CN1529157A - Microflow controlled chip flow-type biochemical analysis instrument and method for detecting biochemical components - Google Patents
Microflow controlled chip flow-type biochemical analysis instrument and method for detecting biochemical components Download PDFInfo
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- CN1529157A CN1529157A CNA03127188XA CN03127188A CN1529157A CN 1529157 A CN1529157 A CN 1529157A CN A03127188X A CNA03127188X A CN A03127188XA CN 03127188 A CN03127188 A CN 03127188A CN 1529157 A CN1529157 A CN 1529157A
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Abstract
Microflow controlled chip 14 is prepared by sticking etched two layers of sheets. Chunnel 21 in decussation is fluted between the said sheets. There are inhalant pore 17 of sample, opposite two inhalant pores 18 for buffer solution, and flowout pore for waste fluid at end point of channel 21 connected to outside. One electrode is inserted into the four pores respectively. Laser emitted from laser source 1 is focused on testing point 24 on the channel 21 in decussation. Fluorescence emitted from matter in channel 21 and received by optical fiber is transferred to spectrum detection system 16 composed of CCD spectrographic detector. The invention possesses features of small size, lightweight, compact structure, and simple operation, as well as optional fluorescent reagent, fast response speed and fluorescence intensities in multiple wavelengths obtained. The invention is applicable to areas such as analyzing biochemistry matter, drug screening and clinical diagnosis.
Description
Technical field
The invention belongs to a kind of method that is applied to the Biochemical Analyzer of biological chemistry, study of pharmacy, biomedical research and clinical diagnosis etc. and uses these Biochemical Analyzer detection nucleic acid, antibody or antigen, peptide class and chemokines etc.
Background technology
The prior art close with the present invention is organic fluorescent dye coding microball and based on the flow cytometer of fluorescent dye coding microball.Quantitative flow cytometry based on the microballoon of fluorochrome label has been used to quantitative measurement cell surface receptor etc. exactly, its result can compare favourably with traditional Scatchard analytic approach, and can be used for Standardization Research between the laboratory, therefore existing several companies begin to produce high-quality fluorescent calibration microballoon.
The organic fluorescent dye coding microball is combined with traditional flow cytometer, carry out the instrument that polycomponent detects simultaneously and go on the market, for example the product of U.S. Luminex company.The structural principle of this flow cytometer as shown in Figure 1.Mainly constitute by LASER Light Source 1, flow chamber 2, light-dividing device and detection system.Flow chamber 2 is sample and the cell that sheath fluid (damping fluid) mixes mutually, often makes with organic glass, optical glass or quartz etc., and be the heart of flow system.Detected sample particle (cell or microballoon) and sheath fluid flow point be not from sample flow hand-hole 3 with sheath fluid ostium 4 enters the stream sample pipe 5 of flow chamber 2 and by the laser radiation of line focus.Adopt the method for air pressure sample introduction that detected sample particle and sheath fluid are flowed.Light-dividing device comprises two dichroic mirror 6.The specific light signal relevant with sample particle reflected or transmission by dichroic mirror 6 by light wavelength, carries out beam split, by bandpass filter 7 and convex lens 8, finally arrives detection system again.Detection system comprises that photomultiplier 9 and 10, two photomultipliers 9 of silicon photoelectric diode and silicon photoelectric diode 10 receive two bundle reflected light and transmitted light respectively and its intensity is detected.
Because flow chamber 2 is done manual work exquisite, size is accurate, require in design on the fluid mechanics, on the optics, all very stable on mechanics and the electricity, thereby have processing difficulties, bigger, the expensive shortcoming of volume.Owing to adopt the method for air pressure sample introduction, need a large amount of sheath fluids simultaneously simultaneously, more increased its microminiaturized difficulty.Owing to adopt photomultiplier 9 and silicon photoelectric diode 10 as detecting device, with dichroic mirror 6 as light-dividing device, make its optical texture quite complicated, regulate also quite difficult, complicated operation need be operated through the personnel of specialized training, and can only detect several specific emission wavelengths, wavelength kind multivalence lattice more is high more, and the instrument volume is also big more.
