Real-time monitoring of ethane in human breath using mid-infrared cavity leak-out spectroscopy

We report on spectroscopic real-time analysis of ethane traces in exhaled human breath. Ethane is considered the most important volatile marker of free-radical induced lipid peroxidation and cell damage in the human body. Our measurements were carried out by means of mid-infrared cavity leak-out spectroscopy in the 3 μm region, a cw variant of cavity ring-down spectroscopy. The spectrometer is based on a CO overtone laser with tunable microwave sidebands. The resulting system proved to be an unique tool with high sensitivity and selectivity for rapid and precise breath testing. With a 5 s integration time, we achieved a detection limit on the order of 100 parts per trillion ethane in human breath. Thus, sample preconcentration is unnecessary. Time-resolved monitoring of the decaying ethane fraction in breath after smoking a cigarette is demonstrated. Received: 13 March 2001 / Published online: 9 May 2001     

Quantum cascade laser-based integrated cavity output spectroscopy of exhaled nitric oxide

A nitric oxide (NO) sensor employing a thermoelectrically cooled, continuous-wave, distributed feedback quantum cascade laser operating at 5.47 μm (1828 cm^-1) and off-axis integrated cavity output spectroscopy was used to measure NO concentrations in exhaled breath. A minimum measurable concentration (3σ) of 3.6 parts-per-billion by volume (ppbv) of NO with a data-acquisition time of 4 s was demonstrated. Five prepared gas mixtures and 15 exhaled breath samples were measured with both the NO sensor and for intercomparison with a chemiluminescence-based NO analyzer and were found to be in agreement within 0.6 ppbv. Exhaled NO flow-independent parameters, which may provide diagnostic and therapeutic information in respiratory diseases where single-breath measurements are equivocal, were estimated from end-tidal NO concentration measurements collected at various flow rates. The results of this work indicate that a laser-based exhaled NO sensor can be used to measure exhaled nitric oxide at a range of exhalation flow rates to determine flow-independent parameters in human clinical trials. PACS 07.07.Df; 33.20.Ea; 42.62.Fi; 87.80.-y     

Ultra-sensitive mid-infrared cavity leak-out spectroscopy using a cw optical parametric oscillator

We report a portable, all-solid-state, mid-infrared spectrometer for trace-gas analysis. The light source is a continuous-wave optical parametric oscillator based on PPLN and pumped by a Nd:YAG laser at 1064 nm. The generated single-frequency idler output covers the wavelength region between 2.35 and 3.75 μm. With its narrow line width, this light source is suitable for precise trace-gas analysis with very high sensitivity. Using cavity leak-out spectroscopy we achieved a minimum detectable absorption coefficient of 1.2×10^-9 /cm (integration time: 16 s), corresponding, for example, to a detection limit of 300 parts per trillion ethane. This sensitivity and the compact design make this trace-gas analyzer a promising tool for various in situ environmental and medical applications. Received: 19 September 2002 / Published online: 15 November 2002 RID="*" ID="*"Corresponding author. Fax: +49-228/733-474, E-mail: frank.kuehnemann@iap.uni-bonn.de     

Online monitoring of ethane traces in exhaled breath with a difference frequency generation spectrometer

We report a transportable mid-infrared laser cavity leak-out spectrometer for online detection of trace gases. The laser spectrometer is based on continuous-wave difference-frequency generation in the wavelength region around 3 μm. Sensitive spectroscopic trace gas monitoring was achieved using a high-finesse ring-down cavity. For difference-frequency generation, we use a periodically poled lithium niobate (PPLN) crystal, pumped by a Nd:YAG laser (signal wave) and a diode laser (pump wave) with a tapered amplifier. A maximum power of 280 μW near λ=3.3 μm is achieved using a pump power of 180 mW at 807 nm, a signal power of 890 mW at 1064.46 nm, and a 50-mm-long PPLN crystal. The resulting system proved to be a unique tool with high sensitivity and specificity for rapid and precise breath testing. We demonstrate spectroscopic online monitoring of ethane traces in exhaled human breath with a precision of 270 parts per trillion (1σ) and a time resolution of 1 s. PACS 42.62.Be; 42.60.-v; 07.57.Ty     

Portable difference-frequency laser-based cavity leak-out spectrometer for trace-gas analysis

