WO1999061895A1

WO1999061895A1 - Diode laser-based breath-compound detection system and method

Info

Publication number: WO1999061895A1
Application number: PCT/US1999/012044
Authority: WO
Inventors: Yizhong Yu; Ramon U. Martinelli
Original assignee: Sarnoff Corporation
Priority date: 1998-05-29
Filing date: 1999-05-28
Publication date: 1999-12-02
Also published as: AU4224299A

Abstract

A diode laser-based trace-gas monitor system (100) accurately measures molecular content and a ratio of molecular content for a trace-gas in a gas sample. A particular monitoring system measures 13CO2 concentration and ratio of 13CO2 and 12CO2 in a breath sample with a sensitivity of approximately one hundred parts per billion. The system includes a sample acquisition section, a cell section, a laser section and a detector section. The sample acquisition section includes a pump (128) and two valves (V1, V2) under the control of a processor. The sample acquisition section causes a sample cell (124) to be filled with a breath sample from a breath-input stream (132). The cell section includes the sample cell containing the sample of breath to be measured for concentrations of 12CO2 and 13CO2, and a reference cell (122) containing a reference sample of gas having a known concentration of 12CO2 and 13CO2. The laser section employs a distributed-feedback (DFB), single-frequency diode laser emitting at, for example, between 2 to 3 micrometer (νm) to probe molecular absorption lines of 12CO2 and 13CO2. The 2 to 3 νm beam emitted from the laser is split into a sample (124) and a reference path signal. The reference path signal passes through th e reference cell, and then detected for calibration. The sample path signal passes through the sample cell and modulation from molecular absorption is synchronously detected. A pair of 12CO2 and 13CO2 absorption lines is selected from the synchronously detected signal and compared to determine relative compound concentrations of 12CO2 and 13CO2 in the breath sample.

Description

DIODE LASER-BASED BREATH-COMPOUND DETECTION SYSTEM AND

METHOD

This application claims the benefit of the filing date of U.S. provisional application no. 60/087,352, filed on May 29, 1998, as attorney docket no. 1004.005PROV.

The present invention is directed to measuring molecular content, and, more particularly, to a system measuring molecular content employing a diode laser.

BACKGROUND OF THE INVENTION

Many applications, especially in the medical or environmental monitoring fields, require a system which measures molecular content of a gas. For example, a factory may monitor content of toxic gases such as HC1 or H S in emissions. However, 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.

As is known, some types of 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 CO₂ content of a breath sample of the individual after ingesting ¹³C-labeled urea. Other methods measure elevated CO₂ content of a breath sample of the individual after ingesting ¹⁴C -labeled urea, but this method is not employed in practice due to the radioactive level of the ¹⁴C -labeled urea. However, since CO₂ concentration in breath varies from person to person, a diagnosis requires measuring a ratio of

CO₂/ CO of the breath sample to determine the presence of Helicobacter Pylori bacterium infection. Statistical studies show a sensitivity of detecting 0.24% change of ¹³CO on breath is required for ulcer diagnosis. Present systems exist which may measure concentrations of ^I3CO and CO₂ and are usually based on mass spectroscopy. These systems have the disadvantages of being large, complex and expensive, These disadvantages prevent widespread use of these systems in physician's offices, where such infections may be detected and treated early on.

Features of selected gases having absorption spectra in the near-infrared range are listed in Table 1. The first column lists commonly measured molecules including water vapor and the atmospheric gases such as methane (CHt), and carbon dioxide (CO₂). Features of toxic gases, such as CO, HF, HCl, and H₂S, are also shown in Table 1. The second column gives the wavelength, λ, of one of the many absorption Unes arising from overtone transitions among the vibrational, rotational or combination absoφtion bands of the respective molecule. The third and fourth columns list strengths, S, of the absoφtion Unes and the atmospheric pressures- broadened half-widths, γ, of the absoφtion lines, respectively.