Said sample particle is the microballoon that adopts fluorescent dye to encode.Because it is nearer that organic dyestuff excitation spectrum and emission spectrum lean on, and peak shape is asymmetric, emission peak " hangover " is serious, and brightness is lower and the photofading phenomenon is more serious.And because the photofading problem, this kind mark microballoon is also unstable, is difficult for preserving.And be difficult to select same excitation source to excite several fluorescent dyes (general＜3 kinds) simultaneously, therefore be difficult to utilize them to make the mark of a large amount of microballoons, commercially available mark microballoon adds up to 64 kinds at present, allegedly will there be the microballoon of 100 kinds of different codings to be about to release, but this compares for ten thousand kinds with the human gene 3-4 that has an appointment altogether, remains far from being enough.
Summary of the invention
The technical problem to be solved in the present invention is to overcome disadvantages of background technology, the method that designs a kind of streaming Biochemical Analyzer and detect biochemical component with quantum point coding microball, make the overall performance of instrument stable, flow chamber and detector volume diminish, detected sample size and the minimizing of sheath fluid consumption, cheap, can the light intensity on all wavelengths be detected the disposable data that obtain each wavelength place; Coding microball brightness height, colour-fast, the easy preservation used can excite more kinds of coding microballs simultaneously with same excitation source, thereby can carry out the while fast detecting to more kinds of biological or chemical components.
The structure of micro-fluidic chip streaming Biochemical Analyzer of the present invention mainly includes: LASER Light Source, micro-fluidic chip analytic system, spectral detection system (the full spectrometer of CCD).
Said micro-fluidic chip is two-layer thin plate through etching and bonding and make, thin plate can glass or plastics or other material, be carved with the passage of right-angled intersection between the two-layer thin slice, the destination county of passage is respectively sample flow hand-hole, relative two buffer solution ostiums, waste liquid tap hole and links to each other with the external world.In sample flow hand-hole, buffer solution ostium, waste liquid tap hole, respectively be inserted with an electrode.The laser that LASER Light Source is sent focuses on the check point of the right-angled intersection passage of micro-fluidic chip behind level crossing, convex lens.The fluorescence that material in the passage sends is received by the optical fiber of chip below, imports spectral detection system then into.Said spectral detection system is meant that a volume only is several cubic centimetres CCD spectroscopic detector, and its inside is used up parallel concave mirror, spectro-grating and array detector by a collimation and constituted, and is connected closely by spiral between optical fiber outlet and CCD spectroscopic detector.
Sample flow hand-hole on the micro-fluidic chip, buffer solution ostium, waste liquid tap hole all are bonded with corresponding liquid storage tank, are used for taking up respectively sample, buffer solution and waste liquid.Be fitted with electrode in each liquid storage tank, they can be made by platinum filament, spun gold, platinized platinum or gold plaque, but consider from aspects such as stability, electric conductivity and costs, select platinum filament the most suitable as electrode.The micro-fluidic chip size is 1-15cm
2, but in order to guarantee a certain size electric field intensity, chip need not be done too much, with 1-6cm
2Be advisable; Every microchannel length is 1-5cm, is best with 0.5-1.5cm; Every microchannel width is 10-150 μ m, is the best with 20-100 μ m.The material of micro-fluidic chip can be monocrystalline silicon, unformed silicon, glass, quartz, epoxy resin, polyureas, poly-ammonia, polystyrene, polymethylmethacrylate and dimethyl siloxane.Can obtain the micro-fluidic chip of the macromolecular material cheap, that depth-to-width ratio is bigger by methods such as chemical method for etching, quasi-molecule laser etching, plastic film method and pressure sinterings.Micro-fluidic chip can use repeatedly, also can disposablely use.
LASER Light Source can be blueness or green semiconductor laser or Argon ion laser, but because that semiconductor laser has a volume is little, need not water-cooled, preheating time is short, advantage such as cheap, and blue laser can excited fluorescent wider range, especially for quantum dot, the quantum dot of various emission wavelengths can use blue laser to excite, so be best with the blue semiconductor laser.
