CN1421699A - Surface plasma resonance biosensor for detecting several biological signals parallelly - Google Patents
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Abstract
The present invention relates to biosensor for detecting several biological signals parallelly based on surface plasma resonance principle. The biosensor consists of substrate, metal film, chemical modifying layer, crosslinking agent layer and biological mono-molecule layer successively. It features that several kinds of biomolecules are combined to different positions of the biological mono-molecule layer, so that it is possible to detect quantitatively the concentrations of specific target molecules in the tested sample. The present invention may be used in detection of disease indexes and has clinical application value. The present invention also provides the preparation process and usage of the biosensor. The biosensor is convenient and sensitivie.
Description
Technical field
The present invention relates to biological technical field, be specifically related to a kind of based on the biology sensors surface plasma body resonant vibration principle, can a plurality of biological signals of parallel detection.
Background technology
2l century is that epoch, particularly bio-science and the computer science of biology development will obtain vigorous growth through merging the bioinformatics that produces.Sensing technology is one of major technique of information science, is the means that information is obtained.The information of utilizing sensing technology to obtain biological sample is the important content of Measurement for Biotechnique development.
Wherein, optical means is because it has non-destructive and highly sensitive characteristics are considered to be ripe and the most best biosensor technique.From 1902, Wood has found surface plasma body resonant vibration first in Experiments of Optics (Surface Plasmon Resonance, SPR) since the phenomenon, the research of SPR instrument and surface plasmon resonance biosensor received publicity always.
Surface plasma body resonant vibration SPR is a kind of physical optics phenomenon.One of necessary condition that forms the SPR phenomenon is that the interface between metal and dielectric exists.When incident light during with a certain specific angle incident, its reflectivity can significantly reduce, and this incident angle is the SPR angle.Attached to the material difference of metal surface, its SPR angle difference, and with a kind of material, attached to the amount difference of metal surface, its SPR angle is also inequality.According to above-mentioned principle, surface plasmon resonance biosensor can be fixed on known biomolecule the metallic film surface of tens nanometer thickness, when it combines with the target biological molecules of complementation, because the change of surface structure will cause the SPR angle to change, and, can learn the kind and the concentration of the target biological molecules of combination according to the change value at SPR angle.At present, spr sensor has been used for the bioanalysis field.
More existing in the world biology sensor products based on the SPR principle, Biacore series of biologic sensor with the Biacore AB of Sweden is an example, its preparation method is that the golden film that 100nm is thick is fixed on the glass matrix, this glass sheet is embedded in a plastic board underedge, and the polymkeric substance that mates with a kind of refractive index and prism is coupled to chip on the glass prism.At the fixing one deck dextran molecule layer of chip surface, it is easier to and other biomacromolecule coupling. it is light source with the light emitting diode, with the linear array light emitting diode as detecting device, detect the intensity of reflected light at different incidence angles place. but this has finished the detection of single-point SPR, once can only detect a kind of material, this is in the application that has to a certain degree limited it.
Summary of the invention
Technical matters to be solved by this invention is to provide a kind of surface plasmon resonance biosensor that can carry out the multiple spot parallel detection on existing SPR technical foundation.
Surface plasmon resonance biosensor of the present invention is made of matrix, metal film, chemical modification object layer, crosslinking chemical layer and biologic single molecular layer successively, and this biologic single molecular layer contains different biomolecule at diverse location.
Matrix of the present invention can be continuous matrix, also can be discontinuous matrix, and material can be selected glass, silicon chip or other hard solid materials for use.Plate the metal film that thickness is 20-90nm in the outside of matrix, preferred Au film of metal film or Ag film.Scribble the chemical modification object layer to produce one deck polyanion surface in metallic film surface, this chemical modification object can be 11-sulfydryl docosandioic acid (MUA), amino thiophenol, amineothiot, sulfydryl ethylenediamine, hexadecane mercaptoalcohol or other sulfur-bearing regents.Surface at chemical modification object is associated with crosslinking chemical, crosslinking chemical can be selected EDAC (1-Ethyl-3 (3-Dimethylamino-propyl) carbodiimide), glutaraldehyde etc. for use, various biomolecules is arranged on the crosslinking chemical layer in certain sequence, as antigen, antibody, hormone, acceptor, biotin, avidin, substrate, enzyme or coenzyme, nucleic acid molecules etc. form the biologic single molecular layer.
