Laser spectroscopy for breath analysis : towards clinical implementation

Detection and analysis of volatile compounds in exhaled breath represents an attractive tool for monitoring the metabolic status of a patient and disease diagnosis, since it is non-invasive and fast. Numerous studies have already demonstrated the benefit of breath analysis in clinical settings/applications and encouraged multidisciplinary research to reveal new insights regarding the origins, pathways, and pathophysiological roles of breath components. Many breath analysis methods are currently available to help explore these directions, ranging from mass spectrometry to laser-based spectroscopy and sensor arrays. This review presents an update of the current status of optical methods, using near and mid-infrared sources, for clinical breath gas analysis over the last decade and describes recent technological developments and their applications. The review includes: tunable diode laser absorption spectroscopy, cavity ring-down spectroscopy, integrated cavity output spectroscopy, cavity-enhanced absorption spectroscopy, photoacoustic spectroscopy, quartz-enhanced photoacoustic spectroscopy, and optical frequency comb spectroscopy. A SWOT analysis (strengths, weaknesses, opportunities, and threats) is presented that describes the laser-based techniques within the clinical framework of breath research and their appealing features for clinical use.Peer reviewe

Breath Analysis Using Laser Spectroscopic Techniques: Breath Biomarkers, Spectral Fingerprints, and Detection Limits

Breath analysis, a promising new field of medicine and medical instrumentation, potentially offers noninvasive, real-time, and point-of-care (POC) disease diagnostics and metabolic status monitoring. Numerous breath biomarkers have been detected and quantified so far by using the GC-MS technique. Recent advances in laser spectroscopic techniques and laser sources have driven breath analysis to new heights, moving from laboratory research to commercial reality. Laser spectroscopic detection techniques not only have high-sensitivity and high-selectivity, as equivalently offered by the MS-based techniques, but also have the advantageous features of near real-time response, low instrument costs, and POC function. Of the approximately 35 established breath biomarkers, such as acetone, ammonia, carbon dioxide, ethane, methane, and nitric oxide, 14 species in exhaled human breath have been analyzed by high-sensitivity laser spectroscopic techniques, namely, tunable diode laser absorption spectroscopy (TDLAS), cavity ringdown spectroscopy (CRDS), integrated cavity output spectroscopy (ICOS), cavity enhanced absorption spectroscopy (CEAS), cavity leak-out spectroscopy (CALOS), photoacoustic spectroscopy (PAS), quartz-enhanced photoacoustic spectroscopy (QEPAS), and optical frequency comb cavity-enhanced absorption spectroscopy (OFC-CEAS). Spectral fingerprints of the measured biomarkers span from the UV to the mid-IR spectral regions and the detection limits achieved by the laser techniques range from parts per million to parts per billion levels. Sensors using the laser spectroscopic techniques for a few breath biomarkers, e.g., carbon dioxide, nitric oxide, etc. are commercially available. This review presents an update on the latest developments in laser-based breath analysis

RES-Q-Trace: A Mobile CEAS-Based Demonstrator for Multi-Component Trace Gas Detection in the MIR

Sensitive trace gas detection plays an important role in current challenges occurring in areas such as industrial process control and environmental monitoring. In particular, for medical breath analysis and for the detection of illegal substances, e.g., drugs and explosives, a selective and sensitive detection of trace gases in real-time is required. We report on a compact and transportable multi-component system (RES-Q-Trace) for molecular trace gas detection based on cavity-enhanced techniques in the mid-infrared (MIR). The RES-Q-Trace system can operate four independent continuous wave quantum or interband cascade lasers each combined with an optical cavity. Twice the method of off-axis cavity-enhanced absorption spectroscopy (OA-CEAS) was used, twice the method of optical feedback cavity-enhanced absorption spectroscopy (OF-CEAS), respectively. Multi-functional software has been implemented (i) for the general system control; (ii) to drive the four different laser sources and (iii) to analyze the detector signals for concentration determination of several molecular species. For the validation of the versatility and the performance of the RES-Q-Trace instrument the species NO, N2O, CH4, C2H4 and C3H6O, with relevance in the fields of breath gas analysis and the detection of explosives have been monitored in the MIR with detection limits at atmospheric pressure in the ppb and ppt range

