KR101198095B1 - Biosensor measurement system using surface plasmon resonance - Google Patents

Abstract

The present invention relates to a biosensor measurement system using surface plasmon resonance. The biosensor measuring system includes a light source for providing light; A biosensor in which incident light provided from the light source is reflected at various reflection intensities by surface plasmon resonance; A lens unit disposed between the light source and the biosensor to focus the light provided from the light source to the biosensor; An array type photodetector configured of a plurality of pixels arranged in an array to sense reflected light reflected from the biosensor; A position modulator for vibrating the array type photodetector at a modulation frequency? A demodulation device which receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the received measurement signal by using a modulation frequency? A control unit controlling driving of the position modulation element, the array type photodetector, and the demodulation device to provide a measurement signal according to a change of a sample in real time; The control unit initially sets one of the pixels of the array-type photodetector as a reference pixel, and provides a measurement signal output from the reference pixel to the demodulation device while driving the position modulator at a modulation frequency. The demodulation device receives and outputs the measured signal demodulated in real time.

Description

Biosensor measurement system using surface plasmon resonance

The present invention relates to a biosensor measuring system using surface plasmon resonance, and more particularly, a linear laser beam can be used to minimize the loss of a light source to improve detection rate and to improve resolution while demodulating only a single pixel. The present invention relates to a biosensor measurement system using surface plasmon resonance.

Surface Plasmon is a collective charge density oscillation of electrons occurring on the surface of a metal thin film, and the surface plasmon waves generated are surface electromagnetic waves propagating along the interface between the metal and the dielectric. Excitation of surface plasmons is caused by the application of an electric field to two medium interfaces with different dielectric functions from outside, that is, the interface between metal and dielectric, which induces surface charges due to the discontinuity of the electric component perpendicular to the two medium interfaces, Oscillations appear as surface plasmon waves. The surface plasmon wave described above, unlike electromagnetic waves in free space, is a wave that vibrates parallel to the plane of incidence and has a polarization component of p-polarization. Therefore, excitation of surface plasmons by optical means is possible only by TM polarized electromagnetic waves.

TM polarized incident wave is totally reflected at the interface of the metal thin film and dissipated wave is exponentially reduced into the metal thin film at the interface, but at a certain angle of incidence and thickness of the thin film, the incident wave in the direction parallel to the interface and the surface plasmon wave coincide If you do, resonance will occur. At this time, the energy of the incident wave is absorbed by the metal thin film so that the reflected wave disappears and the electric field distribution in the direction perpendicular to the interface is exponentially largest and rapidly decreases toward the metal thin film. Surface Plasmon Resonance (hereinafter referred to as 'SPR') is called, and the angle at which the reflectance of the incident light decreases is called the surface plasmon resonance angle.

The resonance angle at which surface plasmon resonance occurs, that is, the angle at which the reflected light is minimized, results in an effective reactive index that changes as the mass of the metal thin film surface layer dielectric increases or the structure changes, resulting in a change in the resonance angle. Therefore, using the principle of SPR, which can measure the change of these materials by optical method, it is possible to change the resonance angle of biochemical reactions such as selective bonding or separation between various biochemicals through proper chemical modification of metal thin film surface layer. SPR sensors are often used as highly sensitive biochemical sensors.

In general, as a SPR-based biosensor, a number of prior arts have been proposed as a method of measuring a change in dielectric constant or refractive index corresponding to a change in a sample on a metal film after coating a metal film on a transparent prism about 50 nm.

The first method is mentioned in US Pat. No. 4,889,427, which is a method of measuring the resonance angle and its change while changing the incident angle θ by using the incident light of a single wavelength light source and a prism having a fixed refractive index n ₀ .

In addition, the second method is a method for measuring a change in wavelength according to resonance conditions in a state in which a multi-wavelength light such as white light is used as a light source and the incident angle θ is fixed in the manner mentioned in US Pat. No. 5,359,681.

The third method focuses on the center of the medium by using a single wavelength light source expanded in the manner mentioned in US Pat. No. 4,844,613 and the like, and receives a multi-channel light such as a photodiode array (PDA). It is a method of measuring the resonance angle without a rotary drive by using a device.