TABLE 1

Given the molecular information of columns three and four of Table 1, peak absoφtion cross-sections σ_p, may be calculated by employing equation (1): σ_p = S/(B() [cm²] (1)

For molecular absoφtion by trace-gas quantities, a total absoφtion, A, may then be approximated by employing equation (2): A = σ_pN L (2) where "N" is the trace-gas concentration, and "L" is the pathlength traversed by a laser beam through a sample of trace-gas. Trace-gas monitoring systems may detect a molecular absoφtion on the order of 10^"6, so sensitivity may be given as in equation (3):

C x L = 10⁶ (N/No) 1 = A 10⁶/(OpN_o) = (OpNoV ' [ppm-m] (3) where N₀ = 2.5 10¹ "cm^"3 and is the atmospheric concentration of molecules at 25°C. The fifth column in Table 1 gives the sensitivity of detection, C x L, for each molecule at atmospheric pressure, P = 760 Torr. All of the gases may be detected at the parts per million- meter [ppm-m] level or lower.

Since monitoring of absoφtion spectra may indicate molecular concentration, 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 absoφtion may be determined.

Sensitivity is proportional to the absoφtion pathlength. Extending the absoφtion 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 σ_p, implying choosing the strongest molecular absoφtion lines possible; therefore, a wavelength of the diode laser is desirably matched to the absoφtion line.

Fundamental absoφtion bands of molecules as shown in Table 1 lie within the mid- and far-infrared range, (8 > 2-:m), and absoφtion linestrengths may be as much as four orders of magnitude greater than they are for the overtone transitions in the near-infrared. These fundamental absoφtion lines, however, are accessed by mid-infrared lead-salt diode lasers that operate at cryogenic temperatures. Hence, monitoring trace gases in the mid-infrared achieves increased sensitivity but with considerable increase in system complexity.

SUMMARY OF THE INVENTION

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 absoφtion line of the first molecular type. 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 absoφtion by the molecular type as the light beam passes through the gas sample. Molecular absoφtion of the light beam by the first molecular type is detected with a detector coupled to the sample cell, and the detected molecular absoφtion is related to the content of the first molecular type in the sample cell.

BRIEF DESCRIPTION OF THE DRAWINGS

The aforementioned features and benefits of the invention will be better understood from a consideration of the detailed description which follows taken in conjunction with the accompanying drawings, m which:

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 absoφtion on a diode laser optical signal by ¹³CO₂ and

19 CO content of breath sample;

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 absoφtion lines as measured by the exemplary system of FIG. 1; FIG. 8 shows an exploded view of spectrometer signal versus wavelength for the absoφtion line for ¹³CO₂ as shown in FIG. 7; and

FIG. 9 illustrates a breath analysis for ¹³C0₂ and ¹²CO₂ content of breath samples for two subjects, one subject a control subject and the other subject having ingested 200mg of ¹³C- doped sodium bicarbonate.

DETAILED DESCRIPTION

The present invention relates to a diode laser-based, trace-gas monitoring system and method that accurately measures a ratio of molecular concentration. In accordance with the present invention, 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 absoφtion 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 μm, for example, in order to increase a sensitivity of the trace-gas monitor system for a given path of light through a gas sample.

A preferred embodiment of the present invention relates to a laser-based trace-gas monitoring system and method that accurately measures a ratio of C0₂ and CO₂ concentration, and hence, a relative rise in the ¹³C0₂ 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 (μm) and probing molecular absoφtion Unes of ¹ C0₂ and ¹³CO₂. A pair of ¹²CO₂ and ¹³C0₂ absoφtion Unes is selected and compared to determine relative compound concentrations of ¹²CO and ¹³CO₂ in the breath sample.

As previously described, the absoφtion spectra of many simple gases lie between 1.2 and 2 μm. Consequently, diode lasers may serve as Ught output beam sources in trace-gas monitoring based on laser-absoφtion spectroscopy in accordance with the present invention. Monitoring systems employing longer wavelength lasers of 2-3 μm have increased sensitivity, and so allow for a reduction of size and/or complexity of the monitoring system. In addition, 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 ¹³C0₂ and ¹²CO₂ trace-gases. The human breath contains about 4% CO₂, and about 1% of the C0₂ is the stable, non-radioactive isotope ' CO₂. C0₂ to ¹²C0₂ 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 ¹²CO₂ and ¹³CO , and reference cell 122, which contains a reference sample of gas having a

