CN101592627A - The making integrated approach of multichannel high-sensitive biosensor - Google Patents
The making integrated approach of multichannel high-sensitive biosensor Download PDFInfo
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Abstract
The invention provides a kind of making integrated approach of multichannel high-sensitive biosensor, at first adopt the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer; Then utilize dimethyl silicone polymer (PDMS) to produce many microfluidic channel; At last the silicon nanowires in the different microfluidic channel is carried out modification, make it to modify different detection antibody or micromolecule, to detect different target molecules.The sensor that this method is made can be used for detecting simultaneously the dissimilar disease association factor (as DNA, RNA, albumen etc.) or virus, has high sensitivity, stablizes, is easy to characteristics such as integrated.
Description
Technical field
The present invention relates to a kind of method of making integrated multichannel high-sensitive biosensor, be specifically related to a kind of method based on SOI fabrication techniques silicon nano-wire biological sensor.
Background technology
At present, diabetes, cardiovascular disease, breathing problem, hepatopathy, cancer are the major diseases that threatens human health.Though medical science and related discipline make constant progress, people still make slow progress on the fast diagnosis and treatment of these diseases; If these diseases can not be found timely that disease almost is to be difficult to treatment when arriving late period.And the reason that disease can not found early is, one, and when early stage, it is not obvious that related diseases is sent out feature, and the associated protein factor quantity of its secretion is less relatively, is not easy to detect with present detection means; Its two, promptly enable to detect relevant disease factor, expense that it is required and time also are many; Therefore, develop and a kind ofly have high sensitivity, detect the sensor of relevant disease fast, cheaply, the diagnosis and treatment of the major disease of harm humans health are had far reaching significance.
Be compared to traditional checkout equipment, field effect FET sensor based on nano wire has following advantage: one, high sensitivity, at first field effect transistor itself just has the effect that signal amplifies, and can a spot of charge signal that effect is got on be amplified; Secondly, since the big specific surface area that nano wire itself is had, quantum confined effect etc., and feasible field effect FET sensor based on nano wire has very high sensitivity (Yi Cui, Science Vol 293,1289～1293,2001); Two, quick, can reach the frequency of GHz based on the speed of the semi-conductor chip of silicon, and based on the field effect FET sensor of silicon nanowires even may reach higher speed, this compares with traditional checkout equipment, its detection speed is very fast; Three, be easy to integrated and high throughput testing, compare with checkout equipment with traditional sensors, have easy of integration and advantage cheaply based on the nanowire field-effect sensor, because the manufacturing process of device is complete and semiconductor technology is thought compatibility, therefore easily with ripe semi-conductor industry and emerging industry compatibilities such as MEMS, thereby can obtain the sensor of feature richness, superior performance.Silicon is very abundant at the content of occurring in nature, and simultaneously, the conventional semiconductor industrial technology can reduce device cost.
The most of sensor that has existed at present is based on the sensor of electrochemical principle, perhaps based on optical principle, also there are some sensors based on field effect FET, even some field effect FET sensors based on nanometer technology are arranged, even also these several modes are combined the sensor of formation.The technology comparative maturity of electrochemical sensor, but compare, solution environmental is required than higher, and volume is also relatively big.And present sensor mainly is to detect at a kind of single target molecule, because a lot of with the molecule of any disease association, and they may be separate; Therefore, detect a kind of existence of disease more accurately, must carry out joint-detection multiple disease factor.Patent CN101144809A utilizes argent as surface plasma excimer, and antigen molecule in chemical group in its finishing and connection is by strengthening the intensity of local surface plasma resonance, the sensitivity that improves biomolecule detection.By comparison, be core with the nano thread structure, adopt field effect transistor to realize signals collecting and amplification, can more effective detection signal.Patent CN1585896A utilizes the FET sensor to detect ion concentration and base sequence, because there are the debye wavelength in charged ion or base sequence in solution, therefore if ion and base sequence are relative when far away from conducting channel, the sensitivity of its detection is sharply decline also.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, a kind of making integrated approach of multichannel high-sensitive biosensor is provided.
