CN100389322C - Nano silicon membrane biological sensor - Google Patents
Nano silicon membrane biological sensor Download PDFInfo
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- CN100389322C CN100389322C CNB02150735XA CN02150735A CN100389322C CN 100389322 C CN100389322 C CN 100389322C CN B02150735X A CNB02150735X A CN B02150735XA CN 02150735 A CN02150735 A CN 02150735A CN 100389322 C CN100389322 C CN 100389322C
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Abstract
The present invention provides a nanometer silicon membrane biological sensor composed of an insulated base, electrode systems, thin membranes made from nanometer silicon, and a protective membrane, wherein each electrode system is arranged on the base and at least comprises a measure electrode and a counter electrode; the thin membranes made from nanometer silicon are combined with the insulated base and the electrode system, and are wrapped on the electrode system; a chemical modification layer and a biomolecule layer are orderly covered on each thin membrane made from nanometer silicon; a test liquid supplying path opening is remained between the electrodes; and the electrode systems are correspondingly embedded and arrayed in a comb shape, and are connected with a conducting wire corresponding to an electrochemistry workstation. The biological sensor has the principle of measuring the concentration of various biological macromolecules in a quantitative mode by measure changes of various electrical parameters at both ends of the nanometer silicon membrane before and after the test liquid to be measured is added. The biological sensor has the advantages of no need of marks, high sensitivity, rapid detection, etc., and has maximum application prospects in the fields of biology, medical researches and clinic.
Description
Technical field:
The present invention relates to biological technical field, be specifically related to a kind ofly can exempt from the nano silicon film biology sensor that mark ground carries out quick and highly sensitive quantitative test the detected object in the test liquid.
Background technology:
Traditional immunologic detection method is that immunolabelling technique is meant the antigen-antibody reaction of carrying out with labelled antigens such as fluorescein, enzyme, radioactive isotope or electron dense material or antibody.With the enzyme linked immunosorbent assay (enzyme linkedimmunosorbent assay) of widespread use in the immunolabelling technique, be called for short enzyme linked immunosorbent assay (ELISA) illustrates immunolabelling technique for example principle below.According to the difference of determination object, enzyme linked immunosorbent assay can adopt different patterns, mainly contains following several:
(1) double antibody sandwich method
Double antibody sandwich method is to detect the most frequently used method of antigen, but is only applicable to two valencys or the above detection of antigens of two valencys, and is not suitable for the mensuration of micromolecule antigen or haptens material.Its measuring principle be with the specific antibody bag by on solid phase carrier, form insolubilized antibody; Add the sample contain determined antigen, make it to combine: add another specific antibody of enzyme labeling again, enzyme labelled antibody is combined with antigen in the solid-phase immunity compound with insolubilized antibody; Add the substrate colour developing then.The amount of the determined antigen in the depth of reaction color and the sample is directly proportional.
(2) indirect method
Be mainly used in detection antibody, its principle be with the specific antigen bag by solid phase carrier, add the sample contain antibody to be measured, make it to combine with solid phase antigen, add enzymic-labelled antibody, add the substrate colour developing after the reaction again.This method can be used multiple TPPA, as detects the antibody of various infectious diseases.
(3) competition inhibition method
Competition inhibition method can be used for detecting big molecular antigen and micromolecule antigen, also can be used to detect antibody, and determined antigen or antibody amount are inversely proportional in the depth of colour developing and the sample.To measure antigen is example, and the antigen in the testing sample combines with insolubilized antibody with the enzyme-labelled antigen competition, and determined antigen content is many more, and the enzyme-labelled antigen that can combine with insolubilized antibody is just few more, and then colour developing is just shallow more.
(4) IgM antibody capture method
Normal and specific IgG exists simultaneously at the specific IgM of some antigen in the serum, and the latter can disturb the evaluation of IgM antibody, and trapping is mainly used in all kinds of IgM early antibodies of detection.Elder generation in carrier, all is fixed on the solid phase all IgM in the serum (comprising specificity and non-specific IgM) with anti-people IgM (chain) antibody sandwich, after IgG is removed in washing, measures specific IgM again.