Optical techniques for breath analysis : from single to multi-species detection

Optical spectroscopy can be used for trace-level gas analysis in different applications, including exhaled breath research. A common approach is the targeted on-line, real-time analysis of small molecules (two to five atoms). Currently, the methodology is normally used for the detection of single analytes at trace levels, or two to three species at most at the same time. The main limitation preventing sensitive multi-species detection has been the limited fast scanning range of the lasers used as light sources. This limitation is currently being eliminated by the availability of optical frequency combs (OFC) which offer wide spectral bandwidths and the benefits of a laser-type light source. Recent advances in mid-infrared OFC technology allow measurements in the so-called molecular fingerprint region of the electromagnetic spectrum, where many molecules have strong fundamental vibrational transitions that enable sensitive detection. Several technical hurdles remain to be overcome, but if these problems can be solved laser absorption spectroscopy has the potential to challenge mass spectrometry in on-line multi-species trace gas analysis.Peer reviewe

Laser Spectroscopy for Atmospheric and Environmental Sensing

Lasers and laser spectroscopic techniques have been extensively used in several applications since their advent, and the subject has been reviewed extensively in the last several decades. This review is focused on three areas of laser spectroscopic applications in atmospheric and environmental sensing; namely laser-induced fluorescence (LIF), cavity ring-down spectroscopy (CRDS), and photoluminescence (PL) techniques used in the detection of solids, liquids, aerosols, trace gases, and volatile organic compounds (VOCs)

Photonic Technology for Precision Metrology

Photonics has had a decisive influence on recent scientific and technological achievements. It includes aspects of photon generation and photon–matter interaction. Although it finds many applications in the whole optical range of the wavelengths, most solutions operate in the visible and infrared range. Since the invention of the laser, a source of highly coherent optical radiation, optical measurements have become the perfect tool for highly precise and accurate measurements. Such measurements have the additional advantages of requiring no contact and a fast rate suitable for in-process metrology. However, their extreme precision is ultimately limited by, e.g., the noise of both lasers and photodetectors. The Special Issue of the Applied Science is devoted to the cutting-edge uses of optical sources, detectors, and optoelectronics systems in numerous fields of science and technology (e.g., industry, environment, healthcare, telecommunication, security, and space). The aim is to provide detail on state-of-the-art photonic technology for precision metrology and identify future developmental directions. This issue focuses on metrology principles and measurement instrumentation in optical technology to solve challenging engineering problems

Pengembangan Sistem Deteksi Gas CO Berkepekaan Tinggi Pada Gas Kelumit Bertekanan Rendah Berbasis Spektroskopi ICOS

Gas hembus pernapasan manusia memilki banyak gas, salah satunya gas karbon monoksida (CO), yang dapat berfungsi sebagai biomarker penyakit tertentu atau tingkat kesehatan seseorang. Telah dikembangkan dalam penelitian ini detektor gas hembus yang memiliki kepekaan dan akurasi yang tinggi serta mampu mendeteksi gas cuplikan dalam tekanan rendah untuk keperluan tersebut. Sistem deteksi berbasis teknik spektroskopi off-axis ICOS (Integrated Cavity Output Spectroscopy) yang dikombinasikan dengan laser QCL (Quantum Cascade Laser) sebagai sumber radiasi telah dikembangkan dalam penelitian ini. Laser QCL dengan panjang gelombang laser sebesar 4610 nm, yang merupakan hasil simulasi yang telah dilakukan sebelumnya, digunakan sebagai sumber radiasi. Sel ICOS dengan panjang 15 cm yang dilengkapi dengan cermin high-finesse diaplikasikan sebagai sel gas cuplikan pada pengukuran gas hembus pernafasan manusia. Sel ini juga berfungsi sebagai rongga resonator untuk meningkatkan kebolehjadian serapan dengan lintasan optik efektif mencapai 400 m. Penelitian telah melalui tahapan persiapan dan konfigurasi sistem, setup dan optimalisasi off-axis ICOS, kalibrasi pengukuran konsentrasi, dan ujicoba pengukuran pada konsentrasi gas kelumit sebesar 2 ppmv, 1 ppmv, dan 0,24 ppmv. Hasil pengujian memperlihatkan bahwa batas deteksi sebesar 1 ppbv dalam waktu akuisisi kurang dari 2 detik telah berhasil dicapai. Batas deteksi terbaik diperoleh sebesar 0,2 ppbv dengan waktu akuisisi sebesar 62 detik. Hasil yang diperoleh memperlihatkan sistem deteksi berbasis ICOS ini telah optimal dan mencapai performa yang diharapkan

