Radiant energy – Luminophor irradiation
Reexamination Certificate
2000-01-19
2002-07-30
Epps, Georgia (Department: 2873)
Radiant energy
Luminophor irradiation
C250S459100, C356S318000
Reexamination Certificate
active
06426505
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to an apparatus and method for the measurement of photoluminescent lifetimes. More specifically, the invention concerns a low cost portable frequency-domain phase fluorometer which operates at a frequency of up to 200 MHz without the need for a cross-correlation detection.
2. Prior Art
The contents of all cited references including literature references, issued patents, published patent applications as cited throughout this application are readily available to those skilled in the art and are hereby expressly incorporated herein by reference as though they were set forth herein in their entirety.
LITERATURE REFERENCES
Anghel, F., C. Iliescu, K. T. V. Grattan, A. W. Palmer and Z. Y. Zhang, “Fluorescent-Based Lifetime Measurement Thermometer for Use at Subroom Temperatures (200-300 K)”, Rev. Sci. Instrum. 66, 2611-2614, 1995.
Bambot, S., R. Holavanahali, J. R. Lakowicz, G. M. Carter and G. Rao, “Phase Fluorometric Sterilizable Optical Oxygen Sensor”, Biotechnology and Bioengineering 43, 1139-1145, 1994.
Chang, Q., L. Randers-Eichhorn, J. R. Lakowicz, G. Rao, “Steam-Sterilizable Fluorescence Lifetime-Based Sensing Film for Dissolved Carbon Dioxide”, Biotechnol. Prog. 14, 326-331, 1998.
Gratton, E. and M. Limkeman, “A Continuously Variable Frequency Cross-Correlation Phase Fluorometer with Picosecond Resolution,” Biophys. J., 315-324, 1983.
Gruber, W. R., P. O'Leary, O. S. Wolfbeis, “Detection of Fluorescence Lifetime Based on Solid-State Technology, and Its Application to Optical Sensing”, Proc. SPIE 2388, 148-158, 1995.
Gryczynski, I., J. Kusba, J. R. Lakowicz, “Effect of Light Quenching on the Emission Spectra and Intensity Decays of Fluorophore Mixtures”, J. Fluorescence 7, 167-183, 1997.
Holavanahali, R., M. Romauld, G. M. Carter, G. Rao, J. Sipior, J. R. Lakowicz and J. D. Bierlein, “Directly Modulated Diode Laser Frequency-Doubled in a KTP Waveguide as an Excitation Source for CO
2
and O
2
Phase Fluorometric Sensors”, J. Biomed. Optics 1, 124-130, 1996.
Hoist, G. A., T. Koster, E. Voges, D. Lubbers, “FLOX an Oxygen-Flux-Measuring System Using a Phase-Modulation Method to Evaluate the Oxygen-Dependent Fluorescence Lifetime”, Sens. Actuators B 29, 231-9, 1995.
Lakowicz, J. R.,
Principles of Fluorescence Spectroscopy.
Plenum Press, New York, 1983.
Lakowicz, J. R. and I. Gryczynski, “Frequency-Domain Fluorescence Spectroscopy”, in
Topics in Fluorescence Spectroscopy,
Vol. 1 Techniques, (J. R. Lakowicz, Ed.), 293-335, 1991.
Lakowicz, J. R., G. Laczko, I. Gryczynski, “2-GHz Frequency-Domain Fluorometer”, Rev. Sci. Instrum. 57, 2499-2506, 1986.
Lakowicz, J. R. and B. Maliwal, “Construction and Performance of a Variable-Frequency Phase-Modulation Fluorometer”, Biophysical Chemistry 21, 61-78, 1985.
Lakowicz, J. R. and B. Maliwal, “Optical Sensing of Glucose Using Phase-Modulation Fluorimetry”, Anal. Chim. Acta. 271, 155-164, 1993.
Levy, R., E. F. Guignon, S. Cobane, E. St. Louis and S. M. Femandez, “Compact, Rugged and Inexpensive Frequency-Domain Fluorometer”, SPIE 2980, 81-89, 1997.
Murtagh, M. T ., D. E. Acklev, M. R. Shahriari, “Development of a Highly Sensitive Fiber Optic O
2
/DO Sensor Based on a Phase Modulation Technique”, Electronics Letters 32, 477-479, 1996.
Ozinskas, A, H. Malak, J. Joshi, H. Szmacinski, J. Britz, R. Thompson, P. Koen and J. R. Lakowicz, “Homogeneous Model Immunoassay of Thyroxine by Phase-Modulation Fluorescence Spectroscopy”, Anal. Biochem. 213, 264-270, 1993.