More than be the various principles of enzyme linked immunosorbent assay in the immunolabelling technique.No matter immunolabelling technique adopts that a kind of method, all need biomolecule is carried out mark, and complex operation, the reaction time is long, relates to plurality of reagents.
At present, generally acknowledge that in the world 0.1～100nm is the nanoscale space.Convenient for research work, 0.1～1 μ m is considered as the sub-micron system size, and 1～100nm is divided into nanometer system size, and size＜1nm is divided into cluster.The material level that the nanoscale space is related is neither macroscopical relatively independent middle field of non-microcosmic again being referred to as sight (mesoscopy) research field that is situated between.The also atypical macrosystem of the both atypical microscopic system in such field, and show four kinds of special effectses that are referred to as nano effect such as surface effect, bulk effect, quantum effect and macro quanta tunnel effect.Nano material is because the singularity of its structure shows many physics, chemical properties that are different from traditional material.The nano material bio-compatibility is good, low cell adhesion, hypotoxicity, conductive performance are high all near the requirement of biological tissue, has clinical value.The thick polymkeric substance of nanometer ultra-fine grain surface coverage one deck 5-10nm can be fixed a large amount of protein or enzyme.
Up to now, as the determined component in the sample is carried out quantitative mode, existing various nano biological sensors propose.Wherein an example is the nano biological sensor of the Charles Lieber of Harvard University chemical laboratory calendar year 2001 development: promptly a kind ofly will the prepared nano-silicon silk that combines sample to be tested be assembled into electrode surface and lead the nano biological sensor that tested sample is analyzed in variation by electricity between potential electrode.
In this nano biological sensor, being prepared as follows of silicon silk:
At first, will gather L-lysine and add in the silicon dioxide substrate, form positively charged poly-L-lysine layer.Add nanogold particle subsequently,, can be adsorbed onto on the poly-L-lysine layer of positive charge, form nano gold layer because nanogold particle is electronegative.Then, the silicon dioxide substrate that forms nano gold layer being put into oxygen plasma district (oxygen plasma) handled 5 minutes.Put into the end of quartz reactor middle and lower reaches subsequently, in the helium that contains 10% silane, grow the nano-silicon silk.
For in conjunction with biomacromolecule, the silicon silk is modified, make silicon silk surface coverage amino silane layer.
Owing to be fixed on the amino silane on silicon silk surface amino is exposed to the surface, so silicon silk surface forms two kinds of end group :-NH
2With ≡ SiOH.When pH value of solution＜7, when promptly acid, the hydrogen ion in the solution combines with amino, formation-NH
3 +So, form one deck positive charge on silicon silk surface, attract the negative charge (electronics) in the silicon silk, and repel the positive charge (hole) in the silicon silk, cause the electricity at silicon silk two ends to lead decline.In like manner, in pH value of solution＞7, when ie in solution is alkalescence, hydroxide ions a large amount of in the solution combine with ≡ SiOH, generate ≡ SiO-, make silicon silk surface form one deck negative charge, attract in the silicon silk positive charge (hole) and repel negative charge (electronics), cause silicon silk electricity to lead increase.
After having fixed biomolecule on silicon silk surface, the pH of regulator solution can make electric charges different on the biomolecule band, utilize above-mentioned principle, use calf serum PBS drips of solution to add on the amino silane layer, make the amino silane laminar surface form the biotin layer the biotinamidocaproyl mark.Add sample to be tested, the electricity of silicon silk is led detect.When containing the Avidin that combines with the biotin specificity in adding sample to be tested, pH changes, and causes the electricity at silicon silk two ends to be led and changes, thereby can detect the response value of Avidin concentration in the tested sample.
The key component of above-mentioned nano biological sensor is the nano-silicon silk, and the making precision prescribed height of nano-silicon silk costs an arm and a leg, and experiment and working condition are very harsh.