19 I ' known concentration of C0₂ and C0 . For one exemplary embodiment, the sample cell 124 may be a 3.4-m, multi-pass absoφtion 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 absoφtion gas sample cell. For other embodiments, 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. For example, for a multi-pass cell having pair of mirrors with 98% reflectivity, the total optical throughput after 100 passes may be only 13 %. For an exemplary embodiment of the present invention employing an optical waveguide for gas-sample cell 124, evanescent wave penetration from the optical waveguide into the surrounding gas sample may be used to sense gas absoφtion. 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. For example, 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 μm 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 absoφtion coefficient are related by the Kramers-Kronig dispersion relationship. When a wavelength of the guided wave matches with the resonance absoφtion band of the trace-gases surrounding the coupler, the output of the coupler would be affected due to the change in refractive index. 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 absoφtion gas sample cell.

Returning to FIG. 1, 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. However, for each breath-input stream 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. In a preferred embodiment, the entire system 100 may be flushed with air or N₂ 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. Such 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 μm 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 ¹²CO and ^l3C0₂ molecular absoφtion lines, as described subsequently, and laser 116 may be a distributed feedback (DFB) single-frequency diode laser. In one embodiment of the present invention, laser 116 probes molecular absoφtion lines of ¹³C0₂ and ¹²C0₂ at 5000.8570 cm^"1 for ¹ C0₂ and 5000.4808 cm^"1 for ¹²CO₂, since this pair of absoφtion lines has large spectrum separation of 11.2 GHz, and there is no, or low, interference in the wavevelengths of interest from H₂0 absoφtion lines.

Although InGaAs/InP DFB diode lasers have been highly developed for telecommunications, these devices typically operate at wavelengths of 1.3 and 1.55 μm. 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 μm. 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 H₂O, CO and C0₂ 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 μm. 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.

For example, on a 5-cm-diameter n⁺InP substrate 202, a 1-μm thick n⁺InP buffer layer and 1.5-μm 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 μm on the cladding layer, the guiding and active layers 208 comprising separate-confinement-heterostructure (SCH) having multiple quantum wells (MQW). The 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-μm lasers and InGaAsP QWs are employed in the 1.39-μm devices. The SCH and barrier layers are of the same composition, having a bandgap of 1 eV for 1.6- and 1.65-μm lasers and 1.1 eV for 1.39-μm lasers.

Next, 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, Λ, of such laser is determined by the free-space wavelength λo and the modal refractive index, n_e of the laser structure, as in equation (4).

Λ = λo/(2n_e) (4)

Once the grating layer 210 is formed, 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 peφendicular to the growth plane. Ridge waveguides 3 to 5 μm 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 front and rear facets receive anti-reflection (R_f = 5%) and high-reflection (R_r = 95%) coatings, respectively. The optical phase shift upon reflection at the rear facet breaks the symmetry between the two degenerate DFB modes, thereby producing single-mode output. After facet coating, 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 μm.

Returning to FIG. 1, 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 ¹³CO₂ and ¹²CO₂ absoφtion 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. Also, an increased tuning rate may be effected by adding an amount of alumina of 125 μm thickness inteφosed 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-μm laser used to detect CO and CO₂. 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.

For a 1.6 μm diode laser exhibiting an abrupt change of sign in the tuning rates and at certain current values the slopes of current-tuning curves change sign abruptly. Below these currents the wavenumber decreases with increasing current, so wavelength increases with increasing current; above these currents the wavenumber increases, so wavelength decreases with increasing current. For this case, 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. As shown in FIG. 4, 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 absoφtion linewidths of CO₂ are in the order of 300 MHz full width/half-maximum, while the separation between ¹³C0₂ and ^I2C0₂ molecular absoφtion lines may be greater than 10 GHz. As described previously, laser 116 may emit having a line width of 10 MHz or less.

However, it may be desirable to generate a set of diode laser operating parameters from collected data around molecular absoφtion peaks which minimizes contributions of laser scanning between peaks that do not contribute to the system sensitivity of signal to noise ratio (SNR). In a preferred embodiment of the present invention, 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 absoφtion peak. Then, laser 116 begins operating at the starting edge of a second absoφtion peak while also shrinking a time span between the two absoφtion peaks. Such modified sweep effectively eliminates the spectrum region between two absoφtion lines, which has little or no contribution to the determination of the ¹³CO₂ to ¹²CO₂ ratio. As more data points are collected around the molecular absoφtion lines, this modification of laser operation of the preferred embodiment may increase observed SNR.

