CN100547396C - A kind of silicon based piezoelectricity thin film sensor and method for making that is applied to biological little quality testing - Google Patents
A kind of silicon based piezoelectricity thin film sensor and method for making that is applied to biological little quality testing Download PDFInfo
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Abstract
The present invention relates to a kind of silicon based piezoelectricity thin film sensor and preparation method who is used for biological little quality testing.Feature of the present invention is on the silicon chip of (100) orientation, and successively deposition has the Bragg reflection horizon of λ/4 (λ is a wavelength) thickness; Then on the Bragg reflection horizon, deposit piezoelectric thin film layer and gold electrode layer; Adopt the graphical technology of related electrode, make the electrode structure that is complementary with the standard microwave measurement thereon; Obtain the silicon based piezoelectricity thin film sensor through relevant annealing temperature; On the silicon based piezoelectricity thin film sensor, successively apply the series of biologic probe, after cleaning, adopt sandwich sandwich technique point sample specificity, can measure the respective change of sensor resonant frequency in conjunction with the biosome trace.And then convert by respective formula and to obtain little quality of biosome to be measured.This multi-functional integrated sensing technology combines with modern biotechnology, can make the high flux of micro-bio-measurement, strong specificity, highly sensitive analysis become possibility.
Description
Technical field
The present invention relates to a kind of silicon based piezoelectricity thin film sensor and method for making that is applied to biological little quality testing, relate to the detection that a kind of silicon based piezoelectricity thin film sensor is applied to biological little quality or rather, embody the application that multi-functional integrated sensing technology combines with modern biotechnology.Belong to biology sensor and make the field.
Background technology
Since nearly half a century, the research and development of biology sensor are paid close attention to by people always, and multiple sensors (as electrochemical sensor, hot biology sensor, piezoelectric biological sensor, semiconductor biology sensor and optical biosensor etc.) is arisen at the historic moment thus.
Specific bond principle between biomacromolecule (as making nucleic acid molecular hybridization, receptor-ligand combination and antigen-antibody reaction) is the basis of the biochip technology that gets up of developed recently.In the prior biological sensor, optical biosensor, hot biology sensor, piezoelectric biological sensor can utilize special, sensitive, the easy biological detection method of these principle research and development.Optical biosensor can transmit the special optical signal (fluorescence or change color etc.) that labeled molecule produces by fibre-optical probe, or application surface plasma resonance know-why is examined and determine special biosome or molecule.Its weak point is the insufficient sensitivity height, and the attached instrument apparatus expensive.Hot biology sensor is to utilize sensitive thermal sensing element to survey the enthalpy change of biological respinse, and the content of indirect determination biomacromolecule, such sensor still is in conceptual phase.Piezoelectric biological sensor then is to utilize molecule to cause crystal oscillator frequency to change in conjunction with the quality increase that causes, with frequency transformation detection of biological molecule.Compare with optical biochip, the outstanding advantage of piezoelectric biological sensor is that to detect direct output signal be electric signal, is convenient to realize robotization, intellectuality, makes it to have calibration, the function of compensation, self diagnosis and network service, be convenient to accurate quantification analysis etc., thereby have great application prospect.But what piezoelectric biological sensor adopted at present all is quartz piezoelectric crystal, and its thickness is subjected to the restriction of technology, attenuate again.Thereby causing its resonance frequency limit is tens of megahertzes, and is difficult to the possibility of raising again.Thereby there are problems such as detection sensitivity is low in such sensor.