We report a portable mid-infrared spectrometer for trace-gas analysis which is based on an all-solid-state difference-frequency-generation laser. The spectrometer provides in situ absorption path lengths of more than 3 km by means of the cavity leak-out method, a cw variant of the cavity ring-down technique. The design, performance, and application of this spectrometer are presented. The light source utilizes difference-frequency generation in a periodically poled lithium niobate (PPLN) crystal pumped by two single-frequency solid-state lasers. A maximum power of 27 μW in the wavelength region near 3.3 μm is achieved using a pump power of 20 mW at 808 nm, a signal power of 660 mW at 1064 nm, and a 50-mm-long PPLN crystal. This corresponds to a conversion efficiency of 0.42 mW/(W² cm). We demonstrate that this portable laser system is suitable as a light source in a cavity leak-out spectrometer. We achieved a minimum detectable absorption coefficient of 1×10^-8/cm (integration time: 2 s), corresponding, for example, to a detection limit of 1 part per billion ethane. This compact trace-gas analyzer with high sensitivity and specificity is promising for various environmental and medical applications. Received: 8 April 2002 / Revised version: 28 May 2002 / Published online: 21 August 2002 RID="*" ID="*"Corresponding author. Fax: +49-211/811-3121, E-mail: muertz@uni-duesseldorf.de     

Infrared laser-spectroscopic analysis of <Superscript>14</Superscript>NO and <Superscript>15</Superscript>NO in human breath

We report on monitoring of nitric oxide (NO) traces in human breath via infrared cavity leak-out spectroscopy. Using a CO sideband laser near 5 μm wavelength and an optical cavity with two high-reflectivity mirrors (R=99.98%), the minimum detectable absorption is 2×10⁻¹⁰ cm⁻¹ Hz^1/2. This allows for spectroscopic analysis of rare NO isotopologues with unprecedented sensitivity. Application to simultaneous online detection of ¹⁴NO and ¹⁵NO in breath samples collected in the nasal cavity is described for the first time. We achieved a noise-equivalent detection limit of 7 parts per trillion for nasal ¹⁵NO (integration time: 70 s).     

Automatically tunable continuous-wave optical parametric oscillator for high-resolution spectroscopy and sensitive trace-gas detection

We present a high-power (2.75 W), broadly tunable (2.75–3.83 μm) continuous-wave optical parametric oscillator based on MgO-doped periodically poled lithium niobate. Automated tuning of the pump laser, etalon and crystal temperature results in a continuous wavelength coverage up to 450 cm^-1 per poling period at <5×10^-4 cm^-1 resolution. The versatility of the optical parametric oscillator as a coherent light source in trace-gas detection is demonstrated with photoacoustic and cavity ring-down spectroscopy. A 17-cm^-1-wide CO₂ spectrum at 2.8 μm and multi-component gas mixtures of methane, ethane and water in human breath were measured using photoacoustics. Methane (at 3.2 μm) and ethane (at 3.3 μm) were detected using cavity ring-down spectroscopy with detection limits of 0.16 and 0.07 parts per billion by volume, respectively. A recording of ¹²CH₄ and ¹³CH₄ isotopes of methane shows the ability to detect both species simultaneously at similar sensitivities. PACS 42.65.Yj; 42.72.Ai; 42.62.Fi     

Trace-gas sensing in the 3.3-μm region using a diode-based difference-frequency laser photoacoustic system

A compact, diode-based difference-frequency laser system combined with a photoacoustic detection scheme is presented for trace-gas sensing. It features a broad, continuous tuning range (3.2–3.7 μm), a narrow line width (154 MHz), and room-temperature operation, and thus allows numerous gas species to be measured both isolated and in mixtures of different gases. Several trace-gas species of environmental interest were detected, and gas mixtures were analysed. The detection limits are in the low-ppmV range, e.g. 1.3 ppmV for methane, 1.8 ppmV for ethane, and 1.2 ppmV for hydrogen chloride. Received: 10 April 2002 / Revised version: 5 June 2002 / Published online: 12 September 2002 RID="*" ID="*"Corresponding author. Fax: +41-1/633-1077, E-mail: Sigrist@iqe.phys.ethz.ch     

Optical parametric oscillator based off-axis integrated cavity output spectroscopy for rapid chemical sensing

An optical parametric oscillator (OPO), pumped by a fiber-amplified diode laser, is combined with off-axis integrated cavity output spectroscopy (OA-ICOS). The cw OPO (power 1.2 W, tunability 3-4 μm, 5 cm(-1) mode-hop-free tuning) has a tuning speed of 100 THz/s, which is ideal for rapid and sensitive trace gas detection. Combined with OA-ICOS, a detection limit of 50 parts per trillion by volume (1×10(12)) of ethane (C(2)H(6)) in nitrogen was obtained in 0.25s at 2997 cm(-1), corresponding to a noise equivalent absorption sensitivity of 4.8×10(-11) cm(-1) Hz(-1/2). The system demonstrates real-time measurements of methane and water in exhaled human breath.     