Purpose of the present invention is achieved through the following technical solutions:
The making integrated approach of multichannel high-sensitive biosensor may further comprise the steps---
(1) adopts the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer;
(2) utilize dimethyl silicone polymer (PDMS) to produce many microfluidic channel;
(3) silicon nanowires in the different microfluidic channel is carried out modification, make it to modify different detection antibody or micromolecule, to detect different target molecules.
Further, the making integrated approach of above-mentioned multichannel high-sensitive biosensor, step () comprises following operation:
1) silicon chip cleans, and silicon chip is respectively at 7: 3 the concentrated sulphuric acid and hydrogen peroxide, and 60 degree heating are 10～15 minutes in 1: 3: 7 ammoniacal liquor and the aqueous hydrogen peroxide solution, 1: 2: 8 hydrochloric acid and aqueous hydrogen peroxide solution, contained organism and the metallic ion of removal silicon chip surface;
2) wafer thinning, earlier with silicon chip in oxidation furnace with wet oxygen or dry-oxygen oxidation, use buffered hydrofluoric acid solution erosion removal silicon dioxide again, make silicon chip reach required thickness, and the surface slightly release souls from purgatory compare less;
3) etching mask growth is with PECVD or plasma sputtering method grow on the silicon chip silicon dioxide or the silicon nitride film of one deck 20～200 nanometer thickness;
4) back of the body grid are made, and with the method for back of the body grid masterplate by deep-UV lithography, again by the IBE dry etching, make on silicon chip and obtain carrying on the back gate pattern earlier;
5) silicon nanowires is made, earlier with the method for silicon nanowires masterplate by deep-UV lithography, use the IBE dry etching again, use tetramethyl ammonium hydroxide solution anisotropic etch silicon again, erosion removal silicon dioxide in 5: 1 buffered hydrofluoric acid solutions at last, thus obtain width at 1～1000nm, height at the good silicon nanowires of the homogeneity of 1～500nm;
6) metallization, with the method for metallization masterplate by deep-UV lithography, the method by peeling off makes silicon chip line and grid, source electrode and drain metallization more earlier;
7) passivation earlier with the method for passivation masterplate by deep-UV lithography, with using the PECVD method, all covers the last layer passivation layer in the place of silicon chip surface except that silicon nanowires and grid, source, drain electrode.
Further, the making integrated approach of above-mentioned multichannel high-sensitive biosensor, step (two) comprises following operation:
1) stamp fabrication utilizes the method for photoetching to make on silicon chip earlier and obtains the microchannel mould;
2) build model, the PDMS performed polymer is poured on the microchannel mould, and placed 24 hours, make it complete polymerization;
3) surface modification, will be under nitrogen protection through the wafer of step (), corrosion is 5 seconds in buffered hydrofluoric acid solution, take out and use ultrapure deionized water rinsing, nitrogen dries up, and oven dry, and silicon chip is immersed in organic decoration solution (as 2-THP, CAE, APTES etc.) under UV-irradiation, handled 2 hours in;
4) shift, the PDMS that polymerization is good transfers to through in the step (two) 3) on the wafer after the surface modification treatment, aim at bonding.
Again further, the making integrated approach of above-mentioned multichannel high-sensitive biosensor, step (three) comprises following operation:
1) surperficial aldehyde radicalization, with glutaraldehyde phosphate buffer (PBS) the mixed liquor reaction of silicon slice placed at 1: 15, (30ml PBS, 2ml glutaraldehyde, PBS are phosphate buffer PH=7.2), reaction is one hour on shaking table;
2) in conjunction with albumen, in conjunction with the corresponding antibodies of last material to be detected;
3) clean, reaction finishes, and cleans 3 times with buffer solution, and is every all over 5 minutes, every all over 2 minutes at interval.