The domestic and international existing many researchs of piezoelectric membrane type resonator, their resonance frequency can reach more than the GHz, and what its structure had is the cavity micro-bridge structure, and what have is photonic crystal resonant layer structure.But be applied in the mobile phone filter field mostly.For the detection of the little quality of biology, study still few.For in conjunction with biological little quality testing, the film Resonator of cavity micro-bridge structure is easily crisp by analysis, and insufficient strength has limited its application; The film Resonator sound construction of tool bragg layer has Application Prospect.And adopt the processing technology on plane, be easy to preparation.Simultaneously such device is because of the resonance electrode difference, preparation method's difference and material system difference, and its resonance performance has very big-difference.Therefore for solving the core content of piezoelectric membrane biology sensor, the THICKNESS CONTROL of promptly how to accomplish piezoelectric crystal.How to improve the premium properties of its piezoelectric thin film layer, how to obtain higher resonance frequency, and in the little quality testing of biology, how to obtain higher detection sensitivity.Thereby be guided out purpose of the present invention.
Summary of the invention
The object of the present invention is to provide a kind of silicon based piezoelectricity thin film sensor and method for making that is applied to biological little quality testing.The present invention adopts " sandwich " sandwich technique of silicon based piezoelectricity film Resonator spare technology of preparing and biomolecule specific bond that conventional quartz crystal piezoelectric sensor is made novelty to improve.Purpose is to prepare high specificity, highly sensitive (pico-gram level), detects rapidly, the piezoelectric membrane biology sensor of convenient (about 1 hour).And biochip technology combined with biology sensor, utilize micromechanics electronic system (MEMS) technology on piezoelectric membrane, to make the miniature piezoelectric resonator array, at the corresponding biological membrane of piezoelectric thin film vibrator spare surface applied, bag closes again, clean, fixing different molecular probe (or be nucleic acid, or be protein), promptly constitute piezoelectric biological chip.
Described piezoelectric biological sensor is made up of three parts: probe biomolecule (antibody or antigen), piezoelectric resonator (being transducer) and testing circuit.Probe biomolecule makes the sensor of making have selectivity, have only when biomolecule to be measured contacts with probe molecule and just react, biomolecule is attracted to the piezoelectric resonator electrode surface with probe molecule, biomolecule breaks away from the piezoelectric resonator electrode surface with probe molecule, thereby causes the change (see figure 1) of harmonic oscillator electrode surface adsorbate quality; Piezoelectric resonator is converted into detectable electric signal with the change of electrode surface adsorbate quality.The present invention has adopted Bragg (Prague) reflection horizon on silicon base, purpose is to utilize one of four molecules of each layer thickness wavelength Bragg reflection, block the dissipation of the logical frequency range acoustic wave energy of band effectively, and should be able to provide the most effective inhibition the other pseudo-sound of bulk acoustic wave resonator complexity; Testing circuit is used for detecting the piezoelectric resonator change of resonance frequency that the change because of electrode surface attachment quality causes.
Molecular probe: in general, the content of material micro-to be checked in the sample is mostly between pik (pg)-nanogram (ng).Concerning the material to be checked that has only the pg level, the molecule number that is bonded on the piezoelectric film is few, for detecting individual gene copy or the extremely low protein molecule of content, need preparation biological property stabilized nano material, this material particle size is about about 15-30nm, weight can not influence the biologically active of antibody with fine combination of antibody about 100pg.This just can use " sandwich " mode (antibody-antigen-in conjunction with the antibody of Au particle) to detect target molecule (biomolecule to be measured), even have only several target molecules to combine with the tool sepcific ligands, because the weight of nano material is increased in about 100pg, thereby the material to be checked of trace also can be detected by piezoelectric sensor.Select corresponding probe protein molecular (certain protein or antiviral antibody), point is on the electrode surface of piezoelectric membrane harmonic oscillator array.High-purity molecular probe is adopted in experiment; For strengthening the attachment fastness of molecular probe on the gold electrode face, adopt the surface chemistry new technology that gold electrode surfaces is handled, activated.
The piezoelectric membrane harmonic oscillator: adopt a kind of piezoelectric membrane harmonic oscillator of new structure, the harmonic oscillator of this structure is to be that the piezoelectric film deposition of λ/2 (λ is a wavelength) is on multilayer λ/4 films that impedance does not wait with thickness.Make the used λ of harmonic oscillator/2 piezoelectric membranes, λ/4 Bragg reflection horizon employing magnetron sputtering or sol-gel process preparation, the harmonic oscillator electrode adopts the magnetron sputtering method preparation, and the harmonic oscillator array adopts conventional MEMS technology preparation.
