Development of Quantum-Cascade Laser Based Biosensor Technolog

University of Houston • University of Houston-Clear Lake • ISSO Annual Report Y2006 • 85-87

Thomas L. Harman

ABSTRACT—Researchers are developing new types of sensitive, selective, real-time gas sensors based on continuous wave and pulsed quantum cascade lasers for various chemical sensing applications, such as medical diagnostics, environmental monitoring, and industrial process control. Tunable laser absorption spectroscopy in the mid-infrared spectral region is a sensitive analytical technique for trace gas quantification. During the past year a nitric oxide (NO) gas sensor was developed based on a novel thermoelectrically cooled, continuous wave, distributed feedback quantum cascade lasers operating at 5.45 mm (1835 cm^-1) and 5.22 mm (1916 cm^-1), and off-axis integrated cavity output spectroscopy (OA-ICOS) combined with a wavelength modulation technique. Its purpose is to determine NO concentrations at the sub-ppbv levels that are essential for such applications. The sensor employs a 50 cm long high-finesse optical cavity that provides an effective pathlength of ~ 700 m. Research efforts achieved a noise equivalent (SNR = 1) minimum detection limit of 0.4 ppbv with a 1 second observation time.

The development of compact optical sensors for nitric oxide detection is of interest for a number of applications, such as environmental monitoring,¹ atmospheric chemistry,² industrial process control,³ combustion studies,⁴ and medical diagnostics.^5,6 NO is involved in many vital physiological processes in the human body. For example, an elevated level of NO in exhaled breath is correlated with airway inflammation in asthmatic patients. Knowledge of NO concentrations in the exhaled breath of these patients may allow health care providers to adjust therapeutic drug dosages.^7,8 For medical diagnostics purposes, it is essential to time-resolve the NO concentration as a function of a breath cycle phase, because the corresponding air samples originate in the different parts of the respiratory tract. This application requires a sensor response time of £1 second and a NO minimum detection sensitivity of < 1 ppbv. Such high sensitivity, rapid response measurements are possible with laser absorption spectroscopy in the fundamental absorption band of NO.

Distributed feedback quantum cascade lasers (DFB QCLs) operating in a pulsed or continuous wave (CW) mode are promising spectroscopic sources because of their narrow linewidths, single mode operation, tunability, output power, reliability, and compactness. Until recently, CW operation of QCLs was possible only at cryogenic temperatures, and room temperature (RT) operation was realized only with pulsed operation at a low duty cycle, but recent developments in QCL technology now permit CW operation at room temperature or temperatures which can be obtained by thermoelectric cooling.^9,10

Goals of the project
In this research, we utilize a novel and now commercially available TEC, CW, DFB quantum cascade laser fabricated by our collaborating team from the University of Neuchatel, Switzerland.⁹ The DFB CW QCL characteristics, such as a narrow laser spectral width (£3 MHz,¹¹ necessary for efficient laser to cavity coupling and high average power, make CW TEC QC lasers more suitable than pulsed QCLs for ICOS-based sensor platforms for real world applications. These systems avoid the size and complications of liquid nitrogen cooling required by earlier QC lasers. The basic sensor platform is an OA-ICOS configuration with a 50 cm long optical cavity. A wavelength modulation technique (harmonic detection) was implemented in order to reach sub-ppbv levels of NO detection sensitivity.

Results
Exhaled nitric oxide (NO) is an important biomarker in asthma and other respiratory disorders. We studied the optical performance of a NO/CO₂ QCL-based sensor employing integrated cavity output spectroscopy capable of real-time NO and CO₂ measurements in a single breath cycle. Furthermore, the off axis ICOS sensor performance was compared to a chemiluminescent NO analyzer and a non-dispersive infrared (NDIR) CO₂ absorption capnograph. Differences between the gas analyzers were assessed by the Bland-Altman method to estimate the expected variability between the gas sensors. The OA-ICOS sensor measurements were in good agreement with the data acquired with the two commercial gas analyzers. The sensor had a noise-equivalent sensitivity (1Û) for NO of 0.4 ppbv with a 1-s averaging time. Potential improvements to the ICOS sensor include incorporating higher reflectivity mirrors and utilizing the stronger NO absorption line at 1900 cm^-1. This work demonstrates the performance characteristics and merits of mid-infrared spectroscopy for exhaled breath analysis.