The present invention in order to the technical scheme that the method that detects biochemical component adopts is: use the luminescent quantum dot coding microball to be carrier, at first activate the hydroxyl of microsphere surface.Then with coding microball and capture antibodies coupling connection, be about to make the mark microballoon on the luminescent quantum dot coding microball that nucleic acid, antibody or materials such as antigen, peptide class or cell factor are adsorbed on different coding.Again it is mixed with testing sample, interact by specificitys such as DNA hybridization reaction, immune responses, the specific nucleic acid in the various testing samples, antibody or antigen, peptide class or cell factor etc. also all are adsorbed onto on the corresponding luminescent quantum dot coding microball.Use the content of correlation factor in the micro-fluidic chip streaming Biochemical Analyzer check and analysis testing sample at last.
The existing size of said luminescent quantum dot coding microball evenly, comprise the polystyrene that various special ratios variety classes luminescent quantum dot encode or the microspheres product of emulsion polymer.It is the microballoon of the transmitted bandwidth＜20nm of 1-20 μ m, quantum dot that the present invention adopts diameter range.The microsphere diameter scope is the best with 2-6 μ m, diameter deviation＜± 5%.
Said coding microball and capture antibodies coupling connection is just modified coding microball, thereon biological and chemical materials such as fixed nucleic acid, antibody or antigen, peptide class, cell factor.
The said mixing with testing sample just makes the probe of microballoon mark combine with corresponding component to be measured in the sample by DNA hybridization reaction, immune response and molecular recognition etc.
In the method that detects biochemical component, sample liquid storage tank institute making alive is 600-1800V, the damping fluid liquid storage tank is 200-1500V, voltage increase then flowing velocity is accelerated, can shorten detection time, but because the influence of various factorss such as electrolysis and Joule heat, optimum voltage is sample cell 1000-1500V, buffer pool is 600-1200V, and operating voltage can be controlled by system operating software.The microballoon number that detects p.s. is 2-500, because detecting device corresponding speed and the restriction of Computer Processing speed and detection time are advisable to detect 30-200 p.s..Testing required sample volume is 0.04-0.5mL, and optimal volume is 0.05-0.1mL.
In the method that detects biochemical component, can adopt the flow injection sampling technique, use a computer the injecting systems that flows is controlled, can directly introduce the sample and the reagent of certain volume, more convenient to operate accurate.
This instrument has special-purpose software kit, uses VC or VB programming, and different types of coding microball can be classified, counted according to its wavelength of fluorescence and corresponding strength, and can be with synchronous being shown on the screen intuitively of the number of various coding microballs.
Miniature streaming Biochemical Analyzer of the present invention, collection sample introduction, liquid current control, waste discharge, beam split are detected on one, volume is little, in light weight, compact conformation can obtain multi-wavelength's fluorescence intensity level simultaneously, and response speed is very fast, reach Millisecond, the long spectrogram of all-wave of the microballoon that each can be flow through is fast noted, thereby can detect maximum millions of kinds of components to be measured simultaneously.Use the full automatic working of micro-fluidic chip energy, and can exempt from cleaning, flow injection continuous sample introduction and waste discharge, each sample size is a μ L level, and can accurately control.Use microchip systems and moving electrofocusing's technology can reduce the instrument volume, add and adopt the CCD spectroscopic detector as detection system, make apparatus structure simpler, and can the light intensity on all wavelengths be detected, the disposable data that obtain each wavelength place, the benefit of doing like this is the restriction that can not be subjected to its kind and emission wavelength when selecting fluorescent reagent, increase dirigibility, thereby make range of application enlarge, dirigibility improves, also make instrumentation become simply, and reduced cost.Because the minimizing of labile factor makes that the overall performance of instrument is also more stable.This instrument has also increased the molecular recognition effect except the function that traditional flow cytometer is arranged, thereby can be widely used in fields such as biochemical analysis, chemical composition analysis, drug screening, clinical diagnosis.
The method of detection biochemical component of the present invention also is used for the flow injection sampling technique miniature streaming Biochemical Analyzer, will improve analysis speed greatly when reducing the instrument volume and weight; Adopt the microchip of development processing voluntarily, the consumption of sample reagent is few, and testing cost is low, greatly reduces the detection cost; The liquid current control of instrument then adopts moving electrofocusing's technology, it is single-row mobile to make microballoon form uniform laminar flow under the encirclement of damping fluid, and each microballoon passes through detecting device singly separately, thereby can obtain the full spectrogram of each coding microball, also saved and used a large amount of sheath fluids to introduce loaded down with trivial details steps such as samples.Advantage of the present invention is the content that one-time detection can obtain multiple nucleic acid, antigen or antibody etc. in the same sample simultaneously, for use in the early detection of diagnosis, antidiastole or the disease of various relevant diseases such as tumour, various inflammation and autoimmune disease etc. and drug screening etc.
