CN107703198A - box and analyzer for fluid analysis - Google Patents

Abstract

The present invention describes fluid box and operating method.Fluid box includes the substrate with the multiple contact pads for being designed as electrically connecting with analyzer, semiconductor chip and reference electrode with sensor array.Fluid box includes with entrance and is connected to the first fluid raceway groove of second fluid raceway groove, and alignment second fluid raceway groove is so that sensor array and reference electrode are arranged in second fluid raceway groove.In first access point, the first connector is set.First connector includes being configured to be passed through without the flexible material for enabling flow through the leakage of the first connector by capillary.Present invention also offers the analyzer for analyzing fluid.

Description

Box and analyzer for fluid analysis

Technical field

Embodiments of the invention are usually related to technical field of semiconductors, more particularly, to the box for fluid analysis And analyzer.

Background technology

Biology sensor is to be used to sense and detect biomolecule and based on electronics, optically and mechanically electrochemistry, detection original Manage the device of operation.Biology sensor including transistor is the electric charge, photon or machine of electrical sensing biological entities or biomolecule The sensor of tool performance.By detecting biological entities or biomolecule itself or by specific reactants and biological entities/biology Interaction and reaction between molecule carry out examinations.Such biology sensor can use semiconductor technology system Make, can soon converted electrical number, and can easily applying to integrated circuit (IC) and MEMS.

Biological specimen is probably a challenge with the interaction of biology sensor in itself.Generally, biological specimen will be included Fluid directly aspirate above the sensing part to biology sensor.This method causes the major part of fluid sample not use, And each sensing area of manual loading is time-consuming.

The content of the invention

According to an aspect of the present invention, there is provided a kind of fluid box, including：Substrate, including multiple contact pads, are configured to Electrically connected with analyzer, semiconductor chip, there is sensor array, and reference electrode；First fluid raceway groove, have first to enter Mouthful, and second fluid raceway groove is connected to, it is directed at the second fluid raceway groove and causes the sensor array and the reference electricity Pole is arranged in the second fluid raceway groove；Sample entrance port, for sample to be placed on into the first fluid raceway groove or described In the path of two fluid channels；First connector, be arranged on the first access point and including being configured to be passed through by capillary and The flexible material of the first connector leakage will not be enabled flow through.

According to another aspect of the present invention, there is provided a kind of fluid box, including：First fluid raceway groove, there is first entrance, And be connected to second fluid raceway groove, be directed at the second fluid raceway groove so that sensor array and reference electrode be arranged on it is described In second fluid raceway groove；Sample entrance port, for sample to be placed on into the first fluid raceway groove or the second fluid raceway groove In path；First connector, it is arranged on the first access point and leads to fluid including being configured to be passed through without by capillary The flexible material of the first connector leakage is crossed, wherein, the capillary is connected to analyzer, and works as the fluid box and institute When stating analyzer physical contact, the capillary passes through first connector.

According to another aspect of the invention, there is provided a kind of analyzer, be configured to be connected with fluid box, the analyzer bag Include：Syringe, it is arranged so that when the fluid box is physically connected to the analyzer, the pin of the syringe and the stream The corresponding input port alignment of body box；Actuator, it is configured to control the operation of the syringe；Sensing module, it is configured to work as institute When stating fluid box and being physically connected to the analyzer, signal is sent and from the stream to the fluid box via multiple conductive welding disks Body box reception signal, wherein, the multiple conductive welding disk contacts corresponding multiple conductive welding disks on the fluid box；And place Device is managed, is electrically connected to the sensing module, and the signal for being configured to receive from the fluid box is described to determine to come from The concentration level of the given analyte of sample in fluid box.

Brief description of the drawings

When reading in conjunction with the accompanying drawings, various aspects of the invention are best understood from described in detail below.Should Pay attention to, the standard practices in industry, all parts are not drawn on scale.In fact, in order to clearly discuss, various parts Size can be arbitrarily increased or decreased.

Fig. 1 shows the figure of the component of exemplary bio sensing box.

Fig. 2 is the sectional view of exemplary double grid dorsal part sensing FET sensor.

Fig. 3 is the circuit diagram of the multiple FET sensors configured in exemplary addressable array.

Fig. 4 is the circuit diagram of the exemplary addressable array of double grid FET sensor and heater.

Fig. 5 is arranged to the sectional view of the exemplary double grid dorsal part sensing FET sensor of pH sensors.

Fig. 6 A show the example that ion is combined with receptive layers.

Fig. 6 B show the change of the threshold voltage in the exemplary FET sensor based on pH.

Fig. 7 is the plan of exemplary biosensors chip.

Fig. 8 shows the system for being used to exemplary biosensors chip being attached to the manufacturing process of processing (handle) layer Row sectional view.

Fig. 9 is the top view of the handle layer with the exemplary biosensors chip for being attached to substrate.

Figure 10 is the schematic diagram of the exemplary fluid box with integrated biologic sensor chip.

Figure 11 is the schematic diagram of some fluid channels in exemplary fluid box.

Figure 12 is the schematic diagram for the exemplary fluid box for being connected to analyzer.

Figure 13 is the flow chart using the illustrative methods of fluid box.

Figure 14 is the sectional view for the biological FET of exemplary double grid dorsal part sensing for detecting DNA.

Figure 15 A show the adhesion of the DNA on receptor surface.

Figure 15 B show that the exemplary double grid dorsal part that the analyte based on pairing combines senses biological FET threshold voltage Change.

Figure 16 is the sectional view that the exemplary double grid dorsal part with the antibody being fixed in its sensed layer senses biological FET.

Figure 17 shows the adhesion of the antigen and antibody on receptor surface.

Figure 18 is the embodiment according to the method 2100 of the manufacture BioFET device of the one or more aspects of the disclosure Flow chart.

