CN1252474C - Magnetic tunnel junction biochip carrier and chip using said carrier and its manufacturing method and method of proceeding detection against biomolecule - Google Patents
Magnetic tunnel junction biochip carrier and chip using said carrier and its manufacturing method and method of proceeding detection against biomolecule Download PDFInfo
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Abstract
The present invention relates to a biological chip carrier of a magnetic tunnel junction, a chip using the carrier, a making method for the chip and a method for detecting biological molecules. The biological chip of a magnetic tunnel junction is formed by processing a multi-layer membrane material. The biological chip of a magnetic tunnel junction is mainly composed of a fixed ferrum magnetic layer, an induction ferrum magnetic layer and a tunnel barrier layer for separating the fixed ferrum magnetic layer from the induction ferrum magnetic layer. Magnetic tunnel junction micro-arrays with different densities can be processed on the multi-layer membrane material with a certain dimension, such as 1cm*1cm, and the minimum area of each tunnel junction is 0.5 mu m*0.5 mu m. The present invention uses the magnetic tunnel junction microarrays after surface treatment as a fixed carrier of biological macromolecules, the giant magnetic resistance generated through the action of magnetic particles on the surface of the magnetic tunnel junction is used as a detection signal, and the varieties and the content of various biological macromolecules on the biological chip of a magnetic tunnel junction are detected.
Description
Technical field
The present invention relates to a kind of magnetic tunnel-junction biochip carrier and adopt chip and preparation method thereof of this carrier and the method that biomolecule is detected.
Background technology
Be used to connect, absorption or the various biomolecule of embedding make its solid phase material with water-insoluble state functionating be referred to as carrier.The existing at present fixation support that comprises hundreds of carrier of material preparations such as inorganic material, natural organic polymer, the organic high molecular polymer of synthetic, various polymer membranes and be used to various materials.Biochip is that the collection modern life science that rises later 1980s, information science, microelectronics, micromachining technology etc. are the biomolecule microanalysis processing platform of one, having important feature such as the integrated and parallelization processing of information height, is the important platform and the instrument of modern life science, medical science and drug development.An important step of making biochip is to select a kind of carrier and fix various active biomolecule on its surface, as protein, nucleic acid, enzyme, polypeptide, antigen, antibody etc., but in existing hundreds of carrier, real be fit to that biochip uses have only a few, the film of making as glass sheet, silicon chip, sheet metal, various organic polymer etc.Biochip must meet the following requirements with carrier material at present:
(1). carrier surface will pass through certain processing, enable to have static reaction or carry out the Activity of Chemical Reaction group, so as with biomolecule coupling mutually.
(2). the biomolecule of combination reaches optimum capacity on the unit's of making carrier.
(3). carrier should be inertia and has enough stability and comprises machinery, physics and chemical stability.
(4). carrier has good bio-compatibility.
In addition, because present biochip test adopts the method for optical detection mostly, comprise transmitted light and reflected light.
This detection method also requires used biochip to have good optical character, can adapt to transmission or catoptrical measurement.Glass sheet is to use a kind of preferably carrier at present, and it has certain advantage than polymeric materials such as nylon.The detection of sheet then need use expensive scanner to finish.
Giant magnetoresistance (Giant Magnetoresistance, be called for short GMR) material is meant a class functional material of resistance generation marked change under the outside magnetic field effect, from M.N.Baibich in 1988 at (Fe/Cr)
nFind after the giant magnetoresistance effect in the material of superlattice multi-layer film structure, people are in succession at Spin Valve (the Spin Valve of " feeromagnetic metal/nonmagnetic metal conducting film/feeromagnetic metal ", SP), (Magnetic TunnelJunction has all found giant magnetoresistance effect in MTJ) for the magnetic tunnel-junction of the membrana granulosa of " feeromagnetic metal/nonmagnetic metal " and " feeromagnetic metal/nonmagnetic metal oxide insulating film/feeromagnetic metal ".Wherein the comprehensive technical indexes of magnetic tunnel-junction occupy the leading position in various GMR materials, has been subjected to the extensive concern of material circle and electronics industry circle.
Induction ferromagnetic layer, nonmagnetic metal oxide insulating layer, fixed ferromagnetic layer are formed core sandwich film, the magnetic tunnel-junction that this membrane material is made can produce giant magnetoresistance effect, middle nonmagnetic metal oxide insulating layer is called tunnel barrier layer again, tunnel barrier layer as thin as a wafer, about 1～the 4nm of thickness is to guarantee to produce the tunneling effect of spinning electron in two ferromagnetic layers.In electronic spin polarization tunnelling process, giant magnetoresistance effect is from most from spinning up electronics and the minority downward density of electronic states asymmetry of (Density of States is called for short DOS) that spins in two ferromagnetic layers.Under the ideal state of not considering spin(-)flip scattering (Spin-flip), electronic spin polarization tunnelling probability only depends on the relative orientation of the magnetization in two ferromagnetic layers in the tunnelling process.When the direction of the magnetization was parallel to each other, the free orientation of most electronics was identical during two ferromagnetic layer materials can be with, and can fill near the Fermi surface (Fermi) between the number of attitude to have the maximum match degree, made the tunnelling current maximum, tunnelling resistance minimum.Otherwise, when the magnetization direction antiparallel, because not matching between the density of electronic states that two ferromagnetic layer materials can be with causes the tunnelling current minimum, and tunnelling resistance maximum.Scientist with this behavior explains is: when spinning electron passes the opposite ferromagnetic layer of direction of magnetization, produce stronger scattering and present high resistance, when spinning electron passes the identical ferromagnetic layer of direction of magnetization, a little less than the spinning electron scattering, be low resistance.Therefore, when applying the external magnetic field effect, make the magnetization turn to the antiparallel attitude from parallel state, or when the antiparallel attitude turns to parallel state, can produce the variation of magneto-resistor, because the transport mechanism of electronics is a tunnel effect in the magnetic tunnel-junction, the tunnel type magneto-resistor so this giant magnetoresistance effect is otherwise known as (Tunnel Magnetoresistance is called for short TMR).Owing to have controlled high junction resistance, low-power consumption, saturation field and a higher relatively field sensitivity, institute is so that magnetic tunnel-junction becomes the sensitiveest present magnetic field induction device.