Above-mentioned biology sensor and the supporting use of SPR detector can realize a plurality of biological signals parallel detections in the biological sample.
Another technical matters to be solved by this invention provides the preparation method of above-mentioned biology sensor.
Biology sensor of the present invention obtains by following technical proposals:
1. at the surperficial plated with gold film of matrix, the thickness that makes metal film is 20-90nm;
2. this matrix is successively at the concentrated sulphuric acid: hydrogen peroxide=1.5-4: ultrasonic cleaning in 1 solution, acetone soln or alcoholic solution, the secondary aqueous solution, drying;
3. this matrix is dipped in the chemical modification object solution that contains sulfydryl and assembled 3-24 hour;
4. in alcoholic solution and secondary aqueous solution, clean drying successively;
5. in crosslinking chemical, assembled 3-24 hour;
6. with sample injector various biomolecules is quantitatively put in certain sequence the diverse location of the stromal surface of handling built in the process above-mentioned steps; Distance between points is greater than lmm, and the concentration of each biomolecule does not wait from 0.05mg/ml2-0.0mg/ml.
7. be dipped in to seal in 0.01-0.5% (w/v) the BSA confining liquid and spend the night 2-8 ℃ of preservation.
A further object of the present invention provides the application of above-mentioned biology sensor in a plurality of biological signals parallel detections.
Biology sensor of the present invention can be used for multiple antigen, antibody, hormone, acceptor, biotin, avidin, substrate, enzyme or coenzyme and the nucleic acid molecules etc. in the parallel detection testing sample.
During detection, the single beam laser that available LASER Light Source is sent scans sensor, and also free space wave filter (Spatial Filter) expands bundle to single beam laser, makes its whole surface of illumination sensor simultaneously.When solution to be measured contact surface plasmon resonance biosensor, each biomolecule of its biologic single molecular layer combines with target molecule specificity in the testing sample solution, and the formation compound changes the surface structure of biologic single molecular layer.This variation can cause the change of the SPR phenomenon at each biomolecule place on this unimolecular layer, can detect the variation at SPR angle by the SPR detector.
Surface plasmon resonance biosensor of the present invention is realized a plurality of biological signals parallel detections by following manner:
1) detects several parts respectively with identical above-mentioned surface plasmon resonance biosensor and contain the multiple target molecule that can combine with the biomolecule specificity on the biology sensor, and each concentration of target molecules is known and the sample that increases progressively successively, by the variation of the SPR angle ω at each biomolecule place on SPR detector record different t, the biology sensors constantly, make the dynamics curve according to the relation of ω and t.
2) by kinetic curve can obtain the reaction reach balance after, the SPR equilibrium angle ω of each biomolecule on the biology sensor
0Be worth, make the correlation curve of this angle value concentration of target molecules C corresponding, promptly obtain ω corresponding to each target molecule with this point
0/ C curve (being called typical curve), above-mentioned typical curve place the detector database standby.
3) when detecting the solution of unknown concentration, with 1) still make the dynamics curve according to the SPR angle ω of each point on the biology sensor and the relation of time t.
4) with 2), find out each SPR equilibrium angle ω by kinetic curve
0Value is with ω
0Value contrasts with the typical curve of corresponding target molecule, can draw the concentration of this target molecule.Thereby reach the purpose of the plurality of target molecule being carried out detection by quantitative.
Present single-point SPR detects and is mainly used in research field, and multiple spot SPR of the present invention detects, and its meaning is application clinically.As: present early detection for tumour, adopt biochemistry detection mostly, but, the detection of single index (single tumor markers) is not sufficient to help the doctor to make right judgement, because false positive and false negative that single index detects are all quite high, therefore a plurality of tumor markerses are carried out parallel detection, can improve the accuracy of diagnosis greatly.
