CN100417931C - Microarray chip detection system - Google Patents
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- CN100417931C CN100417931C CNB2005100632089A CN200510063208A CN100417931C CN 100417931 C CN100417931 C CN 100417931C CN B2005100632089 A CNB2005100632089 A CN B2005100632089A CN 200510063208 A CN200510063208 A CN 200510063208A CN 100417931 C CN100417931 C CN 100417931C
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Abstract
The present invention discloses a microarray chip detection system which comprises an incident light generating system, a reflected light collecting system, a collected light processing system and an objective table placed with a microarray chip, wherein the incident light generating system comprises a laser device, a beam-expanding collimation lens and a cylindrical surface shaper; the reflected light collecting system comprises a bifocal surface Imaging lens group, a color filtering lens and a CCD detector. Compared with an internationally popular biological chip detecting instrument, the present invention has the functions of scanning, digital imaging, etc. and the advantages of simple structure, low cost and low requirement on precision of the mechanical processing, and thereby, the present invention is beneficial to popularization.
Description
Technical field
The present invention relates to microarray chip detection system, particularly relate to a kind of with low costly, and detection sensitivity and resolution are all than higher microarray chip detection system.
Background technology
Biochip technology is a multidisciplinary interleaving techniques that rises in the twentieth century later stage, it is by engineerings such as microelectronics, micromechanics, ray machine electricity software integration integrated technologies, digital processes such as specimen preparation in the life science, chemical reaction and analyzing and testing are integrated in the slight chip, realize processing procedure serialization, integrated and microminiaturized.
The biochip supplies analysis device is that biochip technology moves towards the indivisible specialized instrument and equipment of practical application, by micro-amplification imaging, cofocus scanning, fluorescence detection, and technological means such as digital image processing, the gene differential expression result that the reaction of biochip mesophytization is caused shows with graphic form, is convenient to people and carries out medical analysis or carry out other research.
At present, popular in the world biochip supplies analysis device mainly contains high-grade fluorescent microscope, cofocal scanner and refrigeration CCD imaging system etc.High-grade fluorescent microscope is the simple bio-chip test device that a kind of manual operations is used, the biochip hybridization signal that can carry out is among a small circle observed, also can viewed fluorescence signal collection and storage be generated digital image by the refrigeration CCD digitization system that fluorescent microscope carries, the shortcoming of this high-grade fluorescent microscope is that its range of observation is smaller, generally have only several millimeters, and the observation visual field will be less than 1 millimeter under the high resolving power enlargement factor, its cost is also relatively more expensive, and general price is about 4～50,000 dollars.Cofocal scanner is a kind of popular in the world automatic biological chip detection instrument, can carry out the biochip hybridization input of large tracts of land (25 millimeters * 75 millimeters), intermediate resolution (5 microns～50 microns), and storage generates digital image.The major defect of cofocal scanner is: 1, its detection resolution is decided jointly by the imaging resolution of optical system, the mechanical precision and the scanning motion control accuracy of scanning motion platform, and at present mechanical precision and scanning motion control accuracy significantly improve with regard to very difficult reach 5 microns in large tracts of land scans the application of detection fast after again; 2, cofocal scanner is a kind of work in series mode, the data acquisition transmission speed is subjected to many-sided restrictions such as scanning motion, A/D conversion and data-interface communication, (time long (20 minutes/5 microns resolution) that 20mm * 60mm) detects is difficult to increase substantially its speed to large tracts of land again; 3, cofocal scanner needs to increase the grating chi and guarantees scanning accuracy as feedback element in practical structures, and cost will increase about 1/8; 4, the cofocal scanner overall precision relies on the mechanical precision of scanning motion platform, the cost height of machining.These factors make that the cost of cofocal scanner is very expensive, and general price is about 5～100,000 dollars.Refrigeration CCD imaging system also is a kind of biochip supplies analysis device, can carry out the biochip hybridization input of large tracts of land (tens millimeters), low resolution (＞50 microns), and storage generates digital image, the major defect of this system is: 1, the cost of refrigeration CCD itself is generally about 5000 dollars～20,000 dollars just than higher; 2, use behind the refrigeration CCD in order to improve detection sensitivity, usually adopt the method that prolongs sampling exposure integral time (needing tens seconds or a few minutes), to increase considerably detection time like this, also will speed up the photobleaching of sample in the biochip simultaneously, the serviceable life of reducing chip greatly; 3, present widely used refrigeration CCD imaging system mainly adopts Polaroid mode, detect its resolution and be subjected to serious restriction for carrying out large-area chips, otherwise surveyed area must reduce; If 4 select the CCD chip of big detection area, then its cost will increase at double exponentially.These factors make the general price of refrigeration CCD imaging system about 3～40,000 dollars.