References
¹D. D. Nelson, J. H. Shorter, J. B. McManus, and M. S. Zahniser, "Sub-Part-per-Billion Detection of Nitric Oxide in Air Using a Thermoelectrically Cooled Mid-Infrared Quantum Cascade Laser Spectrometer," Appl. Phys. B, 75 (2002): 343.
²J. H. Steinfeld and S. N. Pandis, Atmospheric Chemistry and Physics: from Air Pollution to Climate Change. New York: Wiley 1998.
³G. Wysocki, A. A. Kosterev, and F. K. Tittel, "Spectroscopic Trace-Gas Sensor with Rapidly Scanned Wavelengths of a Pulsed Quantum Cascade Laser for in situ NO Monitoring of Industrial Exhaust Systems," Appl. Phys. B, 80 (2005): 617.
⁴H. Gupta and L.-S. Fan, "Reduction of Nitric Oxide from Combustion Flue Gas by Bituminous Coal Char in the Presence of Oxygen," Ind. Eng. Chem. Res. 42 (2003): 2536.
⁵C. Roller, K. Namjou, J. D. Jeffers, W. Potter, P. J. McCann, and J. Grego, "Simultaneous NO and CO₂ Measurement in Human Breath with a Single IV-VI Mid-Infrared Laser," Opt. Lett. 27 (2002): 107.
⁶C. Roller, K. Namjou, J. D. Jeffers, M. Camp, A. Mock, P. J. McCann, and J. Grego, "Nitric Oxide Breath testing by Tunable-Diode Laser Absorption Spectroscopy: Application in Monitoring Respiratory Inflammation," Appl. Opt. 41 (2002): 6018.
⁷"Breath Analysis for Clinical Diagnosis and Therapeutic Monitoring," ed. A. Amann and D. Smith. World Scientific, Singapore, (2005): 575-84.
⁸A. D. Smith, D. R. Taylor, "Is Exhaled Nitric Oxide Measurement a Useful Clinical Test in Asthma?" Current Opinion in Allergy and Clinical Immunology 5 (2005): 49.
⁹S. Blaser, D. A. Yarekha, L. Hvozdara, Y Bonetti, A. Miller, M. Giovannini, and J. Faist, "Room-Temperature, Continuous-Wave, Single Mode Quantum-Cascade Lasers at 5.4 mm," Appl. Phys. Lett., 86, (2005): 041109-1.
¹⁰S. Blaser, Y. Bonetti, L. Hvozdara, and A. Mueller (Alpes Laser, Neuchatel, Switzerland), "Quantum-Cascade Lasers for TDLS," 5th International Conference on Tunable Diode Laser Spectroscopy, July 11-15, 2005, Florence, Italy.
¹¹A. A. Kosterev, A. L. Malinovsky, F. K. Tittel, C. Gmachl, F. Capasso, D. L. Sivco, J. N. Baillargeon, A. L. Hutchinson, and A. Y. Cho, "Cavity Ringdown Spectroscopic Detection of Nitric Oxide with Continuous-Wave Quantum-Cascade Laser," Appl. Opt. 40 (2001): 5522.