Embodiment

Disclosure below provides many different embodiments or example for being used to realize the different characteristic for providing theme. The instantiation that component and arrangement are described below is of the invention to simplify.Certainly, these are only example, and are not intended to limitation originally Invention.For example, in the following description, above second component or upper formation first component can include first component and second The embodiment that part is formed in a manner of directly contacting, and can also be included between first component and second component can be with shape Into and/or additional part is set so that the embodiment that first component and second component can be not directly contacted with.In addition, The present invention can repeat reference numerals and/or character in various embodiments.The repetition itself does not indicate each embodiment discussed And/or the relation between configuration.

Moreover, for the ease of description, can use herein such as " in ... lower section ", " ... below ", " bottom ", " ... On ", the space relative terms such as " top " to be to describe an element or part as depicted and another (or other) member The relation of part or part.In addition to the orientation shown in figure, space relative terms are intended to include device in use or operation Different azimuth.Device can otherwise be oriented and (is rotated by 90 ° or in other orientation), and space phase as used herein Corresponding explanation can similarly be made to descriptor.

Term

Unless otherwise prescribed, all technologies used herein and scientific terminology have as of the art common The identical implication that technical staff is generally understood that.With those similar or equivalent any methods described herein and material according to During embodiments of the invention can apply to put into practice or test；Method, device and material will now be described.Institute mentioned herein There are patent and publication to be hereby expressly incorporated by reference, so as to for describing and being disclosed in the publication being employed in conjunction with the invention The material and method of report.

Acronym " FET " used herein refers to field-effect transistor.A kind of very common FET type refers to gold Belong to oxide semiconductor field effect transistor (MOSFET).In history, MOSFET has been the substrate in such as semiconductor crystal wafer Flat surfaces neutralize the planar structure that creates.But the latest developments of semiconductor manufacturing already lead to three-dimensional fin MOSFET Structure.

Term " biological FET " refers to include the FET of the capture agent layer of fixation, the capture agent layer be used as surface receptor with Detect the presence of the target analytes of biological source.According to embodiment, biological FET is that the field-effect with semiconductor variable parallel operation senses Device.A biological FET advantage is the prospect for having unmarked operation.Especially, biological FET makes it possible to avoid such as to utilize Such as the costly and time-consuming marking operation of fluorescence or radioactive probe labelled analyte.One kind described herein is certain types of Biological FET is that double grid dorsal part senses biological FET.It is typically biological source such as, but not limited to egg by the biological FET analytes detected White matter, carbohydrate, lipid, fragment of tissue or their part.However, in a most general sense, biological FET is wider General FET sensor kind sector of breakdown, its can also detect any chemical compound (referred in the art as chemical FET) or including Any other element (being referred to as ISFET in the art) of the ion of such as proton or metal ion.The invention is intended to suitable for All types of sensors (" FET sensor ") based on FET.A kind of this paper certain types of FET sensor is the double grid back of the body Side sensing FET sensor (" DG BSS FET sensors ").

" S/D " refers to the source/drain junctions for two terminals to be formed in tetra- terminals of FET.

" high k " refers to high-k for statement.In the field of semiconductor device structure and manufacturing process, high k refers to greatly In SiO₂Dielectric constant (that is, more than 3.9) dielectric constant.

Term " analysis " typically refer to be related to physics, chemistry, biochemistry or bioanalysis include but is not limited to characterize, The technique or step of test, measurement, optimization, separation, synthesis, addition, filtering, dissolving or mixing.

Term " measure (assay) " typically refers to the technique or step for being related to the analysis of chemical substance or target analytes Suddenly, and including but not limited to the measure based on cell, biochemical measurement, high throughput assay and screening, diagnostic assay, pH are true Fixed, nucleic acid hybridization assays, polymerase activity measure, nucleic acid and protein sequencing, immunoassays are (for example, antibody-antigen binding is surveyed Fixed, ELISA and iqPCR), bisulfites methylation assay, protein determination, albumen for detecting gene methylation pattern Matter combination mensuration (such as protein-protein, protein-nucleic acid and protein ligand combination mensuration), enzymatic determination, coupling enzymatic determination, Kinetic measurement (for example, protein folding dynamics and enzyme kinetics), enzyme inhibitor and activator screening, chemiluminescence With electrochemical luminescence measure, fluoremetry, fluorescence polarization and anisotropy measure, absorbance and colorimetric estimation (for example, Bradford measure, Lowry measure, Hartree-Lowry measure, Biuret measure and BCA measure), chemical assay (for example, For detecting environmental contaminants and contaminants, nano particle or polymer) and drug discovery measure.Device described herein, it is System and method can use or using one kind in these measure that will be used together with any design that FET sensor describes or It is a variety of.

Term " liquid biopsy " is typically referred to compared with the tissue samples of subject, the work obtained from the body fluid of subject Sample sheet.Compared with using tissue samples, generally more desirable capable use body fluid sample implements measure.Use body fluid sample Invasive methods in patient's welfare, carry out the ability of longitudinal disease surveillance and even when being not easy to close situation in histocyte Under (such as in prostate) obtain the ability of express spectra in terms of there is wide significance.For detecting in liquid biopsy sample The measure of target analytes include but is not limited to those described above.As non-limiting examples, liquid biopsy sample can be entered Row circulating tumor cell (CTC) determines.

For example, the capture agent (for example, antibody) being fixed on FET sensor is used for CTC measure to detect Target analytes (for example, tumor cell marker) in liquid biopsy sample.CTC is to flow into vascular system and in example from tumour Such as the cell circulated in blood.Generally, CTC is present in blood circulation with low-down concentration.In order to determine CTC, pass through this Various technologies are enriched with CTC from blood samples of patients or blood plasma known to field.Methods known in the art can be used to carry out CTC Dyeing for specific markers, methods described include but is not limited to method based on cell count (for example, flow cytometer) and Method based on IHC.For devices, systems, and methods as described herein, capture agent can be used to capture or detect CTC, or Person can be using the nucleic acid from CTC, protein or other cellular environments as target analytes target, so as to for combine catch Obtain reagent or detected by capture agent.

