may be enclosed to minimize effects of stray light, dust and temperature variations.
  • Etlon effects due to imperfection of light transmission from all optics may limit detectability of molecular abso ⁇ tion to the order of 10 "6 .
  • For anti- reflection coatings on a refractive optical component having parallel interfaces some small amount of light may be reflected from each interface. Therefore, an optical cavity may be formed between any pair of such parallel interfaces that generates light interference patterns.
  • Etlon effects may be significant only when an abso ⁇ tion detection limit on the order of 10 _6 or lO "3 is approached.
  • One method of reducing Etlon effects employs wedged optical windows on the multi-pass gas sample cell and replaces all the refractive lenses with reflective optics. While it is relatively easy to use a curved mirror to focus the optical beam to a detector, collimating the light beam of the diode laser with a mirror may be relatively difficult.
  • An off-axis parabola mirror such as that employed by LT Ultra-Precisions- Technology GMBH of Germany, may be used for diode laser light output collimation.
  • Detector 126 provides a reference output signal detected from the optical signal received from the reference beam signal passing through reference cell 122.
  • the reference output signal may be provided to a laser controller (not shown) to ensure that the optical signal from the laser 116 always scans within the spectral band of interest.
  • the optical output signal from the sample cell 124 is provided to detector 112.
  • the output signal of detector 112 is then analyzed to probe molecular abso ⁇ tion Unes.
  • FIG. 5 is a graph showing power of a detected ramp output signal D t from an optical path illustrating the effects of wavelength abso ⁇ tion on a diode laser optical signal by 13 CO and 12 CO content of breath sample.
  • the detected ramp signal experiences a power loss, ⁇ P, from P 0 at point 301.
  • the power loss is caused by CO 2 molecular abso ⁇ tion as molecules are excited as described for the general case previously.
  • ⁇ P/ P 0 at point 301 a power loss, ⁇ P/ P 0 at point 301 is given by ⁇ NL, where ⁇ is a abso ⁇ tion cross section of the particular molecule ( I3 CO 2 or 12 CO ), N is a molecular concentration in a sample, and L is a path length of sample beam signal through the sample cell 124. Since ⁇ and L are known for the system, measuring the molecular abso ⁇ tion lines allows measurement of particular molecular concentrations within the breath sample.
  • FIG. 6 is a block diagram of a synchronous detection system as may be employed with detector 112 to measure molecular abso ⁇ tion of the sample beam signal, O ot , from the sample cell 124 of the exemplary system as shown in FIG. 1.
  • detector 112 provides electrical output signal Di and may include both an optical detector 402 and an ampUfier 404.
  • Optical detector 402 translates received optical power from the sample beam signal, O ot , to an electrical signal, and amplifier 404, which may be a variable-gain, lock-in amplifier to compensate abso ⁇ tion signal differences due to the natural abundance difference of l3 C0 2 and 1 C0 2 , as described subsequently.
  • the output signal Di may be synchronously detected with respect to the second harmonic of the modulation signal applied to the laser 116.
  • This method of synchronous detection improves the SNR.
  • the synchronous detection system includes frequency doubler 408 and synchronous detector 406.
  • the RF modulated DC & RAMP signal provided to laser 116 is also provided to frequency doubler 408.
  • Synchronous detector 406 receives both the doubled RF modulated DC & RAMP signal and the output signal Di. Synchronous detector then provides signal d t that represents the modulation applied to RF modulated DC & RAMP signal by molecular abso ⁇ tion.
  • This modulation signal d t may then be spectrally analyzed to provide relative signal power at given wavelength for the l3 CO 2 and 12 CO molecular abso ⁇ tion Unes.
  • the spectral analysis may be displayed on, for example, a personal computer (PC) or standard LCD or video display (not shown).
  • FIG. 7 is a graph of a spectrometer signal of a detected signal power of a second harmonic signal versus wavelength for two abso ⁇ tion lines as measured by the exemplary system of FIG. 1 and employing a laser emitting with a 2 ⁇ m wavelength.
  • the abso ⁇ tion line of 12 CO 2 at 5000.4808 cm “ ' and 13 CO 2 at 5000.8570 cm “ ' are shown.
  • the sample path length is 1 meter, as measured with pressure of 50 Torr at 23°C.
  • a similar synchronous detection method may be employed as that described for the sample beam signal path.
