KR101188233B1

KR101188233B1 - A diagnosis apparatus for biochip

Info

Publication number: KR101188233B1
Application number: KR20100057430A
Authority: KR
Inventors: 최완해
Original assignee: 한국알엠아이(주)
Priority date: 2010-06-17
Filing date: 2010-06-17
Publication date: 2012-10-09
Also published as: KR20110137474A

Abstract

The present invention relates to a diagnostic device for a biochip, and more particularly, by minimizing optical interference and image interference in a process of identifying a target during a DNA analysis or a protein analysis process, the microscopic characteristics of a sample can be analyzed and genes can be analyzed. It can be widely applied to diagnose biochips such as chips, protein chips, and immunodiagnostic chips. By scanning using a laser scanner, it is possible to determine the exact position for sensing highly integrated protein chips as well as speed up the scanning. Innovative and fast, with a variable beam magnifier installed between the combined mirror and the laser scanner, the beam size can be adjusted to match the cell size of the biochip and the color can be adjusted using multiple lasers. Of course, by attaching a control unit to the laser It is possible to control the beam size by attaching the control unit to the adjustable beam expander and laser scanner, and to install the focusing lens and excitation filter on the back of the biochip, and then install the CCD camera. Since the transmitted signal is locally possible, the interference of the CCD signal in each cell in the biochip is eliminated, so that accurate signal measurement is possible and the resolution is increased and a high precision measurement is possible when using a small CCD camera.

Description

Diagnostic apparatus for biochips

The present invention minimizes optical and image interference in the process of identifying targets during DNA analysis or protein analysis, and thus can analyze even minute characteristics of a sample, and diagnose biochips such as gene chips, protein chips, and immunodiagnostic chips. It is widely applicable and can be scanned using a laser scanner, which enables accurate positioning for sensing highly integrated protein chips, as well as significantly faster scanning speeds and variable beam expanders. ) Between the combined mirror and the laser scanner, the beam size can be adjusted according to the cell size of the biochip, color can be adjusted using a plurality of lasers, as well as the control unit attached to the laser intensity of the laser Adjustable beam expander and laser switch You can adjust the beam size by attaching a control unit to you, and by installing the focusing lens and the excitation filter on the back of the biochip in sequence and then installing the CCD camera, the signal transmitted from the CCD camera can be localized. As the interference of the CCD signal in the cell is eliminated, it is possible to precisely measure the signal, as well as a diagnostic device for a biochip capable of high resolution and high resolution when using a small CCD camera.

Generally, biochip refers to the accumulation of biomolecules such as DNA and protein on a small substrate made of glass, silicon, or nylon, and when the DNA is integrated, the DNA chip, protein When accumulated, it is called protein chip.

The DNA chip is a high-density deposit of a huge number of DNA for gene searching. The representative genetic engineering methods that can be replaced by these DNA chips include Southern and Northern blots, mutation detection, and DNA sequencing. The main difference from these methods is that at least hundreds of genes can be searched at the same time. DNA chips can be divided into cDNA chips, oligonucleotide chips, and diagnostic BAC chips for cancer, depending on the size of the genetic material attached.

The DNA chip scanner reads and analyzes information about genetic modifications of patients and objects from cDNA chips, oligonucleotide chips, and diagnostic BAC chips. In addition, the genetic information scanned by the DNA chip scanner is analyzed through the scanner's built-in software, and it has a function of making a database and comparing it with other data servers.

As such, DNA chip scanners can be used to identify specific genes from DNA sequencing information that is emerging from a large number of technologies such as gene isolation and recombination technology, gene transplantation technology, genomic database construction technology, bioinformatics technology, and biochip technology. It is used to find and identify the function of each gene and protein. In particular, it is attracting attention because it can display a large amount of information in a short time and it is easy to automate.

DNA chip scanners are classified into two types according to the light source used, and are classified into a laser method using a laser and a CCD method using white light such as Xenon or a metal halide lamp.

Figure 1 is a schematic diagram showing the basic structure of a DNA chip scanner using a cooled charge coupled detector (CCD) method.

As shown in FIG. 1, the DNA chip scanner includes a light source unit 60 for generating excitation light, a stage unit 70 for fixing the DNA chip, and a camera unit 80 for detecting fluorescence generated from the DNA chip. Is done.

The light source unit 60 generates excitation light by filtering the white light generated from the lamp 61 by filters 65 and 68 having a suitable color according to the type of the dye processed on the DNA chip. The DNA chip 90 fixed to 70) is irradiated to excite the dye. The spontaneous emission emitted from the dye is filtered by an emission filter 81 installed in front of the CCD 85 of the camera unit 80 to image light emitted purely from the dye.