These above-mentioned instruments still exist such or such shortcoming, and its market price also is costliness very, also are not suitable for applying.Therefore, very need a kind of with low costly, and detection sensitivity and resolution are all than the appearance of higher microarray chip detection system.
Summary of the invention
The purpose of this invention is to provide a kind of with low costly, and detection sensitivity and resolution are all than higher microarray chip detection system.
For achieving the above object, the invention provides a kind of microarray chip detection system, the objective table that includes incident light generation system, fluorescence gathering system, collection optical processing system and place micro-array chip, described incident light generation system includes the cylinder reshaper of a laser instrument, a beam-expanding collimation mirror and an oblique fire; Described fluorescence gathering system includes a pair of focal plane imaging lens combination, a color filter and one side battle array ccd detector.
In practical operation, described cylinder reshaper includes two cylindrical mirrors and two lens, and it sets gradually concavees lens, convex lens, a cylindrical mirror and another cylindrical mirror by the beam-expanding collimation mirror.Described bifocal segment imaging lens group includes 12 lens, and it is disposed with concavees lens A, the concavees lens B that comprises two concave surfaces, the convex lens C that comprises two convex surfaces, the concavees lens D that comprises two concave surfaces, the convex lens E that comprises two convex surfaces, the concavees lens F that comprises two concave surfaces, the convex lens G that comprises two convex surfaces, the convex lens H that comprises two convex surfaces, the concavees lens I that comprises a concave surface and a convex surface that comprise a concave surface and a convex surface, comprise two convex surface convex lens J and convex lens K, comprise the concavees lens L of a concave surface and a convex surface.
Above-mentioned collection optical processing system includes a computing machine, and the output terminal of described ccd detector is connected with this computing machine; Ccd detector obtains a width of cloth width of cloth fluorescence signal image corresponding with chip geometrical plane position, and is all temporary in computing machine earlier, carries out image splicing and position correction automatically behind the end of scan again, forms a complete fluorescence biosensor chip input image.Specifically, carry out behind the described end of scan image automatically the method for splicing and position correction be: 1. when image acquisition, the surveyed area scope is outwards suitably enlarged 50 pixels along the edge, generates an a width of cloth original little figure; 2. in the regional extent of 50 pixels in every adjacent two width of cloth little figure edge, seek unique point, calculate the position deviation of same unique point in the little figure of adjacent two width of cloth; 3. adjust the center of little figure according to position deviation, the same unique point in two adjacent little figure can be overlapped fully, the precision of this adjustment can reach 1 pixel; 4. picture mosaic, according to the actual tile size of setting, be the center with the center of 3. calculating the little figure that obtains in the step, from original little figure, cut out the little figure of corresponding actual splicing, be stitched together according to adopting one one width of cloth of figure order then, form final scanning image; By the adjustment of said method, can be with position deviation in the actual scanning at ± 25 pixels with interior error correction to 1 pixel.
In addition, described objective table comprises two stepper motors of precise guide rail, precision lead screw and control platform two dimensional motion; Described collection optical processing system also includes an electronic circuit control board, and described electronic circuit control board is connected between the stepper motor of computing machine and objective table, and computing machine is by electronic circuit control board control step motor movement.
The present invention is owing to take above design, and it has the following advantages:
1, be provided with a cylinder reshaper among the present invention, it can be shaped to the oval hot spot of oblique incidence illumination and be circular light spot, guarantees the homogeneity of oblique incidence illumination hot spot, realizes that it is the detection of throwing light on simultaneously of the large area region of 5mm that biochip is carried out diameter.Compare with the beam shaping scheme of common " ellipsoidal mirror+integrating sphere ", cylindrical mirror combination oblique incidence reshaping structure scheme has simple in structure, and cost is low, characteristics such as easy realization of industrialization; Simultaneously, this oblique incidence means of illumination can effectively reduce the disturbing effect of the reflected light of exciting light to the fluorescence signal receiving end, realizes large tracts of land excitation-detection simultaneously, effectively reduces ground unrest.
