Laser Photo-Acoustic Spectrometer for Medical Gas-Analysis
hoto-acoustic spectroscopy (PAS) is one of the most intensively developing types of spectroscopy. The method is based on photo-acoustic phenomena primarily discovered by A. Bell in 1880 . The effect consists in appearance of acoustic waves when gas is undergone by electromagnetic radiation modulated at acoustic frequencies in the spectral range from UV to IR and corresponding to the absorption bands of the gas.
Application of photo-acoustic effect for analysis of gas mixtures is simple and reliable. Also it possesses high selectivity and allows obtaining results in real-time. Beside that the method has very large dynamic range for concentration sensitivity. This makes possible detection of gases in concentrations differing in tens of thousand times in one sample.
It was found in first experiments on studying photo-acoustic effect that photo-acoustic signal amplification can be caused by acoustic resonance phenomena . Different variants of photo-acoustic cell design were developed. And efficiency of this method was demonstrated with use of them. But due to absence of convenient components like light sources, microphones and electronic PA phenomena was forgotten for more than a half of a century.
In 1970th and 1980th intensive researches on PA detection of different chemicals took place. In PA systems built on the base of CO and CO2 lasers with output power of several Watts level concentration sensitivity towards the detected gas of few ppbv level and even lower was reached [5–9].
Lasers happened to be the perfect optical radiation sources for PAS:
firstly, some lasers have possibility of wavelength tuning in spectral ranges where absorption lines of different gases locate;
secondly, narrow spectral bandwidth increases selectivity of detection gases whose absorption lines locate closely;
thirdly, lasers provides necessary power level at required spectral range that allow use possibilities of PA effect in full.
For PA detection PA cell is the main primary transformer. That is performed as a cavity in which interaction of the studied gas molecules with optical radiation takes place. The acoustic oscillations appearing in PA cell are registered by microphone installed directly in the cavity. The main features of PA cell like small size, mechanical simplicity, and absence of high mechanical accuracy requirements can be realized fully only with an appropriate laser source.
Nowadays CO2 and CO lasers of about 10 W power level are used in PA experiments. Signal to Noise ratio can be increased by installing PA cell directly into laser resonant cavity in which power up to 100 W can be reached . In spite tunable CO2 lasers are rather big and complex systems they already were used in mobile atmosphere monitoring systems in situ .
Recent progress in diode lasers development lead to creation PA gas analyzers based on them [11, 12]. The power level of the available diode lasers in NIR range operating at room temperature is smaller in comparison with CO2 and CO lasers. Consequently sensitivity of detection is limited by ppm level or for some gases somehow lower. Nevertheless that gives possibility to offer alternative solutions especially when small size, reliability and long life time are needed. One of the main advantages of diode lasers is possibility of modulation output radiation intensity and wavelength. Diode lasers have ability to change the wavelength smoothly but within a narrow range (usually not more than one wavenumber) . Tuning range from 20 to 50 nm can be obtained in a diode laser system with external resonant cavity (ECDL) [14, 15].
Progress in the detection of small concentration of gas was obtained by use of quantum cascade lasers (QCL) and optical parametric oscillators (OPO) for PAS. These laser sources possess wide tuning range of sufficient power with narrow spectral linewidth. Recently appeared QCL’s do not become popular because of their high price and foreign trade restrictions. Optical parametric oscillators are effective coherent radiation sources from UV up to IR and even THz range. The principle of OPO operation is three-wave parametric interaction of light waves within a nonlinear crystal. Such interaction provides tuning wavelength in wide spectral range. OPO output power is higher than diode lasers have. This fact is critical to get sensitivity up to ppb-ppm level. The principle of PA detector operation provides linear response of the system even when the variation of the measured concentrations reaches six orders. That simplifies getting analysis results in real time.
Obtained up to date scientific and technical potential of PAS allows using study results in different spheres of life. In particular, use of PAS in medicine seems to be very perspective especially for screening surveys on prophylaxis and prevention of social significant diseases.
It is known that lungs functions in additional to respiratory are metabolic and excretory functions. Gas chemical compounds formed during the exchange reaction, occurring in the lung tissue and throughout the human body, are released through the lungs. For example, acetone is released in the course of fat oxidative reaction, ammonia and hydrogen sulfide – amino acid exchange, saturated hydrocarbon – during unsaturated fatty acids peroxidation. Change the amount and ratio of substance released during breathing is allowed to deduce about metabolic changes and presence of disease.
For example, alkanes and monomethylated alkanes detection in exhaled air allows diagnosis of lung cancer at an early stage , while the standard screening study at lung tumors (radiography and sputum cytology) do not have a sufficient level of information content . In 1999, during researches by professor Phillips et al. were identified 22 volatile organic compounds (mostly alkanes and benzene derivatives), whose content in the exhaled air was significantly higher at patients with lung cancer . Scientists from Italy (Diana Poli et al., 2005) have shown the possibility of using styrene (molecular mass 10–12 M) and isoprenes (10–9 M) in exhaled air as biomarker of tumor process – the correct diagnosis was confirmed at 80% of patients .