However, the conventional scanner has a property that the white light emitted from the lamp basically emits light, but the brightness of the scan area is uneven because it cannot be efficiently focused and irradiated onto the DNA chip. In addition, since the excitation light reflected once after being irradiated onto the DNA chip is discarded without being used again, there is a problem in that a larger lamp is used to obtain light having a desired level of intensity.

In recent years, the genetic map of humans has been completed, and the understanding of human diseases has increased, and the possibility of prolonging life is higher than ever before. Genetic mapping of these genes is expected to make a significant contribution to the relationship between specific genes and diseases, and studies are being actively conducted to analyze proteins directly related to the expression of diseases.

In order to analyze DNA, DNA is separated from a living body, purified, amplified, fixed to a substrate, and then irradiated with light, and a method of analyzing using fluorescence generated is mainly used. Almost similar to the above DNA analysis method is used, except that the amplification process is not necessary for analyzing the protein.

Conventionally, such analytical technology is biased for research, and large expensive equipment is used for analysis. Figure 2 is a schematic diagram showing a laser scanning confocal microscope according to the prior art.

As shown in FIG. 2, the excitation light emitted from the light source unit 60 passes through the objective lens 78 after passing through the 495 nm optical filter 63 and the beam splitter 65 and then the sample 80. Is investigated. At this time, the sample 80 generates fluorescence, and the generated fluorescence passes through the objective lens 78 and passes through the optical splitter 65 and the 520 nm optical filter 67, followed by a charge coupled device (CCD) ( 74,76) to make an image. In this case, since the excitation light passes through the objective lens 78, when observing a plurality of samples, that is, microarray-shaped samples, the sample 80 is accurately fixed to the operating distance of the objective lens 78. In order to move the sample 80 in a planar manner, therefore, expensive equipment having a mechanically complicated structure is required.

However, in the case of a protein chip that can provide direct information on the diagnosis of a disease, there is a demand for a simple diagnosis of a disease in a small hospital or at home, and accordingly, the need for miniaturization of analytical devices increases.

The manufacture of micro chip that preprocesses DNA or protein to be analyzed or lab-on-a-chip that analyzes it and processes the data and shows the result is a semiconductor that has advanced computer and communication. The combination of MEMS (Micro-Electro-Mechanical System) technology derived from process technology and biotechnology has increased the possibility, and MOEMS (Micro-Opto-Electro-Mechanical System) technology applied in optical communication The possibility of making On-a-chip was further enhanced. In other words, the results of the previous studies have found that the micro-elements necessary for fabricating chips, such as fluid passages, valves, pumps, mixers, and separators, can be sufficiently manufactured by MEMS technology. It has been found that isolation and purification of proteins, such as adsorption and adsorption of antibodies, are also possible on chips made of micro devices with a slight modification of conventional methods.

However, the conventional fluorescence measurement method which is widely used in the target identification step, which is the final step of DNA or protein analysis, uses the laser or light source unit 60 as a light source and the optical filters 63 and 67 to separate the fluorescence from the excitation light. In order to measure extremely low power fluorescence, a cooling CCD (74, 76) or a photo-multiplier tube (Photo-Multiplier Tube) is used. For this reason, there have been many difficulties in miniaturizing the measuring device.

In addition, the conventional method of scanning the entire area of the biochip is fast, but precise data cannot be obtained, and the method of scanning a single cell of the biochip can obtain accurate data, but the scanning speed is slow.

Therefore, it is possible to analyze the microscopic characteristics of the sample by minimizing optical interference and image interference in the process of confirming the target during DNA analysis or protein analysis process, and by using a laser scanner, it is precisely positioned for sensing highly integrated protein chips. In addition, the speed of scanning can be dramatically increased, and a variable beam expander can be installed between the combined mirror and the laser scanner to adjust the beam size corresponding to the cell size of the biochip. Colors can be adjusted using two lasers, as well as a control unit attached to the laser to adjust the intensity of the laser, and a CCD camera is installed after installing a focusing lens and an excitation filter on the back of the biochip in sequence. By-pass signals are locally available A situation which is the urgent need for development of a diagnostic device for the precise signal measurement is possible because the interference of the bio-chip CCD signal becomes not in each cell in the chip.