As described above, when an array type light receiving element is used, the amount of light detected by each pixel constituting the light receiving element is very small, and as a result, a signal-to-noise ratio (SNR) is lowered. In addition, in this case, since the light source and the prism are fixed, a wide range of measurement may be performed by increasing the angle at which light is spread or collected in order to detect a large change in resonance angle. In order to measure a wide range, an array-type light receiving device needs to be large, and the light quantity of each pixel becomes smaller since the light receiving elements have to be separated at a wide angle with the same light intensity.

An object of the present invention for solving the above problems is to provide a biosensor measurement system using surface plasmon resonance that can improve the SNR while using an array type photodetector.

It is another object of the present invention to provide a biosensor measuring system using surface plasmon resonance which can improve detection rate while minimizing the loss of a beam of a light source.

A biosensor measuring system using surface plasmon resonance according to a first aspect of the present invention for achieving the above technical problem, a light source for providing light; A biosensor in which incident light provided from the light source is reflected at various reflection intensities by surface plasmon resonance; A lens unit disposed between the light source and the biosensor to focus light provided from the light source to the biosensor; An array type photodetector configured of a plurality of pixels arranged in an array to sense reflected light reflected from the biosensor; A position modulator for vibrating the array type photodetector at a modulation frequency? A demodulation device which receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the received measurement signal by using a modulation frequency? A control unit controlling driving of the position modulation element, the array type photodetector, and the demodulation device to provide a measurement signal according to a change of a sample in real time; The control unit initially sets one of the pixels of the array type photodetector as a reference pixel, and provides a measurement signal output from the reference pixel to the demodulator while driving the position modulator at a modulation frequency. The demodulation device receives and outputs the measured signal demodulated in real time.

In the biosensor measuring system according to the first aspect, in order to set the reference pixel, the control unit detects a measurement signal from all pixels of the array type photodetector with the position modulator turned off, and detects the detected measurement signals. It is preferable to extract a pixel corresponding to the incident angle of which the slope of the reflectance change is the largest, and set the extracted pixel as a reference pixel.

According to a second aspect of the present invention, a biosensor measuring system using surface plasmon resonance includes: a light source providing light; A biosensor in which incident light provided from the light source is reflected at various reflection intensities by surface plasmon resonance; A lens unit disposed between the light source and the biosensor to focus light provided from the light source to the biosensor; An array type photodetector configured of a plurality of pixels arranged in an array to sense reflected light reflected from the biosensor; A light intensity modulation element for changing the light intensity of the light source according to a modulation frequency? A demodulation device which receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the received measurement signal by using a modulation frequency? A control unit for controlling driving of the light intensity modulation element, the array type photodetector, and the demodulation device to provide a measurement signal according to a change of a sample in real time; The control unit initially sets one of the pixels of the array-type photodetector as a reference pixel, modulates the light intensity of the light source at a modulation frequency, and simultaneously demodulates a measurement signal output from the reference pixel. It provides the signal, and receives and outputs the measured signal demodulated in real time by the demodulation device.

In the biosensor measuring system according to the second aspect, in order to set the reference pixel, the controller detects a measurement signal from all the pixels of the array type light detector in a state where the light intensity modulator is turned off, and the detected measurement signal. It is preferable to extract a pixel corresponding to the incident angle of which the slope of the reflectance change has the largest using the above, and to set the extracted pixel as a reference pixel.

In the biosensor measuring system according to the first and second features, the light source preferably outputs a linear laser beam.

In the biosensor measuring system according to the first and second features, the demodulation device is a lock-in amplifier, and it is preferable that the control unit provides a modulation frequency to be used as a reference frequency to the demodulation device.

In the biosensor measuring system according to the first aspect, the position modulator is preferably a piezo actuator.

A biosensor measuring system according to first and second features, the biosensor comprising: a main body made of a transparent material which reflects incident light vertically and emits the light to the array type photodetector; A metal thin film mounted on the reflective surface of the main body; A sample flow channel to be measured can be injected into the inside, the sample flow channel mounted on one surface of the metal thin film; It is preferable that the main body of the biosensor is composed of a prism having a triangular or semi-circular cross section.

The biosensor measuring system according to the present invention can improve the SNR of the measurement signal by modulating and demodulating the measurement signal by moving the array type photodetector or changing the intensity of the output light of the light source while using the array type photodetector.