2, the invention provides a kind of bifocal segment imaging len of forming by 12 eyeglasses, the bifocal segment imaging arrangement that this 12 eyeglasses are formed, can utilize the numerical aperture of object lens to greatest extent, make the fluorescence receiving efficiency reach the diffraction limit theoretical value of system, the fluorescence signal intensity that obtains than common micro-imaging significantly improves.
3, among the present invention, because computing machine carries out image splicing and position correction automatically behind the end of scan, make the machining accuracy of scanning motion platform drop to 10um like this from 2um, motion control drops to 0.5mm from 2um, effectively reduce production technology difficulty and processing cost, can find processing cooperation unit easily, popularize easily.
4, among the present invention, adopt multiple region segmentation method, gridding feature in conjunction with the micro-array chip image is carried out addendum, guarantees accurate discrimination＞95% of image, satisfies the user and obtains the chip image line data of going forward side by side simultaneously and extract request for utilization with analyzing and processing etc.
5, compare with the microlens that performance is close in the world, the lens construction of the present invention's design is simple, and eyeglass quantity is few, and the optical glass material kind of use is few, the processing technology height, and production cost is low.
Description of drawings
Fig. 1 is a structural representation of the present invention;
Fig. 2 is the synoptic diagram of cylinder reshaper spot shaping of the present invention;
Fig. 3 is the disc of confusion synoptic diagram of wide field range among the present invention;
Fig. 4 is the FFT diffraction energy distribution plan of different view field imagings among the present invention.
Embodiment
As shown in Figure 1, be a kind of microarray chip detection system provided by the invention, the objective table 4 that includes incident light generation system 1, fluorescence gathering system 2, collection optical processing system 3 and place micro-array chip.Incident light generation system 1 includes a laser instrument 11, a beam-expanding collimation mirror 12 and a cylinder reshaper 13; Fluorescence gathering system 2 includes a pair of focal plane imaging lens combination 21, a color filter 22 and a ccd detector 23.
In the present embodiment, the cylinder reshaper includes two cylindrical mirrors and two lens, and it sets gradually by beam-expanding collimation mirror 12 and is recessed flat cylindrical mirror 131, plano-convex cylindrical mirror 132, convexo-convex lens 133 and concave-convex lens 134.The parameter of each minute surface in the present embodiment, as shown in the table: (two minute surfaces of being close to, parameter is identical).
Sequence number radius-of-curvature summit, surface spacing glass material surface radius
1 -18.4 1.1 ZK11 5.4
2 ∞, 35.1 air 6.1
3 ∞ 2.9 ZK11 8.2
4 42.2 4.6 air 10.5
5 64.5 3.7 K9 10.3
6 -50.3 1.2 ZF2 10.4
7-140.5 105.3 air 10.4
Illustrate: radius-of-curvature error wherein is ± 3.5, and the summit interval error is ± 0.5, and the surface radius error is ± 1.0.
As can be seen from Figure 1, cylinder reshaper provided by the present invention is oblique fire, as its oblique fire angle of an embodiment is 30 ° ± 10 °, utilize it the oval hot spot of oblique incidence illumination can be shaped to and be circular light spot, guarantee the homogeneity (as shown in Figure 2) of oblique incidence illumination hot spot, realize that biochip is carried out large area lighting to be detected.Compare with the beam shaping scheme of common " ellipsoidal mirror+integrating sphere ", cylindrical mirror combination oblique incidence reshaping structure scheme has simple in structure, and cost is low, characteristics such as easy realization of industrialization.Simultaneously, this oblique incidence means of illumination can effectively reduce the disturbing effect of the reflected light of exciting light to the fluorescence signal receiving end, realizes large tracts of land excitation-detection simultaneously, effectively reduces ground unrest.The strength degradation of selecting suitable oblique incidence angle can make the reflected light of exciting light enter the fluorescence signal receiving light path is zero.This shows that the indirect illumination fluorescence excitation method of this oblique incidence cylinder shaping illumination fluorescence excitation method and cofocal scanner and the reflection (or transmission) of the fluorescent microscope fluorescence excitation method of throwing light on is compared and had obvious superiority.