In magnetic tunnel junction sensor, the magnetic moment of a ferromagnetic layer be fix or pinprick is fixing, and the magnetic moment of another ferromagnetic layer can rotate arbitrarily with external magnetic field.When adding current potential between two ferromagnetic layers, sensor resistance changes along with the tunnel(l)ing current that passes ferromagnetic interlayer insulating film.Giant magnetoresistance effect is that reluctivity is represented with the relative change rate of resistance usually, as follows formula:
ΔR＝(R
a-R
ρ)/R
a
Wherein, R
ρAnd R
aResistance value when being illustrated respectively in the parallel and antiparallel of following two ferromagnetic layer magnetization direction of external magnetic field effect 11.
Biabich equals molecular beam epitaxy (the Molecular BeamExtention that has reported the earliest with complexity and costliness in 1988, MBE) Fe (25nm)/Co (1nm)/Fe (25nm) sandwich structure of technology preparation, relatively magneto-resistor is the membrane system of 1.5% GMR effect, the comparatively simple sputter manufacturing technology of development is subsequently simplified the multilayer film formation techniqueflow greatly.The magnetic tunnel junction device that the giant magnetoresistance that at room temperature obtains reaches about 20% was just reported in nineteen ninety-five.For observing significant giant magnetoresistance effect, the magnetic tunnel-junction of preparation requires: (1). and the spin polarizability that reaches the ferromagnetic thin film layer wants big, promptly avoids oxidation in the preparation process; (2). oxide barrier is enough high, and promptly shortcoming such as densification and free of pinholes makes electronics transport with the tunnelling form; (3). under the outside magnetic field, the magnetization of two ferromagnetic layers is parallel or arranged anti-parallel arbitrarily.In recent years, along with the development of magnetic tunnel-junction composition material and updating of processing technology, obtain the higher tunnel junction of giant magnetoresistance effect under a series of room temperatures.Can parallel or arranged anti-parallel for the magnetization that makes two ferromagnetic layers, it has adopted deposition pinning layer, the antiferromagnetic coupling of deposition and layer, makes ferromagnetic layer have different technology such as coercive force by the control preparation condition and has obtained various magnetic tunnel-junction.Except that the core sandwich film of forming magnetic tunnel-junction; sometimes also can increase the protective seam of induction ferromagnetic layer in the magnetic tunnel-junction processing, also claim cap layer, the antiferromagnetic coupling layer of fixed magnetization intensity direction; also claim inverse ferric magnetosphere, or be beneficial to the various function film layers such as crystal seed layer that obtain dense film.The material of being made up of jointly core sandwich film and other function film layer is called multi-layer film material.Magnetic tunnel-junction by this multi-layer film material processing is called magnetic tunnel junction device with the device that external power supply, detecting device are connected.Fig. 1 is a tunnel junction device structural representation of fixing one of them ferromagnetic layer by antiferromagnetic coupling and layer.This magnetic tunnel junction device 16 is connected and composed with power supply 2 and signal detector 1 by lead 3 and lead 10 by magnetic tunnel-junction 15.Power supply 2 is used to provide and detects electric current I s, and 1 of signal detector is used to be determined under the situation that external magnetic field exists because the variation of induction ferromagnetic layer 5 direction of magnetization produces the size of giant magnetoresistance value.Magnetic tunnel-junction 15 mainly is made up of ferromagnetic electrode 13, ferromagnetic electrode 14, tunnel barrier layer 6 and lead 3 and 10.Ferromagnetic electrode 14 is made of fixed ferromagnetic layer 7, inverse ferric magnetosphere 8 and crystal seed layer 9.Fixed ferromagnetic layer 7 and inverse ferric magnetosphere 8 couplings and, its magnetization direction 12 is fixed; Crystal seed layer 9 is mainly used in the optimization interfacial structure; Ferromagnetic electrode 13 mainly is made up of induction ferromagnetic layer 5 and cap layer 4, and cap layer 4 is used for the protection on magnetic tunnel-junction 15 surfaces.Induction ferromagnetic layer 5 separates by tunnel barrier layer 6 non magnetic, insulation with fixed ferromagnetic layer 7.Do not having under the situation of externally-applied magnetic field, 11 are depicted as the magnetization direction of induction ferromagnetic layer 5; 12 are depicted as the magnetization direction of fixed ferromagnetic layer 7, its vertical paper plane from outside to inside, at this moment, the magnetization direction of two ferromagnetic electrodes 13,14 11,12 is vertical mutually.
Sensor device with giant magnetoresistance effect, be mainly used in existence, power, direction and the variation etc. that detect magnetic field, compare with traditional magnetic resistance sensor, giant magnetoresistance is because it is highly sensitive, good reliability, characteristics such as measurement range is wide, the life-span is long, volume is little, anti-adverse environment, Magnetic Sensor, high density and super-high density computing machine playback head (Read Head) and magnetic random memory (Magnetic RandomAccess Memory, field such as MRAM) have been widely used in.The IBM Corporation of the U.S. in 1994 uses the Spin Valve playback head of giant magnetoresistance effect first, obtains 1,000,000,000 hard disk surface density record per square inch; To 1996, the surface density of hard disk reached 5,000,000,000 per square inch.The expection capacity of hard disk density in the future will realize 4,000 and even 10,000 hundred million per square inch.Meanwhile, the magnetic random memory of giant magnetic resistor material processing and fabricating, also received the concern of computer realm, the employing of estimating MRAM can realize the storage density of 10Gbit/cm2 and the storage speed of 0.5ns, so magnetic playback head and magnetic random memory have significant values and application prospect in the research and development of next generation computer.