Substantive distinguishing features and obvious improvement that technical solution of the present invention is outstanding are mainly reflected in:
The biology sensor of multichannel high-sensitive of the present invention is made and integrated approach, adopt PDMS and insulating material to make microchannel, silicon nanowires in each passage is modified respectively, make it possible to detect dissimilar biomolecule, by the information of these biomolecule is carried out Conjoint Analysis, can detect disease more accurately.And, by the contrast passage that is provided with, can reduce false drop rate to reducing error, improve the accuracy that detects.Simultaneously, adopt silicon nanowires, have advantages such as the transducer sensitivity of raising and reduction chip size as the core cell that detects.Adopt top-down method to make sensor component, can combine, and solved the arrangement and the lithography alignment problem of nano wire, can improve the precision of element manufacturing, reduce bad ratio defective product, thereby reduce chip cost with conventional semiconductor processing.Adopt passivation layer that device is protected, avoided the infiltration of hydrone, electric current etc. in next step reaction, prolonged the life-span of sensor.The sensor that this method is made can be used for detecting simultaneously the dissimilar disease association factor (as DNA, RNA, albumen etc.) or virus, has high sensitivity, stablizes, is easy to advantages such as integrated.
Description of drawings
Below in conjunction with accompanying drawing technical solution of the present invention is described further:
Fig. 1 in the element manufacturing of the present invention on soi wafer the sectional view of growthing silica;
Fig. 2 makes sectional view for back of the body grid in the element manufacturing of the present invention;
Fig. 3 obtains the device architecture sectional view of silicon nanowires for after passing through common deep-UV lithography in the element manufacturing of the present invention behind the TMAH wet etching;
Fig. 4 is for metallizing in the element manufacturing of the present invention, obtains device architecture sectional view after grid, source, the drain electrode;
Fig. 5 for surface passivation in the element manufacturing of the present invention after device profile map;
Fig. 6 has made device architecture sectional view behind the microchannel for the present invention;
Fig. 7 is a surface modification of the present invention, in the modification sensor construction sectional view after the detection molecules;
Fig. 8 is doping process sectional view in the element manufacturing of the present invention;
Fig. 9 is a surface modification of the present invention, in the modification sensor construction sectional view after the detection molecules;
Figure 10 is for passing through beamwriter lithography, the device architecture sectional view that obtains behind the IBE dry etching in the element manufacturing of the present invention;
Figure 11 is a surface modification of the present invention, in the modification sensor construction sectional view after the detection molecules.
The implication of each Reference numeral sees the following form among the figure:
| Reference numeral | Implication | Reference numeral | Implication | Reference | Implication | |
| 1 | Silicon substrate | 2 | Substrate silicon dioxide | 3 | |
|
| 4 | The FET fet gate | 5 | FET field effect transistor source electrode | 6 | The drain electrode of FET |
|
| 7 | Silicon nanowires | 8 | The silicon nitride passivation |
9 | |
|
| 10 | |
11 | The |
12 | The antibody recognition unit |
| Reference numeral | Implication | Reference numeral | Implication | Reference | Implication | |
| 13 | The antibody recognition unit | 14 | The chemical group of modifying on the |
15 | |
|
| 16 | Silicon nanowires | 17 | Silicon nanowires |
Embodiment
The invention provides a kind of making and integrated approach of highly sensitive multichannel biological and chemical sensor.By soi wafer, utilize the anisotropic wet caustic solution to obtain silicon nanowires, produce field effect FET transistor from top to bottom with the method for conventional semiconductor processing; Next utilize dimethyl silicone polymer (PDMS) to produce the microfluid hyperchannel; At last, adopt the method for chemistry that the silicon nanowires in the different microchannels is carried out modification, go up different antibody or micromolecule thereby modify.The sensor of Zhi Zuoing can be used for detecting simultaneously the dissimilar disease association factor (as DNA, RNA, albumen etc.) or virus in this way.This biology sensor has high sensitivity, and is stable, is easy to advantages such as integrated.Simultaneously, this manufacture method can be compatible mutually with conventional semiconductor processing, can carry out large-scale production, is convenient to reduce cost.