  • the reference cell may contain a very high concentration of C0 and 12 C0 2 , a variable gain amplifier and/or second harmonic synchronous detection may not be required.
  • the temperature of the breath sample may be brought to within a preferred temperature range for measurement.
  • the breath sample may be warmed using a preheating process of the sample cell 124.
  • temperature regulation may be employed for any temperature sensitive components to increase sensitivity of SNR.
  • the benefits of temperature regulation may possibly be achieved by cooUng the breath sample.
  • the breath-input stream passes through heater 108 to bring to the temperature of a portion of breath sample input to the sample cell 124 to the temperature of the gas in sample cell 124 as provided by heating process of heater 110.
  • FIG. 8 illustrates an exemplary breath sample analysis for 13 C0 2 and 12 CO 2 content of breath samples for two subjects: a first breath content, denoted by square graph points, from a control subject and a second subject's breath content, denoted by circular graph points, from a second subject having ingested 200mg of 13 C-doped sodium bicarbonate.
  • a sensitivity of precisely detecting 0.24% change of 13 CO 2 in a breath sample is desirable for ulcer diagnosis.
  • the wavelength of the diode laser desirably centers on a pair of CO 2 and 'CO 2 lines that are close enough together so that they can both be seen in a single scan of the laser frequency, and the l3 CO line strength should be as close to a maximum as possible. For example, these conditions are met for line pairs at 5000.8570 cm “1 ( 13 CO 2 ) and 5000.4808 cm “1 ( 12 C0 2 ).
  • Selecting a pair of 12 CO 2 and 13 C0 molecular abso ⁇ tion Unes may use one or more of the following selection criteria.
  • linestrength of the molecular abso ⁇ tion lines is desirably as strong as possible;
  • each abso ⁇ tion line is desirably spectrally separated for signal resolution;
  • each abso ⁇ tion Une is located in a clear spectral region that is free of contaminant abso ⁇ tion, such as water vapor abso ⁇ tion;
  • the 12 CO 2 and 13 C0 2 detection signals should be about equal in magnitude for maximum sensitivity and signal-to-noise ratio (SNR); and
  • each abso ⁇ tion Une cross-section should exhibit, at the same time, as similar and as small a temperature dependence as possible.
  • the natural abundance of 13 CO 2 in total CO 2 content of air may typically be about 1%. Consequently, for accurate measurement, a 19 CO 2 abso ⁇ tion line may have an abso ⁇ tion strength that is desirably about two orders of magnitude weaker than that of a paired 13 CO 2 abso ⁇ tion Une in order to provide a comparable abso ⁇ tion for detection.
  • a pair of abso ⁇ tion lines located at 4974.41 cm " ' for 13 CO 2 and 4974.33 cm '1 for 1 C0 2 meets these criteria.
  • a theoretical calculation shows that for this particular pair, the 12 CO 2 Unestrength changes about 2%/°C while the 13 C0 2 linestrength changes about -0.3%/°C.
  • breath sample temperature of the sample cell 124 may be controlled by heaters 108 and 110.
  • FIG. 3 employs as
  • a pair of exemplary molecular abso ⁇ tion Unes suitable for the variable gain detection is located at 5000.8570 cm '1 , linestrength 7.15xl0 -24 cm/mol. ( 13 CO 2 ) and 5000.4808 cm 1 , linestrength 4.77xl0 "22 cm/mol. ( 12 C0 2 ). These molecular abso ⁇ tion Unes are separated by 11.3 GHz.
  • the l CO 2 linestrength derived from the HITRAN Ustings may have 13 CO 2 molecule natural abundance factored in; the actual linestrength for the 13 CO 2 should be in the order of that of 10 " •22 " cm/mol.
  • C0 2 molecules absorb more strongly in longer wavelength. Based on HITRAN Ustings, an improvement in detection sensitivity of two orders of magnitude SNR may be obtained if laser 116 operates at 2.73 ⁇ m.
  • Table 2 lists exemplary abso ⁇ tion sensitivities for C0 2 molecules for laser operating wavelengths of 1.432 m to 2.779 m. As shown in Table 2, the sensitivity increases as diode laser wavelength increases, with corresponding factors of improvement.
  • This increased SNR as a function of increased laser operating wavelength may enable detection of 0.0024% change of 13 CO 2 molecular content in a breath sample when sample cell 124 is a 1 -meter cell.
  • the passlength of sample cell 124 may be reduced if 0.24% change of 13 CO 2 molecular content in a breath sample is required.
  • passlength of sample cell 124 may be reduced to 1 cm while keeping the 0.24% change detectabiUty.
  • HITRAN Ustings are employed to select different pairs of molecular abso ⁇ tion Unes for laser 116 operating at higher wavelengths.