Giant magnetic resistor material has certain advantage aspect the sensing of Weak magentic-field, for this reason, 1998, D.R.Baselt etc. utilize spin valve structure investigation of materials based on the biochip of giant magnetoresistance effect, and be referred to as micro-sphere array calculating instrument (Bead ARray Counter, BARC), though the Spin Valve material preparation process is comparatively ripe, this biosensor technique based on spin valve structure still has the following disadvantages:
(1). the magnetoresistive ratio of Spin Valve is less, only is 5～10% usually, and is therefore lower based on the biochip sensitivity of this kind giant magnetoresistance effect;
(2). the material power consumption height of spin valve structure, output voltage is low, the background noise height, and higher background noise can influence the accuracy of measurement result;
(3). because the restriction of sensitivity, this technology is with the label of micron-sized magnetic-particle as tested biomolecule, by biomolecule being detected that magnetic-particle produces than low-intensity external magnetic field, the rate of change of giant magnetoresistance only is 4%, if use littler nano magnetic particle to serve as a mark, then detecting less than giant magnetoresistance is worth changing.
The objective of the invention is to avoid above-mentioned weak point of the prior art, and the magnetic tunnel-junction biochip carrier of a kind of high density of utilizing magnetic tunnel-junction preparation or super-high density is provided and adopts chip and preparation method thereof of this carrier and the method that biomolecule is detected.Detection sensitivity height of the present invention, the accuracy height, checkout equipment is simple.
Purpose of the present invention can reach by following measure:
At first obtain the magnetic tunnel-junction of certain density, and design corresponding circuit by known magnetic tunnel-junction manufacturing technology; After it is carried out certain surface treatment, biomolecule such as protein, nucleic acid, polysaccharide etc. are fixed on the surface of magnetic tunnel-junction by biochip point sample instrument; Determined bio-target molecule carries out the mark of nanometer or micron order magnetic-particle; The bio-target molecule that is marked with magnetic-particle carries out incubation reaction with the identification molecule that is fixed on the magnetic tunnel-junction biochip, removes some nonspecific molecules; With reacted magnetic tunnel-junction biochip, insert the mensuration of carrying out resistance or voltage in the circuit, according to the position and the intensity that produce electric signal, determine various biomacromolecule kinds and content on the magnetic tunnel-junction biochip.
A kind of magnetic tunnel-junction biochip carrier mainly is made of magnetic tunnel-junction 15, and this magnetic tunnel-junction 15 mainly comprises tunnel barrier layer 6, the substrate 17 of ferromagnetic electrode 13, non magnetic insulation and is arranged at ferromagnetic electrode 14 in the substrate 17; Described ferromagnetic electrode 13 mainly comprises induction ferromagnetic layer 5, described ferromagnetic electrode 14 mainly comprises fixed ferromagnetic layer 7, and described tunnel barrier layer 6 is arranged at the tunnel barrier layer 6 that comprises first ferromagnetic electrode 13, non magnetic insulation, the substrate 17 of induction ferromagnetic layer 5 and fixed ferromagnetic layer 7 and is arranged at second ferromagnetic electrode 14 in the substrate 17; Described first ferromagnetic electrode 13 mainly comprises induction ferromagnetic layer 5, and described second ferromagnetic electrode 14 mainly comprises fixed ferromagnetic layer 7, and described tunnel barrier layer 6 is arranged at and constitutes core sandwich film between induction ferromagnetic layer 5 and the fixed ferromagnetic layer 7; Its special character is: described magnetic tunnel-junction 15 surfaces are coated with biomolecule fixed bed 18, constitute magnetic tunnel-junction biochip carrier 19.
Above-mentioned second ferromagnetic electrode 14 can comprise coupling and in the inverse ferric magnetosphere 8 on fixed ferromagnetic layer 7 surfaces.
Induction ferromagnetic layer 5 surfaces of above-mentioned first ferromagnetic electrode 13 can be provided with cap layer 4.
The bottom of above-mentioned second ferromagnetic electrode 14 can be provided with crystal seed layer 9.
Above-mentioned induction ferromagnetic layer 5 can be the ferromagnetic material that coercive force is less and giant magnetoresistance effect is bigger; Said fixing ferromagnetic layer 7 can be the bigger ferromagnetic material of giant magnetoresistance effect; Above-mentioned tunnel barrier layer 6 can be metal oxide or AlN.
The thickness of above-mentioned tunnel barrier layer 6 is advisable with 1～4nm; The metal oxide of above-mentioned tunnel barrier layer 6 can be Al
2O
3Or MgO.
A kind of magnetic tunnel-junction biochip, its special character is: it comprises magnetic tunnel-junction biochip carrier 19 and addressable biomolecule 20, described addressable biomolecule 20 is with scheduling magnetic tunnel-junction biochip carrier 19 surfaces.