The biosensor measurement system according to the present invention extracts the photodetector having the largest change in reflectance gradient among the photodetectors constituting the array type photodetector, and demodulates only the measurement signal output from the extracted photodetector. As a result, instead of demodulating all the measurement signals output from all the photodetectors, only demodulating the measurement signal of the pixel corresponding to the incident angle with the largest change in the reflectance change, not only minimizes signal processing, but also relatively SNR. It will be possible to improve.

5 is a graph showing the reflectance with respect to the incident angle in order to explain the change in reflectance by surface plasmon resonance. Referring to FIG. 5, the change in reflectance at the resonance angle 'a' is very small compared to other incidence angles, and the slope of the reflectance change at the incident angle 'b' is very large. The change in signal at a large incidence angle 'b' is very large. Accordingly, the measurement signal output from the pixel corresponding to the incident angle 'b' having a large gradient of reflectance change is improved in SNR relative to the measurement signals output from the pixels corresponding to other incident angles.

6 is a diagram for explaining the case of using a circular laser beam and a linear laser beam. As shown in FIG. 6B, the biosensor measuring system according to the present invention uses a light source that provides a linear laser beam so that the linear laser beam is reflected from the biosensor and proceeds to the array type photodetector. When using a circular laser beam as shown in Fig. 6 (a), the loss of the beam occurs in the linear array type photodetector. However, as shown in FIG. 6B, when the linear laser beam is used, the loss of the beam in the array type photodetector may be minimized.

1 is a block diagram schematically illustrating a biosensor measuring system using surface plasmon resonance according to a first embodiment of the present invention.
2 exemplarily shows a linear laser beam output from a light source.
3 is a flowchart sequentially illustrating an operation of the biosensor measuring device according to the first embodiment of the present invention.
4 is a schematic diagram of a biosensor measuring system using surface plasmon resonance according to a second exemplary embodiment of the present invention.
FIG. 5 is a graph illustrating the reflectance with respect to the incident angle shown to explain that the reflectance is changed by surface plasmon resonance.
FIG. 6 is a diagram illustrating beam loss in the case of using a circular laser beam and a linear laser beam.

1st Example

Hereinafter, with reference to the accompanying drawings will be described in detail the structure and operation of the biosensor measuring apparatus using the surface plasmon resonance according to the first embodiment of the present invention.

1 is a block diagram schematically illustrating a biosensor measuring system using surface plasmon resonance according to a first embodiment of the present invention. Referring to FIG. 1, the biosensor measuring apparatus 10 according to the first embodiment of the present invention may include a biosensor 100, a light source 110, a lens unit 120, an array type photodetector 130, and position modulation. An element 140, a controller 150, and a demodulation device 160 are provided.

The biosensor 100 includes a body portion 102, a metal thin film 104, and a sample flow channel 106. The main body portion 102 of the biosensor may be a prism, a diffraction grating, or the like of a transparent medium. The prism employed as the main body portion is composed of a transparent medium having a high refractive index, and preferably has a cross section in the form of a triangle or a semicircle. The main body has an entrance surface, a reflection surface, and an exit surface, and light provided from the light source enters the entrance surface, is reflected vertically from the reflection surface, and proceeds to the array type photodetector 130 through the exit surface. The metal thin film 104 is made of a metal such as gold (Au) or silver (Ag), and is mounted on the reflective surface of the body portion. The sample flow channel 106 is a channel into which a sample is injected and flows, and a reactant coupled to an antigen and antibody reaction with a biomaterial corresponding to the sample to be injected may be fixedly mounted in the sample flow channel. The sample flow channel is mounted on one surface of the metal thin film.

In the biosensor having the above-described structure, the reflection intensity and the resonance angle due to the surface plasmon generated in the metal thin film are changed according to the samples injected into the sample injection channel, and the change is detected through the array type photodetector 130. Done.

The light source 110 outputs light to be provided to the biosensor. The biosensor measuring system according to the present invention preferably uses a light source that outputs a linear laser beam in order to minimize the loss of light. 2 exemplarily shows a linear laser beam output from a light source. A light source for outputting a linear laser beam can be realized by appropriately disposing an optical lens having a focusing lens in front of an existing light source and a linear aperture in a central region.