Publications
Bakhirkin, Y., A. A. Kosterev, R. Curl, F. K. Tittel, D. A. Yarekha, L. Hvozdara, M. Giovannini, and J. Faist. "Sub-ppbv Nitric Oxide Concentration Measurements Using CW Room-Temperature Quantum Cascade Laser-Based Integrated Cavity Spectroscopy," Appl.Phys. B 82 (2006): 149-54.
McCurdy M., Y. A. Bakhirkin, and F. K. Tittel. "Quantum Cascade Laser-Based Integrated Cavity Output Spectroscopy of Exhaled Nitric Oxide," Applied Physics B 85 (2006): 445-52.
McCurdy, M., Y. Bakhirkin, G. Wysocki, and F. K. Tittel. "Performance of an Exhaled Nitric Oxide and Carbon Dioxide Sensor Using Quantum Cascade Laser-Based Integrated Cavity Output Spectroscopy," J. of Biomedical Optics (November 2006). (Submitted.)
Miller, J. H., Y. A. Bakhirkin, T. Ajtai, F. K. Tittel, C. J. Hill, and R. Q. Yang. "Detection Of Formaldehyde Using Off-Axis Integrated Cavity Output Spectroscopy with an Interband Cascade Laser," Applied Physics B 85 (2006): 391-96.
Tittel, F. K., Y. Bakhirkin, A. Kosterev, and G. Wysocki. "Recent Advances in Trace Gas Detection Using Quantum and Interband Cascade Lasers," The Review of Laser Engineering 34 (2006): 275-82.
Tittel, F. K., Y. A Bakhirkin, R. F. Curl, A. A. Kosterev, M. M. McCurdy, S. G. So, and G. Wysocki. "Laser-Based Chemical Sensor Technology: Recent Advances and Applications," Advanced Environmental Monitoring. Berlin: Springer Verlag, 2006. (Accepted.)
Tittel, F. K., G. Wysocki, A. Kosterev, and Y. Bakhirkin. "Semiconductor Laser-Based Trace Gas Sensor Technology: Recent Advances and Applications," Middle Infrared Coherent Sources and Applications, Eds. M. Ebrahimzadeh and I. Sorokina, Springer NATO Science Series, 2006. (Accepted).

Presentations
Bakhirkin, Y. A., A. A. Kosterev, T. Ajtai, R. Q. Yang, and F. K. Tittel. "Quartz-Enhanced Photoacoustic Spectroscopy Based Formaldehyde Sensor Using a Mid-IR Interband Cascade Laser," SPIE Optics East Conf., Boston, MA, Oct. 1-4, 2006.
McCurdy, M., Y. A. Bakhirkin, F. K. Tittel, and A. Sharafkhaneh. "Quantum Cascade Laser-Based Nitric Oxide Detection in Exhaled Breath of Patients with Chronic Obstructive Pulmonary Disease," Laser Application to Chemical Security and Environmental Analysis (LACSEA 2006), Incline Village, NV, Feb. 5-9, 2006.
Miller, H. J, Y. A. Bakhirkin, T. Ajtai, F. K. Tittel, C. J. Hill, B. Yang, and R. Q. Yang. "Detection of Formaldehyde Using Off-Axis Integrated Cavity Output Spectroscopy with an Interband Cascade Laser," Laser Application to Chemical Security and Environmental Analysis (LACSEA 2006), Incline Village, NV, Feb. 5-9, 2006.
Miller, H. J., B. McAdrew, A. A. Kosterev, Y. A. Bakhirkin, G. Wysocki, F. K. Tittel, and R. Q. Yang. "Development of Optical Trace Gas Monitoring Technology for NASA Human Space Flight," Habitation 2006, Orlando, FL, Feb. 5-8, 2006.
Tittel, F. K., Y. A. Bakhirkin, A. A. Kosterev, M. McCurdy, S. So, and G. Wysocki. "Semiconductor Laser-Based Trace Gas Sensor Technology: Advances and Opportunities," 36th Winter Colloquium on the Physics of Quantum Electronics, Snowbird, UT, Jan. 2-6, 2006.
Tittel, F. K., Y. A. Bakhirkin, A. Kosterev, and R. F. Curl. "Advances and Applications of Semiconductor-Based Trace Gas Sensor Technology (Enviro & Biom)," Laser Application to Chemical Security and Environmental Analysis (LACSEA 2006), Incline Village, NV, Feb. 5-9, 2006.
Tittel, F. K., Y. A. Bakhirkin, R. F. Curl, A. A. Kosterev, R. Lewicki, S. So, and G. Wysocki. "L-PAS Based Gas Sensor Development at Rice: Jan. 2005-May 2006," PNNL L-PAS Team Meeting, Laguna Beach, CA, June 12, 2006.
Tittel, F. K., Y. Bakhirkin, R. F. Curl, A. A. Kosterev, R. Lewicki, M. McCurdy, S. So, and G. Wysocki. "Recent Advances and Applications of Semiconductor Laser-Based Gas Sensor Technology," University of Duesseldorf, Germany, July 4, 2006.
Tittel, F. K., Y. Bakhirkin, R. F Curl, A. A. Kosterev, R. Lewicki, M. McCurdy, S. So, G. Wysocki, R. Maulini, J. Faist, L. Diehl, M. Trocolli, and F. Cappasso. "High Resolution Spectroscopy and Trace-Gas Detection with State-of-the Art Thermoelectrically-Cooled cw Mid-Infrared Quantum Cascade Lasers," The 2nd International Workshop on Quantum Cascade Lasers, Brindisi, Italy, Sept. 6-9, 2006.
Tittel, F. K., Y. A. Bakhirkin, A. A. Kosterev, G. Wysocki, and R. F. Curl. "Laser-Based Chemical Sensor Technology: Recent Advances and Applications," The 6th International Symposium on Advanced Environmental Monitoring, Heidelberg, Germany, June 27-30, 2006.