Summary of the invention:
Technical matters solved by the invention is the defective that overcomes above-mentioned nano-silicon silk, and nano material-Nano thin film is incorporated biology sensor, provide a kind of have higher operability, can sensitivity and the nano silicon film biology sensor of quantitative determination test liquid.
Nano silicon film biology sensor disclosed by the invention by the insulativity substrate, be arranged on and measure electrode and the electrode system of counter electrode, the nano-silicon made membrane that combines with insulativity substrate and electrode system and the diaphragm that is wrapped on the electrode system are formed suprabasil comprising at least; Wherein be coated with chemical modification layer and bio-molecule layer successively on the nano-silicon made membrane, leave test liquid supply passageway mouth between electrode; Electrode system is arranged with the chimeric pectination of correspondence, and is connected with the corresponding lead of electrochemical workstation by pin.Nano-silicon made membrane and electrode system are positioned on the dielectric base, and the nano-silicon made membrane mixes silicon layer and combines between electrode system and with height in the electrode system.
Described nano-silicon made membrane is a nano silicon film, its thickness is in the nanoscale space, be generally 5-100nm, according to different tested sample, can carry out chemical modification to this nano-silicon made membrane, the sensitive element that has recognition function on fixing, this sensitive element can be the various biomacromolecules that combine with the testing molecule specificity such as enzyme, antigen, antibody, hormone, nucleic acid etc.The chemical modification reagent that among the present invention sensitive element is fixed to the nano silicon film surface can be all reagent that biomacromolecule can be fixed to the nano silicon film surface, and for example: the 3-amino silane, this reagent constitutes the chemical modification layer.
Described electrode system mixes silicon-metal alloy by height to be made, and metal part is divided into conductive material commonly used such as aluminium, silver etc. in the electrode system.Electrode system is exposed to airborne part and has all wrapped up protective material, for example: Si
3N
4, to prevent that electrode system is oxidized and to avoid electrode system to contact with tested sample liquid.For sensitive membrane is that the mensuration mode of electrochemical change on the nano silicon film has and only comprises and measure electrode and two utmost point modes of counter electrode and three utmost point modes that added contrast electrode that three utmost point modes can be measured more accurately.Two utmost point mode electrode systems of nano biological sensor are arranged with the chimeric pectination of correspondence, have increased the surface area of electrode system, the sensitivity that more helps improving the nano silicon film biology sensor.
Described " electrochemical workstation " is meant employed detecting instrument.
Another technical matters to be solved by this invention is the method for making that discloses above-mentioned nano silicon film biology sensor.
Nano silicon film biology sensor of the present invention makes by following technical proposals:
At first utilize SOI (silicon-On-Insulator) technology, by photoetching corrosion, by SiO
2Form silicon made membrane and the electrode system height of thickness in the nanoscale space in the insulativity substrate of making and mix silicon layer; By splash-proofing sputtering metal, mix on the silicon layer to form at height and comprise the electrode system of measuring electrode metal part and counter electrode metal part, be exposed to airborne part at electrode system and deposit protective seam such as Si
3N
4Photoetching corrosion exposes test liquid supply passageway mouth; Cover chemical modifier then on nano silicon film, dry back forms the chemical modification layer; Again certain density biomolecule solution is covered on the chemical modification layer, leave standstill hypsokinesis and go, form bio-molecule layer; Seal the chemical modification layer that does not combine with calf serum solution at last with biomolecule.
Principle of the present invention is the ion sensitive isfet principle after improving.When the thickness of silicon fiml reached nanoscale, the specific surface area of silicon fiml increased, and chemical activity strengthens.Chemical modification is carried out on the nano silicon film surface, and the sensitive element that has recognition function on fixing, this sensitive element can be the various biomacromolecules that combine with the testing molecule specificity such as enzyme, antigen, antibody, hormone, nucleic acid etc.When this sensitive element with after testing molecule specificity in the test liquid combines, can cause the variation of Nano thin film electrochemical properties, this variation is detected by the detecting instrument that is connected with electrode system, finally can read the response value that is present in testing molecule concentration in the test liquid on detector.During detection, can set different electrical quantitys according to different objects to be measured and measure, promptly can measure to add and be carried in nano-silicon made membrane two ends before and after the sample to be tested liquid and measure the variation of various electrical quantitys between electrode and the counter electrode (comprise that impedance, electricity are led, electric capacity, electric current etc.).Thereby detection by quantitative goes out the concentration of testing molecule in the sample to be tested.