The surface plasma resonance biosensor of a plurality of biological signals of parallel detection of the present invention, easy to use, detect sensitivity, help accurately to detect various diseases, have clinical value widely.
Description of drawings
Fig. 1 surface plasmon resonance biosensor structure and detection synoptic diagram
(1) is LASER Light Source, (2) be spatial filter (Spatial Filter), (3) be optical coupling device, (4) be photodetector, (5) (6) (7) (8) constitute biology sensor, and (5) are the matrix of metal-plated membrane, and (6) are the chemical modification object layer, (7) be that crosslinking chemical (8) is the unimolecule biological membrane, (9) are testing sample.
Biomolecule point sample synoptic diagram on Fig. 2 sensor
Fig. 3 ω/t kinetic curve synoptic diagram
Fig. 4 typical curve synoptic diagram
Fig. 5 A1, A2, B1, B2 represent embodiment 1 point of sample respectively, the 5.1,5.2,5.3, the 5.4th, and corresponding to the curve of the reflectivity I/ incident angle A of an A1, A2, B1, B2
ω/t kinetic curve that Fig. 6 6.1,6.2,6.3,6.4 is respectively A1 among Fig. 5, A2, B1, B2 point is corresponding
Fig. 7 7.1,7.2,7.3,7.4 is respectively the ω of embodiment 1AFP, CEA, PSA, Ferritin
0/ C typical curve
Embodiment
The selection of material:
1) is coated with the glass sheet of Au film
2) chemical modification object: 11-sulfydryl docosandioic acid (MUA)
3) crosslinking chemical: 0.1%EDAC
4) anti-AFP (alpha-fetoprotein) monoclonal antibody of biomolecule: 0.6mg/ml, anti-CEA (carcinomebryonic antigen) monoclonal antibody of 1.0mg/ml, anti-PSA (prostate specific antigen) monoclonal antibody of 0.5mg/ml, anti-Ferritin (ferritin) monoclonal antibody of 0.5mg/ml.
Above-mentioned monoclonal antibody all derives from U.S. Biodesign company
5) blood serum sample: derive from the Shanghai City Sixth People's Hospital.The preparation method:
1) glass sheet that will be coated with the Au film is at the concentrated sulphuric acid: each ultrasonic cleaning is 5 minutes in the solution of hydrogen peroxide=7: 3, alcoholic solution, the secondary aqueous solution, and room temperature dries up;
2) above-mentioned slide is dipped in the middle room temperature assembling of 11-sulfydryl docosandioic acid (MUA) 24 hours;
3) respectively cleaned 5 minutes in alcoholic solution and secondary aqueous solution successively, room temperature dries up;
4) be dipped in the crosslinking chemical 0.1%EDAC solution room temperature assembling 24 hours
5) with micro sample adding appliance the anti-free-PSA monoclonal antibody of the anti-PSA monoclonal antibody of the anti-CEA monoclonal antibody 0.5mg/ml of the anti-AFP monoclonal antibody of 0.6mg/ml, 1.0mg/ml, 0.5mg/ml is quantitatively put diverse location built in above-mentioned stromal surface as shown in Figure 5; Distance between points is 2.5mm, and the point sample amount is 1ul.
As Fig. 5, some A1: anti-AFP monoclonal antibody, some A2: anti-CEA monoclonal antibody, some B1: anti-PSA monoclonal antibody, some B2: anti-Ferritin monoclonal antibody
6), be dipped in to seal in 0.1% (W/V) BSA confining liquid and spend the night.
Detect serum with above-mentioned biology sensor.Above-mentioned biology sensor is placed on optical coupling device such as Fig. 1 (3), make test serum contact its surface, photoelectric detector (4) can write down the variation of the SPR phenomenon at each monoclonal antibody place on the biology sensor, as among Fig. 5 5.1,5.2, shown in 5.3,5.4, the process Computer Processing can draw the ω/t kinetic curve of each point, and the kinetic curve of each point as shown in Figure 6.From Fig. 6 .1 to 6.4, can be respectively to draw the SPR equilibrium angle ω of anti-AFP, CEA, PSA, Ferritin
0, with equilibrium angle ω
0Corresponding with the typical curve of each target molecule, as Fig. 7, from Fig. 7 .1 to 7.4, can draw the concentration of AFP, CEA, PSA, Ferritin in this serum: CEA concentration is 24ng/ml; AFP concentration is 17ng/ml; PSA concentration is 3ng/ml; Ferritin concentration is 205ng/ml.