Description of drawings
Fig. 1 is the structure principle chart of the flow cytometer of background technology.
Fig. 2 is the structure principle chart of micro-fluidic chip streaming Biochemical Analyzer of the present invention.
Fig. 3 is the micro-fluidic chip outside drawing.
Fig. 4 is solution and a microballoon mobility status synoptic diagram in the microchannel.
Embodiment
Embodiment 1 further specifies the structure of the present invention and the course of work in conjunction with the accompanying drawings
In the accompanying drawing, 1 is LASER Light Source, preferably blue semiconductor laser; 12 is level crossing; 13 is convex lens; 14 is micro-fluidic chip, several microns to more than the 100 microns wide passages 21 that two right-angled intersections are arranged in it, 21 four destination counties have sample flow hand-hole 17, relative two buffer solution ostiums 18, waste liquid tap hole to link to each other with the external world respectively in the microchannel, sample flow hand-hole 17, buffer solution ostium 18, be bonded with corresponding liquid storage tank above the waste liquid tap hole 20 respectively, respectively insert an electrode in it; 24 is detection zone, is positioned on the passage 21 of waste liquid tap hole 20; 15 is optical fiber, and the one end is relative with the check point 24 of right-angled intersection passage 21, and the other end closely links to each other with detection system 16; Detection system 16 is the CCD spectroscopic detector.
During test sample, the laser beam of being sent by LASER Light Source 1 focuses on the check point 24 at about 50 μ m places, downstream of the right-angled intersection point of micro-fluidic chip 14 behind level crossing 12 and convex lens 13.Coding microball is Laminar Flow under the encirclement of damping fluid, and can be single-row right-angled intersection place by passage 21, each independent microballoon sends the fluorescence signal of multiple different wave length and can be collected by an end of optical fiber 15 just after laser excitation, and, carry out the long check and analysis of all-wave by optical fiber 15 importing detection systems 16.
The light intensity signal of top gained is converted to and can by software the difference of wavelength of fluorescence on each microballoon and intensity be distinguished by after the digital signal of computer Recognition, and every kind of coding is counted respectively, draws the detection conclusion according to data characteristics at last.
Institute's making alive also can be by the unified control of computing machine on the electrode.Software uses VC or VB language to programme, and the number of every kind of coding microball can be presented on the screen intuitively.
Sample is introduced and waste liquid is drawn all and can be finished by the flow injection system, can realize the several samples METHOD FOR CONTINUOUS DETERMINATION, need not to clean micro-fluidic chip 14.
Detection system 16 also can use a plurality of photomultipliers as detecting device, adopt a plurality of bitintability optical filters separately with various monochromatic light, thereby detect the intensity of various wavelength fluorescent on each microballoon, though this kind method response speed is very fast, sensitivity is higher, but device is quite complicated, and it is huge much bigger that volume is also wanted.
Contained antigen in embodiment 2 test sample:
1, coding microball is vibrated in vortex oscillation device and ultrasonator it is suspended evenly; Adding sulfuration N-hydroxy-succinamide (Sulfo-NHS) mixing adds 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide salt (EDC) then and mixes vibration in aforementioned suspending liquid, places 20min in room temperature, with the carboxyl activation of microsphere surface.
2, the microballoon after the activation cleans 3 times with PBS solution, uses the whirlpool suspendible then, adds capture antibodies rapidly, vibrates under room temperature after mixing and hatches 30min, and the centrifugal 15min of 200g abandons supernatant.
3, microballoon is suspended in and contains among the BSA and 0.02% polysorbas20 of 1mg/mL, hatch 30min for 4 ℃, the centrifugal 15min of 200g abandons supernatant; With above-mentioned damping fluid microballoon is washed twice, make in its cell culture fluid that is suspended in 1mL, hatch 20min for 4 ℃; With the hemacytometer counting, regulating the microballoon concentration that suspends is 2 * 10
6/ mL, and in 4 ℃ of dark places placements;
4, testing sample is mixed in small test tube with the microballoon that is connected with each strain specific antibodies, the suspendible vibration is hatched 30min for 4 ℃; The centrifugal 15min of 200g abandons supernatant.