Sensor construction as shown in figure 11; silicon substrate 1, substrate silicon dioxide 2 and top layer silicon 3 threes have constituted the SOI three-decker; FET field effect transistor metal source 5, drain electrode 6 and grid 4; and comprised silicon nanowires 7; chemical group of modifying on the nano wire 14 and antibody 10, antibody recognition unit (11,12,13) have also comprised silicon nitride passivation protective seam 8 at last; dimethyl silicone polymer (PDMS) 9, and the microfluidic channel 15 that forms.Sensor is based on N type or the making of P type (100) soi wafer.Silicon nanowires 7 height are between 1～1000 nanometer, and halfwidth is between 1～500 nanometer, and angle beta=125.26 are spent, and the silicon nanowires homogeneity is good, and is regular.The method for making of silicon nanowires 7 is to make by anisotropic etchs such as KOH, TMAH, EDP, RbOH, LiOH or CsOH solution, and the concentration of solution is 1%～75%.Add isopropyl alcohol (IPA) in the described corrosive liquid, the concentration of IPA is that the method for making of 0%～50% silicon nanowires 7 is to obtain by ion beam etching (IBE), reactive ion beam etching (RIBE) (RIE), dark silicon inductively coupled plasma etching dry etchings such as (dark silicon ICP).The quantity of integrated silicon nanowires 7 is between 1～200 in sensor.The material of silicon nitride passivation protective seam 8 is that silicon nitride film, silica membrane, spin-coating glass (comprise PSG; BPSG), improvement silicon dioxide (fluorinated silica; HSQ), BN Si; can also be organic class, comprise polyimide, fluorinated polyimide, Fluoro-polymkeric substance, Si-O-C polyblend etc.Can use method growths such as CVD, PECVD or LPCVD, SOD, sputter.Passivation layer covers sensor surface silicon nanowires and other outer places of metal electrode.Film protection sensor surface, and form microfluidic channel.Microfluidic channel 15 is to be formed together by silicon nitride passivation protective seam 8 and dimethyl silicone polymer (PDMS) 9, and the quantity of microfluidic channel is between 1～200, and microfluidic channel is to carry out chemical modification, and the reaction vessel of target detection.Chemical group 14 that specificity is modified can be allylamine, 11-bromo decyltrichlorosilane (11-bromoundecyltrichlorosilane, BUTCS), 2-methyl esters ethyl trichlorosilane (2-(carbomethoxy) ethyltrichlorosilane, CMECS), octyl group trichlorosilane (n-octyltrichlorosilane, OTCS), 9-alkenyl amino butyl formate (dec-9-enyl-carbamic acid tert-butyl ester, CAE), ammonia propyl trichlorosilane (3-aminopropyl triethoxylsilane, APTES).Antibody 10 is different in different microfluidic channel 15, relevant detection biomolecule (as DNA, RNA, albumen etc.), and antibody recognition unit (11,12,13) also are different.The input of sensor is target molecule damping fluid to be detected to be drawn in the microchannel by microflow channels with peristaltic pump, and specific being combined on the corresponding antibody molecule.The change that this has caused sensor electrical to be led.Thereby change chemical signal into electric signal and detect by peripheral testing circuit.All contain a reference channel in each sensor, this passage and unmodified chemical group and antibody.The microchannel of each detection all should have a contrast passage mutually, and what flow through in the passage is not contain the corresponding buffer solution that detects target molecule.
Example I
(1) adopt the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer:
1) silicon chip cleans, and silicon chip boiled 15 minutes with 7: 3 concentrated sulphuric acids and hydrogen peroxide 60 degree earlier, took out the ultrapure water rinsing then, uses 1: 3: 7 ammoniacal liquor and aqueous hydrogen peroxide solution to boil the rinsing of taking-up ultrapure water 10 minutes again; Next 60 degree heating 10 minutes in 1: 2: 8 hydrochloric acid and aqueous hydrogen peroxide solution are taken out and are used the ultrapure water rinsing, and nitrogen dries up; With buffered hydrofluoric acid solution corrosion in 5: 15 seconds, take out, use the ultrapure water rinsing, nitrogen dries up; 100 degree oven dryings 10 minutes; Through cleaning, remove contained pollution organism and the metallic ion of silicon chip surface;