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Abstract

L'invention concerne un système de contrôle (100) d'un gaz à l'état de traces utilisant une diode laser, ce système permettant de mesurer précisément la concentration moléculaire et le rapport de concentration moléculaire d'un gaz à l'état de trace dans un échantillon gazeux. Un système de contrôle particulier permet notamment de mesurer la concentration de 13CO2 et le rapport de 13CO2 à 12CO2 dans un échantillon d'haleine, pour une sensibilité atteignant environ cent parties par milliard. Ce système comprend une partie acquisition d'échantillon, une section cellule, une section laser, et une section détecteur. La section acquisition d'échantillon, qui comprend une pompe (128) et deux soupapes (V1, V2) commandées par un processeur, permet de remplir une cellule d'échantillon (124) avec un échantillon d'haleine à partir d'un flux d'expiration entrant (132), ladite section cellule renfermant ladite cellule d'échantillon qui contient l'échantillon d'haleine destiné à être mesuré pour détecter les concentrations de 13CO2 et de 12CO2, une cellule de référence comprenant un échantillon de gaz de référence présentant une concentration connue de 13CO2 et de 12CO2. La section laser utilise une diode laser à rétroaction répartie (DFB) monofréquence, émettant par exemple entre 2 et 3 micromètres (νm) pour sonder des lignes d'absorption moléculaire de 13CO2 et de 12CO2. Le faisceau de 2 à 3 νm émis depuis cette diode est divisé en un échantillon (124) et un signal à trajet de référence (122), lequel traverse la cellule de référence pour permettre être ensuite calibré après avoir été détecté. Le signal à trajet d'échantillonnage traverse la cellule d'échantillon, toute modulation de l'absorption moléculaire étant détectée dans le même temps. Deux lignes d'absorption de 13CO2 et de 12CO2 sont choisies à partir de ce signal, puis comparées de manière à déterminer les concentrations respectives de 13CO2 et de 12CO2 dans ledit échantillon d'haleine.
PCT/US1999/012044 1998-05-29 1999-05-28 Systeme et procede de detection d'un compose d'haleine a l'aide d'une diode laser WO1999061895A1 (fr)

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AU42242/99A AU4224299A (en) 1998-05-29 1999-05-28 Diode laser-based breath-compound detection system and method

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US8735298P 1998-05-29 1998-05-29
US60/087,352 1998-05-29
US13300798A 1998-08-12 1998-08-12
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DE10020615A1 (de) * 2000-04-27 2001-11-08 Glukomeditech Ag Verfahren zur langzeitstabilen und gut reproduzierbaren spektrometrischen Messung der Konzentrationen der Bestandteile wässriger Lösungen sowie Vorrichtung zur Durchführung dieses Verfahrens
US7300408B2 (en) 2001-08-16 2007-11-27 Isis Innovation Limited Spectroscopic breath analysis
WO2011076803A1 (fr) * 2009-12-24 2011-06-30 Humedics Gmbh Dispositif de mesure et procédé pour analyser un gaz échantillon par spectroscopie d'absorption infrarouge
CN102353634A (zh) * 2011-06-15 2012-02-15 西安毅达信息系统有限公司 烟气气体含量激光在线检测系统的在线标定方法
US8399837B2 (en) 2008-11-19 2013-03-19 Isis Innovation Limited Apparatus for measurement of gas concentrations in breath
CN104568837A (zh) * 2011-11-28 2015-04-29 横河电机株式会社 激光气体分析仪
CN105547970A (zh) * 2015-12-22 2016-05-04 中国科学院苏州生物医学工程技术研究所 一种流式细胞仪激发光源系统及校正方法
WO2016083576A3 (fr) * 2014-11-28 2016-07-21 Argos Messtechnik Gmbh Dispositif d'analyse de gaz, en particulier d'air expiré
CN106969800A (zh) * 2017-05-03 2017-07-21 东南大学 一种利用单条谱线同时测量气体温度和浓度的装置和方法
CN108982413A (zh) * 2018-10-12 2018-12-11 上海禾赛光电科技有限公司 激光气体检测装置及校正方法
CN110308076A (zh) * 2019-06-28 2019-10-08 中国矿业大学 一种自适应的煤泥水沉降速度检测装置及工作方法
CN112957621A (zh) * 2021-02-01 2021-06-15 南京航空航天大学 硼中子俘获治疗定位及呼吸监测系统和应用其的方法
CN114235742A (zh) * 2021-12-17 2022-03-25 中国石油大学(华东) 基于呼吸气体大类标志物复合光谱检测系统及方法