When detecting target analytes on CTC or from CTC, for example, expression or target analytes including CTC Increase potentially contributes to subject being accredited as with the cancer that may make a response to particular treatment (for example, and target analysis The related cancer of thing) or allow to optimize the therapeutic scheme with the antibody for example for target analytes.CTC is measured and quantitatively may be used To provide the stage on such as tumour, the reaction to treatment, progression of disease or the information of combinations thereof.From detection CTC's The information that target analytes obtain may be used as biomarker for example diagnose in advance, predicting or pharmacodynamics.In addition, CTC measure for liquid biopsy sample can be used alone or the additional tumor marker with solid biopsy sample analyzes knot Close and use.

Term " identification " typically refers to the knot based on target analytes with capture agent known to its feature (identity) Close to determine the process of the feature of target analytes.

Term " measurement " typically refer to based on the combination of target analytes and capture agent come determine the amount of target analytes, The process of quantity, quality or property.

Term " quantitative " typically refers to determine the number of target analytes based on the combination of target analytes and capture agent The process of amount or concentration.

Term " detection " typically refers to determine depositing for target analytes based on the combination of target analytes and capture agent Or the process that is not present.Detection includes but is not limited to identification, measurement and quantified.

Term " chemistry " refers to material, compound, mixture, solution, emulsion, dispersant, molecule, ion, dimer, all Such as the macromolecular of polymer or protein, biomolecule, sediment, crystal, chemical composition part or group, particle, nanometer Grain, reagent, reaction product, solvent or fluid, any one therein can exist with solid-state, liquid or gaseous state, and lead to It is often analysis object.

Term " reaction " refers at least one chemical substance, and is usually directed to (in chemistry, biochemistry and biology In the case of conversion) destroy or formed physics, chemistry, biochemistry or the bioconversion of one or more keys, such as covalent bond, Non-covalent bond, Van der Waals key, hydrogen bond or ionic bond.The term includes typical chemical reaction, such as synthetic reaction, neutralizes instead Should, decomposition reaction, displacement reaction, reduction-oxidation reaction, precipitation, crystallization, combustion reaction and polymerisation, and covalently with it is non- Covalent bond, phase transformation, color change, mutually formed, crystallized, dissolving, change, the temperature change of luminous, light absorbs or emission characteristic Or the macromolecular of heat absorption or transmitting, conformation change (conformational change) and such as protein folding or Unfolding.

" capture agent " used herein is the molecule or compound for being capable of combining target analyte or destination agent, and it can It is attached directly or indirectly to the material of basic solid.Capture agent can be chemical substance, specifically naturally occurring mesh Mark analyte (for example, antibody, polypeptide, DNA, RNA, cell, virus etc.) or any material that target analytes can be prepared, and And capture agent can combine one or more target analytes in the assay.

" target analytes " used herein are that the material that the present invention detects is used in test sample.Target analytes Can be chemical substance, specifically naturally occurring capture agent (such as antibody, polypeptide, DNA, RNA, cell, virus etc.) Or any material of capture agent can be prepared, and target analytes can combine one or more captures and try in the assay Agent." target analytes " also include any antigenic substance, antibody and combinations thereof.Target analytes can include protein, Peptide, amino acid, carbohydrate, hormone, steroids, vitamin, including for therapeutic purposes and manage those medicines and The metabolin or antibody of those medicines, bacterium, virus and any of above material that are managed for illegal objective.

" test sample " used herein refer to using the present invention detection and measure the composition including target analytes, Solution, material, gas or liquid.Test sample can include the other components in addition to target analytes, and it can have The physical attribute of liquid or gas, and can be any size or volume, include the mobile stream of such as liquid or gas.As long as Other materials not combination of jamming target analyte and capture agent or the first binding constituents (member) and the second binding constituents Specific binding, then test sample can include any material in addition to target analytes.The example of test sample includes But it is not limited to naturally occurring and non-naturally occurring sample or combinations thereof.Naturally occurring test sample can be synthetic Or synthesis.Naturally occurring test sample includes the body liquid or body of any position separation out of subject body or on body Liquid, including but not limited to blood, blood plasma, serum, urine, saliva or sputum, spinal fluid, cerebrospinal fluid, liquor pleurae, nipple suction Liquid, lymph, respiratory tract, enteron aisle and urogenital tract liquid, tear, saliva, breast milk, lymphatic system liquid, seminal fluid, cerebrospinal fluid, device System liquid, ascites, tumour cystic fluid, amniotic fluid and combinations thereof in official, and such as underground waste water or waste water, soil extract Thing, the air sample related to the environmental samples or food of pesticide residue.

The material detected can include such as nucleic acid (including DNA and RNA), hormone, different pathogen and (including cause The biological reagent of its host disease or disease, such as virus (such as H₇N₉Or HIV), protozoan is (for example, cause the malaria of plasmodium Disease) or bacterium (such as Escherichia coli or mycobacterium tuberculosis)), protein, antibody, various medicines or therapeutic agent or including hydrogen Or other chemistry or biological substance, nonionic molecule or compound, such as polysaccharide, chemical combination bin contents of other ions Etc. (member) small chemical compound etc..Detection or the parameter determined can include but is not limited to such as pH changes, lactose change Change, change in concentration, the particle in time per unit and other specification, wherein, fluid flows within a period of time above device To detect particle, such as sparse particle.

As used herein, the term " fixation " used relative to such as capture agent includes trying the capture of molecule level Agent is substantially attached to surface.It is, for example, possible to use including noncovalent interaction (for example, electrostatic force, Van der Waals force and hydrophobic boundary The dehydration in face) adsorption technology and covalent bonding technology capture agent is fixed to the surface of backing material, wherein functional group Or joint (linker) helps capture agent being attached to surface.Can the property based on substrate surface, carrying capture agent Medium and the property of capture agent capture agent is fixed to the surface of backing material.In some cases, can change first Become (modify) substrate surface with the functional group engaged with surface.Then functional group can with binding biomolecules or biology or Chemical substance is so that they to be fixed thereon.