Returning to FIG. 1, 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 CO₂ to ^l2C0₂. Using the measured power of the reference beam signal detected after passing through the reference cell 122, a controller, not shown, 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.

To improve performance of specific embodiments, all optics may be anti-reflection coated and wedged optical windows to reduce etalon effects that increase noise and reduce stability. Also, 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 absoφtion 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 absoφtion 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 absoφtion 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 absoφtion on a diode laser optical signal by ¹³CO and ¹²CO content of breath sample. As shown in FIG. 5, the detected ramp signal experiences a power loss, ΔP, from P₀ at point 301. The power loss is caused by CO₂ molecular absoφtion as molecules are excited as described for the general case previously. As is known, a power loss, ΔP/ P₀ at point 301 is given by σNL, where σ is a absoφtion cross section of the particular molecule (^I3CO₂ or ¹²CO ), N is a molecular concentration in a sample, and L is a path length of sample beam signal through the sample cell 124. Since σ and L are known for the system, measuring the molecular absoφtion 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 absoφtion of the sample beam signal, O_ot, from the sample cell 124 of the exemplary system as shown in FIG. 1. For the preferred embodiment of the present invention, 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 absoφtion signal differences due to the natural abundance difference of ^l3C0₂ and ¹ C0₂, 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. As shown in FIG. 6, 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 absoφtion. This modulation signal d_t may then be spectrally analyzed to provide relative signal power at given wavelength for the ^l3CO₂ and ¹²CO molecular absoφtion 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 absoφtion lines as measured by the exemplary system of FIG. 1 and employing a laser emitting with a 2 μm wavelength. The absoφtion line of ¹²CO₂ at 5000.4808 cm^"' and ¹³CO₂ at 5000.8570 cm^"' are shown. For the measured values of FIG. 7, the sample path length is 1 meter, as measured with pressure of 50 Torr at 23°C.

For the detector 126 of FIG. 1 detecting optical power of the reference beam signal from the reference cell 122, a similar synchronous detection method may be employed as that described for the sample beam signal path. However, since the reference cell may contain a very high concentration of C0 and ¹²C0₂, a variable gain amplifier and/or second harmonic synchronous detection may not be required.

To reduce absoφtion line-strength fluctuation due to temperature change, the temperature of the breath sample may be brought to within a preferred temperature range for measurement. For the exemplary embodiment, the breath sample may be warmed using a preheating process of the sample cell 124. Further, temperature regulation may be employed for any temperature sensitive components to increase sensitivity of SNR. In an alternative embodiment, the benefits of temperature regulation may possibly be achieved by cooUng the breath sample. Returning to FIG. 1 , 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.

As described previously, CO₂ content, and the ratio of ¹³C0₂/¹²CO , of a breath sample of the individual changes after ingesting ¹³C-labeled urea. FIG. 8 illustrates an exemplary breath sample analysis for ¹³C0₂ and ¹²CO₂ 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 ¹³C-doped sodium bicarbonate. A sensitivity of precisely detecting 0.24% change of ¹³CO₂ in a breath sample is desirable for ulcer diagnosis. When light of a certain wavelength is emitted and passed through the breath sample of the sample cell 124, ¹³CO₂ and ¹²CO₂ molecules are excited by energy of different light wavelengths. This molecular absoφtion at each wavelength Une may be measured. As wavelength increases, molecular absoφtion increases and so may be easier to detect. As is known, HI RAN Ustings may be used to select molecular absoφtion wavelengths, or lines. HITRAN listings for selecting absoφtion lines as employed in accordance with the exemplary embodiments of the present invention may be found in L.S. Rothman, "The HITRAN Database: 1986 Edition," Appl. Opt. 26, 4058 (1987) which is incoφorated herein by reference.

The wavelength of the diode laser desirably centers on a pair of CO₂ and 'CO₂ lines that are close enough together so that they can both be seen in a single scan of the laser frequency, and the ^l3CO 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 (¹³CO₂) and 5000.4808 cm^"1 (¹²C0₂).