PCF-Based Cavity Enhanced Spectroscopic Sensors for Simultaneous Multicomponent Trace Gas Analysis

A multiwavelength, multicomponent CRDS gas sensor operating on the basis of a compact photonic crystal fibre supercontinuum light source has been constructed. It features a simple design encompassing one radiation source, one cavity and one detection unit (a spectrograph with a fitted ICCD camera) that are common for all wavelengths. Multicomponent detection capability of the device is demonstrated by simultaneous measurements of the absorption spectra of molecular oxygen (spin-forbidden b-X branch) and water vapor (polyads 4v, 4v + δ) in ambient atmospheric air. Issues related to multimodal cavity excitation, as well as to obtaining the best signal-to-noise ratio are discussed together with methods for their practical resolution based on operating the cavity in a “quasi continuum” mode and setting long camera gate widths, respectively. A comprehensive review of multiwavelength CRDS techniques is also given

Absolute laserspektrometrische Stoffmengenanteilmessungen: Möglichkeiten für rückführbare Atemanalytik

Laser spectroscopic techniques such as tunable diode laser absorption spectroscopy (TDLAS), quantum cascade laser absorption spectroscopy (QCLAS) and cavity ring down spectroscopy (CDRS) have been shown to be capable of performing absolute amount fraction measurements of gas species such as CO2 and CO. These techniques have been proven to be very sensitive, selective and have real-time responses. The aim of this work was to: perform absolute amount fraction measurements of breath gas species using TDLAS, QCLAS and CRDS, reliably quantify breath gas species, address metrological data quality objectives, i.e. uncertainty and traceability issues, as well as define and reduce the uncertainty of amount fraction results from the typical 10 % to levels suitable to fit breath analysis purposes, 5 % and below. Thus, aiming at traceable amount fraction results, measurements have been performed using TDLAS, QCLAS and CRDS based on the absolute method TILSAM. GUM compliant uncertainty budgets for spectrometric amount fraction results were developed. TDLAS in combination with single-pass and multipass gas cells has been used to perform absolute measurements of the CO2 amount fractions. To check the TDL spectrometer for its feasibility for absolute amount fraction measurements and to be operated on the basis of the TILSAM method, gravimetric gas mixtures of CO2 in the range of 20 to 60 mmol•mol-1 were quantified. At the 50 mmol•mol-1 level (exhaled breath level) the relative standard uncertainties of the spectrometric CO2 amount fraction results are in the ±0.7 % range. The intra-pulse mode QCLAS has been utilized to measure absolute CO amount fractions at the 100 µmol•mol-1 and 1000 µmol•mol-1 levels based on the TILSAM method. Although, not at the exhaled breath level of 1-3 µmol•mol-1, the feasibility of intra-pulse mode QCLAS for CO measurements has been shown. The standard uncertainty of the CO amount fraction results, limited by the uncertainties of the line strengths used which were in the range of 2-5 % relative, are in the range of ±2.3 % relative. A CRDS spectrometer has been used to carry out absolute CO2 amount fraction measurements referring to the TILSAM method. The spectrometric results were in good agreement with the respective gravimetric reference values. The standard uncertainties of the CO2 amount fraction results, also limited by the uncertainty of the used line strength, were in the range of ±2.1 % relative. In a separate measurement, it has been shown in coperation with other partners that CO amount fractions in the nmol•mol-1 levels can be quantified using CRDS. It has been found that the TILSAM method suffers from the unavailability of traceable line data. Thus, line strengths and broadening coefficients of CO2 in the ro-vibrational band around 2 µm have been measured. The derived line data are in agreement to a high degree with published data. Compared to literature, improved GUM compliant standard uncertainties in the ±0.6 % range for the measured line strengths have been reported. The validity of the absolute method, TILSAM, has been further proven in a measurement campaign. The TDLAS-based quantifications were performed on CO2 at the 300 and 500 µmol•mol-1 level. The spectrometric results