The lens unit 120 includes a convex lens and the like, and is disposed between the light source and the biosensor to focus the light provided from the light source to the main body of the biosensor.

In the array type photodetector 130, a plurality of pixels are arranged in an array form, and each pixel may be a photodiode, an optical amplifier, an imaging device such as a CCD, or the like.

The demodulation device 150 receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the input measurement signal at a modulation frequency ω, which is a reference frequency, and outputs the demodulated signal. The demodulation device 150 may be configured as a lock-in amplifier.

The position modulator 140 is coupled to the array type photodetector to move the array type photodetector from side to side in a longitudinal direction, and may be configured as a piezo actuator. The position modulator vibrates the array type photodetector at a modulation frequency ω according to a driving signal provided from the controller 150. The controller provides information about the same modulation frequency ω to the position modulator and demodulator.

The controller 150 controls operations of the position modulator 140, the array type photodetector 130, and the demodulator 150. The control unit controls the ON / OFF of the position modulator 140 or provides a position signal to the position modulator for driving the position modulator according to the modulation frequency ω. In addition, the controller controls the operations of the array type photodetector and the demodulation device, so that the change of the sample reacting in real time using the measurement signals output from the array type photodetector.

Hereinafter, the operation of the controller 150 will be described in detail with reference to FIG. 3. 3 is a flowchart sequentially illustrating an operation of the biosensor measuring device according to the first embodiment of the present invention. Referring to FIG. 3, the biosensor measuring apparatus initially turns off the position modulator (step 300), receives a measurement signal from all pixels of the array type photodetector while the array type photodetector is fixed, and receives the received signal. The measurement signals are analyzed to select a pixel corresponding to the incident angle having the greatest slope of the reflectance change and set the reference pixel (step 310). Next, the position modulator is turned on and driven according to a preset modulation frequency ω (step 320). The array type photodetector vibrates according to the modulation frequency and simultaneously transmits the measurement signal output from the reference pixel to the demodulator (step 330). The demodulation device demodulates the measurement signal using the modulation frequency and provides it to the control unit (step 340). Through this process, it is possible to observe the change in the demodulated measurement signal, it is possible to check the change in the signal according to the response of the sample in real time.

Second Example

4 is a schematic diagram of a biosensor measuring system using surface plasmon resonance according to a second exemplary embodiment of the present invention. Hereinafter, the structure and operation of the biosensor measuring system according to the second embodiment of the present invention will be described in detail with reference to FIG. 4. Referring to FIG. 4, the biosensor measurement system 40 according to the second embodiment of the present invention may include a biosensor 400, a light source 410, a lens unit 420, an array type photodetector 430, and light intensity. The modulation device 440, the control unit 450 and the demodulation device 460 is provided. Since the biosensor, the light source, the lens unit, the array type photodetector and the demodulation device according to the second embodiment are the same as those of the first embodiment, overlapping description is omitted.

The biosensor measuring system according to the present embodiment is characterized by modulating the intensity of light output from the light source using the light intensity modulation element 440 according to the modulation frequency ω. The controller 450 controls the light intensity modulation element 440 to modulate the intensity of light output from the light source at a modulation frequency. The light intensity modulation device modulates the intensity of the output light of the light source by adjusting the intensity of the power source of the light source according to the modulation frequency provided from the controller.

Hereinafter, the operation of the controller 450 will be described sequentially. The controller 450 detects a measurement signal output from all pixels of the array type photodetector in a state where the intensity of the output light of the light source is not modulated initially. Using the detected measurement signals, a pixel corresponding to the incident angle having the greatest slope of the reflectance change is extracted. Set the extracted pixel as the reference pixel. Next, the light intensity modulation element is driven to modulate the output light intensity of the light source at the modulation frequency. While modulating the light intensity, a measurement signal output from the reference pixel is provided to a demodulator to demodulate at a modulation frequency. The controller outputs the demodulated measurement signals in real time. As a result, the biosensor measuring system according to the present invention can check in real time the change of the sample injected into the sample flow channel of the biosensor.

Although the present invention has been described above with reference to preferred embodiments thereof, this is merely an example and is not intended to limit the present invention, and those skilled in the art do not depart from the essential characteristics of the present invention. It will be appreciated that various modifications and applications which are not illustrated above in the scope are possible. And differences relating to such modifications and applications should be construed as being included in the scope of the invention as defined in the appended claims.