In sum, the silicon based piezoelectricity thin film sensor that is used for biological little quality testing provided by the invention is made up of probe biomolecule, transducer and testing circuit three parts, it is characterized in that
A, described transducer are piezoelectric vibration device, and its structure is:
1. on the silicon substrate of (100) orientation or contain SiO
2Deposition Bragg reflection horizon on the silicon substrate of layer, reflector thickness is 1/4 of a wavelength;
2. deposit piezoelectric thin film layer on the Bragg reflection horizon, thin layer thickness is 200-5000nm; Resonance frequency is 100M-10GHZ;
4. deposit electrode layer on piezoelectric thin film layer, thickness is 100-500nm;
The structure of B, described probe biomolecule is that coating is closed through bag in conjunction with corresponding biological membrane on piezoelectric resonator, forms the sandwich pattern of biological nano material-material-antigen/antibody to be checked.
Described SiO
2Layer thickness is 100nm-1000nm.
Described piezoelectric thin film layer be λ/2 (λ is a wavelength) have a C-axle preferrel orientation piezoelectric membrane, be piezoelectricity or ferroelectric thin films such as ZnO, AlN or PZT, frequency is higher than the conventional quartz sensor.
Described electrode layer is the golden film good with the biological membrane associativity.
The making step of piezoelectric thin film vibrator spare is in the sensor provided by the present invention:
(1) on the silicon substrate of (100) orientation or contain SiO
2The Bragg reflection horizon of 1/4 wavelength that two kinds of acoustic resistance differences of alternating growth are big respectively on the substrate of layer;
(2) on the Bragg reflection horizon, deposit piezoelectric thin film layer;
(3) depositing electrode layer on piezoelectric thin film layer;
(4) adopt the graphical technology of related semiconductor, make the electrode structure that is complementary with the standard microwave measurement;
(5) obtain silicon based piezoelectricity film Resonator spare through 100-800 ℃ of annealing.
The monocrystalline silicon piece in described taking (100) crystal orientation or contain SiO
2The silicon substrate of layer through complete substrate cleaning, uses the Bragg reflection horizon of magnetron sputtering apparatus or sol-gel process tool λ/4 (λ the is wavelength) thickness that two kinds of acoustic resistance differences of alternating growth are big respectively, is Pt, ZnO, or is SiO
2, W, and each layer crystal is to, all smooth densification of structure, and equal tool preferred orientations.
The graphical technology of making the suitable electrode pattern of radio-frequency measurement is for relevant etching technics, as wet etching, stripping technology (lift-off) or dry method ion etching.Figure such as Fig. 4 and be shown in Figure 7.
Describedly anneal under 100-800 ℃ of condition, annealing time is 1 minute-120 minutes, makes the resonance performance of sensor more perfect after the annealing.
Described on resonator coating and measure each step in conjunction with corresponding biological membrane (probe biomolecule).It is to apply on resonator in conjunction with biological membrane, and bag closes again, cleans, and drop biological fluids to be tested behind the immune association reaction between the biomolecule of solidifying on biomolecule in the biological fluids and the resonator, after cleaning repeatedly, is tested change of resonance frequency more again.
