Sensors, methods of manufacture and sensing methods

Details Sensors, methods of manufacture and sensing methods Sensors, methods of manufacture and sensing methods

2001-09-12

2003-04-01

Pham, Hao Q. (Department: 2877)

Optics: measuring and testing

Refraction testing

C436S164000, C422S082050

Reexamination Certificate

active

06542229

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to sensing. More particularly, the present invention relates to apparatus and methods for sensing refractive index changes by monitoring the energy transfer between a chromophore acceptor and a donor.
BACKGROUND OF THE INVENTION
Optical sensors, including sensors that monitor absorbance changes and refractive index changes proximate a sensing area are used in the fields of chemical, biochemical, biological or biomedical analysis, process control, pollution detection and control, and other areas. Luminescent (including fluorescent and phosphorescent) markers also find a wide variety of applications in science, medicine and engineering. These sensors and techniques are adaptable to a wide variety of samples including biological samples and extracts (such as physiological fluids, nucleic acid and/or protein-containing solutions, microbial cultures, etc.), environmental samples (such as water sources), industrial, especially chemical reagents, products and wastes, etc.
Surface-plasmon resonance (SPR) is a popular sensing technique in the pharmaceutical industry and biological research. SPR is but one of a large class of optical biosensors collectively referred to as evanescent wave-based detectors. This class includes film waveguide grating couplers, film prism waveguide couplers and long-period grating waveguide couplers. The essential feature of all these techniques is that a standing “evanescent” wave is generated above the sensing surface by a short wavelength's distance from the surface (approximately 100-200 nm) that is sensitive to the local dielectric environment. By changing the local refractive index, the standing wave is altered, requiring either a new angle of incident light to set up the “resonance condition” or inducing a phase shift of the reflected light. Since all proteins, independent of sequence, contribute almost the same refractive index per unit mass, this technique can serve as a mass detector. A linear correlation between resonance angle shift and surface protein concentration has been demonstrated, allowing real time detection of mass change without the need for labeling. All evanescent wave techniques are variations on this essential theme.
One limitation of evanescent wave methods is that they do not readily lend themselves to miniaturization. This limitation makes massive deployment of similar sensing elements on small surfaces extremely problematic. Another limitation of these techniques is that the sensitivity of these optical sensors is limited by many factors such as signal to noise ratio such that the sensitivity of these techniques are usually limited to about 10
−5
or 10
−6
Moles/liter in the sensing area.
Another known sensing technique is the monitoring of the energy transfer between a luminescent donor-acceptor pair as a function of the changing distance between the donor-acceptor pair. Luminescent structures are either man-made (see, e.g., Alivisatos, A. P., “Perspectives on the Physical Chemistry of Semiconductor Nanocrystals,” Journal of Physical Chemistry, 100, 31, pp. 13226-13239 (1996); Chan, W. C. and Nie, S., “Quantum Dot Bioconjugates for Ultrasensitive Nonisotopic Detection,” Science, 281, pp. 2016-2018, (1998); Davies, J. H. and Long, A. R. (eds.), Physics of Nanostructures,” St. Andrews, Institute of Physics Publicshing Ltd., (1992)) or naturally occurring (see, e.g., Glazer, A. N. and Mathies, R. A., “Energy-transfer fluorescent reagents for DNA analyses, “Current Opinions in Biotechnology,” 8 (1), pp. 94-102, (1997); Yardley, J. T., “Introduction to Molecular Energy Transfer,” New York, Academic Press (1980). An example of a man-made structure is a semiconductor sandwich (e.g., GaAs disposed between AlGaAs layers), which shares all of the attributes of a transition dipole structure that both absorbs and emits light and is directional. For more details on these structures, refer to the Chan and Nie and Davies references, the entire contents of which are incorporated herein by reference. These structures, which may be referred to as quantum dots, quantum wires, quantum well structures, or nanocrystals, can be coated to stabilize them in various solutions. More commonly, however, luminescent pairs of donors and acceptors typically include luminescent molecules such as dyes or lanthanides having light absorption and emission properties. For a review of Fluorescent Resonance Energy Transfer, see, Selvin (1994) Fluorescence Resonance Energy Transfer, in Biochemical Spectroscopy, a volume of Methods in Enzymology, Academic Press, Ed. Kenneth Sauer.
U.S. Pat. No. 5,639,615 describes measuring luminescent energy transfer between lanthanide chelate acceptor-donor pairs. The resonance energy transfer described in U.S. Pat. No. 5,639,615 involves detecting the distance between a donor and an acceptor in a portion of a sample by exposing a sample including the donor located at a first position and the acceptor located at a second position to light at a first wavelength capable of inducing a first electronic transition in the donor. The spectral overlap of the donor emission and acceptor absorption is sufficient to enable energy transfer from the donor to the acceptor as measured by a detectable decrease of donor luminescence intensity or a detectable increase in acceptor luminescence intensity. Then the intensity of a first emission of light from the sample portion at a second wavelength is detected, which results from a second electronic transition in the donor. The intensity of the first emission of light correlates with the distance between the first and second positions. In other words, the closer the positions, the greater the energy transfer and the greater the decrease in energy emitted from the donor. An alternative scheme described in U.S. Pat. No. 5,639,615 involves the detection of the intensity of a second emission of light from sample portion at a third wavelength, in which the third wavelength is longer than the first wavelength and results from an electronic transition in the acceptor. The intensity of the second emission of light inversely correlates with the distance between the first and second positions of the sample portion. Thus, the closer the positions, the greater the energy transfer and the greater the acceptor luminescence.
The general method described in U.S. Pat. No. 5,639,615 may be used to measure the static or dynamic distance between two positions, for example, two atoms or molecules. In particular, the method can be used to monitor the status of a polymerase chain reaction. In this instance, the sample portion may include a target nucleic acid strand having a first strand portion and a probe nucleic acid strand labeled proximal to one end with the acceptor and proximal to the other end with the donor. Thus, the donor and the acceptor are separated from each other by the opposite ends of the second strand. The first and second strands are sufficiently complementary to hybridize under annealing conditions. If the second strand is of sufficient length to provide a detectable difference in the aggregate energy transfer from the donor to the acceptor upon hybridization of the first and second strands, as compared with the aggregate energy transfer from the donor to the acceptor when the first and second strand portions are not hybridized, a detectable difference in energy transfer can be measured. The detectable difference is measured as at least one of a detectable decrease or quenching of donor luminescence or detectable increase in acceptor luminescence, and the distance between the acceptor and donor, as a function of changing luminescence, indicates whether the nucleic acid strands have hybridized. Thus, as the reaction proceeds, the stepwise increase in the amount of target nucleic acid is reflected in a stepwise decrease in energy transfer.
The sensitivity of methods using resonance energy transfer as a function of the changing distance between the donor-acceptor pair can be as high as 10
−12
Moles/liter. Although these conventional res

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