Term " nucleic acid " typically refers to one group of nucleotides being connected to each other by phosphodiester bond, and refers to naturally occurring Nucleic acid, wherein, naturally occurring nucleotides is connected to the nucleic acid existing for nature, the nucleic acid can be such as DNA and/or RNA, wherein, DNA is included with the de- of any one of adenine, guanine, cytimidine and the thymidine being connected to each other Oxygen ribonucleotide and/or RNA include any one with adenine, guanine, cytimidine and the uracil being connected to each other Ribonucleotide.In addition, non-naturally occurring nucleotides and non-naturally occurring nucleic acid are in the range of the nucleic acid of the present invention. Example include peptide nucleic acid (PNA), have the peptide nucleic acid (PHONA) of phosphate group, bridging nucleic acid/locked nucleic acid (BNA/LNA) and Morpholino nucleic acid.Another example includes the nucleic acid and nucleic acid analog of chemical modification, such as methyl phosphonate DNA/RNA, thio Phosphate DNA/RNA, phosphoramidate DNA/RNA and 2'-O- methyl DNA/RNA.Nucleic acid includes those that can change.Example Such as, phosphate group, sugar and/or base that can as needed in labeling nucleic acid.Appointing for nucleic acid marking known in the art What material can be used in marking.The example includes but is not limited to radio isotope (for example, 32P, 3H and 14C), DIG, biology Plain, fluorescent dye (such as FITC, Texas, cy3, cy5, cy7, FAM, HEX, VIC, JOE, Rox, TET, Bodipy493, NBD And TAMRA) and luminescent substance (for example, acridinium ester).

Aptamers used herein refer to the oligonucleic acid or peptide molecule for being bound to specific target molecules.Initially in nineteen ninety (Ellington and Szostak 1990,1992；Tuerk and Gold 1990) disclose using single-chain nucleic acid (aptamers) as The concept that affinity molecule combines for protein, and in the presence of target, energy of the aptamers based on short sequence Power is folded into the unique three-dimensional structure combined with high-affinity and specific target.Eugene W.M Ng et al. It is that selection is used for the oligonucleotide ligand that high-affinity is bound to molecular targets that aptamers were disclosed in 2006.

Term " antibody " used herein refer to it is non-covalent, combine corresponding antigen reversibly and in a specific way The polypeptide of immunoglobulin class.For example, naturally occurring IgG antibody is include being connected with each other by disulfide bond at least two The tetramer of weight (H) chain and two light (L) chain.Each heavy chain is by weight chain variable district (being abbreviated as VH herein) and light chain constant district's groups Into.Heavy chain constant region is made up of three domains CH1, CH2 and CH3.Each light chain is by light chain variable district (being abbreviated as VL herein) and gently Chain constant region forms.Constant region of light chain is made up of a domain CL.VH and VL areas can be further subdivided into more conservative area The super variable region (being referred to as complementarity-determining region (CDR)) that domain (being referred to as framework region (FR)) is spread.Each VH and VL is in the following sequence It is made up of three CDR and four FR arranged from amino terminal to carboxyl terminal：FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.Three CDR form the about 15-20% of variable domain.The variable region of heavy chain and light chain includes and the combination of antigen interactions Domain.The constant region of antibody can adjust immunoglobulin and host tissue or the factor (including immune system various cells (such as Effector cell)) and typical replenishment system the first component (C1q) combination (Kuby, Immunology, 4th ed., Chapter 4.W.H.Freeman&Co.,New York,2000)。

Term " antibody " includes but is not limited to monoclonal antibody, human antibody, humanized antibody, chimeric antibody and antiidiotype (anti-Id) antibody (including for example for the anti-Id antibody of antibody of the present invention).Antibody can be any isotype/class (such as IgG, IgE, IgM, IgD, IgA and IgY) or subclass (for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).

Term " polymer " " refers to by two or more building blocks (buildingblocks) for repeating connection each other Any material or compound of (" mers ") composition.It is already integrated in together for example, " dimer " is two of which building block Compound.Polymer includes both condensation polymer and addition polymers.The representative instance of condensation polymer include polyamide, polyester, protein, Wool, silk, polyurethane, cellulose and polysiloxanes.The example of addition polymers is polyethylene, polyisobutene, polyacrylonitrile, poly- (vinyl chloride) and polystyrene.Other examples include such as conductive or photorefractive polymer the electrically or optically spy with enhancing The polymer of property (such as nonlinear optical properties).Polymer includes both straight chain and branch polymer.

Biological sensing box is summarized

Fig. 1 shows to be integrated to form the general introduction of each component of exemplary bio sensing box 102.Biological sensing box 102 can include multiple fluid channels, and it is configured to control fluid toward and away from can detect existing for target analytes The flowing of sensing the feedback of position.

In this exemplary embodiment, biological sensing box 102 includes the array of FET sensor 104.The structure of FET sensor 104 Into the sensor cluster of biological sensing box 102.FET sensor 104 can be arranged to array and carry out individually addressing to detect FET Binding events at the surface of sensor sensed layer.In one embodiment, FET sensor 104 senses including double grid dorsal part FET Device.In an alternative embodiment, the other kinds of sensor based on FET sensor can be used.

Biological sensing box 102 includes bioelectric interface 106.Bioelectric interface 106 can be connected to double grid dorsal part sensing FET sensing Device 104, in order to carry out the association reaction that can be detected at the surface of double grid dorsal part sensing FET sensor 104.It is various The biomolecule of type can form the portion of the bioelectric interface 106 of such as DNA or RNA aptamers and antibody (only lifting several examples) Point.It will be discussed in detail herein about bioelectric interface and its chemistry of correlation and the more details of Biological Strength.