A kind of method for making of magnetic tunnel-junction biochip carrier, its special character is: the making step of this method is as follows
1]. the making of magnetic tunnel-junction membraneous material
(1). with the high vacuum of magnetron sputtering or ion beam sputtering or ultrahigh vacuum sputter at substrate 17 surface sputtering one deck fixed ferromagnetic layers 7;
(2). prepare tunnel barrier layer 6 on fixed ferromagnetic layer 7 surfaces with the method for nitrogen reaction or autoxidation, plasma oxidation;
(3). at tunnel barrier layer 6 surface sputtering one decks induction ferromagnetic layer 5, form the core sandwich film of magnetic tunnel-junction multi-layer film material;
(1). adopt photo-engraving process, allow light see through to be carved with the mask of wiring diagram to be radiated at the multi-layer film material surface, the etching hollow out obtains the microarray of magnetic tunnel-junction 15 uniform, that area is small; Described photoetch is to adopt ultraviolet light, extreme ultraviolet, X-light or ion beam projected light to carry out etching;
3]. the making of magnetic tunnel-junction biochip carrier
On magnetic tunnel-junction 15 surfaces, sprayed biological molecule fixed bed 18 forms magnetic tunnel-junction biochip carrier 19.
The method for making of above-mentioned magnetic tunnel-junction membraneous material comprises can be provided with the inverse ferric magnetosphere 8 formation magnetic tunnel-junction multi-layer film materials that one deck is coupled with it in fixed ferromagnetic layer 7 bottoms.
The making of above-mentioned magnetic tunnel-junction membraneous material can be included in the bottom of this core sandwich membraneous material and make one deck crystal seed layer 9 formation magnetic tunnel-junction multi-layer film materials by the method for sputter.
The magnetization direction 12 of said fixing ferromagnetic layer 7 can adopt pinprick or antiferromagnetic coupling and form to fix.
Above-mentioned method with oxidation or plasma oxidation prepares tunnel barrier layer 6 and can comprise, deposition one deck tunnel barrier layer 6 used metal simple-substances adopt the method for autoxidation or plasma oxidation to prepare metal oxide formation tunnel barrier layer 6 then earlier; Above-mentioned method with the nitrogen reaction prepares tunnel barrier layer 6, can metal nitride directly be deposited on fixed ferromagnetic layer 7 surfaces with the method for reactive sputtering or directly sputter when laying.
The preparation of above-mentioned magnetic tunnel-junction 15 can be included in magnetic tunnel-junction microarray table and spray cap layer 4, fills and leads up the etching openwork part, and in the punching of the position of magnetic tunnel-junction 15, makes magnetic tunnel-junction 15 expose out.
A kind of method for making of magnetic tunnel-junction biochip, its special character is: this method is that addressable biomolecule 20 is fixed on magnetic tunnel-junction biochip carrier 19 surfaces, forms the magnetic tunnel-junction biochip.
Above-mentioned addressable biomolecule 20 is fixed on magnetic tunnel-junction biochip carrier 19 surfaces can be by the method for physisorption or chemical bonding.
Above-mentioned method by physisorption or chemical bonding can be to utilize biochip point sample instrument, by the spotting needle of orderly arrangement, addressable biomolecule 20 is arranged on the magnetic tunnel-junction biochip carrier 19.
Above-mentioned addressable biomolecule can be protein, nucleic acid, oligonucleotides, polysaccharide etc.
A kind of method that adopts the magnetic tunnel-junction biochip that biomolecule is detected, its special character is: the detection step of this method is as follows
(1). magnetic nano-particle is to the mark of target molecule
With magnetic tunnel-junction as biochip carrier 19, adopt nanometer or micron order magnetic-particle label as target molecule, detected target molecule is marked on the nanometer or micron order magnetic-particle with superparamagnetism, at the particle surface coated polymer, and rhetorical function group, be marked on the biomolecule by affine or covalent bond, make magnetic particle immobilization on antibody molecule;
(2). react between addressable biomolecule 20 and the detected molecules of interest, micron order or the nano-scale magnetic particle that is marked on the determined target material is fixed on biochip surface;
(3). add external magnetic field paramagnetic magnetic-particle is produced magnetization, outer magnetic field direction is vertical mutually with the magnetic tunnel-junction plane;
(4). by attached to magnetic tunnel-junction surface magnetism magnetic field that particulate produces tunnel junction being responded to the variation of the magneto-resistor that effect causes of ferromagnetic layer 5 behind the detection of biological chemical reaction, write down electric signal in the testing process, determine the kind and the content of detected biomolecule.
The present invention compared with prior art has following advantage:
1. highly sensitive; The magneto-resistor of magnetic tunnel-junction of the present invention changes can reach 20～40%, and therefore, the magnetic tunnel-junction biochip test is highly sensitive, can accomplish Single Molecule Detection;
2. accuracy height; Magnetic tunnel-junction biochip signal to noise ratio (S/N ratio) height of the present invention, background interference is little, therefore has higher accuracy;
3. not nonoculture of magnetic tunnel-junction of the present invention is that biological chip carrier uses, and goes back the important devices of double as electromagnetics method testing goal biomolecule;
4. compare with biochip test fluorescent scanning instrument commonly used at present, this pick-up unit of the present invention is simply portable, measures as using signal amplifier; Also more be adapted to the detection of the pathogenic microorganism of aspects such as clinical scene and battlefield, epidemic-stricken area check;
5. because each magnetic tunnel-junction all can constitute a magnetic-inductive device, so can obtain the magnetic tunnel-junction biochip of high density and super-high density;
6. carrier of the present invention can be made numerous genetic chips, as oligonucleotide chip, cDNA chip, protein chip, polysaccharide chip etc., and can be widely used in the research of expression of nucleic acid spectrum, DNA clinical detection, antigen/anti-chip, polysaccharide chip etc., and can be widely used in numerous areas such as the research of expression of nucleic acid spectrum, DNA clinical detection, antigen/antibody detection, polypeptide detection and biological warfare agent detection.
Description of drawings
Fig. 1 is the structural representation of magnetic tunnel junction device of the present invention;
Fig. 2 is the structural representation of magnetic tunnel-junction biochip of the present invention.