A calibration-free ammonia breath sensor using a quantum cascade laser with WMS 2f/1f

The amount of ammonia in exhaled breath has been linked to a variety of adverse medical conditions, including chronic kidney disease (CKD). The development of accurate, reliable breath sensors has the potential to improve medical care. Wavelength modulation spectroscopy with second harmonic normalized by the first harmonic (WMS 2f/1f) is a sensitive technique used in the development of calibration-free sensors. An ammonia gas sensor is designed and developed that uses a quantum cascade laser operating near 1,103.44 cm^?1 and a multi-pass cell with an effective path length of 76.45 m. The sensor has a 7 ppbv detection limit and 5 % total uncertainty for breath measurements. The sensor was successfully used to detect ammonia in exhaled breath and compare healthy patients to patients diagnosed with CKD.     

Noninvasive molecular identification of particulate matter in lungs by Raman microspectrometry

A new method for the analysis of particulate matter in lungs is proposed. It combines the exhaled breath condensate technique and Raman spectroscopy. The sampling method is noninvasive, which is suitable for the detection of occupational exposure to dust. The chemical composition of dust particles is assessed by Raman microspectroscopy. The effectiveness of this method as a means of identifying markers of occupational exposure to mica dust is evaluated. Copyright © 2011 John Wiley & Sons, Ltd.     

Mid-infrared cavity leak-out spectroscopy for ultrasensitive detection of carbonyl sulfide

We present a ringdown absorption spectrometer based on a continuous-wave CO laser in the mid-infrared spectral region near lambda = 5 microm. Using a linear ringdown cavity (length, 0.5 m) with R > = 99.99% mirrors, we observed a noise-equivalent absorption coefficient of 7 x 10(-11) cm(-1) Hz(-1/2). This is 2 orders of magnitude improved compared with previous values. With this setup we studied the spectroscopic detection of carbonyl sulfide (here abbreviated OCS) traces in ambient air and in exhaled breath. We achieved a detection limit of 7 parts in 10(12) (parts per trillion) OCS in ambient air, which is unprecedented and shows great promise for environmental and biomedical applications.     

Resonant photoacoustic simultaneous detection of methane and ethylene by means. of a 1.63-μm diode laser

A compact multi-component trace-gas detector based on the resonant photoacoustic technique and a NIR external cavity diode laser has been developed. It has been characterized using a mixture of ethylene and methane diluted in ambient air. A spectroscopic investigation of combination bands and overtones between 5900 and 6250 cm^-1, obtained with an IR pulsed laser photoacoustic spectrometer, allowed us to find a wavelength region where the 2ν₃ overtone of CH₄ and the ν₅+ν₉ combination band of C₂H₄ show uncongested rotational lines. Using a single-mode scan of the diode laser in this region, around 6150 cm^-1, the sensitivity for the simultaneous detection of ethylene and methane is 8 ppm/mW and 40 ppm/mW respectively. Factors affecting the sensitivity and selectivity of the detection system and possible improvements suitable to reach the sub-ppm detection limit are discussed. Received: 1 August 2001 / Revised version: 28 November 2001 / Published online: 7 February 2002 An erratum to this article is available at .     

Qualitative and quantitative determination of human biomarkers by laser photoacoustic spectroscopy methods

The hypothesis that blood, urine and other body fluids and tissues can be sampled and analyzed to produce clinical information for disease diagnosis or therapy monitoring is the basis of modern clinical diagnosis and medical practice. The analysis of breath air has major advantages because it is a non-invasive method, represents minimal risk to personnel collecting the samples and can be often sampled. Breath air samples from the human subjects were collected using aluminized bags from QuinTron and analyzed using the laser photoacoustic spectroscopy (LPAS) technique. LPAS is used to detect traces of ethylene in breath air resulting from lipid peroxidation in lung epithelium following the radiotherapy and also traces of ammonia from patients subjected to hemodialysis for treatment of renal failure. In the case of patients affected by cancer and treated by external radiotherapy, all measurements were done at 10P(14) CO₂ laser line, where the ethylene absorption coefficient has the largest value (30.4 cm⁻¹ atm⁻¹), whereas for patients affected by renal failure and treated by standard dialysis, all measurements were performed at 9R(30) CO₂ laser line, where the ammonia absorption coefficient has the maximum value of 57 cm⁻¹ atm⁻¹. The levels of ethylene and ammonia in exhaled air, from patients with cancer and renal failure, respectively, were measured and compared with breath air contents from healthy humans. Human gas biomarkers were measured at sub-ppb (parts per billion) concentration sensitivities. It has been demonstrated that LPAS technique will play an important role in the future of exhaled breath air analysis. The key attributes of this technique are sensitivity, selectivity, fast and real time response, as well as its simplicity.     