Therefore, the present invention has been conceived to solve the above problems, by minimizing optical interference and image interference in the process of identifying the target during DNA analysis or protein analysis, diagnostics for biochips that can analyze the fine characteristics of the sample The purpose is to provide a device.

Another object of the present invention is to provide a diagnostic device for a biochip that can be widely applied to diagnose biochips such as gene chips, protein chips, and immunodiagnostic chips.

Still another object of the present invention is to provide a diagnostic device for a biochip that can accurately detect the position of the highly integrated protein chip by scanning using a laser scanner, as well as dramatically speed up the scanning. have.

Another object of the present invention is to provide a diagnostic device for a biochip that can adjust the beam size corresponding to the cell size of the biochip by installing a variable beam expander between the combined mirror and the laser scanner.

Still another object of the present invention is to provide a diagnostic device for a biochip that can adjust color using a plurality of lasers, as well as attach a control unit to the laser to control the intensity of the laser.

Still another object of the present invention is to provide a diagnostic apparatus for a biochip that can adjust a beam size by attaching a control unit to a variable beam expander and a laser scanner.

It is still another object of the present invention to sequentially install a focusing lens and an excitation filter on the back of a biochip, and then install a CCD camera, so that the signals transmitted from the CCD camera can be localized so that interference of the CCD signal in each cell in the biochip can be achieved. This eliminates the need for precise signal measurement, as well as providing diagnostic devices for biochips with increased resolution and high-precision measurements when using compact CCD cameras.

Diagnostic device for a biochip of the present invention for achieving the above object comprises a laser light source unit for emitting a laser light from the light source; A mirror for receiving the laser light emitted from the laser light source unit; A variable beam expander which receives the laser beam passing through the mirror and adjusts the beam size according to the cell size of the biochip; A laser scanner for reflecting the parallel light via the beam expander at a predetermined angle while vibrating up, down, left, and right; A scanner driver for driving the laser scanner; An objective lens in which light reflected from the laser scanner is incident and emitted as parallel light to collect light for irradiating cells on a biochip substrate; A biochip in which biomolecules, which are cells for DNA, protein, and immunodiagnosis, are integrated on a substrate made of glass, silicon, or nylon to receive parallel light emitted from the objective lens; A focusing lens for focusing white light passing through the biomolecules of the biochip; An excitation filter which receives the white light focused through the focusing lens and transmits the excitation light having a predetermined wavelength; A CCD camera which acquires an image from the excitation light passing through the excitation filter; .

In the present invention, since the laser light source unit emits a plurality of laser lights from a plurality of lasers having different wavelengths, it is possible to adjust the color of the laser light.

In the present invention, in the case of installing a plurality of lasers having different wavelengths in order to adjust the color of the laser light in the laser light source unit coupling mirror for combining the laser light emitted from the plurality of laser; It characterized in that it further comprises.

In the present invention, it is possible to adjust the beam size by attaching a control unit to the variable beam expander and the laser scanner.

In the present invention, it is possible to adjust the intensity of the laser by attaching a control unit to the laser light source.

In the present invention, the focusing lens is characterized by using a spherical lens or an aspherical lens, and using a concave lens and a convex lens or a concave lens and a convex lens in combination.

In the present invention, the CCD camera is characterized in that it comprises a linear image element and an area image element, including a time delayed integration (TDI) sensor.

In the present invention, since the focusing lens and the excitation filter are sequentially installed at the rear of the biochip, and then the CCD camera is installed, the signal transmitted from the CCD camera is locally possible, so that the interference of the CCD signal in each cell in the biochip is reduced. Characterized in that disappeared.

As described above, the diagnostic device for a biochip according to the present invention has the following effects.

First, the present invention can analyze the fine properties of the sample by minimizing optical interference and image interference in the process of identifying a target during DNA analysis or protein analysis.

Second, the present invention is characterized in that the beam size can be adjusted by attaching a control unit to the variable beam expander and the laser scanner.

Third, according to the present invention, by using a laser scanner, it is possible to grasp the exact position for sensing the highly integrated protein chip as well as to dramatically speed up the scanning.

Fourth, the present invention can adjust the beam size corresponding to the cell size of the biochip by installing a variable beam expander between the combined mirror and the laser scanner.

Fifth, the present invention can adjust the color using a plurality of lasers as well as the control unit attached to the laser can adjust the intensity of the laser.

Sixth, the present invention can control the beam size by attaching a control unit to the variable beam expander and laser scanner.