Funding and proposals
Tittel, F. K. "Advanced Trace Gas Monitoring Technology for NASA Human Space Flight," NASA, March 1, 2003-March 31, 2007. $414,242.
Tittel, F. K. "Broadly Tunable Infrared Quantum Cascade Laser Technology for Remote Sensing," Department of Energy, STTR Subaward from Aerodyne Inc., July 1, 2006-June 15, 2007. $50,000.
Tittel, F. K. "Development of QEPAS-Based Sensor Systems and Applications," National Science Foundation (MIRTHE ERC), May 1, 2006-April 30, 2007. $78,185.
Tittel, F. K. "High Resolution Spectroscopy with Lasers," Welch Foundation, June 1, 2003-May 31, 2006.
Tittel, F. K. "Low-Cost Integrated IR Quartz- Enhanced Photoacoustic Gas Sensor," NSF, STTR Subaward from Ekips Technologies, Jan. 1, 2006-Dec. 31, 2006. $50,000.
Tittel, F. K., NASA-JSC Graduate Fellowship for Matt McCurdy, July 1, 2005-June 30, 2006. $24,000.
Tittel, F. K. "Optical Carbon Dioxide Field Isotope Ratiometer Department of Energy," SBIR Subaward from Vistaphotonics," Aug. 1, 2006-July 31, 2008. $120,000.
Tittel, F. K. "Quantum Cascade Laser-Based Sensors for Chemical and Environmental Analysis," Texas Advanced Technology Program, Rice University PI., Jan. 1, 2003-Aug. 30, 2006. $187,380.
Tittel, F. K. "Quantum Cascade Laser Photoacoustic Sensor for Chemical Warfare Agent Detection," Pacific Northwest National Laboratory, Rice University, PI, Jan. 3, 2005-Sept. 30. 2006. $210,000.
Tittel, F. K. "Quartz Enhanced Photoacoustic Spectroscopy Methane System Development," Savannah River National Laboratory, May 31, 2006-Sept. 30, 2007. $135,674.
Tittel, F. K. "Shipboard Atmospheric Propagation Measurements, Department of Defense, Subaward from Aculight Inc., Oct. 1, 2006-Feb. 22, 2007. $26,000.
Tittel, F. K. "Ultra-Sensitive Detection of Aerosol Precursors Including Ammonia," Aculight, Botthell, WA, Sept. 9, 2005-March 26, 2006. $26,000.

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