The thickness of nano silicon film belongs to the nanoscale space equally, and its making is easy with respect to the nano-silicon silk, have higher operability, and surface area is big, can be in conjunction with more biomacromolecule.Simultaneously, the present invention has adopted the assay method that can select different electrical parameters to measure according to different samples to be tested on the mensuration to sample to be tested, make quantitative measurement more become sensitive.
Method of operating of the present invention is as follows:
1, measurement standard sample, set up standard working curve (or obtaining experimental formula):
At first, set the electrochemical parameter that to measure, comprise that impedance, electricity are led, electric capacity, electric current etc.: secondly, the standard model of known variable concentrations is added to the nano silicon film surface of different sensors respectively along the test liquid supply passageway, electrode system is connected into circuit and applies ± alternating voltage of 0.005-± 0.5V to nano silicon film two end electrodes system, measure the electrochemical parameter of the standard model of variable concentrations, in two-dimensional coordinate system, set up standard working curve (or obtaining experimental formula) by electrochemical parameter value and the concentration measured.
2, when measuring sample to be tested, sample to be tested is added in another sensor, under the condition determination identical with step 1, measure the electrochemical parameter value at the nano silicon film two ends that load sample to be tested, draw the response value of the testing molecule concentration that is present in the tested sample liquid according to the standard working curve of above-mentioned steps 1 acquisition.
Still a further object of the present invention is to disclose the application in the immune detection outside exempting from marked body of above-mentioned nano silicon film biology sensor.
Nano silicon film biology sensor of the present invention can detect separately or integrated after be used for the detection of a plurality of different samples to be tested simultaneously.
Nano silicon film biosensor response of the present invention is fast, amount of samples is few, can realize continuous monitoring on the throne; Simultaneously easy to use, need not usage flag reagent; And usable range is wide, can be used for biomedical sector and detect materials such as anaphylactogen, antigen, antibody, microorganism.Also can be applicable to environment, chemical industry, pharmacy, legal medical expert, the monitoring in fields such as drugs, biological weapons.
Below in conjunction with drawings and Examples the present invention is further described, but is not limited to this.
Description of drawings:
Fig. 1 is embodiment 1, nano silicon film sensor vertical cut-away schematic view
Wherein 1 is dielectric base, and 2 is the silicon made membrane, and 3 is 3-amino silane layer (chemical modification layer), and 4 is bio-molecule layer, and 5 for the electrode system height mixes silicon layer, and 6 for measuring the electrode metal part, and 7 is counter electrode metal part, and 8 is Si
3N
4Protective seam, 9 is test liquid supply passageway mouth, 10 is Si lamella base.
Fig. 2 is Fig. 1 nano silicon film biology sensor schematic top plan view.
Wherein 11 is pin, with being connected with corresponding lead of electrochemical workstation; 2 is the silicon made membrane, and 6 for measuring the electrode metal part, and 7 is counter electrode metal part.