Seventh, the present invention is to install the focusing lens and the filter in the back of the biochip sequentially and then install the CCD camera, so that the signal transmitted from the CCD camera is locally possible, so that the interference of the CCD signal in each cell in the biochip is eliminated. This enables precise signal measurement, as well as increased resolution and high precision measurements when using a compact CCD camera.

1 is a schematic diagram showing the basic structure of a DNA chip scanner using a conventional cooled charge coupled detector (CCD) method.
Figure 2 is a schematic diagram showing a laser scanning confocal microscope according to the prior art.
3 is a view showing the configuration of a diagnostic device for a biochip according to an embodiment of the present invention.
4 is a view showing a form of sensing a highly integrated protein chip using a laser scanner of a diagnostic device for a biochip according to an embodiment of the present invention.

Looking at a preferred embodiment of the present invention together with the accompanying drawings as follows, when it is determined that the detailed description of the known art or configuration related to the present invention may unnecessarily obscure the subject matter of the present invention The detailed description will be omitted, and the following terms are terms defined in consideration of functions in the present invention, which may vary according to intentions or customs of users or operators, and the definitions are used to describe the diagnostic apparatus for the biochip of the present invention. It should be made based on the contents throughout the specification.

3 is a view showing the configuration of a diagnostic device for a biochip according to an embodiment of the present invention, Figure 4 is a high-density protein chip sensing using a laser scanner of the diagnostic device for a biochip according to an embodiment of the present invention It is a figure which shows the form to make.

Hereinafter, a diagnostic apparatus for a biochip according to a preferred embodiment of the present invention will be described in detail with reference to the accompanying drawings.

3 and 4, the diagnostic apparatus 100 for a biochip according to an embodiment of the present invention is a laser light source 101, a mirror 102, a coupling mirror 103, a beam expander 104 , Laser scanner 105, scanner driver 106, objective lens 107, biochip 108, focusing lens 109, excitation filter 110, CCD camera 111, control unit 112, etc. do.

3 and 4, the diagnostic apparatus for a biochip includes a laser light source unit 101 for emitting a laser light from the light source; A mirror 102 for receiving the laser light emitted from the laser light source unit; A variable beam expander (104) for receiving a laser beam passing through the mirror and adjusting a beam size corresponding to a cell size of a biochip; A laser scanner (105) for reflecting parallel light via the beam expander at a predetermined angle while vibrating up, down, left, and right; A scanner driver (106) for driving the laser scanner; An objective lens 107 which receives light reflected from the laser scanner and exits as parallel light and collects light for irradiating cells on a biochip substrate; A biochip 108 in which biomolecules, which are cells for DNA, protein, and immunodiagnosis, are integrated on a substrate made of glass, silicon, or nylon to receive parallel light emitted from the objective lens; A focusing lens 109 for focusing white light passing through the biomolecules of the biochip; An excitation filter 110 which receives the white light focused through the focusing lens and transmits the excitation light having a predetermined wavelength; A CCD camera 111 for obtaining an image from the excitation light passing through the excitation filter; Combination mirror 103 is configured to combine the laser light emitted from the plurality of laser when installing a plurality of laser having a different wavelength to adjust the color of the laser light in the laser light source unit; .

The function of each technical means constituting the diagnostic device for the biochip is as follows.

The laser light source unit 101 emits laser light from the light source. In this case, the laser light source unit 101 emits a plurality of laser light from a plurality of lasers having different wavelengths, thereby controlling the color of the laser light, and attaching a control unit 112 to the laser light source unit 101 to You can adjust the intensity.

In addition, 488 nm-laser may be used as the laser light source when measuring by using Fluorescein isothiocyanate (FITC) as a fluorescent material, and 633 nm-HeNo laser when measuring by using APC (Allophyco-cyanin) as a fluorescent material. A laser diode can be used, and it is preferable to use a laser diode when miniaturization is aimed at.

The mirror 102 receives the laser light emitted from the laser light source unit.

The coupling mirror 103 combines the laser light emitted by the plurality of lasers when a plurality of lasers having different wavelengths are installed in order to adjust the color of the laser light in the laser light source unit.

The variable beam expander 104 receives the laser beam passing through the mirror and adjusts the beam size corresponding to the cell size of the biochip.

The laser scanner 105 reflects the parallel light via the beam expander at a predetermined angle while vibrating up, down, left, and right. In this case, the beam size can be adjusted by attaching the control unit 112 to the variable beam expander 104 and the laser scanner 105.

The scanner driver 106 drives the laser scanner.

The objective lens 107 collects light to be irradiated to the cells on the biochip substrate by the light reflected from the laser scanner is incident and emitted as parallel light.