from the different laboratories were in good agreement, expressed by a degree of equivalence being in the 1 % range, with the respective comparison reference values (CRVs).Laserbasierte Spektroskopietechniken, wie z.B. die abstimmbare Diodenlaser-Absorptionsspektroskopie (TDLAS), die Quantenkaskadenlaser-Absorptionsspektroskopie (QCLAS) oder die "Cavity Ring-Down" Spektroskopie (CRDS) haben gezeigt, dass sie in der Lage sind, absolute Gaskonzentrationen von molekularen Spezies wie CO2 oder CO zu messen. Diese Laser-basierten Techniken sind sehr nachweisempfindlich, selektiv und können in „Real-Time-Response“ arbeiten. Das Ziel dieser Arbeit war es, absolute Stoffmengenanteile von Molekülspezies in Gasgemischen mit Hilfe von TDLAS, QCLAS und CRDS zu messen, zuverlässig zu quantifizieren und dabei messtechnische Datenqualitätsmerkmale, wie Messunsicherheit und Rückführbarkeit zu adressieren. Hintergrund für die Aufgabenstellung war es, die Anwendung dieser Spektroskopietechniken und der entwickelten Analyseverfahren in der Atemanalytik vorzubereiten. Messunsicherheiten sollten hierzu definiert und ggf. verringert werden. Die Unsicherheit der bestimmten Stoffmengenanteile konnte dabei von typischen 10% auf ein Niveau von 5 % und weniger reduziert werden, was für Atemanalysezwecke ausreichend ist. Die mittels TDLAS, QCLAS und CRDS ausgeführte Stoffmengenanteilsbestimmung basierte auf der sog. TILSAM-Methode. GUM-konforme Unsicherheitsbudgets für spektrometrische Stoffmengenanteilsmessungen wurden entwickelt. Um absolute Messungen von CO2 Stoffmengeanteile durchführen zu können, wurden Single-Pass- und Multi-Pass-Gaszellen in Kombination mit TDLAS verwendet. Zur Überprüfung des Einsatzes des TDLAS-Spektrometers für die Machbarkeit von absoluten Stoffmengenanteilsmessungen, die auf der Grundlage des TILSAM-Verfahrens durchgeführt werden, wurden gravimetrisch hergestellte Gasgemische von CO2 in Stickstoff im Bereich von 20 bis 60 mmol•mol-1 CO2 quantifiziert. Auf der 50 mmol•mol-1 Ebene (Atemluftkonzentration) konnte eine relative Standardmessunsicherheit der spektrometrischen CO2-Bestimmung von ± 0,7% demonstriert werden. Intrapuls-QCLAS wurde verwendet, um absolute CO-Konzentrationen im Bereich von 100 µmol•mol-1 bis 1000 µmol•mol-1 gemäß der TILSAM-Methode zu messen. Damit konnte die Machbarkeit der Intrapuls-QCLAS für absolute CO-Stoffmengenmessungen gezeigt werden. Die relative Standardmessunsicherheit der bestimmten CO-Stoffmengenanteile ist durch die Unsicherheiten der Eingangsgröße Linienstärke limitiert, die mit 2-5% spezifiziert waren, und lag damit im Bereich von ± 2.3%. Die Güte der spektrometrisch mit TDLAS und QCLAS bestimmten Stoffmengenanteile wurde anhand eines Vergleiches mit jeweiligen gravimetrischen Referenzwerten bestimmt. Darüber hinaus wurde auch ein CRDS-Spektrometer zur Durchführung absoluter CO2-Stoffmengenanteilsmessungen auf Basis der TILSAM-Methode eingesetzt. Die spektrometrisch erzielten Ergebnisse waren in guter Übereinstimmung mit den jeweiligen gravimetrischen Referenzwerten. Die relative Standardmessunsicherheit der CO2-Stoffmengenanteile wurde ebenfalls durch die Unsicherheit der verwendeten Linienstärke beschränkt, und lag im Bereich von ±2,1%. Da bekannt war, dass die Anwendung der TILSAM-Methode durch die Nichtverfügbarkeit von rückgeführten Spektralliniendaten, wie die Linienstärke, beschränkt ist, wurden Linienstärken und Verbreiterungskoeffizienten von CO2 auch im Rahmen dieser Arbeit bestimmt. Dafür wurden Absorptionslinien im ro-vibronischen Kombinationsschwingungsband von CO2 um 2 µm ausgewählt. Die so abgeleiteten Liniendaten stimmen zu einem hohen Grad mit den veröffentlichten Literaturdaten überein. Im Vergleich zu diesen werden die im Rahmen dieser Arbeit ermittelten Daten aber mit einem GUM-konformen Unsicherheitsbudget angegeben. Die entsprechenden Standardmessunsicherheiten der Linienstärken liegen dabei im Bereich von ± 0,6%. Die in dieser Arbeit weiterentwickelte TILSAM-Methode konnte darüber hinaus in einer internationalen Messkampagne eingesetzt werden. Die TDLAS-basierte Quantifizierung von CO2 wurde bei 300 und 500 µmol•mol-1 durchgeführt. Die spektrometrisch erzielten Ergebnisse aus den verschiedenen Labors waren in guter Übereinstimmung mit dem Referenzwert, ausgedrückt durch einen Grad der Übereinstimmung (Degree-of-Equivalence) im Bereich von 1%