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Cited By (25)

* Cited by examiner, † Cited by third party
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DE10020615C2 (de) * 2000-04-27 2002-02-28 Glukomeditech Ag Verfahren zur langzeitstabilen und gut reproduzierbaren spektrometrischen Messung der Konzentrationen der Bestandteile wässriger Lösungen sowie Vorrichtung zur Durchführung dieses Verfahrens
DE10020615A1 (de) * 2000-04-27 2001-11-08 Glukomeditech Ag Verfahren zur langzeitstabilen und gut reproduzierbaren spektrometrischen Messung der Konzentrationen der Bestandteile wässriger Lösungen sowie Vorrichtung zur Durchführung dieses Verfahrens
US7300408B2 (en) 2001-08-16 2007-11-27 Isis Innovation Limited Spectroscopic breath analysis
US8399837B2 (en) 2008-11-19 2013-03-19 Isis Innovation Limited Apparatus for measurement of gas concentrations in breath
AU2010334907B2 (en) * 2009-12-24 2013-08-29 Humedics Gmbh Measuring device and method for analysing a test gas by means of an infrared absorption spectroscopy
CN102711605A (zh) * 2009-12-24 2012-10-03 休姆迪奇有限责任公司 用于通过红外吸收光谱法来分析试样气体的测量装置和方法
JP2013515950A (ja) * 2009-12-24 2013-05-09 ヒューメディックス ゲーエムベーハー 赤外線吸収分光法により試料ガスを分析する測定装置およびその分析方法
EA022246B1 (ru) * 2009-12-24 2015-11-30 Хумедикс Гмбх Измерительное устройство и метод исследования пробного газа при помощи инфракрасной абсорбционной спектроскопии
WO2011076803A1 (fr) * 2009-12-24 2011-06-30 Humedics Gmbh Dispositif de mesure et procédé pour analyser un gaz échantillon par spectroscopie d'absorption infrarouge
US9541497B2 (en) 2009-12-24 2017-01-10 Humedics Gmbh Measurement device and method for analyzing a sample gas by infrared absorption spectroscopy
CN102353634A (zh) * 2011-06-15 2012-02-15 西安毅达信息系统有限公司 烟气气体含量激光在线检测系统的在线标定方法
US9671333B2 (en) 2011-11-28 2017-06-06 Yokogawa Electric Corporation Laser gas analyzer
CN104568837A (zh) * 2011-11-28 2015-04-29 横河电机株式会社 激光气体分析仪
EP2910927A1 (fr) * 2011-11-28 2015-08-26 Yokogawa Electric Corporation Alayseur de gaz laser
US9347877B2 (en) 2011-11-28 2016-05-24 Yokogawa Electric Corporation Laser gas analyzer
WO2016083576A3 (fr) * 2014-11-28 2016-07-21 Argos Messtechnik Gmbh Dispositif d'analyse de gaz, en particulier d'air expiré
CN105547970A (zh) * 2015-12-22 2016-05-04 中国科学院苏州生物医学工程技术研究所 一种流式细胞仪激发光源系统及校正方法
CN105547970B (zh) * 2015-12-22 2018-09-18 中国科学院苏州生物医学工程技术研究所 一种流式细胞仪激发光源系统及校正方法
CN106969800A (zh) * 2017-05-03 2017-07-21 东南大学 一种利用单条谱线同时测量气体温度和浓度的装置和方法
CN108982413A (zh) * 2018-10-12 2018-12-11 上海禾赛光电科技有限公司 激光气体检测装置及校正方法
CN110308076A (zh) * 2019-06-28 2019-10-08 中国矿业大学 一种自适应的煤泥水沉降速度检测装置及工作方法
CN112957621A (zh) * 2021-02-01 2021-06-15 南京航空航天大学 硼中子俘获治疗定位及呼吸监测系统和应用其的方法
CN112957621B (zh) * 2021-02-01 2022-04-22 南京航空航天大学 硼中子俘获治疗定位及呼吸监测系统和应用其的方法
CN114235742A (zh) * 2021-12-17 2022-03-25 中国石油大学(华东) 基于呼吸气体大类标志物复合光谱检测系统及方法
CN114235742B (zh) * 2021-12-17 2023-07-25 中国石油大学(华东) 基于呼吸气体大类标志物复合光谱检测系统及方法

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