Optics: measuring and testing – Of light reflection
Reexamination Certificate
2001-11-13
2004-08-31
Mathews, Alan (Department: 2851)
Optics: measuring and testing
Of light reflection
Reexamination Certificate
active
06784999
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods and measuring instruments or sensors for use in biological, biochemical, and chemical testing, and particularly to methods, instruments, and the use of instruments which utilize surface plasmon resonance (SPR) for detecting molecules or monitoring structural and electronic changes in the molecules with ultra-high resolution and ultra-fast response times.
BACKGROUND OF THE INVENTION AND PRIOR ART
Surface plasmon resonance (SPR) is the oscillation of the plasma of free electrons which exists at a metal boundary. These oscillations are affected by the refractive index of the material adjacent the metal surface. It is this phenomenon that is used to detect minute changes in the refractive index of a surface and forms the basis of various sensor mechanisms. Surface plasmon resonance spectroscopy has emerged as a powerful technique in recent years for detection and analysis of chemical and biological substances in many research areas and industrial applications, such as surface science, biotechnology, environment, drug and food monitoring, and medicine. In biological sensors, detection of antibodies and their reactions with antigens using SPR is of primary interest in biomedical diagnostics, where the presence of antibodies associated with a bacteria or virus is an important indication of infection. SPR has also been applied to gene probes where deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) binding to a defined sequence in target analytes can be employed. In addition, SPR has found applications in detecting trace amount of toxic agents in air or in water for environmental protection or for chemical/biological warfare alert. Finally, SPR-based sensors are promising in food industry for detecting chemical and biological contamination in food. In all these application, improving the resolution and time response of SPR detection is of vital importance.
Surface plasmon resonance may be achieved by using the evanescent wave which is generated when a p-polarized light beam is totally internally reflected at the boundary of a medium, e.g. a glass prism, which has a high dielectric constant. A paper describing the technique has been published under the title “Surface plasmon resonance for gas detection and biosensing” by Lieberg, Nylander and Lundstrom in Sensors and Actuators, Vol. 4, page 299. The widely used methods for detecting SPR are based on attenuated total reflection (ART) of a collimated laser beam is incident on a glass body, usually a prism, on which a thin metal film is coated. When the incident light reaches an appropriate angle the reflection decreases sharply to a minimum, corresponding to the excitation of surface plasmon waves in the film. The total internal reflection is detected with a photodetector as a function of incident angle which is varied by rotating the prism. The photo detector is also rotated in order to catch the reflected light. When the incident beam reaches an appropriate angle, the reflection decreases sharply to a minimum that appears as a dip in the reflectivity vs. incident angle plot. The angular resolution achieved by this rotating prism approach is typically 10
−2
-10
−3
deg (degrees), limited by errors in the angular position and noise in the intensity of the reflected light. For comparing different SPR detection techniques, the SPR resolution is often described in terms of the smallest detectable change in the refractive index for an analyte [refractive index units (RIU)]. The above angular resolution corresponds to 10
−5
-10
−6
RIU at a wavelength of 630 nm. For higher angular resolutions, a large distance between the prism and the photodetector is required which makes the setup not only bulky but also more susceptible to mechanical noise and thermal drift. The response time is slow because of the mechanical movements in the setup.
Mechanical movements can be avoided by fixing the photodetector at an angle near resonance and measuring the intensity change in their reflection due to SPR angular shift. A major advantage of this approach is that the response time is only limited by the photodetector and the associated electronics which can be as fast as nanoseconds. A drawback, however, is that the relationship between the intensity and the sensitivity of the resonance angle measurement is dependent on the angle at which the photodetector is fixed. Major limitations in the resolution of the method come from fluctuation in the intensity of the laser and from thermal and mechanical drift in the setup.
Another widely use ATR-based method also fixes the position of the prism and replaces the collimated incident light in the above setups with a fixed convergent beam that covers a range of incident angles. This method is generally disclosed in “The ATR method with focused light—application to guided waves on a grating” by E. Kretschmann, Vol. 26, number 1, Optics Communications, 1978, and in U.S. Pat. No. 4,997,278 by Finaln et. al. The reflections from different incident angles are collected simultaneously with a linear diode array (LDA) or charge coupled device (CCD) detector. This method involves no mechanical movements, but simultaneous detection of many channels (e.g., 1024 in a typical LDA) slows down the response time. The typical angular resolution is 10
−2
-10
−3
deg or 10
−5
-10
−6
RIU. As in the method with a rotating prism, high angular resolution of this method requires a large distance between the prism and the photodetector.
The above setups involve reflection intensity versus incident angle (an angle-scan system); SPR has also been detected by modulating the wavelength of incident light as described by Caruso, F., et al. (J. Appl. Phys., 1998, 83, 1023). The wavelength modulation causes modulation in the reflection intensity which is monitored with a lock-in amplifier and provides an accurate measurement of the SPR dip position. Using an acousto-optic tunable filter (AOTF), it was demonstrated that a wavelength change of 0.0005 nm, corresponding to 5×10
−7
RIU at a wavelength of 630 nm, can be detected. When applied to DNA-SH adsorption on gold, the signal to noise ratio of the AOTF SPR is six times better than that achieved by an angle-scan system.
As mentioned above, these methods suffer two major drawbacks: slow response time and limited angular resolution. The former one prevents the methods from detecting a fast process, such as the initial adsorption process of molecules onto surfaces, gas interactions, reactions between surface bound molecules and molecules in solution, and fast conformational changes in adsorbed proteins. The later one limits the sensitivity of SPR for detecting small amounts of molecules or small structural or conformational changes in molecules. In the first method, the response is slow because of mechanical movements involved in the method. The second method has no mechanical movements, but simultaneously detecting may channels (e.g., 1024 in a typical linear diode array) slows down the response time. For both methods, the angular resolution is typically poorer than 10
−3
degrees (typically on the order of 10
−2
). For high angular resolution, both methods require a large distance between the sample and the detector, which makes the setups more susceptible to mechanical noise and thermal drift. Large distances, however, deteriorate the quality of the detected beam and makes to the SPR instruments bulky. For a given sample-detector distance, the resolution of the first method is limited by the precision of measuring the angular position of the prism. The resolution of the second method is limited by the number of channels (pixels) in the photo detector array and the noise level in the measured intensity in each channel. Improved resolution can be obtained using a software routine to fit the data collected by either the first or the second methods, however, this fitting procedure requires extra time and its reliability depends on the accuracy of
Boussaad Salah
Huang Wenlue
Tao Nongjian
Marshall & Gerstein & Borun LLP
Mathews Alan
The Florida International University Board of Trustees
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