In the present embodiment, the bifocal segment imaging lens group includes 12 lens, and it is disposed with the concavees lens A51 that comprises a concave surface and a convex surface, the concavees lens B52 that comprises two concave surfaces, the convex lens C53 that comprises two convex surfaces, the concavees lens D54 (radius-of-curvature of one of them concave surface is very big) that comprises two concave surfaces, the convex lens E55 that comprises two convex surfaces, the concavees lens F56 (radius-of-curvature of one of them concave surface is very big) that comprises two concave surfaces, the convex lens G57 that comprises two convex surfaces, the convex lens H58 that comprises two convex surfaces, the concavees lens I59 that comprises a concave surface and a convex surface, the convex lens J60 that comprises two convex surfaces, the concavees lens L62 that comprises the convex lens K61 of two convex surfaces and comprise a concave surface and a convex surface.The bifocal segment imaging lens group is the parameter of each minute surface in the present embodiment, and is as shown in the table: (two minute surfaces of being close to, parameter is identical).
Sequence number radius-of-curvature summit, surface spacing glass material surface radius
1 -6.4 5.1 ZK11 4.4
2-5.4 0.2 air 5.4
3 -24.1 1.8 ZF2 6.2
4 50.2 0.5 air 7.5
5 67.5 5.1 ZK7 8.3
6-13.3 0.8 air 9.4
7 -106.0 2.5 ZF2 9.8
8 30.4 5.6 ZK7 10.5
9-25.5 0.5 air 10.5
10 -306.5 2.5 ZF2 10.5
11 26.5 4.3 ZK7 10.5
12-98.2 80 air 10.5
13 97.5 8.5 ZK7 15.5
14-31.5 4.4 air 15.5
15 -21.2 6.1 ZF2 15.5
16-267.5 0.2 air 15.5
17 49.3 6.2 ZF7 15.5
18-215.7 0.21 air 15.5
19 27.1 8.1 ZK7 15.5
20 -55.3 4.2 ZF2 15.5
21-160.1 16.7 air 15.5
Illustrate: radius-of-curvature error wherein is ± 1.0, and the summit interval error is ± 0.5, and the surface radius error is ± 1.0.
Disperse fluorescence through what biochip inspired, successively by concavees lens A, concavees lens B, convex lens C, concavees lens D, convex lens E, behind concavees lens F and the convex lens G, fluorescence excitation was received and was collimated into directional light output with very big numerical aperture (NA＞0.7) this moment, then, colour filter by color filter 22, filter laser illuminator and other parasitic light, again successively by convex lens H, concavees lens I, convex lens J, convex lens K and concavees lens L, fluorescence excitation was assembled and was imaged on the sensor cover battle array of ccd detector 23 this moment, and last optical excitation signal is collected by ccd detector 23 and carried out opto-electronic conversion and import computing machine.
The bifocal segment imaging arrangement that this 12 eyeglasses are formed can utilize the numerical aperture of object lens to greatest extent, makes the fluorescence receiving efficiency reach the diffraction limit theoretical value of system, and the fluorescence signal intensity that obtains than common micro-imaging significantly improves; Handle at the coating process that these eyeglass processing backs adopt the film coefficient design proposal of multilayer anti-reflection film to carry out high permeability, the transmitance of single eyeglass＞99.9%, entire system sees through efficient and reaches more than 90%.Make the fluorescence signal detection sensitivity of system improve 2 orders of magnitude like this than conventional imaging system, therefore can adopt plain edition low-light (level) CCD to replace refrigeration CCD, nearly 100,000 yuan of the price of refrigeration CCD, but also the long-time integration that need carry out several minutes could obtain a panel height sensitivity image, thereby the production cost that effectively reduces instrument has improved sweep velocity (ordinary video picking rate, 25 frames (or 25 images)/second) simultaneously.