Widely tunable mode-hop free external cavity quantum cascade laser for high resolution spectroscopic applications

An external cavity (EC) quantum cascade laser (QCL) configuration with the thermoelectrically cooled gain medium fabricated using a bound-to-continuum design and operating in continuous wave at ∼5.2 μm is reported. The EC architecture employs a piezo-activated cavity mode tracking system for mode-hop free operation suitable for high resolution spectroscopic applications and multiple species trace-gas detection. The performance of the EC-QCL exhibits coarse single mode tuning over 35 cm^-1 and a continuous mode-hop free fine tuning range of ∼1.2 cm^-1. PACS 07.07.Df; 42.55.Px; 42.62.Fi; 42.60.Fc     

Simultaneous NO and CO(2) measurement in human breath with a single IV-VI mid-infrared laser

A tunable diode laser absorption spectroscopy (TDLAS) system equipped with a IV-VI mid-IR laser operating near 5.2>mu;m was used to measure exhaled nitric oxide (eNO) and carbon dioxide (CO(2)) simultaneously in human breath over a single exhalation. Breath was sampled in real time, and eNO levels were measured from seven volunteers, two steroid-naive asthmatics and five nonasthmatics. Measured CO(2) levels were used as an internal standard to verify correct breath collection and calculate eNO values. Calculated eNO concentrations agreed well with reported values for asthmatic and nonasthmatic individuals.     

Ultrasensitive laser spectroscopy for breath analysis

At present there are many reasons for seeking new methods and technologies that aim to develop new and more perfect sensors for different chemical compounds. However, the main reasons are safety ensuring and health care. In the paper, recent advances in the human breath analysis by the use of different techniques are presented. We have selected non-invasive ones ensuring detection of pathogenic changes at a molecular level. The presence of certain molecules in the human breath is used as an indicator of a specific disease. Thus, the analysis of the human breath is very useful for health monitoring. We have shown some examples of diseases’ biomarkers and various methods capable of detecting them. Described methods have been divided into non-optical and optical methods. The former ones are the following: gas chromatography, flame ionization detection, mass spectrometry, ion mobility spectrometry, proton transfer reaction mass spectrometry, selected ion flow tube mass spectrometry. In recent twenty years, the optical methods have become more popular, especially the laser techniques. They have a great potential for detection and monitoring of the components in the gas phase. These methods are characterized by high sensitivity and good selectivity. The spectroscopic sensors provide the opportunity to detect specific gases and to measure their concentration either in a sampling place or a remote one. Multipass spectroscopy, cavity ring-down spectroscopy, and photo-acoustic spectroscopy were characterised in the paper as well.     

Methods and instruments of high-resolution transient THz spectroscopy for diagnostics of socially important diseases

The results of spectroscopy of exhaled breath using specially developed THz spectrometers for noninvasive medical diagnostics of diabetes, pre-cancer states, and oncological diseases of the gastrointestinal tract organs, as well as for monitoring the efficiency of radiotherapy from the dynamics of nitrogen oxide content, are presented. The fine structure of DNA spectrum in the range of 300 to 375 GHz is investigated using a high-precision spectrometer composed of a frequency synthesizer (based on a backward-wave oscillator) and a high-Q cavity.     

3.5-μm high-resolution gas sensing employing a LiNbO3 QPM-DFG waveguide module

Diode laser technology coupled with a wavelength-conversion unit to produce mid-infrared narrow bandwidth laser light applicable to trace-gas detection and with the potential for high-resolution spectroscopy is described. Quasi-phase-matched difference-frequency generation (QPM-DFG) in a compact and fibre-coupled periodically poled lithium niobate (PPLN) waveguide module mixing 1063 and 1525-nm radiations has been adopted for generating 34 μW of 3.5-μm wavelength laser light. Optical detection methods, including sensitive wavelength modulation spectroscopy and a rapid wavelength chirp technique, have been employed with a single-pass cell to investigate methane and formaldehyde absorption profiles around 2855 cm⁻¹, as proof of principle experiments for high sensitivity and resolution spectroscopy on atmospherically important molecules.     

Methods of highly sensitive gas analysis of molecular biomarkers in study of exhaled air

The methods of highly sensitive gas analysis of molecular biomarkers in exhaled air were reviewed. Specific features of the analysis of the chemical content of exhaled air at the level of microconcentrations as well as general requirements for the applied instrumental approach were discussed. The experimental data demonstrating a relationship between some light gas molecules and organ pathology and the possibility of using such molecules as biomarkers were reviewed. Basic approaches to highly sensitive gas analysis on the basis of gas chromatography, mass spectroscopy, electrochemical sensors, UV chemiluminescence, and IR spectroscopy were considered from the point of view of their possible application to the analysis of breath content. Characteristics of the spectral gas analysis based on tunable diode lasers were analyzed in details. The possibility of applying diode laser spectroscopy to biomedical diagnostics based on highly sensitive gas analysis of human breath content was discussed.