Simultaneously, 1. amplify, contain the biological immune body of heavy amount nanometer Au micelle on the special biosome in biological fluids again in conjunction with one deck for the biosome mass effect that makes combination in the immune response.The sandwich mode of this " sandwich " can make the variation of the biosome quality that combines with piezoelectric film sensor more remarkable, plays and measures the effect that quality is amplified at double;
2. for the silicon based piezoelectricity thin film sensor can be reused, its corresponding follow-up cleaning fluid has the cleaning function that makes the complete separating sensor of probe biomolecule;
3. has the testing circuit of measuring the respective resonant frequency wave band in making.And can make the miniature piezoelectric resonator array, at the fixing different molecular probe of each sensor surface or be certain nucleic acid or be certain protein, promptly constitute the silicon based piezoelectricity biochip.Can realize the detection of multichannel biological sample.Specifically be to adopt traditional testing circuit and the method for frequency analysis: Fig. 1 (a) thereof to be the BVD equivalent circuit diagram of piezoelectric resonator, utilize the circuit of Fig. 1 (b) can detect the resonance frequency of harmonic oscillator, can be with conventional semiconductor technology preparation.Frequency analysis is according to classics response resonance formula
As can be known, can calculate the quality of corresponding combination by the variation of frequency.Wherein: μ is the modulus of shearing of piezoelectric, and ρ is the density of piezoelectric, and A is the resonator area.F is a frequency of operation.Δ f, Δ m are respectively the frequency of variation and the quality of variation.
To sum up, sensor provided by the invention and method for making are to adopt the good piezoelectric membrane replacement quartz wafer of deposition quality on the silicon chip, development microminiaturization, array, multichannel integrated piezoelectric thin film bio sensor.Yet whether piezoelectric biological sensor can be used for the biological detection of trace, depends on the sensitivity (pg level) of its detection fully.The piezoelectric biological sensor detection limit of existing report far can not satisfy the needs of practical application about 100ng." sandwich " pattern of the employing silicon based piezoelectricity film Resonator spare technology of preparing that the present invention proposes and biological nano material-material to be checked (the antigen/antibody)-antibody/antigen of biomolecule specific bond is to significantly improve the method for resonance frequency and detection sensitivity.Make the sensitivity of piezoelectric membrane biology sensor reach the pg level.Develop many probe units or be 16 * 16 with actual application value, or be 2 * 2 high sensitivity (pg level), hyperchannel, integrated silicon-based piezoelectric film sensor, and extensive, the integrated biology sensor that has an actual application value for further research and development is established technical foundation.
Description of drawings
The BVD equivalent electrical circuit of Fig. 1 (a) piezoelectric resonator
(b) piezoelectric resonator resonance frequency oscillatory circuit figure
Fig. 2 is preparation technology's synoptic diagram of silicon based piezoelectricity film Resonator spare
(a): the Si sheet of (100) orientation or contain the SiO of 100nm-1000nm
2Layer
(b): with the method growth Bragg reflection horizon of physics or chemistry
(c): the Bragg reflection horizon for preparing a plurality of cycles with the method for physics or chemistry
(d): on the Bragg reflection horizon in a plurality of cycles with the method growth piezoelectric thin film layer of physics or chemistry
(e): the method growth Au electrode of on piezoelectric thin film layer, using physics
The electrode domain figure that Fig. 3 the present invention is designed, graphic making photolithographic mask version thus
Fig. 4 bag is by the TEM picture of biological nano material
Fig. 5 is the detection synoptic diagram of the bioprobe sandwich sandwich mode of silicon based piezoelectricity thin film sensor
(a): original state
(b): after process biological curing bag closes
(c): behind the protein coupling reaction
Fig. 6 shows in conjunction with the change of resonance frequency of measuring behind the biosome
The electrode domain figure of Fig. 7 example 2, graphic making lay photoetching mask plate thus
Fig. 8 shows in conjunction with the change of resonance frequency of measuring behind the biosome
1 is (100) orientation silicon chip among the figure; 2 are the low velocity of sound layer of Pt; 3 is the high velocity of sound layer of ZnO; 4 is the ZnO piezoelectric film layer; 5 is the Au electrode layer; 6 is antibody molecule; 7 is antigen molecule; 8 nm of gold micelles
Embodiment
Embodiment 1: the preparation of silicon based piezoelectricity thin film bio sensor, its step is
(1) Zhi Bei piezoelectric resonator with a plurality of Bragg reflection horizon.Be on (100) orientation Si sheet of 3 inches, to adopt multi-target magnetic control sputtering Pt/ZnO Bragg reflection horizon at diameter.Before the beginning, vacuumize and make the base vacuum degree reach 2 * 10
-4Pa is heated to 300 ℃ to the substrate Si sheet again.Sputtering power is respectively direct current 100W and radio frequency 200W; The sputter air-flow is respectively argon gas (Ar) 50sccm and argon gas (Ar): oxygen (O
2), 25: 25sccm; The sputter operating air pressure is respectively 1.7 * 10
-1Pa and 1.8 * 10
-1Pa; Adopt the method for the continuous sputter of many targets to prepare the Bragg reflection horizon.The hundreds of nanometers of each thickness.[Fig. 2 (a)～(c)].