2) wafer thinning, earlier with silicon chip in oxidation furnace with wet oxygen or dry-oxygen oxidation, and then with buffered hydrofluoric acid solution erosion removal silicon dioxide; Through repeating several steps, make silicon chip reach required thickness, and the surface slightly release souls from purgatory compare less;
3) etching mask growth as shown in Figure 1, is the silicon dioxide or the silicon nitride mask 16 of 20～100 nanometer thickness with methods such as PECVD or the plasma sputtering layer thickness of growing on silicon chip;
4) back of the body grid are made, and as shown in Figure 2, with the method for back of the body grid masterplate by deep-UV lithography, again by reactive ion etching RIE, make on silicon chip and obtain carrying on the back gate pattern earlier;
5) silicon nanowires is made, as shown in Figure 3, earlier with the method for silicon nanowires masterplate by deep-UV lithography, use the RIE dry etching again, use tetramethyl ammonium hydroxide solution anisotropic etch silicon again, at last erosion removal silica 16 in 5: 1 buffered hydrofluoric acid solutions, thereby obtain width at 10～100nm, height is at the good silicon nanowires of the homogeneity of 25～80nm, and wherein the β angle is 125.26 degree, and the quantity of nano wire is 36;
6) metallization, as shown in Figure 4, with the method for metallization masterplate by deep-UV lithography, the method by peeling off makes silicon chip line and grid again, source electrode and drain metallization earlier;
7) passivation as shown in Figure 5, earlier with the method for passivation masterplate by deep-UV lithography, with the method with PECVD, all covers the last layer silicon nitride passivation in the place of silicon chip surface except that silicon nanowires and grid, source, drain electrode;
(2) utilize dimethyl silicone polymer (PDMS) to produce many microfluidic channel:
1) stamp fabrication utilizes the method for photoetching to make on silicon chip earlier and obtains the microchannel mould;
2) build model, as shown in Figure 6, the PDMS performed polymer is poured on the microchannel mould, and placed 24 hours, make it complete polymerization;
3) shift, the PDMS that polymerization is good transfers on the device of making, and aims at bonding;
(3) surface of silicon nanowires is modified and the target molecule detection:
1) surface amination, will be under nitrogen protection through the wafer of step (two), corrosion is 5 seconds in buffered hydrofluoric acid solution, take out and use ultrapure deionized water rinsing, nitrogen dries up, and oven dry, it is in 0.1～2% 3-aminopropyltriethoxywerene werene (APTES) ethanolic solution that wafer is immersed in concentration, reaction is 2 hours under the room temperature;
2) surperficial aldehyde radicalization, with the glutaraldehyde PBS mixed liquor reaction of silicon slice placed at 1: 10, (15ml PBS, 1.5ml glutaraldehyde, PBS are phosphate buffer PH=7.2), reaction is one hour on shaking table;
3) in conjunction with albumen, as shown in Figure 7, detect the significant albumen of hepatitis B: the buffer solution of HBsAg, HBsAb, HBeAg, HBeAb, HBcAb corresponding monoclonal antibody is placed on peristaltic pump respectively and is drawn into that (each marker protein flows through 2 microchannels respectively in 11 different fluid channel, also having one in addition is the reference channel of not modifying monoclonal antibody, always have 11 microchannels, each microchannel has 3 nano wires), reaction is at room temperature spent the night;
4) clean, reaction finishes, and cleans 3 times with buffer solution, and is every all over 5 minutes, every all over 2 minutes at interval.