Biological sensing box 102 includes the chip package 108 of each rank (level), and double grid dorsal part sensing FET is passed Sensor integrated chip is into fluid environment.Biological sensing box 102 also include with microfluidic channels fluid assembly 110, with In management liquid is conveyed to FET sensor 104.Fluid assembly 110 also includes fluid intake, for from biological sensing box 102 outside conveying fluidly connects.

The integrated of each component in biological sensing box 102 is generated available for the compact of many each biological sensing applications And portable platform.It can be produced using the FET sensor with integrated fluid component when using low sample volume accurate As a result.In addition, biological sensing box 102 is configurable to operate in a manner of entirely autonomous by analyzer, then after use It is disposed.

Description herein is divided into four major parts, so that the component of biological sensing box 102 is more fully described.Part I Arrangement and the manufacture of double grid dorsal part biology FET sensor 104 will be described.Part II will describe packaging technology.Part III will Fluid assembly 110 is described, and further describes the interaction between biological sensing box 102 and analyzer.Last part will The details applied on biology and each biological sensing using double grid dorsal part FET sensor 104 is provided.

Double grid dorsal part FET sensor

Double grid dorsal part FET sensor forms sensitive and is easy to what is arranged using semiconductor fabrication and biological capture reagent Sensor.Although traditional MOSFET has the single gate electrode for being connected to single electrical nodes, double grid dorsal part sensing FET passes Sensor has two gate electrodes, and each gate electrode is connected to different electrical nodes.First in two gate electrodes is herein Referred to as front-side gate, and second in two gate electrodes is referred to herein as back-side gate.Front-side gate and back-side gate Both are configured so that each to charge and/or discharge in operation, and so as to which each influences double grid dorsal part sensing FET Electric field between the source/drain terminal of sensor.Front-side gate is conductive, and it is distinguished by front-side gate dielectric and raceway groove From, and be configured to be charged and discharged by connected circuit.Dorsal part grid generally by dorsal part gate-dielectric with Channel region separates, and the biological functional sensed layer including being arranged on dorsal part gate-dielectric.Electric charge on dorsal part grid Measure for whether occur bio-identification reaction function.In the typical operation of double grid dorsal part sensing FET sensor, by front-side gate The voltage charged in predetermined voltage range.The voltage of front-side gate determines the corresponding conductance of the channel region of FET sensor Rate.The change of the relatively small amount of electric charge on dorsal part grid changes the electrical conductivity of channel region.This change of electrical conductivity shows Bio-identification is reacted.

One advantage of FET sensor is the prospect for having unmarked operation.Especially, FET sensor makes it possible to keep away Exempt from the costly and time-consuming marking operation such as with such as fluorescence or radioactive probe labelled analyte.

With reference to figure 2, exemplary double grid dorsal part sensing FET sensor 200 is shown.Double grid dorsal part sensing FET sensor 200 wraps Include the control gate 202 to be formed above substrate 214, and intermediate dielectric 215 and substrate by being arranged on substrate 214 214 separation.Substrate 214 also includes source area 204, drain region 206 and the ditch between source area 204 and drain region 206 Road area 208.In embodiment, substrate 214 has the thickness between about 100nm and about 130nm.It is suitable to use CMOS technology technology forms grid 202, source area 204, drain region 206 and channel region 208.Grid 202, source area 204, drain electrode Area 206 and channel region 208 form FET.Separation layer 210 is set on the side relative with grid 202 of substrate 214.At one In embodiment, separation layer 210 has about 1 μm of thickness.In the present invention, it is provided with the side of the substrate 214 of grid 202 Referred to as " front side " of substrate 214.Similarly, it is referred to as " dorsal part " in the side for being provided with the substrate 214 of separation layer 210.

Opening 212 is provided in separation layer 210.Opening 212 can be with the rough alignment of grid 202.In other embodiments, Opening 212 is more than grid 202, and can extend in the top of multiple double grid dorsal part sensing FET sensors.Can be positioned at ditch Boundary layer (not shown) is set in the opening 212 on the surface in road area 208.Operable boundary layer is used to position and fix to provide The interface of one or more acceptors, so as to for detecting biomolecule or biological entities.There is provided herein on boundary layer more More details.

Double grid dorsal part sensing FET sensor 200 is included to drain region 206 (Vd 216), source area 204 (Vs 218), grid The electric contact piece of pole structure 202 (front-side gate 220) and/or active area 208 (for example, dorsal part grid 222).It should be noted that the back of the body Substrate 214 or any boundary layer of the top of substrate 214 need not be physically contacted in side grid 222.Therefore, although traditional FET makes The conductance of semiconductor between being controlled source electrode with gate contact and drained (for example, raceway groove), but double grid dorsal part sensing FET Sensor 200 allows the acceptor to be formed on the opposite side of FET device to control conductance, and grid structure 202 provides another grid Extremely control conductance.Therefore, double grid dorsal part sensing FET sensor 200 can be used in detection surrounding environment and/or in opening 212 The specific biomolecule of one or more or biological entities, what each embodiment as used in this article discussed in more detail.

Double grid dorsal part sensing FET sensor 200 can be connected to additional passive block, such as resistor, capacitor, electricity Sensor and/or fuse etc；With other active blocks, including P-channel field-effect transistor (PEFT) transistor (PFET), N-channel field effect transistor Manage (NFET), mos field effect transistor (MOSFET), high voltage transistor and/or high frequency transistor；Other Suitable component；And/or combinations thereof.It should also be understood that the additional implementation for double grid dorsal part sensing FET sensor 200 Example, can add additional part in double grid dorsal part sensing FET sensor 200, and can replace or remove and be described Some parts.The U.S. Patent application and Publication No. the 2014/th that jointly owned Publication No. the 2013/0200438th No. 0252421 U.S. Patent application can find on double grid dorsal part sensing FET sensor 200 exemplary fabrication schedule more More details.