The biochip 108 is a cell in which biomolecules, such as DNA, protein, and immunodiagnostic cells, are integrated on a substrate made of a material such as glass, silicon, or nylon in order to receive parallel light emitted from the objective lens.

The focusing lens 109 focuses white light that has passed through biomolecules of the biochip. Here, the focusing lens 109 uses a spherical lens or an aspherical lens, and the aspherical lens shows better focusing ability than a conventional spherical lens. In addition, the focusing lens 109 may use a concave lens or a convex lens, or may use a combination of a concave lens and a convex lens.

The excitation filter 110 receives the white light focused through the focusing lens and transmits the excitation light having a predetermined wavelength.

The CCD camera 111 acquires an image from the excitation light passing through the excitation filter. Here, the CCD camera 111 includes a linear image element and an area image element including a time delayed integration (TDI) sensor. In this case, since the focusing lens 109 and the excitation filter 110 are sequentially installed at the rear of the biochip 108 and then the CCD camera 111 is installed, the signals transmitted from the CCD camera are locally available. The interference of the CCD signal in the cell is eliminated.

As shown in FIG. 4, the high-density protein chip is sensed by using a laser scanner of a diagnostic device for a biochip, while the light reflected from the laser scanner 105 moves to cells that are biomolecules of the protein chip. Diagnose the protein chip from the images obtained from the investigation.

Therefore, by scanning the cells of the protein chip biomolecules using a laser scanner it is possible to determine the exact position for sensing the cells of the highly integrated protein chip.

As described above, various substitutions, modifications, and changes can be made by those skilled in the art without departing from the technical spirit of the present invention, and thus, the embodiments and the accompanying drawings are limited. It doesn't happen.

As described above, the present invention is applicable to a laser scanner-based CCD sensing system, and can be widely applied to diagnose biochips such as gene chips, protein chips, and immunodiagnostic chips.

100: diagnostic device 101: laser light source
102: mirror 103: combined mirror
104: beam expander 105: laser scanner
106: scanner driver 107: objective lens
108: biochip 109: focusing lens
110: excitation filter 111: CCD camera
112: control unit

Claims

In the diagnostic device for a biochip,
A laser light source unit emitting laser light from the light source;
A mirror for receiving the laser light emitted from the laser light source unit;
A variable beam expander which receives the laser beam passing through the mirror and adjusts the beam size according to the cell size of the biochip;
A laser scanner for reflecting the parallel light via the beam expander at a predetermined angle while vibrating up, down, left, and right;
A scanner driver for driving the laser scanner;
An objective lens in which light reflected from the laser scanner is incident and emitted as parallel light to collect light for irradiating cells on a biochip substrate;
A biochip in which biomolecules, which are cells for DNA, protein, and immunodiagnosis, are integrated on a substrate made of glass, silicon, nylon, etc. to receive the parallel light emitted from the objective lens;
A focusing lens for focusing white light passing through the biomolecules of the biochip;
An excitation filter which receives the white light focused through the focusing lens and transmits the excitation light having a predetermined wavelength;
A CCD camera which acquires an image from the excitation light passing through the excitation filter; Diagnostic device for a biochip, characterized in that it comprises a.

The method of claim 1,
The laser light source unit emits a plurality of laser light from a plurality of laser having a different wavelength, so that the diagnostic device for a biochip, characterized in that the color of the laser light can be adjusted.

3. The method according to claim 1 or 2,
A coupling mirror configured to combine laser beams emitted from the plurality of lasers when a plurality of lasers having different wavelengths are installed in order to adjust the color of the laser light in the laser light source unit; Diagnostic device for a biochip, characterized in that it further comprises.

The method of claim 1,
Diagnosis apparatus for a biochip, characterized in that the variable beam expander, and a control unit attached to the laser scanner can adjust the beam size.

3. The method according to claim 1 or 2,
And a control unit attached to the laser light source unit to adjust the intensity of the laser.

The method of claim 1,
The focusing lens is a spherical lens or an aspherical lens, and a concave lens and a convex lens or a concave lens and a convex lens in combination using a diagnostic device for a biochip.

The method of claim 1,
The CCD camera includes a linear image element and an area image element including a time delayed integration (TDI) sensor.

The method of claim 1,
Since the CCD camera is installed after the focusing lens and the excitation filter are sequentially installed at the rear of the biochip, the signal transmitted from the CCD camera is locally possible, so that the interference of the CCD signal in each cell of the biochip is eliminated. Diagnostic device for biochips.