Claims (10)
1, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection, this biology sensor is successively by matrix, metal film, chemical modification object layer, crosslinking chemical layer and biologic single molecular layer constitute, and it is characterized in that the diverse location of this biologic single molecular layer contains different biomolecule
2, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1, it is characterized in that wherein said biologic single molecular layer point has antigen, antibody, hormone, acceptor, biotin, avidin, substrate, enzyme or coenzyme and nucleic acid molecules.
3, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1 is characterized in that wherein said matrix selects glass, silicon chip or other hard solid materials for use.
4,, it is characterized in that wherein said matrix is continuous or discrete matrix as the surface plasmon resonance biosensor of a plurality of biological signals of the described parallel detection of claim l.
5, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1 is characterized in that wherein said metal film is that thickness is at the Au of 20-90nm film or Ag film.
6, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1 is characterized in that the used chemical modifier of wherein said chemical modification object layer is 11-sulfydryl docosandioic acid, amino thiophenol, amineothiot, sulfydryl ethylenediamine, hexadecane mercaptoalcohol or other sulfur-bearing regents.
7, the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1 is characterized in that the crosslinking chemical that wherein said crosslinking chemical layer is selected for use is EDAC or glutaraldehyde.
8, the preparation method of the surface plasmon resonance biosensor of a plurality of biological signals of parallel detection as claimed in claim 1 is characterized in that this biology sensor obtains by following technical proposals:
1) at the surperficial plated with gold film of matrix, the thickness that makes metal film is 20-90nm;
2) this matrix is successively at the concentrated sulphuric acid: ultrasonic cleaning in the solution of hydrogen peroxide=1.5-4: l, acetone soln or alcoholic solution, the secondary aqueous solution, drying;
3) this matrix is dipped in the chemical modification object solution that contains sulfydryl and assembled 3-24 hour;
4) in alcoholic solution and secondary aqueous solution, clean drying successively;
5) in crosslinking chemical, assembled 3-24 hour;
6) with sample injector various biomolecules is quantitatively put diverse location built in above-mentioned stromal surface in certain sequence; Distance between points is greater than lmm, and the concentration of used biomolecule does not wait from 0.05mg/ml-20.0mg/ml;
7) be dipped in to seal in 0.01-0.5% (w/v) the BSA confining liquid and spend the night 2-8 ℃ of preservation.
9, the application of surface plasmon resonance biosensor as claimed in claim 1 in a plurality of biological signals parallel detections, it is characterized in that this sensor can be used for the multiple antigen of parallel detection, antibody, hormone, acceptor, biotin, avidin, substrate, enzyme or coenzyme and nucleic acid molecules.
10, the application of surface plasmon resonance biosensor as claimed in claim 8 in a plurality of biological signals parallel detections is characterized in that its detection realizes by following manner:
A) detect several parts respectively with identical above-mentioned surface plasmon resonance biosensor and contain the multiple target molecule that can combine with the biomolecule specificity on the biology sensor, and each concentration of target molecules is known and the sample that increases progressively successively, by the variation of the SPR angle ω at each biomolecule place on SPR detector record different t, the biology sensors constantly, make the dynamics curve according to the relation of ω and t;
B) by kinetic curve can obtain the reaction reach balance after, the SPR equilibrium angle ω of each biomolecule on the biology sensor
0Be worth, make the correlation curve of this angle value concentration of target molecules C corresponding, promptly obtain ω corresponding to each target molecule with this point
0/ C typical curve, this typical curve place the detector database standby;
C) when detecting the solution of unknown concentration, with 1) still make the dynamics curve according to the SPR angle ω of each point on the biology sensor and the relation of time t;
D) find out each SPR equilibrium angle ω by kinetic curve
0Value is with ω
0Value contrasts with the typical curve of corresponding target molecule, can draw the concentration of this target molecule.Thereby reach the purpose of the plurality of target molecule being carried out detection by quantitative.