In addition, the lens set that the biochip scanning that this 12 eyeglasses are formed detects, field range reaches 2mm, can realize the chip area of 2 millimeters of one-time detection like this, reduces scanning times effectively, shortens detection time.Simultaneously, it is simple in structure, and good manufacturability and cost are low, and can improve detection sensitivity, the scanning resolution of biochip scanning-detecting system, makes it have long operating distance.In the present embodiment, numerical aperture is 0.72, and operating distance is 3.22mm.
In the present embodiment, collect optical processing system 3 and include a computing machine 31 and an electronic circuit control board 32, the output terminal of described ccd detector 23 is connected with computing machine 31; Ccd detector 23 obtains a width of cloth width of cloth fluorescence signal image corresponding with chip geometrical plane position, all temporary in computing machine 31 earlier, behind the end of scan, carry out image splicing and position correction automatically again, form a complete fluorescence biosensor chip input image.What deserves to be mentioned is that automatically the method for splicing and position correction is for being that 50 pixels are sought feature locations in interior image edge overlay region at width to carry out image behind the end of scan, the calculating location deviation is revised when the picture mosaic by software then.Specific implementation method is: 1. when image acquisition the surveyed area scope is outwards suitably enlarged 50 pixels along the edge, generate an a width of cloth original little figure; 2. in the regional extent of 50 pixels in every adjacent two width of cloth little figure edge, seek unique point, calculate the position deviation of same unique point in the little figure of adjacent two width of cloth; 3. adjust the center of little figure according to position deviation, the same unique point in two adjacent little figure can be overlapped fully, the precision of this adjustment can reach 1 pixel; 4. picture mosaic, according to the actual tile size of setting, be the center with the center of 3. calculating the little figure that obtains in the step, from original little figure, cut out the little figure of corresponding actual splicing, be stitched together according to adopting one one width of cloth of figure order then, form final scanning image; Adjust by above-mentioned method, can be with position deviation in the actual scanning at ± 25 pixels with interior error correction to 1 pixel.
The objective table 4 of placing micro-array chip comprises two stepper motors of precise guide rail, precision lead screw and control platform two dimensional motion, and these can directly be buied from market, do not give unnecessary details at this.
Electronic circuit control board 32 in the above-mentioned collection optical processing system 3 comprises (not shown) such as motor drive controller, singlechip chip (or dsp chip), CPLD chip, optical coupling isolator and some conductor terminals.Motor drive controller is used to manage the motion of stepper motor; Singlechip chip (or dsp chip) is used for control store instruction, the management control flow; The CPLD chip is used for some basic parameters and the variable of storage system initialization process; Optical coupling isolator is used to separate the forceful electric power and the light current control of integrated circuit board; Conductor terminal is used for transmission current and signal, and IO interface is provided.Certainly, above-mentioned motor drive controller, singlechip chip (or dsp chip), CPLD chip, optical coupling isolator and some conductor terminals etc. all belong to the category of prior art, and it can directly be buied in market, does not just do too much giving unnecessary details at this.
Electronic circuit control board 32 is connected between the stepper motor of computing machine 31 and objective table 4, and computing machine just can pass through electronic circuit control board control step motor movement, thereby the control stage movement scans the position that chip is different.
Among the present invention, because computing machine carries out image splicing and position correction automatically behind the end of scan, make the machining accuracy of scanning motion platform drop to 10um like this from 2um, motion control drops to 0.5mm from 2um, effectively reduce production technology difficulty and processing cost, can find processing cooperation unit easily, popularize easily.
The present invention is by above-mentioned design, and the specific performance index that it can reach is as follows:
1, the detection resolution of system less than 2 microns (greater than 550 lines right/mm), can realize fine scanning like this to detected object.
2, the operating distance of system's object lens can reach 3.22 millimeters, is fit to the special three-dimensional structure of biochip is detected requirement.
3, the numerical aperture of system's phosphor collection object lens (NA) is 0.72, helps collecting more fluorescence signal.
4, system in a bigger field range to four kinds of visible light (laser wavelength lambda
1The fluorescence λ of=532 nanometers and its correspondence
2=570 nanometers, laser λ
3The fluorescence λ of=633 nanometers and its correspondence
4=670 nanometers) achromatism, spherical aberration, the application need of suitable multiple LASER Excited Fluorescence, the disc of confusion of wide field range is as shown in Figure 5.