Embodiment:
The preparation of embodiment 1, nano silicon film biology sensor
As shown in Figure 1, utilize SOI (silicon-On-Insulator) technology, by photoetching corrosion, by SiO
2Form thick silicon made membrane 2 and the electrode system height of 50nm in the insulativity substrate 1 of making and mix silicon layer 5.By sputtered aluminum, mix on the silicon layer to form at height and comprise the electrode system of measuring electrode metal part 6 and counter electrode metal part 7, be exposed to airborne part deposition Si at electrode system
3N
4 Protective seam 8, photoetching corrosion expose test liquid supply passageway mouth 9, and width is 5 μ m.In sensitive membrane is on the nano silicon film 2, the 3-amino silane that drips 20 μ l 1% (volume ratio) is to covering the nano silicon film surface fully, at room temperature leave standstill hypsokinesis in 30 minutes and remove 3-amino silane solution, slowly wash with redistilled water, drying is 1 hour in 60 ℃ baking oven, forms amino silane layer 3 (chemical modification layer).Then, drip the mixed solution 20 μ l of 0.25mg/ml HGH (HumanGrowth Hormone) antibody and 1% (volume ratio) glutaraldehyde, cover the amino silane layer, at room temperature leave standstill hypsokinesis in 30 minutes and remove above-mentioned mixed solution, slowly wash with redistilled water, form antibody layer 4 (bio-molecule layer).Afterwards, drip 3-4.5g/100ml standard calf serum solution to the antibody layer surface with sealing not with the amino silane layer of HGH antibodies, under 37 ℃ of conditions, left standstill 30 minutes, the standard of inclining calf serum solution slowly washs antibody layer 4 with redistilled water.At SiO
2Insulativity substrate bottom grows Si lamella base 10, and this structure is determined by raw material structure.
In order to make measurement more accurate, can in electrode system, add contrast electrode.One end of contrast electrode inserts in the tested sample that has dripped on nano silicon film, and the other end is connected into electrochemical workstation by lead.
Fig. 2 is the vertical view of Fig. 1 nano silicon film biology sensor.
Connect mensuration electrode 6 and counter electrode 7 at nano silicon film 2 two ends, electrode system is arranged with the chimeric pectination of correspondence, and is connected with the corresponding lead of electrochemical workstation by pin 11.
The detection of embodiment 2, sample solution concentration
In two nano silicon film biology sensors that make by embodiment 1 method, add the HGH antigen standard items that concentration known is respectively 65.0ng/ml, 5.5ng/ml respectively.Under 37 ℃ of conditions, left standstill 30 minutes, make it to be combined on the antibody layer.Electrode system is connected into circuit, under the condition of fixed frequency (1000Hz), applies ± alternating voltage of 0.5V to nano silicon film two end electrodes system, the resistance value of measuring the standard model of two variable concentrations is respectively 56.5 * 10
7Ω and 16.1 * 10
7Ω.By formula C=k*lg (Z
1-Z
0(wherein C is for adding the concentration of sample, and a and k are unknown constant, Z for)-a
1For adding the resistance value of sample, Z
0=1.5 * 10
7Ω is not for adding the blank resistance value of any sample) calculate a and k value, be respectively 831.7 and 102.6.In another nano silicon film biology sensor, add sample to be tested liquid (the specificity HGH antigen that contains unknown concentration), under 37 ℃ of conditions, left standstill 30 minutes.The resistance value of measuring this testing sample under the same conditions is 16.3 * 10
7Ω.The above-mentioned formula of substitution: C=102.6*lg (16.3 * 10
7-1.5 * 10
7The response value that)-831.7 (a and k measure by standard items) obtain being present in the antigen concentration that combines with the HGH antibody specificity in the sample to be tested liquid is 6.5ng/ml.Use three identical nano silicon film biology sensors of specification in the measurement of above-mentioned testing sample, used formula is the experiment experience formula.
Claims (9)
1. nano silicon film biology sensor, it is characterized in that this sensor by the insulativity substrate, be arranged on and measure electrode and the electrode system of counter electrode, the nano-silicon made membrane that combines with insulativity substrate and electrode system and the diaphragm that is wrapped on the electrode system are formed suprabasil comprising at least; Wherein the nano-silicon made membrane is coated with chemical modification layer and bio-molecule layer on dielectric base and be between the electrode system and mix silicon layer and combine with height in the electrode system successively on the nano-silicon made membrane, leaves test liquid supply passageway mouth between electrode.
2. a nano silicon film biology sensor as claimed in claim 1 is characterized in that wherein said nano-silicon made membrane thickness is 5-100nm.