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| CN100399027C (en) * | 2004-10-20 | 2008-07-02 | 国家海洋环境监测中心 | Surface plasma resonance rapid detection method for paralytic shellfish poisoning |
| CN100429503C (en) * | 2006-02-17 | 2008-10-29 | 湖南大学 | Method for raising surface plasma resonance sensor sensitivity by using nano gold grain catalytic growing |
| CN100520394C (en) * | 2005-03-08 | 2009-07-29 | 中国科学院电子学研究所 | Single-channel multi-parameter surface plasms resonance tester |
| CN1894576B (en) * | 2003-11-19 | 2010-04-28 | 比恩诺尔股份公司 | Method and apparatus for actuating surface plasma resonance measuring |
| CN1971267B (en) * | 2005-11-23 | 2010-11-10 | 财团法人工业技术研究院 | Wave-guide coupling surface plasma resonance biosensor |
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- 2001-11-23 CN CN 01132289 patent/CN1218180C/en not_active Expired - Lifetime
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| CN1894576B (en) * | 2003-11-19 | 2010-04-28 | 比恩诺尔股份公司 | Method and apparatus for actuating surface plasma resonance measuring |
| CN101069087B (en) * | 2004-06-11 | 2011-06-08 | 高级科学研究理事机构 | Device and method for detecting dielectric refractive index variation |
| CN100399027C (en) * | 2004-10-20 | 2008-07-02 | 国家海洋环境监测中心 | Surface plasma resonance rapid detection method for paralytic shellfish poisoning |
| CN100520394C (en) * | 2005-03-08 | 2009-07-29 | 中国科学院电子学研究所 | Single-channel multi-parameter surface plasms resonance tester |
| CN1971267B (en) * | 2005-11-23 | 2010-11-10 | 财团法人工业技术研究院 | Wave-guide coupling surface plasma resonance biosensor |
| CN100429503C (en) * | 2006-02-17 | 2008-10-29 | 湖南大学 | Method for raising surface plasma resonance sensor sensitivity by using nano gold grain catalytic growing |
| CN101109747B (en) * | 2007-08-09 | 2011-04-20 | 中国科学院长春光学精密机械与物理研究所 | Surface plasma body resonant vibration and flexible flat plate wave combined detection biologic sensor |
| CN103389278B (en) * | 2012-05-11 | 2016-01-20 | 中国科学院电子学研究所 | A kind of Solid-state ultrathin film absorption spectrum measurement and corresponding spectral measurement device |
| CN103389278A (en) * | 2012-05-11 | 2013-11-13 | 中国科学院电子学研究所 | Solid-state ultrathin film absorption spectrum measurement method and corresponding spectral measurement device |
| CN103454253A (en) * | 2013-06-25 | 2013-12-18 | 复旦大学 | Organic phosphorus detection method based on surface plasmon resonance |
| CN103454253B (en) * | 2013-06-25 | 2016-04-06 | 复旦大学 | Based on the organic phosphorus detection method of surface plasma body resonant vibration |
| CN103472237A (en) * | 2013-09-18 | 2013-12-25 | 四川大学华西第二医院 | Bio-sensitive chip as well as preparation method and use thereof |
| CN103472237B (en) * | 2013-09-18 | 2015-02-25 | 四川大学华西第二医院 | Bio-sensitive chip as well as preparation method and use thereof |
| CN103675281A (en) * | 2013-11-26 | 2014-03-26 | 中国检验检疫科学研究院 | Method for detecting cucumber mosaic virus by surface plasmon resonance sensor |
| CN103675281B (en) * | 2013-11-26 | 2016-02-10 | 中国检验检疫科学研究院 | Surface plasma resonance sensor is utilized to detect the method for cucumber mosaic virus |
| CN108700513A (en) * | 2015-09-24 | 2018-10-23 | 拉克里赛恩斯有限责任公司 | Optical sensor, system and use its method |
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