(2) preparation of piezoelectric thin film layer: on the Bragg reflection horizon, prepare piezoelectric membrane.Adopt the multi-target magnetic control sputtering instrument, forvacuum is 1.4 * 10
-4Pa, substrate heat to 300 ℃, charge into argon gas and oxygen and respectively are 25sccm and 25sccm; Magnetron sputtering power is radio frequency 200W, and sputtering pressure is 0.18Pa.The hundreds of nanometers of thickness.[Fig. 2 (d)]
(3) preparation electrode A u film adopts the multi-target magnetic control sputtering instrument, and still in a same vacuum chamber, vacuum tightness is 2.0 * 10
-4Pa, underlayer temperature are 25 ℃ of room temperatures.Feeding sputter gas Ar is 50sccm, and sputtering power is direct current 50W, and the sputter operating air pressure is 0.21Pa.The hundreds of nanometers of thickness.[Fig. 2 (e)]
(4) carry out short annealing thermal treatment at rapid heat-treatment furnace, heating rate is 20 ℃/s, and after 400 ℃, temperature retention time is 300 seconds.Whole annealing process is carried out under oxygen atmosphere, the oxygen vacancy defect that easily causes when annealing to replenish, and this can make that the piezoelectric membrane performance is more intact.
The electrode pattern of the various and microwave frequency compatibility of (5) preparing.To upper strata Au electrode patternization, adopt the semiconductor figure metallization processes of standard.The technology that promptly adopts gluing, exposure, development, burn into to remove photoresist.(Fig. 3)
The microwave signal of each harmonic oscillator of (6) measuring.The equipment that adopts is 40GHz HP8722D vector network analyzer and Cascade height temperature control probe station.
(7) coating is in conjunction with corresponding biological membrane on the resonator, and bag closes again, cleans.Adopt the sandwich sandwich technique, point sample specific biological trace is behind the immune association reaction between the biomolecule of solidifying on biomolecule in the biological fluids and the resonator, again through cleaning repeatedly.(Fig. 4 and Fig. 5)
The variation of the harmonic peak behind the harmonic oscillator binding biomolecules of (8) measuring, and by the biological little quality that responds resonance formula calculations incorporated.(Fig. 6)
Embodiment 2:
On embodiment 1 described whole film Resonator spare preparation technology basis, change the preparation method of the Bragg layer in the processing step (1): the sputter gas flow of sputter Pt and ZnO is adjusted to argon gas 100sccm and oxygen 50sccm respectively, argon gas 50sccm, and then raising sputter operating air pressure is respectively 0.40Pa and 0.37Pa; The also corresponding oxygen argon flow that changes into of preparation piezoelectric thin film layer is oxygen 50sccm in processing step (2), argon gas 50sccm, and improving the sputter operating air pressure is 0.37Pa.And change film thickness to change characteristic resonant frequency; In processing step (5), adopt the electrode structure (Fig. 7) of better figure, prepare silicon based piezoelectricity thin film bio sensor equally, and realized the skew of harmonic peak behind the binding biomolecules more accurately.(Fig. 8)
Above-mentioned enforcement will help understands the present invention, but does not limit content of the present invention.