Figure 18 is the embodiment according to the method 2100 of the manufacture BioFET device of the one or more aspects of the disclosure Flow chart.Method 2100 starts from frame 2102, wherein providing substrate.Substrate can be Semiconductor substrate (for example, wafer).Partly lead Body substrate can be silicon substrate.Alternatively, substrate can include other elements semiconductor, such as germanium；Including carborundum, arsenic Gallium, gallium phosphide, indium phosphide, the compound semiconductor of indium arsenide and/or indium antimonide；Including SiGe, GaAsP, AlInAs, AlGaAs, GaInAs, GaInP and/or GaInAsP alloy semiconductor；Or its combination.In one embodiment, substrate is exhausted Edge body semiconductor-on-insulator (SOI) substrate.SOI substrate can include what is formed by such as isolating the technique of (SIMOX) by noting oxygen Buried oxide (BOX) layer and/or other suitable techniques.Substrate can include doped region, such as p traps and n traps.

Method 2100 then proceedes to frame 2104, and wherein field-effect transistor (FET) is formed on substrate.FET can be wrapped Include grid structure, source region, drain region and the channel region of insertion source region and drain region.Source electrode, drain electrode and/or Channel region can be formed on the active area of Semiconductor substrate.FET can be n-type FET (nFET) or p-type FET (pFET).Example Such as, regions and source/drain can include the n-type dopant or p-type dopant for depending on FET configurations.Grid structure can include Gate dielectric, grid electrode layer and/or other suitable layers.In one embodiment, gate electrode is polysilicon.Other examples The gate electrode of property includes metal gate electrode, and it includes the materials such as Cu, W, Ti, Ta, Cr, Pt, Ag, Au；Suitable metallization Compound such as TiN, TaN, NiSi, CoSi；It is combined；And/or other suitable conductive materials.In one embodiment, grid electricity Medium is silica.Other examples gate-dielectric includes silicon nitride, silicon oxynitride, has the electricity of high-k (high k) Medium, and/or its combination.

Method 2100 then proceedes to frame 2106, wherein forming opening at the back side of substrate.Opening can include being formed The groove in one or more layers on substrate back including FET device.Opening can be exposed below grid and body structure Region (for example, neighbouring FET raceway groove).In one embodiment, it is open under the grid and active/channel region of exposure FET device The active area (for example, silicon active area) in face.Can use suitable photoetching process formed opening, with substrate provide pattern and Etch process from the back side to remove material, until the body structure of FET device exposes.Etch process includes Wet-type etching, dry ecthing, Plasma etching and/or other suitable techniques.

Then, method 2100 proceeds to frame 2108, wherein forming boundary layer in the opening.Boundary layer can be formed in FET Grid structure below exposure active area on.Boundary layer can be combined compatible (for example, friend with biomolecule or biological entities Alright).For example, boundary layer can provide combination interface for biomolecule or biological entities.Boundary layer can include dielectric material, lead Electric material and/or other suitable materials for keeping acceptor.Exemplary interfaces material includes high-k dielectric film, metal, gold Belong to oxide, dielectric and/or other suitable materials.As another example, exemplary interfaces material includes HfO₂、Ta₂O₅、 Pt, Au, W, Ti, Al, Cu, the oxide of these metals, SiO₂、Si₃N₄、Al₂O₃、TiO₂、TiN、SnO、SnO₂、SrTiO₃、 ZrO₂、La₂O₃；And/or other suitable materials.Such as physical vapour deposition (PVD) (PVD) (sputtering), chemical vapor deposition can be used Product (CVD), plasma enhanced chemical vapor deposition (PECVD), sub-atmospheric CVD (APCVD)) etc. CMOS technology Form boundary layer.Low pressure chemical vapor deposition (LPCVD), high-density plasma CVD (HDPCVD) or ald (ALD).In embodiment In, boundary layer includes multiple layers.

Method 2100 then proceedes to frame 2110, wherein acceptor for example enzyme, antibody, part, peptide, nucleotides, organ cell, Organism or tissue fragment are placed on boundary layer for detecting target biological molecules.

With reference to figure 3, show to be connected to the exemplary addressable array 300 of bit line 306 and the FET sensor 304 of wordline 308 Schematic diagram.It should be noted that term bit line and wordline are similar with the array structure in memory device for indicating herein Thing, however, being not intended that memory device or storage array must be included in an array.Addressable array 300 can have such as There is analog employed in other semiconductor devices of dynamic random access memory (DRAM) array.For example, join above The opening position being present in capacitor in DRAM array can be formed by examining the double grid dorsal part sensing FET sensor 200 of Fig. 2 descriptions. Schematic diagram 300 is only exemplary, and can be appreciated that other configurations are possible.

FET sensor 304 is approximately similar to double grid dorsal part sensing FET sensor 200.FET 302 is configured to provide for being situated between Connection between the drain terminal and bit line 306 of FET sensor 304.By this way, FET 302 is similar to DRAM array In access transistor.In this exemplary embodiment, FET sensor 304 is double grid dorsal part sensing FET sensor, and is wrapped Include：Grid is sensed, is provided by the acceptor material being arranged on the dielectric layer of FET active regions, the FET active areas are arranged on instead Answer opening position；And control gate, provided by the gate electrode (for example, polysilicon) being arranged on the dielectric layer of FET active regions.

Schematic diagram 300 shows that array is formed, and the array is advantageously possible for detecting the minimum by being incorporated into FET sensor 304 The small signal variation that biomolecule or biological entities are provided.Allow to reduce using the array format of bit line 306 and wordline 308 defeated Enter/the quantity of o pads.Signal intensity can be strengthened using amplifier, to improve the circuit arrangement with schematic diagram 300 Device detectability.In embodiment, when set particular word line 308 and bit line 306, corresponding access transistor 302 Will conducting (for example, as switch).When the grid of related FET sensor 304 is (for example, such as double grid dorsal part sensing FET sensor 200 dorsal part grid 222) have influenceed by the presence of biomolecule electric charge when, FET sensor 304 will transmit electronics simultaneously The field-effect charging of device is induced, so as to modulate electric current (such as I_ds).Electric current is (for example, I_ds) or threshold voltage (V_t) change can For indicating the detection of associated biomolecules or biological entities.Therefore, the device with schematic diagram 300 can realize bio-sensing Device application, including the application with differential sensing, so as to for improving sensitivity.