The invention will be further described below in conjunction with specific embodiment:
1. the preparation technology of magnetic tunnel-junction biochip carrier of the present invention is as follows
1]. the preparation of magnetic tunnel-junction membraneous material
The magnetic tunnel-junction multi-layer film material can utilize the high vacuum of existing magnetron sputtering or ion beam sputtering or ultrahigh vacuum sputter to prepare on a kind of substrate 17 surfaces.Usually induction ferromagnetic layer 5 uses the material that coercive force is less and giant magnetoresistance effect is bigger; Fixed ferromagnetic layer 7 uses the bigger material of giant magnetoresistance effects, its magnetization direction 11 can adopt pinprick or antiferromagnetic coupling and etc. form fixed.Tunnel barrier layer 6 can adopt metal oxide, uses maximum Al that is
2O
3Also can use A1N, MgO etc.Tunnel barrier layer 6 should be fine and close, and thickness is 1～4nm, can adopt existing autoxidation, reactive sputtering, directly several different methods preparations such as sputtering sedimentation, plasma oxidation.As utilize the plasma oxidation legal system to be equipped with barrier layer, general first sputtering sedimentation layer of aluminum, under the situation that keeps original vacuum tightness, sample is moved into the plasma oxidation chamber that links to each other with sputtering chamber with mechanical arm, accurately control oxidizing process, as distance between oxygen pressure, sample and the sputtering target etc., obtain the thick Al of 1～2nm
2O
3Tunnel barrier layer 6; For making magnetic tunnel junction device 16 have higher reluctivity, can prepare crystal seed layer 9 earlier at substrate surface, so that other layers of material densification, even, smooth, along certain direction growth.
With above-mentioned prior art can prepare have induction ferromagnetic layer 5/ tunnel barrier layer 6/ fixed ferromagnetic layer 7 architectural features such as Co/Al
2O
3/ Ni
80Fe
20With Co, Fe doping/Al
2O
3/ Ni
80Fe
20Multilayer film and have induction ferromagnetic layer 5/ tunnel barrier layer 6/ fixed ferromagnetic layer 7/ inverse ferric magnetosphere 8 architectural features as CoFe/Al
2O
3The multi-layer film material of materials such as/CoFe/MnIr.Also can adopt existing multilayer film technology of preparing, with the material that designs voluntarily, preparation multi-layer film material as shown in Figure 2.
2]. the preparation of magnetic tunnel-junction
Operation, the researchist is also at research and utilization extreme ultraviolet photolithographic, ion beam projection lithography innovation fabrication techniques magnetic tunnel-junction.
Adopt the magnetic tunnel-junction of above-mentioned photoengraving or ion beam etching technology preparation, area is more little, and its detection sensitivity is just high more.After obtaining the microarray of magnetic tunnel-junction by etching, for preventing to respond to the oxidation of ferromagnetic layer 5, also need add formation protective seams such as applying silicon oxide, fill and lead up the part of etching hollow out, and, the magnetic tunnel-junction upper conductor is connected in the punching of the position of magnetic tunnel-junction.
3]. the making of magnetic tunnel-junction biochip carrier
Magnetic tunnel-junction according to said method obtains has formed magnetic tunnel-junction biochip carrier through after certain surface treatment, and all do not destroy its structure, can carry out the method for physisorption or chemical reaction again and all can use on magnetic tunnel-junction.
Method 1: after multi-layer film material obtains magnetic tunnel-junction through etching and processing, surface spraying one deck silicon nitride (SiN
3) to prevent corrosion, spraying plating one deck is thin golden again on its surface then, its thickness can use the technology of thermal spray or electron beam spraying about 300nm～1 μ m.
Method 2: adopt the method for handling glass sheet or silicon chip at present, certain chemical treatment is carried out on the surface of magnetic tunnel-junction, make it have certain chemical functional group as amino, carboxyl etc.After obtaining magnetic tunnel-junction, surface spraying layer of silicon dioxide (SiO2), then silica surface is handled with concentrated acid, make its surperficial hydroxyl activation, add silylating reagent N-(2-(aminoethyl)-3-aminopropyl trimethoxysilane (N-(2-aminoethyl)-3-aminopropyltrimethoxysilane), react 20min in acid medium, obtaining finishing has ammonia to remember magnetic tunnel-junction.Except that above-mentioned silylating reagent, also can use following reagent, 3-aminopropyl trimethoxysilane (3-aminopropyltrimethoxysilane), 3-aminopropyl triethoxysilane (3-aminopropyltriethoxysilane) etc.Having amino magnetic tunnel-junction carrier surface, add reagent and amino reaction such as glutaric anhydride, can be translated into carboxyl again.
2. the preparation of magnetic tunnel-junction biochip
Biochip carrier 19 through after the surface treatment can be used for preparing different biochips by the method for physisorption or chemical bonding.Be about to different types of addressable biomolecule 20 and be fixed on magnetic tunnel-junction biochip carrier surface, form the new biochip product of a class, i.e. the magnetic tunnel-junction biochip as protein, nucleic acid, oligonucleotides, polysaccharide etc.As magnetic tunnel-junction protein-chip, magnetic tunnel-junction polypeptide chip, magnetic tunnel-junction DNA chip, magnetic tunnel-junction oligonucleotide chip, magnetic tunnel-junction polysaccharide chip etc.It is to utilize existing biochip point sample instrument mostly that this biochip is made, and by the spotting needle of orderly arrangement, biological sample is arranged on the magnetic tunnel-junction biochip carrier 19 regularly.