5, system can utilize the numerical aperture of object lens to greatest extent, and the fluorescence receiving efficiency reaches the diffraction limit theoretical value of system, and the FFT diffraction energy of different view field imagings distributes as shown in Figure 6, and the fluorescence signal intensity that obtains than common micro-imaging significantly improves.
6, system's object lens front focal length is 13.37 millimeters, and system imaging magnifier back focal length is 29.75 millimeters.
Claims (5)
1. microarray chip detection system, the objective table that includes incident light generation system, fluorescence gathering system, collection optical processing system and place micro-array chip, it is characterized in that: described incident light generation system includes the cylinder reshaper of a laser instrument, a beam-expanding collimation mirror and an oblique fire; Described cylinder reshaper includes two cylindrical mirrors and two lens, and it sets gradually concavees lens, convex lens, a cylindrical mirror and another cylindrical mirror by the beam-expanding collimation mirror; Described fluorescence gathering system includes a pair of focal plane imaging lens combination, a color filter and one side battle array ccd detector.
2. microarray chip detection system according to claim 1, it is characterized in that: described bifocal segment imaging lens group includes 12 lens, and it is disposed with the concavees lens A that comprises a concave surface and a convex surface, the concavees lens B that comprises two concave surfaces, the convex lens C that comprises two convex surfaces, the concavees lens D that comprises two concave surfaces, the convex lens E that comprises two convex surfaces, the concavees lens F that comprises two concave surfaces, the convex lens G that comprises two convex surfaces, the convex lens H that comprises two convex surfaces, the concavees lens I that comprises a concave surface and a convex surface, the convex lens J and the convex lens K that comprise two convex surfaces, the concavees lens L that comprises a concave surface and a convex surface.
3. microarray chip detection system according to claim 1 and 2 is characterized in that: described collection optical processing system includes a computing machine, and the output terminal of described ccd detector is connected with this computing machine; Ccd detector obtains a width of cloth width of cloth fluorescence signal image corresponding with chip geometrical plane position, and is all temporary in computing machine earlier, carries out image splicing and position correction automatically behind the end of scan again, forms a complete fluorescence biosensor chip input image.
4. microarray chip detection system according to claim 3, it is characterized in that: carry out behind the described end of scan image automatically the method for splicing and position correction be: 1. when image acquisition, the surveyed area scope is outwards suitably enlarged 50 pixels along the edge, generates an a width of cloth original little figure; 2. in the regional extent of 50 pixels in every adjacent two width of cloth little figure edge, seek unique point, calculate the position deviation of same unique point in the little figure of adjacent two width of cloth; 3. adjust the center of little figure according to position deviation, the same unique point in two adjacent little figure can be overlapped fully; 4. picture mosaic, according to the actual tile size of setting, be the center with the center of 3. calculating the little figure that obtains in the step, from original little figure, cut out the little figure of corresponding actual splicing, be stitched together according to adopting one one width of cloth of figure order then, form final scanning image.
5. microarray chip detection system according to claim 3 is characterized in that: described objective table comprises two stepper motors of precise guide rail, precision lead screw and control platform two dimensional motion; Described collection optical processing system also includes an electronic circuit control board, and described electronic circuit control board is connected between the stepper motor of computing machine and objective table, and computing machine is by electronic circuit control board control step motor movement.
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| CN105629453A (en) * | 2016-03-10 | 2016-06-01 | 德诺杰亿（北京）生物科技有限公司 | Fluorescence microscope |
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| CN111323397B (en) * | 2018-12-14 | 2023-03-28 | 深圳华大生命科学研究院 | Optical imaging system, imaging detection system and method and gene sequencing method |
| CN109630912A (en) * | 2019-02-27 | 2019-04-16 | 合刃科技（武汉）有限公司 | Lighting device, machine vision equipment and illumination adjustments method |
| CN109870441B (en) * | 2019-03-27 | 2021-05-04 | 浙江大学 | Frequency shift-based three-dimensional super-resolution optical section fluorescence microscopic imaging method and device |
| WO2021016801A1 (en) * | 2019-07-29 | 2021-02-04 | 深圳市速腾聚创科技有限公司 | Receiving optical system, laser light receiving module, laser radar, and light adjustment method |
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