With reference to figure 4, exemplary layout 400 is presented.Exemplary layout 400 includes being configured to individually addressable pixel 402 The access transistor 302 and FET sensor 304 of array 401.Array 401 can include any amount of pixel 402.For example, battle array Row 401 can include 128 × 128 pixels.Other arrangements can include the non-of 256 × 256 pixels or such as 128 × 256 pixels Rectangular array.

Each pixel 402 includes：Access transistor 302 and double grid dorsal part sensing FET sensor 304；And other assemblies, It may include one or more heaters 408 and temperature sensor 410.In this example, access transistor 302 is n-channel FET.n Channel fet 412 is also used as the access transistor of temperature sensor 410.In the illustrative examples, although this is not must Need, but FET 302 and 412 grid connects jointly.Can individually it be sought using column decoder 404 and row decoder 406 The each pixel 402 in location (and its related component).In an example, each pixel 402 is micro- with about 10 microns × about 10 The size of rice.In another example, each pixel 402 has about 5 microns × about 5 microns of a size, or with about 2 microns × about 2 microns of size.

Column decoder 406 and row decoder 404 can be used for the conduction and cut-off (ON/ for determining n-channel FET 302 and 412 OFF) state.Turn on n-channel FET 302 and provide electric current to the S/D areas of double grid dorsal part sensing FET sensor 304.When turn on these During device, electric current I_dsFET sensor 304 is flowed through, and electric current I can be measured_ds。

Heater 408 can be used for locally increasing the temperature around double grid dorsal part sensing FET sensor 304.It can make Heater 408 is constructed with any of technology for such as forming the metal pattern with the high current passed through.Heating Device 408 can also be thermo-electric heaters/coolers, such as Peltier devices.(can such as it make during specific biological test DNA or RNA denaturation, or provide more preferably combining environmental for specific biomolecule) use heater 408.Temperature sensor 410 local temperatures that can be used for around measurement double grid dorsal part sensing FET sensor 304.In one embodiment, control can be created Fed back with controlling temperature using heater 408 and being received from temperature sensor 410 in loop processed.In another embodiment, heat Device 408 can be thermo-electric heaters/coolers, and the cooler allows the component part active cooling in pixel 402.

With reference to figure 5, there is provided the sectional view of exemplary double grid dorsal part sensing FET sensor 500.Double grid dorsal part sensing FET Sensor 500 is an embodiment of double grid dorsal part sensing FET sensor 200, therefore marks elder generation with Fig. 2 component symbol Fig. 2 of preceding description element, and their description is not repeated herein.Double grid dorsal part sensing FET sensor 500 includes grid 202nd, source area 204, drain region 206 and channel region 208, wherein source area 204 and drain region 206 are formed in substrate 214.Grid Pole 202, source area 204, drain region 206 and channel region 208 form FET.It should be noted that as various equivalent modifications will be understood that As, Fig. 5 each component is not intended to drawn to scale and in order to which visual convenience is exaggerated.

In the exemplary embodiment, double grid dorsal part sensing FET sensor 500 is connected to each metal interconnecting layer 502, metal Interconnection layer 502 electrically connects with forming each doped region in substrate 214 and the formation of other devices.Association area can be used Manufacturing process known to technical staff carrys out making metal interconnect layer 502.

Double grid dorsal part FET sensor 500 can include the body region 504 separated with source area 204 and drain region 206.It is main The carrier concentration that body area 504 can be used in active area 208 of the biasing between source area 204 and drain region 206.Therefore, Negative voltage bias can be applied to body region 504 to improve the sensitivity of double grid dorsal part FET sensor 500.In one embodiment In, body region 504 electrically connects with source area 204.In another embodiment, the electrical ground of body region 504.

Double grid dorsal part FET sensor 500 can be connected to the additional circuit 506 of the manufacture in substrate 214.Circuit 506 Any amount of MOSFET element, resistor, capacitor or inductor can be included, to form auxiliary operation double grid dorsal part sensing The circuit of FET sensor 500.For example, column decoder 406 and row decoder 404 can be formed in circuit 506.Circuit 506 can To be deposited including any amplifier, analog-digital converter (ADC), digital analog converter (DAC), voltage generator, logic circuit and DRAM Reservoir (only enumerates several examples).Can be with integrating additional electricity in the identical substrate 214 of double grid dorsal part FET sensor 500 All or part of component on road 506.It should be appreciated that the multiple FET for being each approximately similar to double grid dorsal part FET sensor 500 are passed Sensor is desirably integrated on substrate 214 and is connected to additional circuit 506.In another example, separated with substrate 214 it is another All or part of component of additional circuit 506 is provided in semi-conductive substrate.In a further example, with double grid dorsal part FET Some components of additional circuit 506 are integrated in the identical substrate 214 of sensor 500, and it is another being separated with substrate 214 Some components of additional circuit 506 are provided in Semiconductor substrate.

Again referring to Fig. 5 illustrative examples, double grid dorsal part sensing FET sensor 500 includes being deposited on the top of separation layer 210 With the boundary layer 508 in the opening of the top of channel region 208.In one embodiment, boundary layer 508 has between aboutWith AboutBetween thickness.Boundary layer 508 can be such as hafnium silicate, hafnium oxide, zirconium oxide, aluminum oxide, tantalum pentoxide, Hafnium oxide-aluminum oxide (HfO₂-Al₂O₃) alloy or any combination of them high-k dielectric material.Following article will be for biology Discussed in more detail in the part of sensing, boundary layer 508 may be used as being attached the support of capture agent.