Example II
(1) adopt the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer:
1) silicon chip cleans, silicon chip is spent with 7: 3 concentrated sulphuric acids and hydrogen peroxide 60 earlier and was boiled 15 minutes, take out the ultrapure water rinsing then, use 1: 3: 7 ammoniacal liquor and aqueous hydrogen peroxide solution to boil again 10 minutes, take out the ultrapure water rinsing, next 60 degree heating 10 minutes in 1: 2: 8 hydrochloric acid and aqueous hydrogen peroxide solution, take out and use the ultrapure water rinsing, nitrogen dried up, with buffered hydrofluoric acid solution corrosion in 5: 15 seconds, take out, use the ultrapure water rinsing, nitrogen dries up, 100 degree oven dryings 10 minutes, through cleaning, remove contained pollution organism and the metallic ion of silicon chip surface;
2) wafer thinning, earlier with silicon chip in oxidation furnace with wet method or dry oxidation, and then, through and repetition several steps with buffered hydrofluoric acid solution erosion removal silicon dioxide, make silicon chip obtain required thickness, and the surface slightly release souls from purgatory compare less;
3) back of the body grid are made, and with the method for back of the body grid masterplate by deep-UV lithography, again by reactive ion etching RIE, make on silicon chip and obtain carrying on the back gate pattern earlier;
4) the N ion injects, and growth layer of silicon dioxide mask on silicon chip with the method for n type ion injecting mask by deep-UV lithography, injects by phosphorus or arsenic ion more earlier, and silicon is mixed, and removes silicon dioxide mask with buffered hydrofluoric acid solution;
5) the P ion injects, and as shown in Figure 8, growth layer of silicon dioxide mask on silicon chip with the method for p type ion implantation mask by deep-UV lithography, injects by the boron ion more earlier, and silicon is mixed, and removes silicon dioxide mask with buffered hydrofluoric acid solution;
6) etching mask growth is the silicon dioxide or the silicon nitride mask of 20～100 nanometer thickness with methods such as PECVD or the plasma sputtering layer thickness of growing on silicon chip;
7) silicon nanowires is made, earlier with the method for silicon nanowires masterplate by deep-UV lithography, use the RIE dry etching again, use tetramethyl ammonium hydroxide solution anisotropic etch silicon again, erosion removal silicon dioxide in 5: 1 buffered hydrofluoric acid solutions at last, thereby obtain width at 10～100nm, height is at the good silicon nanowires of the homogeneity of 25～80nm, and the quantity of nano wire is 66;
8) metallization, with the method for metallization masterplate by deep-UV lithography, the method by peeling off makes silicon chip line and grid, source electrode and drain metallization more earlier;
9) passivation earlier with the method for passivation masterplate by deep-UV lithography, with the method with PECVD, all covers the last layer silicon nitride passivation in the place of silicon chip surface except that silicon nanowires and grid, source, drain electrode;
(2) utilize dimethyl silicone polymer (PDMS) to produce many microfluidic channel:
1) Mold Making utilizes the method for photoetching to make on silicon chip earlier and obtains the microchannel mould;
2) build model, the PDMS performed polymer is poured on the microchannel mould, and placed 24 hours, make it complete polymerization;
3) shift, the PDMS that polymerization is good transfers on the device of making, and aims at bonding;
(3) silicon nanowires to zones of different carries out modification, makes it to modify different detection antibody, to detect different target molecules:
1) surface modification, will be under nitrogen protection through the wafer of step (two), corrosion is 5 seconds in buffered hydrofluoric acid solution, take out and use ultrapure deionized water rinsing, nitrogen dries up, and oven dry, it is in 0.1～2% the ammonia propyl trichlorosilane (APTES) that silicon chip is immersed in concentration, reaction is 2 hours under the room temperature;
2) surperficial aldehyde radicalization, with the glutaraldehyde PBS mixed liquor reaction of silicon slice placed at 1: 15, (30ml PBS, 2ml glutaraldehyde, PBS are phosphate buffer PH=7.2), reaction is one hour on shaking table;
3) in conjunction with albumen, as shown in Figure 9, the serum tumor marker CEA of lung cancer, NSE, CYFRA21-1, TPA, CA15-3, the buffer solution of CA242 corresponding monoclonal antibody is drawn into peristaltic pump respectively that (wherein each label damping fluid all flow into corresponding N type district passage respectively in 20 different fluid channel, p type island region passage and contrast passage, also there is one not modify the N type of monoclonal antibody and the reference channel of P type in addition respectively, always have 20 microchannels, 3 nano wires are arranged) in each microchannel, reaction is at room temperature spent the night, wherein silicon nanowires 7, silicon nanowires 16 and silicon nanowires 17 are respectively N type and P type silicon nanowires, and the antibody recognition unit 13 that is connect respectively on it is the same with antibody recognition unit 12;
4) clean, reaction finishes, and cleans 3 times with buffer solution, and is every all over 5 minutes, every all over 2 minutes at interval.