Spencer, R. D. and G. Weber, “Measurement of Sub-Nanosecond Fluorescence Lifetime with a Cross-Correlation Phase Fluorometer”, Ann. N. Y. Acad. Sci. 158, 361-376, 1969.
Sipior, J., G. Carter, J. R. Lakowicz, G. Rao, “Single Quantum Well Light Emitting Diodes Demonstrated as Excitation Sources for Nanosecond Phase-Modulation Fluorescence Lifetime Measurements”, Rev. Sci. Instrum. 67, 3795-3798, 1996.
Szmacisnki, H., J. R. Lakowicz, “Optical Measurements of pH Using Fluorescence Lifetimes and Phase-Modulation Fluorometry”, Anal. Chem. 65, 1668-1674, 1993.
Thompson, R. B., Z. Ge, M. W. Patchan and C. A. Fierke, “Performance Enhancement of Fluorescence Energy Transfer-Based Biosensors by Site-Directed Mutagenesis of the Transducer”, J. Biomed. Optics 1, 131-137,1996.
Zhang, Z., K. T. V. Grattan, A. W. Palmer, “A Novel Signal Processing Scheme for a Fluorescence Based Fiber-Optic Temperature Sensor”, Rev. Sci. Instrum. 62, 1735-42, 1991.
U.S. Patents
5,141,312
August 25, 1992
Thompson et al.
5,504,337
April 2, 1996
Lakowicz et al.
5,818,582
October 6, 1998
Femandez et al.
Numerous chemical and biochemical research tools, remote sensing devices, and immunodiagnostic test methods are based on some form of photoluminometric analysis (e.g., fluorometry and phosphorimetry). Although the disclosure herein primarily focuses on a fluorometric apparatus and method of analysis, the terms used herein such as fluroescence, fluorophore and fluorometer, are to be construed to include the meaning of phosphorescence, phosphor and phosphorimeter, respectively.
Fluorometry offers a wide range of advantages over other spectroscopic methods (e.g., colorimetry). These advantages include low detection limits and the potential for minimally invasive measurements in biological samples. However, simple intensity based methods are prone to artifacts because any change in fluorescence intensity, regardless of origin, can flaw the analysis. Specifically, intensity measurements can suffer from interferences caused by light scattering, variations in the intensity of the source or excitation light, photobleaching, contaminating chromophores, or changes in the collection geometries. To circumvent the limitations of intensity measurements, Lakowicz and other researchers developed methods based on measuring the fluorescence lifetime of a fluorophore in the time or frequency domain (Lakowicz et al. (1986); Zhang et al. (1991); Gruber et al. (1995); Holst et al. (1995); and Murtagh et al. (1996)). Fluorescence lifetime analysis has been used, for example, to study: rotational and molecular diffusion; energy transfer kinetics and other excited state reactions; and collisional quenching (Lakowicz, 1983). Fluorescence lifetime analysis has also been used in the development of immunoassays (Ozinskas, 1993); sensors for the measurement of pH (Szmacisnki et al., 1993); temperature (Anghel et al., 1995); glucose (Lakowicz and Maliwal, 1993); metal ions (Thompson et al., 1996); oxygen (Bambot et al., 1994); and carbon dioxide (Holavanahali et al., 1993).
Various methods for measuring fluorescence lifetimes are common to the art and include both time domain and frequency domain methods. In time domain methods, the fluorescence lifetime of a sample is determined from an analysis of the fluorescence decay that is elicited by a pulsed excitation. In general, a sample is excited with a brief pulse of light and the time-dependent decay in fluorescence intensity is measured. However, the measurement of the decay in fluorescence intensity is difficult as light sources typically yield pulses with durations of several nanoseconds. As a result, one must either correct for the pulse width or select an alternative light source which can yield pulses of a duration shorter than the average lifetime being measured. Generally such pulsed picosecond light sources are not only expensive but add to the technical complexity of the system. A further difficulty of time domain methods is the need to measure the entire duration of the time-resolved fluorescence decay. This difficulty is generally minimized by exciting the sample with repetitive pulses that are spaced at time intervals greater than a factor of five times the decay time, to avoid overlap of the decay pulses. However, if repetitive pulses are used, the decay in fluorescence intensity must be reconstructed using either a stroboscopic or photon counting method (Lakowicz, 1983). Further, one must also correct for the finite width of the light pulse and the response time of the detection system when using a photon c
Harms Peter
Rao Govind
Epps Georgia
Hanig Richard
Sughrue & Mion, PLLC
University of Maryland Biotechnology Institute
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