3. a nano silicon film biology sensor as claimed in claim 1 is characterized in that the various biomacromolecules that combine with the testing molecule specificity are enzyme, antigen, antibody, hormone or nucleic acid in the wherein said bio-molecule layer.
4. a nano silicon film biology sensor as claimed in claim 1 is characterized in that wherein said chemical modification layer is the reagent layer that biomacromolecule can be fixed to the nano silicon film surface.
5. a nano silicon film biology sensor as claimed in claim 4 is characterized in that wherein said chemical modification layer is the 3-amino silane.
6. nano silicon film biology sensor as claimed in claim 1 is characterized in that wherein said electrode system is by measuring two utmost point modes that electrode and counter electrode form or three utmost point modes that added contrast electrode; In two utmost point modes, electrode system is arranged with the chimeric pectination of correspondence, and is connected with the corresponding lead of electrochemical workstation by pin.
7. a nano silicon film biology sensor as claimed in claim 1 is characterized in that wherein said electrode system material selection height mixes silicon-metal alloy.
8. the described nano silicon film biology sensor of claim 1 application in the immune detection outside exempting from marked body, it is characterized in that this sensor is carried in the variation that various electrical quantitys between electrode and the counter electrode are measured at nano-silicon made membrane two ends before and after measure adding test liquid, exempt from the quantitative measurement of mark ground and be fixed on tested sample on the nano-silicon made membrane.
9. the preparation method of a nano silicon film biology sensor as claimed in claim 1 is characterized in that the preparation of this sensor comprises: at first utilize the SOI technology, by photoetching corrosion, by SiO
2Form silicon made membrane and the electrode system height of thickness in the nanoscale space in the insulativity substrate of making and mix silicon layer; By splash-proofing sputtering metal, mix on the silicon layer to form at height and comprise the electrode system of measuring electrode metal part and counter electrode metal part, be exposed to airborne part at electrode system and deposit protective seam; Photoetching corrosion exposes test liquid supply passageway mouth; Cover chemical modifier then on nano silicon film, dry back forms the chemical modification layer; Again certain density biomolecule solution is covered on the chemical modification layer, leave standstill hypsokinesis and go, form bio-molecule layer; Seal the chemical modification layer that does not combine with calf serum solution at last with biomolecule.
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| CNB02150735XA CN100389322C (en) | 2002-11-27 | 2002-11-27 | Nano silicon membrane biological sensor |
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| CN100389322C true CN100389322C (en) | 2008-05-21 |
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| CN100415896C (en) * | 2004-08-16 | 2008-09-03 | 中国科学院电子学研究所 | Creatine-kinase biosensor and its detergent preparation method |
| CN103412017B (en) * | 2013-03-11 | 2016-02-10 | 中国人民解放军疾病预防控制所 | A kind of method for quick of pathogenic microorganism and checkout equipment |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1146016A (en) * | 1995-02-28 | 1997-03-26 | 松下电器产业株式会社 | Biosensor |
| US5922537A (en) * | 1996-11-08 | 1999-07-13 | N.o slashed.AB Immunoassay, Inc. | Nanoparticles biosensor |
| WO2002031183A1 (en) * | 2000-10-10 | 2002-04-18 | Bioforce Nanosciences, Inc. | Nanoscale sensor |
-
2002
- 2002-11-27 CN CNB02150735XA patent/CN100389322C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1146016A (en) * | 1995-02-28 | 1997-03-26 | 松下电器产业株式会社 | Biosensor |
| US5922537A (en) * | 1996-11-08 | 1999-07-13 | N.o slashed.AB Immunoassay, Inc. | Nanoparticles biosensor |
| WO2002031183A1 (en) * | 2000-10-10 | 2002-04-18 | Bioforce Nanosciences, Inc. | Nanoscale sensor |
Non-Patent Citations (2)
| Title |
|---|
| 离子敏场效应晶体管. 丁辛芳等.传感器技术，第4期. 1995 |
| 离子敏场效应晶体管. 丁辛芳等.传感器技术，第4期. 1995 * |
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