EXAMPLE III
(1) adopt the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer:
1) silicon chip cleans, silicon chip is spent with 7: 3 concentrated sulphuric acids and hydrogen peroxide 60 earlier and was boiled 15 minutes, take out the ultrapure water rinsing then, use 1: 3: 7 ammoniacal liquor and aqueous hydrogen peroxide solution to boil again 10 minutes, take out the ultrapure water rinsing, next 60 degree heating 10 minutes in 1: 2: 8 hydrochloric acid and aqueous hydrogen peroxide solution, take out and use the ultrapure water rinsing, nitrogen dried up, with buffered hydrofluoric acid solution corrosion in 5: 15 seconds, take out, use the ultrapure water rinsing, nitrogen dries up, 100 degree oven dryings 10 minutes, through cleaning, remove contained pollution organism and the metallic ion of silicon chip surface;
2) wafer thinning, earlier with silicon chip in oxidation furnace with wet method or dry oxidation, and then, through and repetition several steps with buffered hydrofluoric acid solution erosion removal silicon dioxide, make silicon chip obtain required thickness, and the surface slightly release souls from purgatory compare less;
3) back of the body grid are made, and with the method for back of the body grid masterplate by deep-UV lithography, again by reactive ion etching RIE, make on silicon chip and obtain carrying on the back gate pattern earlier;
4) silicon nanowires is made, and as shown in figure 10, with the method for silicon nanowires masterplate by beamwriter lithography, uses the RIE dry etching more earlier, obtains width at 10～100nm, and height is at the good silicon nanowires of the homogeneity of 25～80nm, and the quantity of nano wire is 12;
5) metallization, with the method for metallization masterplate by deep-UV lithography, the method by peeling off makes silicon chip line and grid, source electrode and drain metallization more earlier;
6) passivation earlier with the method for passivation masterplate by deep-UV lithography, with the method with PECVD, all covers the last layer silicon nitride passivation in the place of silicon chip surface except that silicon nanowires and grid, source, drain electrode;
(2) utilize dimethyl silicone polymer (PDMS) to produce many microfluidic channel:
1) stamp fabrication utilizes the method for photoetching to make on silicon chip earlier and obtains the microchannel mould;
2) build model, the PDMS performed polymer is poured on the microchannel mould, and placed 24 hours, make it complete polymerization;
3) surface modification will be through the wafer of step () under nitrogen protection, and corrosion is 5 seconds in buffered hydrofluoric acid solution, take out and use ultrapure deionized water rinsing, nitrogen dries up, and oven dry, silicon chip is immersed in the allylamine ethanolic solution, under ultraviolet light (256nm) irradiation, handled 12 hours;
4) shift, the PDMS that polymerization is good transfers to through in the step (two) 3) on the wafer after handling, aim at bonding;
(3) silicon nanowires to zones of different carries out modification, makes it to modify different detection antibody, to detect different target molecules:
1) surperficial aldehyde radicalization, with the glutaraldehyde PBS mixed liquor reaction of silicon slice placed at 1: 15, (30ml PBS, 2ml glutaraldehyde, PBS are phosphate buffer PH=7.2), reaction is one hour on shaking table;
2) in conjunction with albumen, as shown in figure 11, the buffer solution that detects the significant albumen PSA of prostate cancer corresponding antibodies is used in peristaltic pump and is drawn in 3 different fluid channel, and reaction is at room temperature spent the night;
3) clean, reaction finishes, and cleans 3 times with buffer solution, and is every all over 5 minutes, every all over 2 minutes at interval.
In sum, the biology sensor of multichannel high-sensitive of the present invention is made and integrated approach, adopt PDMS and insulating material to make microchannel, silicon nanowires in each passage is modified respectively, make it possible to detect dissimilar biomolecule, by the information of these biomolecule is carried out Conjoint Analysis, can detect disease more accurately.And, by the contrast passage that is provided with, can reduce false drop rate to reducing error, improve the accuracy that detects.Simultaneously, adopt silicon nanowires, have advantages such as the transducer sensitivity of raising and reduction chip size as the core cell that detects.Adopt top-down method to make sensor component, can combine, and solved the arrangement and the lithography alignment problem of nano wire, can improve the precision of element manufacturing, reduce bad ratio defective product, thereby reduce chip cost with conventional semiconductor processing.Adopt passivation layer that device is protected, avoided the infiltration of hydrone, electric current etc. in next step reaction, prolonged the life-span of sensor.