Can prepare the different magnetic tunnel-junction biochip product of high, medium and low density by biochip point sample instrument as requested.Present point sample instrument specification difference, it is also different therefore to put sample preparation point size, and the sampling point diameter range can be between 75 μ m～200 μ m.The area of each point is 128 μ m * 128 μ m meter, and distance between points is 2 μ m, then can put nearly 6000 points for every square centimeter.Therefore, can produce the magnetic tunnel-junction biochip that a certain size can cover the mankind or mouse full gene sequence or up to ten thousand somes protein examples of some system fully.Because each magnetic tunnel-junction all is inductors of a giant magnetoresistance, corresponding electromagnetics signal output can be arranged, therefore,, just can determine the result as long as there is a target molecule to be fixed on its surface.The method of making the magnetic tunnel-junction biochip is as follows:
Method 1: contain sulfydryl in antibody or the protein macromolecule structure, can carry out sulfhydrylation at 3 or 5 ends when oligonucleotide probe is synthetic modifies, because gold has stronger affinity with these biomolecule that contain sulfydryl, can be with above-mentioned sample as containing the oligonucleotides sample 5000～30 of sulfydryl, 000 kind, with dissolving in the porous plate, then with point sample instrument with the sample proper alignment have gold plating magnetic tunnel-junction biochip carrier surface, form the magnetic tunnel-junction oligonucleotide chip.A part of structure of magnetic tunnel-junction oligonucleotide chip as shown in Figure 2.Wherein carrier inside is manufactured with regularly arranged magnetic tunnel-junction, contains one deck gold at the magnetic tunnel-junction carrier surface, makes that thus the oligonucleotide probe of sulfhydrylation is fixed on its surface.
Method 2: can be by the chemical functional group on the magnetic tunnel-junction biochip carrier with the bioactive molecule covalent coupling at carrier surface.Have two aldehyde radicals on the coupling agent glutaraldehyde molecule of bifunctional group as utilization, respectively with carrier on amino and protein or antibody molecule in amino reaction, protein or antibody are fixed on the biochip carrier surface carry out immobilization, can obtain magnetic tunnel-junction protein or antibody chip.
Method 3: containing the magnetic tunnel-junction carrier surface of carboxyl function group, can utilize coupling agent 1-EDC mediation, the biomolecule formation amido link by carrier surface carboxyl and amino labeled and biomolecule is fixed on carrier surface.
3. magnetic tunnel-junction bio-chip test method of the present invention
Magnetic tunnel-junction biochip of the present invention has following different with magnetic recording material when detecting:
1]. institute adds external magnetic field paramagnetic magnetic-particle is produced magnetization, and directly the induction ferromagnetic layer 5 of magnetic tunnel-junction is not exerted an influence.Outer magnetic field direction and tunnel junction plane orthogonal.
2]. by attached to magnetic tunnel-junction surface magnetism magnetic field that particulate produces the effect of tunnel junction induction ferromagnetic layer 5 being caused the variation of magneto-resistor behind the detection of biological chemical reaction, can determine the kind and the content of detected biomolecule.
With the cobalt particle of about 12 nanometers of diameter the example that act as on the magnetic tunnel-junction surface:
Because particle diameter is very little, heat energy is enough to make the magnetic moment of cobalt particle to point to any direction, and cobalt particle at room temperature shows superparamagnetism and nonferromagnetic like this.If we add a magnetic field H, the cobalt particle magnetic moment that can measure so is:
μ
*＝μ[coth(μH/kT)-kT/μH]
Wherein μ is the magnetic moment of cobalt particle, and k is a Boltzmann constant, and T is a temperature.Function in the square bracket is called as Lang Zhiwan (Langevin) function.If H=0, Langevin function are zero, just cobalt particle shows the feature of superparamagnetism.In the present embodiment, all cobalt particles are paramagnetism during mark, but need to make the enough ferromagnetism of cobalt particle performance in testing process again, promptly require Langevin function to reach more than 0.8,
μH/kT＞5
For the cobalt particle of one 12 nanometer diameter, its volume is V=9 * 10
-19Cm
3, the magnetization is M=1400emu/cm
3, if ignore the magnetic anisotropy energy of cobalt particle, μ=MV=1.26 * 10 so
-15Emu, required externally-applied magnetic field are H＞5kT/ μ=166Oe.The magnetic moment that cobalt particle can measure in this magnetic field is 0.8 μ=1.0 * 10
-15Emu.
A cobalt particle is equivalent to a magnetic dipole, and the magnetic field that its produces is directly proportional with its magnetic moment, and with its cube being inversely proportional to the distance of observation point.If cobalt particle is positioned on the magnetic tunnel-junction 30nm, the magnetic field intensity that produced in magnetic tunnel-junction of cobalt is so:
H＝μ/r
3＝1.0×10
-15emu/(30×10
-7cm)
3≈36Oe
Magnetic tunnel-junction can be designed to accurately measure the shape in magnetic field that cobalt particle produces.The resistance that the magnetic tunnel-junction of 0.5 micron length of side has 0.5 megaohm, under 500 millivolts of junction voltages, externally-applied magnetic field can cause that amplitude reaches 20% * 500 millivolt=100 millivolts voltage signal.Because being limited in scope of magnetic field that cobalt particle produces approximately only accounts for 4% of magnetic tunnel-junction area (0.25 square micron), therefore the net signal that can measure by magnetic tunnel-junction is 4% * 100 millivolt=4 millivolts.This signal is stronger, is enough to use modern electronic devices, accurately measures as simple amplifier.
Two committed steps in the testing process:
1]. magnetic nano-particle is to the mark of target molecule
To the particle mark that detected target molecule has superparamagnetism with a class, these inorganic magnetic material surfaces are through polymer overmold, and are modified with COOH, NH
2Deng functional group, be marked on the biomolecule by affine or covalent bond.The magnetic particle that contains carboxyl terminal is modified the labeling process on the amino oligonucleotide probe endways, both connect by forming the covalency amido link, be the labeling process of magnetic particle on the biotinylated antibody molecule that coats by Avidin, because the firm interaction of Avidin-biotin makes magnetic particle be able to immobilization on antibody molecule.Label should reach uniform particle diameter, does not assemble the characteristics of good stability.