It is ascertained that for bronchial asthma exacerbation is characteristically ammonia concentration increasing in exhaled air 250–300 in time [20, 21]. In different clinical forms of pulmonary tuberculosis has high level of propane (C3H8) in the exhaled air [22, 23]. In the case of chronic nonspecific pulmonary diseases exacerbation in exhaled air appears aldehydes .
Thereby, exhaled air analysis allows detection pathology with some nosological forms, when other diagnostic methods are low-sensitive, nonspecific and uninformative. For example, in the case of bronchial asthma important role are played timely diagnostic. For majority of patients light forms of diseases cannot be detected, and consequently a treatment cannot be provided in time, that influences a disease prognosis. Early detection of bronchial asthma development at children will allow providing treatment with less aggressive therapeutic approach, more safety and get favorable prognosis for a disease up to full recovery.
Exhaled air analysis also allows doing body response monitoring on anti-inflammatory therapy. To date, considerable results of researches of volatile biomarkers for bronchopulmonary diseases in exhaled air are known.
PAS gas analysis in medicine has on specific feature – noninvasive sampling and absence of harmful effect on patient.
Researches of spectral features of exhaled air from patients with different diagnosis were carried out in Siberian State Medical University (Tomsk). PAS method in combination with tunable CO2-lasers developed by Special technologies, Ltd. (Novosibirsk) was used for analysis. Results are shown on the Fig.1.
Samples of exhaled air of four groups of patients were tested. The first group is healthy (control group), second group – pulmonary diseases (COPD, asthma, pneumonia), third group – different diseases (IHD, gastric ulcer, duodenal ulcer), fours group– tuberculosis in different stages.
Absorption spectra were processed by statistic methods and integral estimates 1 and 2 were calculated. These estimates provide defining tuberculosis with specificity over 95%.
Basing on the scientific background obtained in SSMU laser PA spectrometer LaserBreeze was developed in Special technologies, Ltd. LaserBreeze is built on the base of PA and OPO (Patents RF No. 133355, 139181, 85330). LaserBreeze provides measuring concentration of at least 20 biomarkers whose presence in sample correlates with severity of a particular disease (asthma, COPD, pneumonia, acute bronchitis). Measuring biomarker concentration in "Analysis’ mode takes only 2 minutes. The main technical features are shown in Table.
The designed spectrometer consists of Laser Source, Photo-acoustic Detector (PAD) with sample injection unit and Electronic Control Unit. Developed by Special Technologies, Ltd. optical parametrical oscillator (OPO) with wavelength tuning 2.5 10.7 µm is used as Laser Source. This OPO is pumped by Q-switched Nd: YLF laser at 1.053 µm. Extremely wide wavelength tuning range was obtained by using two types of nonlinear elements. Spectral range 2.5 4.5 µm was covered by OPO based on periodically poled MgO doped lithium niobate MgO: PPLN. Using mercury thiogallate crystal as nonlinear element of OPO allows to obtain wavelength tuning range from 4,3 to 10.7 µm. Moreover, in the first case – wavelength tuning is obtained by means of cross linear moving of MgO: PPLN over the pumping beam. In the second case wavelength tuning is provided by rotation of HGS crystal relative to the optical axis. Fig. 2 shows optical scheme of LaserBreeze spectrometer (Nd: YLF laser – pumping laser (wavelength 1,053 µm); FI – Faraday isolator; M1-M4 – mirrors of OPO cavities; M5, M6, M9, M10 – reflecting mirrors; M8 – reflecting mirror placed on motorized translation stage; λ/2 – halfwave plate; L1 – lens; M7 -dichroic mirror; M11 – Brewster plate from ZnSe, PAD – photo-acoustic detector; RS – reference sell filled with special prepared gas mixture; PD – pyroelectric photodetector; PC – personal computer).
Registration of biomarker absorption spectra is carried out by means of resonant PAD. Reference cell is placed in PAD and contains special prepared gas mixture consisting of C3H6O, CH4, N2O, CF4 and SF6. Reference sell is used as spectral reference for absorption spectra analysis.
Sample injection unit provides sample temperature, humidity and pressure measuring, sample injection in to PAD for sample analysis and purging spectrometer pneumatic path with fresh air after analysis.
Pyroelectric detector (PD) is used for measuring OPO power and normalizing the PAD signals. Measured electrical signals from PAD and PD go to the electronic control unit for data processing. Electro-mechanical elements are controlled by the electronic control unit. Processed data are displayed on the screen of PC.
Outer view of LaserBreeze spectrometer is shown on the Fig.3. Spectrometer LaserBreeze operates in 3 modes:
recording of absorption spectra of the sample in all spectral range for further processing by means of mathematical statistic methods, e. g. Principal Component Analysis (PCA). PCA allows discover not evident correlations in large data arrays. Particular in diagnostics PCA allows reliable dividing different groups of patients;
concentration measurements of a set of gases in a sample for detailed analysis of patient’s state;
continuous monitoring of concentration of one compound in real time for treatment efficiency control especially when strong drugs are used.
In conclusion we would notice that for today the developed spectrometer LaserBreeze is a platform for different scientific researches. Such researches can help us to create much simple and not so expensive systems specialized for particular application or diseases.