Selecting a pair of ¹²CO₂ and ¹³C0 molecular absoφtion Unes may use one or more of the following selection criteria. First, linestrength of the molecular absoφtion lines is desirably as strong as possible; second, each absoφtion line is desirably spectrally separated for signal resolution; third, each absoφtion Une is located in a clear spectral region that is free of contaminant absoφtion, such as water vapor absoφtion; fourth, the ¹²CO₂ and ¹³C0₂ detection signals should be about equal in magnitude for maximum sensitivity and signal-to-noise ratio (SNR); and fifth, each absoφtion Une cross-section should exhibit, at the same time, as similar and as small a temperature dependence as possible.

For example, the natural abundance of ¹³CO₂ in total CO₂ content of air may typically be about 1%. Consequently, for accurate measurement, a 19 CO₂ absoφtion line may have an absoφtion strength that is desirably about two orders of magnitude weaker than that of a paired ¹³CO₂ absoφtion Une in order to provide a comparable absoφtion for detection. For example, a pair of absoφtion lines located at 4974.41 cm^"' for ¹³CO₂ and 4974.33 cm^'1 for ¹ C0₂ meets these criteria. However, a theoretical calculation shows that for this particular pair, the ¹²CO₂ Unestrength changes about 2%/°C while the ¹³C0₂ linestrength changes about -0.3%/°C. For a preferred embodiment of the present invention at least 0.24% detectability is desirable; however, for this exemplary pair of absoφtion lines, a change of 1°C in a breath sample in sample cell 124 may result in a false measurement. For embodiments in which absoφtion Une pairs are chosen in which each of the pair exhibit different temperature dependency, breath sample temperature of the sample cell 124 may be controlled by heaters 108 and 110.

However, since measurement time may be Umited to a short period, it may be desirable to select a pair of lines whose absoφtion Unestrengths have either similar or low temperature dependencies. Ground state population that, as is known in the art, follows the Boltzmann distribution mainly determines absoφtion Unestrength. Consequently, selecting a pair of Unes with similar temperature dependencies yields a pair of absoφtion lines either corresponding to a ground energy state near 3/2 KT joules or to the same energy ground state. However, if a pair of absoφtion Unes has the same energy ground state, their absoφtion Unestrengths are approximately equal; therefore, selection of a pair of lines that has both two orders of magnitude difference in linestrength and same rate of change with temperature may not be possible.

Consequently, the preferred embodiment of the present invention in FIG. 3 employs as

19 amplifier 404 of the detector 112 a variable-gain ampUfier that attenuates the stronger CO₂ signal, which may be 100-times stronger, during a laser spectral sweep so that both signals have about the same amplitude. A pair of exemplary molecular absoφtion Unes suitable for the variable gain detection is located at 5000.8570 cm^'1, linestrength 7.15xl0^-24 cm/mol. (¹³CO₂ ) and 5000.4808 cm ¹, linestrength 4.77xl0^"22 cm/mol. (¹²C0₂). These molecular absoφtion Unes are separated by 11.3 GHz. The ^l CO₂ linestrength derived from the HITRAN Ustings may have ¹³CO₂ molecule natural abundance factored in; the actual linestrength for the ¹³CO₂ should be in the order of that of 10^" •22 ^" cm/mol.

Further, C0₂ 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 μm. Table 2 lists exemplary absoφtion sensitivities for C0₂ 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.

Table 2

This increased SNR as a function of increased laser operating wavelength may enable detection of 0.0024% change of ¹³CO₂ molecular content in a breath sample when sample cell 124 is a 1 -meter cell. Equivalently, the passlength of sample cell 124 may be reduced if 0.24% change of ¹³CO₂ molecular content in a breath sample is required. For example, passlength of sample cell 124 may be reduced to 1 cm while keeping the 0.24% change detectabiUty. As before, HITRAN Ustings are employed to select different pairs of molecular absoφtion Unes for laser 116 operating at higher wavelengths.