2]. the detection of biochip
This detection method adopts the electromagnetics principle, promptly mainly detects nano particle is responded to ferromagnetic layer 5 to magnetic tunnel-junction biochip carrier in the magnetic field that self is produced by external magnetic field magnetization back the giant magnetoresistance value that influence produced.React between addressable biomolecule and the detected molecules of interest, micron order or the nano-scale magnetic particle that is marked on the determined target material is fixed on biochip surface, utilize signal amplifier that the variation of electric signal in the testing process is measured.
For large-scale biochip, need a series of lug plate of design, and each magnetic tunnel-junction is connected by lead by address decoder.Can comprise line and alignment by the wide contact lead of 0.5 μ m between each tunnel junction and the lug plate, with the address decoder of 7 numerical digits connect around.Outside connection line, also need process the integrated circuit that signal amplifier is formed, when needing to detect, magnetic tunnel-junction can be inserted and carve in advance in the good P.e.c., the reaction that takes place on the biochip be determined by the electric signal of selecting any horizontally-arranged lead and vertical setting of types lead to read their point of crossing (being magnetic tunnel-junction).
4. lift row
Example 1. magnetic tunnel-junction oligonucleotide chips:
Prepare composite film material shown in Figure 5, wherein basalis can be SiO
2Deng material, orlop Ta is suprabasil lead, FeMn layer inverse ferric magnetosphere 8, and purpose is to make the magnetization direction 11 of fixed ferromagnetic layer 7CoFe keep certain, the NiFe of FeMn inverse ferric magnetosphere below 8 is crystal seed layer 9.Middle Al
2O
3Be tunnel barrier layer 6, NiFe and CoFe form induction (freedom) ferromagnetic layer jointly, and the Ta of the superiors is the protective seam of induction ferromagnetic layer 5.
The preparation of magnetic tunnel-junction biochip carrier comprises: at first, etching hearth electrode on base material, the magnetic tunnel-junction membrane material for preparing is placed on the electrode, on membrane material, process the magnetic tunnel-junction of certain density, carry out SiO on the tunnel junction surface by photoetch
2Cover, punching covers top electrode at last in the above then.
At the thin gold of the magnetic tunnel-junction that processes surface spray one deck, the oligonucleotide probe of synthetic sulfydryl modification as required, and with point sample instrument with different probe stationary on the tunnel junction surface, after the drying, tunnel junction oligonucleotide chip packing is preserved in order to detecting.
Example 2. magnetic tunnel-junction protein-chips
With reference to the method in people's invention documents such as Moodera, preparation has CoFe/Al
2O
3The magnetic tunnel-junction composite film material of/NiFe structure prepares tunnel junction with the method for ion beam milling.Tunnel junction is placed on the bottom electrode, add one deck then and have amino SiO
2Diaphragm is a coupling agent with the glutaraldehyde, utilizes the amino on the protein that it is coupled at the surface of magnetic tunnel-junction, and by after certain surface immobilized processing, packing is preserved.
Example 3. usefulness magnetic tunnel-junction oligonucleotide chips are to the detection of gene
Utilize biotin labeled primer, working sample is carried out RT-PCR, then with oligonucleotide chip on probe carry out hybridization reaction, buffer solution for cleaning, remove the nonspecific reaction thing, the magnetic-particle that Avidin is coated places oligonucleotide chip to hatch then, air-dry after, place pick-up unit, detect the size of its magnitude of voltage.
Claims (18)
1. magnetic tunnel-junction biochip carrier, mainly be made of magnetic tunnel-junction (15), this magnetic tunnel-junction (15) mainly comprises tunnel barrier layer (6), the substrate (17) of first ferromagnetic electrode (13), non magnetic insulation and is arranged at second ferromagnetic electrode (14) in the substrate (17); Described first ferromagnetic electrode (13) mainly comprises induction ferromagnetic layer (5), described second ferromagnetic electrode (14) that is arranged in the substrate (17) mainly comprises fixed ferromagnetic layer (7), and described tunnel barrier layer (6) is arranged at and constitutes core sandwich film between induction ferromagnetic layer (5) and the fixed ferromagnetic layer (7); It is characterized in that: described magnetic tunnel-junction (15) surface is coated with biomolecule fixed bed (18), constitutes magnetic tunnel-junction biochip carrier (19).
2. magnetic tunnel-junction biochip carrier as claimed in claim 1 is characterized in that: described ferromagnetic electrode (14) comprises coupling and in the inverse ferric magnetosphere (8) on fixed ferromagnetic layer (7) surface.
3. magnetic tunnel-junction biochip carrier as claimed in claim 1 or 2 is characterized in that: induction ferromagnetic layer (5) surface of described ferromagnetic electrode (13) is provided with cap layer (4).
4. magnetic tunnel-junction biochip carrier as claimed in claim 3 is characterized in that: the bottom of described ferromagnetic electrode (14) is provided with crystal seed layer (9).
5. magnetic tunnel-junction biochip carrier as claimed in claim 4 is characterized in that: described induction ferromagnetic layer (5) is the ferromagnetic material that coercive force is less and giant magnetoresistance effect is bigger; Described fixed ferromagnetic layer (7) is the bigger ferromagnetic material of giant magnetoresistance effect; Described tunnel barrier layer (6) is a metal oxide.
6. magnetic tunnel-junction biochip carrier as claimed in claim 5 is characterized in that: the thickness of described tunnel barrier layer (6) is 1～4nm; The metal oxide of described tunnel barrier layer 6 can be Al
2O
3Or MgO.