5, adding is hatched 45min for 4 ℃ with the anti-species specificity IgG antibody of the organic dyestuff mark of quantum dot or other color; The centrifugal 15min of 200g abandons supernatant.Clean twice to remove excessive detection antibody with PBS, be suspended in the PBS-FTN solution of 50 μ L; The sample of above-mentioned processing is put into the sample cell above the chip of this miniature streaming Biochemical Analyzer, carried out analyzing and testing.
6, negative control group is set: each sample is all established non-special control group, replaces specific antibody with PBS, and all the other operations are the same.
1, activates the hydroxyl process of microsphere surface with embodiment 2.
2, add IL-1,2,6, acceptors such as 12 respectively in every kind of microballoon, every kind of microballoon mixes back vibration under room temperature and hatches 30min corresponding to a kind of acceptor, and the centrifugal 15min of 200g abandons supernatant;
3, microballoon is suspended in and contains among the BSA and 0.02% polysorbas20 of 1mg/mL, hatch 30min for 4 ℃, the centrifugal 15min of 200g abandons supernatant; With above-mentioned damping fluid microballoon is washed twice, make in its cell culture fluid that is suspended in 1mL, hatch 20min for 4 ℃; With the hemacytometer counting, regulating the microballoon concentration that suspends is 2 * 10
6/ mL, and in 4 ℃ of dark places placements;
4, add the solution 100 μ L that contain cell factor to be measured, hatch 45min in 4 ℃; In the centrifugal 15min of 200g, discard supernatant.
5, add IL-1,2,6, the antibody such as 12 of the quantum dot of another serial color or fluorochrome label, mix in small test tube with the microballoon that is connected with various acceptors, vortex oscillation is hatched 45min for 4 ℃; In the centrifugal 15min of 200g, discard supernatant; Clean twice to remove excessive detection antibody with PBS, add 50 μ L PBS (containing 0.1% sodium azide) damping fluids, last machine analysis.Measure the percentage composition of every kind of cell factor.
6, negative control group is set: with embodiment 2.
Embodiment 4 microballoon labeled oligonucleotide probes carry out genetic test
1, activates the hydroxyl process of microsphere surface with embodiment 2.
2, add a kind of among the oligonucleotides segment F1, F2, F6, F12 of a kind of microballoon of coding and IL-1,2,6,12 genes in each test tube, every kind of microballoon is corresponding to a kind of oligonucleotides segment; 15min-30min is hatched in the rearmounted room temperature of mixing, dark place, in the centrifugal 15min of 200g, discards supernatant.
3, microballoon is suspended in and contains among the BSA and 0.02% polysorbas20 of 1mg/mL, hatch 30min for 4 ℃, the centrifugal 15min of 200g abandons supernatant; With above-mentioned damping fluid microballoon is washed twice, make in its cell culture fluid that is suspended in 1mL, hatch 20min for 4 ℃; With the hemacytometer counting, regulating the microballoon concentration that suspends is 2 * 10
6/ mL, and in 4 ℃ of dark places placements;
4, add testing sample 10 μ L, 30min is hatched in the room temperature dark place, and the centrifugal 15min of 200g discards supernatant.
5, add the quantum dot of another serial color or IL-1,2,6, oligonucleotide fragment R1, the R2 of 12 genes, each 5 μ L (F and R sequence are not complementary) of R6, R12 of fluorochrome label; 15min-30min is hatched in the rearmounted room temperature of mixing, dark place, and the centrifugal 15min of 200g discards supernatant; Clean twice to remove excessive detection antibody with PBS, add 50 μ L PBS (containing 0.1% sodium azide) damping fluids, the percentage composition of every kind of oligonucleotides is measured in last machine analysis.
6, negative control group is set: each sample is all established non-special control group, replaces specific probe with PBS, and all the other are the same.
Embodiment 5 microballoon mark peptides carry out the detection specificity acceptor
1, activates the hydroxyl process of microsphere surface with embodiment 2.