Thus, there is provided a diode laser-based breath-compound detection system and method which measures ratio of ¹³CO2/'²C0₂ concentration in a breath sample. Although the devices are illustrated and described herein with reference to certain specific embodiments, the present invention is nevertheless not intended to be limited to the devices shown. Rather, it is understood that various modifications may be made to the devices by those skilled in the art within the scope and range of equivalents of the claims and without departing from the spirit of the invention.

Claims

What is claimed is: 1. A trace-gas monitoring system for determining a content of a first molecular type comprising: a sample cell adapted to collect a gas sample having the first molecular type; a diode laser coupled to the sample cell and emitting a light beam having a first wavelength and a first spectral width on the order of a wavelength and less than a spectral width of an abso╧åtion line of the first molecular type; and a detector coupled to the sample cell and adapted to detect the molecular abso╧åtion of the light beam by the first molecular type, wherein the light beam is passed from the diode laser, through the gas sample of the sample cell to the detector, the light beam experiencing a molecular abso╧åtion by the molecular type passing through the gas sample, and the detector detects the molecular abso╧åtion of the light beam, the molecular abso╧åtion related to the content of the first molecular type.

2. The invention as recited in claim 1, wherein the gas sample includes a second molecular type, the diode laser emits the light beam having a second wavelength and a second spectral width on the order of the wavelength and less than the spectral width of an abso╧åtion line of the second molecular type, the light beam passing through the gas sample experiences a molecular abso╧åtion by the second molecular type, and the detector is further adapted to detect the molecular abso╧åtion of the light beam by the second molecular type and relates the detected molecular abso╧åtion of the first and second molecular types to a ratio of the content of the first and second molecular types.

3. The invention as recited in claim 2, wherein each gas sample is collected from a breath stream after ingesting a ¹³C-compound and the ratio relates ¹³CO₂ content and ¹²C0₂ content and is used to indicate an ulcer.

4. The invention as recited in claim 2, wherein the light beam of the diode laser is tuned so as to emit at the first and second wavelengths by varying at least one of a current and a temperature of the laser diode.

5. The invention as recited in claim 4, wherein the current signal is further modulated by a carrier, and the detector includes a synchronous detector, the synchronous detector i) converting a detected power of the light beam from the sample cell into a detected current signal, ii) receiving the modulated carrier, and iii) synchronously detecting the molecular abso╧åtion of the first and second molecular types as a second harmonic modulation of the current signal based on the modulated carrier.

6. A method of determining a content of a first molecular type comprising the steps of: a) collecting a gas sample having the first molecular type; b) emitting, by a diode laser, a light beam having a first wavelength and a first spectral width on the order of a wavelength and less than a spectral width of an abso╧åtion line of the first molecular type; c) passing the light beam through the gas sample, the light beam experiencing a molecular abso╧åtion by the first molecular type; d) detecting the molecular abso╧åtion of the light beam by the first molecular type; and e) relating the molecular abso╧åtion of the light beam to the content of the first molecular type.

7. The method as recited in claim 6, wherein the gas sample includes a second molecular type, the method further comprising the steps of: f) emitting, by the diode laser, the light beam having a second wavelength and a second spectral width on the order of the wavelength and the less than spectral width of an abso╧åtion line of the second molecular type; g) passing the light beam through the gas sample, the light beam experiencing a molecular abso╧åtion by the second molecular type; h) detecting the molecular abso╧åtion of the light beam by the second molecular type; and wherein the relating step e) relates a ratio of the molecular abso╧åtion of the first and second molecular types to a ratio of the content of the first and second molecular types.

8. The method as recited in claim 7, wherein the collecting step a) collects each gas sample from a breath stream after ingesting a ¹³C-compound and the ratio relates ^l3CO₂ content and ^l2CO₂ content and is used to indicate an ulcer.

9. The method as recited in claim 7, wherein the emitting steps b) and f) each include the step of varying at least one of a current and a temperature operating the laser diode so as to tune the diode laser to emit the light beam at the first and second wavelengths, respectively.

10. The method as recited in claim 7, further including the step of i) modulating the current signal by a carrier, and the detecting steps d) and h) each further include the steps of 1) converting a detected power of the light beam from the sample cell into a detected current signal, 2) receiving the modulated carrier, and 3) synchronously detecting the molecular abso╧åtion of the first and second molecular types as a second harmonic modulation of the current signal based on the modulated carrier.