Optics: measuring and testing – Of light reflection
Reexamination Certificate
1999-05-26
2002-07-23
Rosenberger, Richard A. (Department: 2877)
Optics: measuring and testing
Of light reflection
Reexamination Certificate
active
06424418
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a sensor apparatus for measuring an object in a sample using light. More particularly it relates to a sensor apparatus for detecting or measuring a specific substance by using the interaction between light and a surface plasmon wave caused by the total-reflection of light on a metal thin film provided on a light-transmitting medium. The typical sensor apparatus is a nucleic-acid detecting device, in which a vertical cavity surface emitting laser (VCSEL) and a sensor array, such as an array of charge-coupled devices (CCDs), are arranged on a common substrate, and an optical system composed of integrally formed substrate, light-transmitting medium and metal thin film is employed.
2. Related Background Art
Conventionally, oxidation-reduction reaction of a measurement object, color reaction of a measurement object with color reagent, and the like have been used in chemical sensors for measuring sample concentrations. In those cases, when a highly-sensitive, highly-selective sensor is needed, it is preferable that the measurement object is used as a substrate and a biosubstance with a strong affinity for the substrate, such as an antibody for an antigen, is used for the substrate. Where the measurement object is nucleic acid, then a so-called probe nucleic acid can be preferably used. In this probe nucleic acid, a portion of a base arrangement in the nucleic acid is replaced by a complementary base arrangement.
Recently, a highly-sensitive method has been proposed to optically measure a change in the dielectric constant which accompanies a biochemical reaction (see Japanese Patent Application Laid-Open No. 61(1986)-292045). In this method, the interaction between light and surface plasmon wave is used. The surface plasmon wave is generated under a total-reflection condition of light on a metal thin film provided on a light-transmitting medium. Its principle of measurement is as follows.
FIG. 6
illustrates the structure of the above-discussed prior art measuring apparatus. In
FIG. 6
, light emerging from a light source
31
enters a prism
32
(a light-transmitting medium), is reflected at a reflective surface of the prism
32
, and is detected by a photodetector
33
. A spacer layer
34
of a buffer medium, a metal film
35
and an organic material layer
36
(an insulator) are serially desposited on the reflective surface of the prism
32
. A sample fluid
37
of a measurement object is in contact with an external surface of the organic material layer
36
.
A surface plasmon wave is defined herein as an electromagnetic wave generated at the interface between a metal and an insulator. This wave can be optically induced when the resonance condition determined by refractive index (i.e., dielectric constant) in the vicinity of the interface between the metal and the insulator and its thickness is satisfied. Initially, p-polarized light is caused to impinge on the light-transmitting medium with the metal thin film thereon such that a total reflection of the light occurs at the metal thin film. Then, an evanescent wave occurs with a wave number depending on the incident angle of light at the interface between the metal thin film and the light-transmitting medium. On the other hand, the surface plasmon wave is generated on an outer surface (a surface in contact with the insulator) of the metal thin film due to a tunneling effect of light. The surface plasmon resonance occurs when wave numbers of the evanescent wave and the surface plasmon wave respectively created on both faces of the metal thin film are coincident with each other. At this time, part of energy of the incident light is used to induce energy of the surface plasmon wave.
The intensity of light reflected at the metal thin film is equal to a difference between the intensity of the incident light and the light intensity lost by the excitation of the surface plasmon wave, based on the energy conservation law. Therefore, the surface plasmon resonance can be measured by measuring the incident-angle dependency of the intensity of the reflected light. The resonance condition is determined from the wavelength of incident light, its incident angle, complex dielectric constants of light-transmitting medium and metal thin film, complex dielectric constant of a sensor's sensitive film provided on the metal thin film, and so forth. When the complex dielectric constant varies due to the biochemical reaction in the sensitive film, the resonance condition is changed. Hence, under the condition of a constant wavelength, the light incident angle for causing the surface plasmon resonance is varied. When this variation of the light incident angle is detected, the substrate concentration of the biochemical reaction, i.e., concentration of the measurement object, can be obtained.
Since the surface plasmon wave is generated in a region within about several hundred nanometers on the metal thin film, the biochemical reaction between substrate and biosubstance causing the change in the dielectric constant must be effected in this region. Therefore, a very thin film will suffice to form the sensitive film with the biosubstance fixed thereon. Further, only the neighborhood of the metal thin film can be measured in the surface plasmon resonance, so even a colored sample and a suspended sample can be measured without the influences of the color or suspension.
Hitherto, a detecting sensor of an antigen of protein, and the like have been developed using the surface plasmon resonance (for example, BIAcore by Phalmasia Co.). In this sensor, an organic thin film as the sensitive film is provided on the metal film on which the surface plasmon resonance occurs, and an antibody is fixed in the organic thin film. When the fixed antibody is selectively bonded to the antigen in the measurement object, the dielectric constant of the organic thin film is slightly changed. This change can be measured from a change in the resonant angle. This principle can also be used in a nucleic-acid sensor and the like, in which an organic thin film as the sensitive film is provided on the metal film on which the surface plasmon resonance occurs, and a nucleic acid or the like is fixed in the organic thin film. When the fixed target nucleic acid or probe nucleic acid is selectively bonded to probe nucleic acid or target nucleic acid in the measurement object, the dielectric constant of the organic thin film is slightly changed and this change can be measured from a change in the resonant angle.
Such a measuring apparatus using the surface plasmon resonance is disclosed in Japanese Patent Application Laid-Open Nos. 5(1993)-18890, 6(1994)-58873, 6(1994)-167443, 6(1994)-265336, 7(1995)-174693, “Sensors and Actuators B329 (1995) pp. 268-273”, or “Sensors and Actuators B32 (1996) pp. 149-155”, for example. In those apparatuses, a metal thin film is formed on a prism, and the surface plasmon resonance created by incidence light from outside of the prism is measured by a detector disposed on the outside of the prism. In those apparatuses, the incident angle of light incident on the metal thin film needs to be varied to measure a change in the resonant angle. Hence, the apparatus becomes relatively large including light source, prism, detector, movable device, and so forth. Accordingly, a sensor apparatus with a large elasticity is difficult to fabricate based on such a construction.
Further, the metal thin film for creating the surface plasmon resonance can achieve a sufficiently exact measurement with a very small area. Therefore, there have also been proposed sensor-type apparatuses in which only the measuring portion is shaped into a minute configuration. For example, “Sensors and Actuators B34 (1996) pp. 328-333” proposed a sensor using an optical fiber. Since the group velocity of light propagated through an optical fiber is determined from its wavelength, incident and reflection angles of light totally reflected at the interface between the core and the cladding of the fiber are dependent
Kawabata Yuji
Nomoto Tsuyoshi
Okamoto Tadashi
Sakata Hajime
Sakuranaga Masanori
Canon Kabushiki Kaisha
Fitzpatrick ,Cella, Harper & Scinto
Rosenberger Richard A.
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