2, add a kind of among a kind of microballoon of coding and IL-1,2,6,12 peptide section F1, F2, F6, the F12 in each test tube, every kind of microballoon is modified a kind of peptide; 15min-30min is hatched in the rearmounted room temperature of mixing, dark place, in the centrifugal 15min of 200g, discards supernatant.
3, microballoon is suspended in and contains among the BSA and 0.02% polysorbas20 of 1mg/mL, hatch 30min for 4 ℃, the centrifugal 15min of 200g abandons supernatant; With above-mentioned damping fluid microballoon is washed twice, make in its cell culture fluid that is suspended in 1mL, hatch 20min for 4 ℃; With the hemacytometer counting, regulating the microballoon concentration that suspends is 2 * 10
6/ mL, and in 4 ℃ of dark places placements;
4, add testing sample, the room temperature lucifuge is hatched 30min, and the centrifugal 15min of 200g discards supernatant.
5, add the quantum dot of another serial color or IL-1,2,6, antibody RAb1, the RAb2 of 12 acceptors, each 5 μ L of RAb6, RAb12 of fluorochrome label; 15min-30min is hatched in the rearmounted room temperature of mixing, dark place, and the centrifugal 15min of 200g discards supernatant; Clean twice to remove excessive detection antibody with PBS, add 50 μ L PBS (containing 0.1% sodium azide) damping fluids, the percentage composition of every kind of peptide is measured in last machine analysis.
6, negative control group is set: with embodiment 2.
Claims (5)
1, a kind of micro-fluidic chip streaming Biochemical Analyzer, its structure includes LASER Light Source (1), spectral detection system (16), and promptly the CCD spectroscopic detector is characterized in that, and its structure also has micro-fluidic chip (14); Said micro-fluidic chip (14) is two-layer thin plate through etching and bonding and make, be carved with the passage (21) of right-angled intersection between the two-layer thin slice, the destination county of passage (21) is respectively sample flow hand-hole (17), relative two buffer solution ostiums (18), waste liquid tap hole (20) and links to each other with the external world.In sample flow hand-hole (17), buffer solution ostium (18), waste liquid tap hole (20), respectively be inserted with an electrode; The laser that LASER Light Source (1) is sent focuses on the check point (24) of the right-angled intersection passage of micro-fluidic chip (14) behind level crossing (12), convex lens (13); The fluorescence that material in the passage (21) sends is received by the optical fiber (15) of micro-fluidic chip (14) below, imports spectral detection system (16) then into.
2, according to the described micro-fluidic chip streaming of claim 1 Biochemical Analyzer, it is characterized in that the sample flow hand-hole (17) on micro-fluidic chip (14), buffer solution ostium (18), bonding liquid storage tank above the waste liquid tap hole (20); Electrode is inserted in each liquid storage tank, and electrode is platinum filament or spun gold or platinized platinum or gold plaque.
According to claim 1 and 2 described micro-fluidic chip streaming Biochemical Analyzers, it is characterized in that 3, said LASER Light Source (1) is blue or green semiconductor laser.
4, the application of a kind of micro-fluidic chip streaming Biochemical Analyzer of claim 1 in detecting biochemical component is characterized in that, uses the luminescent quantum dot coding microball to be carrier; At first activate the hydroxyl of microsphere surface; Secondly with coding microball and capture antibodies coupling connection, be about to nucleic acid, antibody or antigen, peptide class or cell factor and be adsorbed on the microballoon of encoding, make the mark microballoon with luminescent quantum dot; Mix with testing sample once more, interact, the specific nucleic acid in the testing sample, antibody or antigen, peptide class or cell factor are adsorbed onto on the corresponding luminescent quantum dot coding microball by specificity; Use the content of correlation factor in the micro-fluidic chip streaming Biochemical Analyzer check and analysis testing sample at last.
5, according to the application of the described micro-fluidic chip streaming of claim 4 Biochemical Analyzer in detecting biochemical component, it is characterized in that, using micro-fluidic chip streaming Biochemical Analyzer to detect in the biochemical component, sample liquid storage tank (17) institute making alive is 600-1800V, and damping fluid liquid storage tank (18) institute making alive is 200-1500V.
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