Above instrument is a concrete exemplary applications of the present invention, and protection scope of the present invention is not constituted any limitation.All employing equivalents or equivalence are replaced and the technical scheme of formation, all drop within the rights protection scope of the present invention.
Claims (4)
1. the making integrated approach of multichannel high-sensitive biosensor is characterized in that: may further comprise the steps---
(1) adopts the silicon nanowires of method making from top to bottom FET field effect transistor based on soi wafer;
(2) utilize dimethyl silicone polymer to produce many microfluidic channel;
(3) silicon nanowires in the different microfluidic channel is carried out modification, make it to modify different detection antibody or micromolecule, to detect different target molecules.
2. the making integrated approach of multichannel high-sensitive biosensor according to claim 1, it is characterized in that: described step () comprises following operation:
1) silicon chip cleans, and silicon chip is respectively at 7: 3 the concentrated sulphuric acid and hydrogen peroxide, in 1: 3: 7 ammoniacal liquor and the aqueous hydrogen peroxide solution, 1: 2: 8 hydrochloric acid and aqueous hydrogen peroxide solution in 60 degree heating 10～15 minutes, contained organism and the metallic ion of removal silicon chip surface;
2) wafer thinning, earlier with silicon chip in oxidation furnace with wet oxygen or dry-oxygen oxidation, use buffered hydrofluoric acid solution erosion removal silicon dioxide again, make silicon chip reach required thickness;
3) etching mask growth is with PECVD or plasma sputtering method grow on the silicon chip silicon dioxide or the silicon nitride film of one deck 20～200 nanometer thickness;
4) back of the body grid are made, and with the method for back of the body grid masterplate by deep-UV lithography, again by the IBE dry etching, make on silicon chip and obtain carrying on the back gate pattern earlier;
5) silicon nanowires is made, earlier with the method for silicon nanowires masterplate by deep-UV lithography, use the IBE dry etching again, use tetramethyl ammonium hydroxide solution anisotropic etch silicon again, erosion removal silicon dioxide in 5: 1 buffered hydrofluoric acid solutions at last, thus obtain width at 1～1000nm, height at the good silicon nanowires of the homogeneity of 1～500nm;
6) metallization, with the method for metallization masterplate by deep-UV lithography, the method by peeling off makes silicon chip line and grid, source electrode and drain metallization more earlier;
7) passivation earlier with the method for passivation masterplate by deep-UV lithography, with using the PECVD method, all covers the last layer passivation layer in the place of silicon chip surface except that silicon nanowires and grid, source, drain electrode.
3. the making integrated approach of multichannel high-sensitive biosensor according to claim 1, it is characterized in that: described step (two) comprises following operation:
1) stamp fabrication utilizes the method for photoetching to make on silicon chip earlier and obtains the microchannel mould;
2) build model, the PDMS performed polymer is poured on the microchannel mould, and placed 24 hours, make it complete polymerization;
3) surface modification will be through the wafer of step () under nitrogen protection, and corrosion is 5 seconds in buffered hydrofluoric acid solution, take out and use ultrapure deionized water rinsing, nitrogen dries up, and oven dry, wafer is immersed in the organic decoration solution, under UV-irradiation, handled 2 hours;
4) shift, the PDMS that polymerization is good transfers to through on the wafer after the surface modification treatment, aims at bonding.
4. the making integrated approach of multichannel high-sensitive biosensor according to claim 1, it is characterized in that: described step (three) comprises following operation:
1) surperficial aldehyde radicalization, in 1: 15 glutaraldehyde phosphate buffer mixed liquor, reaction is one hour on shaking table with silicon slice placed;
2) in conjunction with albumen, in conjunction with the corresponding antibodies of last material to be detected;
3) clean, reaction finishes, and cleans 3 times with buffer solution, and is every all over 5 minutes, every all over 2 minutes at interval.
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| WO2003042683A1 (en) * | 2001-11-16 | 2003-05-22 | Bio-X Inc. | Fet type sensor, ion density detecting method comprising this sensor, and base sequence detecting method |
| CN101144809B (en) * | 2007-10-17 | 2013-02-27 | 中国科学院光电技术研究所 | High sensitivity nano biosensor production method |
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