Portable spectroscopy system for ultra-sensitive, real-time measurement of breath ethane

This thesis describes the development, characterisation and application of a portable spectroscopy system for ultra-sensitive, real-time detection of breath ethane. In healthcare, breath ethane is a widely accepted marker of free radical-induced cell damage and may be used to indicate changes in oxidative stress. The aim was to deliver a compact instrument capable of long-term, on-site use in a clinical environment, while also retaining the high performance previously achieved by lab-based systems at the University of Glasgow. The newly developed instrument has a sensitivity of 70 parts per trillion with a 1 Hz sampling rate. The system incorporates a cryogenicallycooled lead-salt laser and uses a second derivative wavelength modulation detection scheme. A thermally-managed closed-loop refrigeration system has eliminated the need for liquid coolants. The instrument has been field-tested to ensure target performance is sustained in a range of environments, both indoor and outdoor. It has since been used in a number of pilot clinical studies, both off-site and on-site, in which breath ethane was monitored as a marker of oxidative stress. The three main clinical areas investigated were dialysis, radiotherapy and intensive care. In the intensive care study, the instrument was modified to enable automatic breath sampling of inspired and expired gases of ventilated patients. This technique proved highly successful and the instrument then remained at the Southern General hospital, where it continued to be used as part of a wider study into breath ethane in intensive care patients. The use of the new spectroscopy system has enabled ultra-sensitive, rapid analysis of a large number of breath samples. The use of the new instrument, in particular for continual breath monitoring, has enabled the detection of short-lived fluctuations in breath ethane, yielding some interesting findings in a number of pilot clinical studies. Our results suggest that breath ethane may be used as an indicator of dynamic changes in oxidative stress. Further studies will be required to determine if such monitoring is of clinical benefit. Chapter 1 gives a general introduction to spectroscopy and some background to our project. A number of spectroscopic techniques and laser sources are discussed, along with a review of previous work in ethane detection. In chapter 2 some background theory of molecular spectroscopy is given, with a more detailed discussion of the wavelength modulation technique. Chapter 3 describes in detail the development of the portable spectroscopy system. The achieved performance and factors contributing to this performance are discussed in chapter 4. The field test of the instrument is reported on in chapter 5. In chapter 6 the application of the technology to breath analysis and the current challenges in this field are discussed. Example breath ethane measurements for healthy controls are provided. The clinical pilot studies conducted using the new system in areas of dialysis, intensive care and radiotherapy are discussed in chapters 7, 8, and 9 respectively. Chapter 10 contains the thesis summary and conclusions, with suggestions for future work