Claims (9)
1, a kind of silicon based piezoelectricity thin film sensor that is used for biological little quality testing is made up of probe biomolecule, transducer and testing circuit three parts, it is characterized in that
A, described transducer are piezoelectric vibration device, and its structure is:
1. on the silicon substrate of (100) orientation or contain SiO
2The big Bragg reflection horizon of two kinds of acoustic resistance differences of alternating growth respectively on the silicon substrate of layer with 1/4 thickness;
2. deposit piezoelectric thin film layer on the Bragg reflection horizon, thin layer thickness is 200-5000nm; Resonance frequency is 100M-10GHZ;
3. deposit electrode layer on piezoelectric thin film layer, thickness is 100-500nm;
The structure of B, described probe biomolecule is that coating is closed through bag in conjunction with corresponding biological membrane on piezoelectric resonator, forms the sandwich pattern of biological nano material-material-antigen/antibody to be checked.
2, by the described silicon based piezoelectricity thin film sensor that is used for biological little quality testing of claim 1, it is characterized in that described piezoelectric thin film layer is the piezoelectric thin film layer of C axle preferrel orientation, described piezoelectric thin film layer is ZnO, AlN or PZT.
3, by the described silicon based piezoelectricity thin film sensor that is used for biological little quality testing of claim 1, it is characterized in that described SiO
2Layer thickness is 100nm-1000nm.
4,, it is characterized in that described electrode layer is golden film by the described silicon based piezoelectricity thin film sensor that is used for biological little quality testing of claim 1.
5,, it is characterized in that the sensitivity Da Pike level of described silicon based piezoelectricity thin film sensor by claim 1 or the 2 described silicon based piezoelectricity thin film sensors that are used for biological little quality testing.
6, make the method that is used for the silicon based piezoelectricity thin film sensor of biological little quality testing as claimed in claim 1, it is characterized in that adopting the sandwich method of sandwich of silicon based piezoelectricity film Resonator spare preparation method and biomolecule specific bond, utilize the micromechanics electronic system technology on piezoelectric thin film layer, to make the miniature piezoelectric resonance array, at the corresponding biological membrane of piezoelectric thin film vibrator spare surface applied, bag closes again, clean, fixing different molecular probe constitutes piezoelectric biological chip; Concrete making step is:
(1) on the silicon substrate of (100) orientation or contain SiO
2The Bragg reflection horizon of 1/4 wavelength that two kinds of acoustic resistance differences of alternating growth are big respectively on the substrate of layer;
(2) on the Bragg reflection horizon, deposit piezoelectric thin film layer;
(3) depositing electrode layer on piezoelectric thin film layer;
(4) adopt the graphical technology of related semiconductor, make the electrode structure that is complementary with the standard microwave measurement;
(5) obtain silicon based piezoelectricity film Resonator spare through 100-800 ℃ of annealing.
7, by the described method for making that is used for the silicon based piezoelectricity thin film sensor of biological little quality testing of claim 6, it is characterized in that
1. the described graphical technology of step (4) is wet etching, stripping technology or dry method ion etching;
2. the annealing time of step (5) is 1-120 minute.
8, by the application of described each the described silicon based piezoelectricity thin film sensor of claim 1-5, it is characterized in that the biological micro quality testing, according to response resonance formula, the variation that goes out corresponding biosome quality by the change calculations of frequency.
9, by the application of the described silicon based piezoelectricity thin film sensor of claim 8, it is characterized in that the resonance formula that responds is
ρ is the density of piezoelectric in the formula, and A is the resonator area, and f is a frequency of operation, and Δ f, Δ m are respectively the frequency of variation and the quality of variation.
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| CN103760336B (en) * | 2014-01-02 | 2016-01-20 | 中国科学院苏州生物医学工程技术研究所 | A kind of linear array ZnO nano-wire heterojunction LED biology sensor and preparation method |
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