7. one kind is adopted the chip of magnetic tunnel-junction biochip carrier according to claim 1, it is characterized in that: it comprises magnetic tunnel-junction biochip carrier (19) and addressable biomolecule (20), and described addressable biomolecule (20) is fixed in magnetic tunnel-junction biochip carrier (19) surface.
8. method for making of magnetic tunnel-junction biochip carrier according to claim 1, it is characterized in that: the making step of this method is as follows
1]. the making of magnetic tunnel-junction membraneous material
(1). with the high vacuum of magnetron sputtering or ion beam sputtering or ultrahigh vacuum sputter at substrate (17) surface sputtering one deck fixed ferromagnetic layer (7);
(2). prepare tunnel barrier layer (6) on fixed ferromagnetic layer (7) surface with the method for nitrogen reaction or autoxidation, plasma oxidation;
(3). at tunnel barrier layer (6) surface sputtering one deck induction ferromagnetic layer (5), form the core sandwich film of magnetic tunnel-junction multi-layer film material;
2]. the making of magnetic tunnel-junction
Adopt photo-engraving process, allow light see through to be carved with the mask of wiring diagram to be radiated at the multi-layer film material surface, the etching hollow out obtains the microarray of magnetic tunnel-junction uniform, that area is small (15); Described photoetch is to adopt ultraviolet light, extreme ultraviolet, X-light or ion beam projected light to carry out etching;
3]. the making of magnetic tunnel-junction biochip carrier
On magnetic tunnel-junction (15) surface, sprayed biological molecule fixed bed (18) forms magnetic tunnel-junction biochip carrier (19).
9. as the method for making of magnetic tunnel-junction biochip carrier as described in the claim 8, it is characterized in that: the making of described magnetic tunnel-junction membraneous material is included in fixed ferromagnetic layer (7) bottom and the inverse ferric magnetosphere (8) that one deck is coupled with it is set constitutes the magnetic tunnel-junction multi-layer film material.
10. as the method for making of magnetic tunnel-junction biochip carrier as described in claim 8 or 9, it is characterized in that: the bottom that the making of described magnetic tunnel-junction membraneous material is included in this core sandwich membraneous material is made one deck crystal seed layer (9) by the method for sputter and is constituted the magnetic tunnel-junction multi-layer film material.
11. the method for making as magnetic tunnel-junction biochip carrier as described in the claim 10 is characterized in that: the magnetization direction (12) of described fixed ferromagnetic layer (7) adopts pinprick or antiferromagnetic coupling and form to fix.
12. method for making as magnetic tunnel-junction biochip carrier as described in the claim 11, it is characterized in that: described method with oxidation or plasma oxidation prepares tunnel barrier layer (6) and comprises, the used metal simple-substance of deposition one deck tunnel barrier layer (6) adopts the method for autoxidation or plasma oxidation to prepare metal oxide formation tunnel barrier layer (6) then earlier; Described method with the nitrogen reaction prepares tunnel barrier layer (6), and the method with reactive sputtering or directly sputter when laying directly is deposited on fixed ferromagnetic layer (7) surface with metal nitride.
13. method for making as magnetic tunnel-junction biochip carrier as described in claim 8 or 9, it is characterized in that: the preparation of described magnetic tunnel-junction (15) is included in magnetic tunnel-junction microarray surface spraying cap layer (4), fill and lead up the etching openwork part, and, make magnetic tunnel-junction (15) expose out in the punching of the position of magnetic tunnel-junction (15).
14. the method for making of a magnetic tunnel-junction biochip is characterized in that: this method is that addressable biomolecule (20) is fixed on magnetic tunnel-junction biochip carrier (19) surface, forms the magnetic tunnel-junction biochip.
15. the method for making as magnetic tunnel-junction biochip as described in the claim 14 is characterized in that: described addressable biomolecule (20) is fixed on magnetic tunnel-junction biochip carrier (19) surface is method by physisorption or chemical bonding.
16. method for making as magnetic tunnel-junction biochip as described in claim 14 or 15, it is characterized in that: described method by physisorption or chemical bonding is to utilize biochip point sample instrument, by the spotting needle of orderly arrangement, addressable biomolecule (20) is arranged on the magnetic tunnel-junction biochip carrier (19).
17. as the method for making of magnetic tunnel-junction biochip as described in the claim 16, it is characterized in that: described addressable biomolecule is protein, nucleic acid, oligonucleotides or polysaccharide.
18. to the method that biomolecule detects, it is characterized in that: the detection step of this method is as follows as magnetic tunnel-junction biochip as described in the claim 7 for an employing
1]. magnetic nano-particle is to the mark of target molecule
With magnetic tunnel-junction as biochip carrier (19), adopt nanometer or micron order magnetic-particle label as target molecule, detected target molecule is marked on the nanometer or micron order magnetic-particle with superparamagnetism, at the particle surface coated polymer, and rhetorical function group, be marked on the biomolecule by affine or covalent bond, make magnetic particle immobilization on antibody molecule;
2]. react between addressable biomolecule (20) and the detected molecules of interest, micron order or the nano-scale magnetic particle that is marked on the determined target material is fixed on biochip surface;
3]. add external magnetic field paramagnetic magnetic-particle is produced magnetization, outer magnetic field direction is vertical mutually with the magnetic tunnel-junction plane;
4]. by attached to magnetic tunnel-junction surface magnetism magnetic field that particulate produces tunnel junction being responded to the variation of the magneto-resistor that effect causes of ferromagnetic layer (5) behind the detection of biological chemical reaction, write down electric signal in the testing process, determine the kind and the content of detected biomolecule.
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