The biosensor measuring system according to the present invention not only accurately detects various kinds of biomaterials injected into the biosensor using surface plasmon resonance, but also detects the reaction state and the change state of a sample such as biomaterials injected into the biosensor. You can check in real time.

10, 40: biosensor measuring device
100, 400: Biosensor
110, 410: light source
120, 420: Lens part
130, 430: array type photodetector
140: position modulator
150, 450: control unit
160, 460: demodulation device
440: light intensity modulation element

Claims (9)

A light source for providing light;
A biosensor in which incident light provided from the light source is reflected at various reflection intensities by surface plasmon resonance;
A lens unit disposed between the light source and the biosensor to focus light provided from the light source to the biosensor;
An array type photodetector configured of a plurality of pixels arranged in an array to sense reflected light reflected from the biosensor;
A position modulator for vibrating the array type photodetector at a modulation frequency?
A demodulation device which receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the received measurement signal by using a modulation frequency?
A control unit controlling driving of the position modulation element, the array type photodetector, and the demodulation device to provide a measurement signal according to a change of a sample in real time;
The control unit initially sets one of the pixels of the array type photodetector as a reference pixel, and provides a measurement signal output from the reference pixel to the demodulator while driving the position modulator at a modulation frequency. And a biosensor measurement system using surface plasmon resonance, characterized in that for receiving and outputting a measurement signal demodulated in real time by a demodulation device. The method of claim 1, wherein the controller sets the reference pixel.
Detecting a measurement signal from all the pixels of the array type photodetector while the position modulator is turned off, extracting a pixel corresponding to the angle at which the gradient of reflectance change is greatest using the detected measurement signals, and extracting the extracted pixel. The biosensor measuring system using the surface plasmon resonance, characterized in that to set to a reference pixel. A light source for providing light;
A biosensor in which incident light provided from the light source is reflected at various reflection intensities by surface plasmon resonance;
A lens unit disposed between the light source and the biosensor to focus light provided from the light source to the biosensor;
An array type photodetector configured of a plurality of pixels arranged in an array to sense reflected light reflected from the biosensor;
A light intensity modulation element for changing the light intensity of the light source according to a modulation frequency?
A demodulation device which receives a measurement signal from a single pixel among the pixels of the array type photodetector, demodulates the received measurement signal by using a modulation frequency?
A control unit for controlling driving of the light intensity modulation element, the array type photodetector, and the demodulation device to provide a measurement signal according to a change of a sample in real time;
The control unit initially sets one of the pixels of the array-type photodetector as a reference pixel, modulates the light intensity of the light source at a modulation frequency, and simultaneously demodulates a measurement signal output from the reference pixel. The biosensor measuring system using surface plasmon resonance, characterized in that for receiving and outputting the demodulated measurement signal in real time by the demodulation device. The method of claim 3, wherein the controller sets the reference pixel,
Detecting a measurement signal from all the pixels of the array type photodetector while the light intensity modulation device is turned off, extracting a pixel corresponding to the angle at which the gradient of the reflectance change is the largest using the detected measurement signals, and extracting the extracted signal. A biosensor measuring system using surface plasmon resonance, characterized by setting a pixel as a reference pixel. The biosensor measuring system using surface plasmon resonance according to any one of claims 1 to 4, wherein the light source outputs a linear laser beam. The surface plasmon according to any one of claims 1 to 4, wherein the demodulation device is a lock-in amplifier, and the control unit provides a modulation frequency to be used as a reference frequency to the demodulation device. Biosensor measurement system using resonance. The biosensor measuring system using surface plasmon resonance according to claim 1, wherein the position modulator is a piezo actuator. The biosensor according to any one of claims 1 to 4, wherein the biosensor
A main body part made of a transparent material which reflects incident light vertically and emits the light to the array type light detecting part;
A metal thin film mounted on the reflective surface of the main body;
A sample flow channel to be measured can be injected into the inside, the sample flow channel mounted on one surface of the metal thin film;
Biosensor measurement system using the surface plasmon resonance, characterized in that it comprises a. The biosensor measuring system using surface plasmon resonance according to claim 8, wherein the main body of the biosensor is composed of a prism having a triangular or semicircular cross section.

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