The exemplary operation of the double grid dorsal part FET sensor 500 as pH sensors will now be described.In brief, flow Body grid 510 is used to provide to the electrical contact of " second grid " of double grid dorsal part sensing FET sensor.Sensed in double grid dorsal part Solution 512 with given pH value is provided above the response location of FET sensor 500, and fluid grid are placed in solution 512 Pole 510.The pH of solution generally with the hydrogen ion [H in solution⁺] concentration it is relevant.Boundary layer 508 on channel region 208 The accumulation of the ion of near surface will influence the formation of inversion layer in channel region 208, and the channel region 208 is in source area 204 and leakage Conductive path is formed between polar region 206.This can be measured by the change of the electrical conductivity of FET sensor.In one embodiment In, during sensing, fluid grid 510 is used as the grid of transistor, and grid 202 keeps floating.In another embodiment, exist During sensing, fluid grid 510 is used as the grid of transistor, and grid 202 is biased with given voltage.For example, grid 202 can be with According to voltage bias of the application between -2V and 2V, and the scanned fluid grid 510 between certain voltage range.Another In embodiment, during sensing, fluid grid 510 is with given voltage (or ground connection) biasing, and grid 202 is used as the grid of transistor Pole (for example, the inswept certain voltage range of its voltage).Fluid grid 510 can be formed by platinum, or can be by electrochemical credit Any other commonly used material in analysis for reference electrode is formed.Most common reference electrode is that stable voltage is about 0.230V Ag/AgCl electrodes.

Fig. 6 A show to be bound to the ion on the surface of boundary layer 508 in solution.The top atomic layer description of boundary layer 508 For various hanging [O^-], [OH] and [OH₂ ⁺] key.When ion gathers on the surface, summary table surface charge influences the threshold value of transistor Voltage.As used herein, threshold voltage is the conductive path that minority carrier is formed between the source electrode of FET sensor and drain electrode The minimum potential between the grid and source electrode between FET sensor needed for footpath.Total electrical charge is also directly relevant with the pH value of solution, Because higher accumulation of positive charges shows low ph value, and higher negative electrical charge accumulation then shows high ph-values.Fig. 6 B are shown due to n ditches The change of threshold voltage caused by different pH value in road FET sensor.It can be seen that threshold voltage increase 59mV is big Cause to show that the pH value of solution increases by 1.In other words, when the voltage needed for measurement conducting transistor, a pH change causes summary table The equivalent electric charge in face is 59mV.

Chip package

With reference to figure 7, the exemplary plan view of semiconductor chip 702 is shown.Chip 702 includes sensor array 704, optional Reference electrode 706, analog circuit 708 and I/O pads 716.Chip 702 can be that silicon, GaAs or indium phosphide (only lift several realities Example).Chip 702 can have about 3mm × about 2.5mm size.

Such as above shown in Fig. 2 and Fig. 5, sensor array 704 represents the array of double grid dorsal part sensing FET sensor. For example, in Fig. 4, the array may be arranged to the row-column matrix of pixel as depicted.Identical or different capture can be used Each FET sensor in reagent functionalized sensing device array 704, to implement biological sensing to each analyte.

Reference electrode 706 can be patterned on the identical chips 702 including sensor array 704.Reference electrode 706 can With along X or Y-direction and the rough alignment of sensor array 704 so that can be in 706 liang of sensor array 704 and reference electrode Fluid channel is placed above person.In another embodiment, the reference electrode of offer elsewhere 706 outside chip 702.

Reference electrode 706 can include any material with relative stabilizing potential.Exemplary reference electrode material includes Platinum or Ag/AgCl.The described Ag/AgCl electrodes of manufacture on the surface of a substrate are it is known in the art that for example passing through Moschou Et al. in 2015《Sensor》The article that upper 15th (8) roll up the 18102-18113 pages " is manufactured using commercially available PCB technologies Ag/AgCl puppet reference electrodes surface and electrical characterization ".

Analog circuit 708 can include the circuit relevant with the operation of sensor array 704.Therefore, analog circuit 708 can To be configured to provide signal to sensor array 704 while being connected with each interface of I/O pads 716 and measure to come to be somebody's turn to do The signal of sensor array.In one embodiment, analog circuit 708 includes serial peripheral interface (SPI) 712 and sensor array Column circuits 714.In this embodiment, the interval between sensor array 704 and sensor array circuitry 714 not less than about 135 Micron.

SPI 712 can be serial interface circuit, to promote the He of sensor array circuitry 714 being described in more detail below Data transfer between analyzer unit.For those skilled in the relevant art, the general behaviour for the SPI that would be well understood Make.Sensor array circuitry 714 can include any amount of reference voltage generator, operational amplifier, low pass filter, ADC and DAC, to provide signal and from the reception signal of sensor array 704 to sensor array 704.

In an example, sensor array circuitry 714 can be used to produce bias reference voltage, with to sensor array The body region of given FET sensor or one group of FET sensor in 704 provides about -0.24 volt of negative bias voltage.Work as implementation During sensing, can also be provided to the fluid grid of the given FET sensor in sensor array 704 or one group of FET sensor can Adjust voltage.

When the signal (example that measurement receives from the given FET sensor in sensor array 704 or one group of FET sensor Such as Ids) when, before by resulting signal output to I/O pads 716, sensor array circuitry 714 can receive measurement These signals are simultaneously transmitted by signal by transimpedance amplifier, i.e., electric current-to-electric pressure converter, followed by one or more Individual additional amplifying stage, low pass filter and final ADC., can also be by from measurement signal before measurement by magnification signal In subtract background AC signals to reduce the noise in measurement signal.Exported in temperature signal to before I/O pads 716, can be with Amplification, filtering simultaneously (are received by ADC transmission temperature signals from one or more of sensor array 704 temperature sensor ).

In various embodiments, can be along peripheral patterned multiple I/O pads 716 of chip 702.Can provide than by Actual input used in each component of chip 702 and the more I/O pads of output.In one embodiment, lead connects Conjunction technology can be used for for each I/O pads 716 being connected to another substrate or packaging part engaged with chip 702.It is specific at one In embodiment, peripheral patterned 32 I/O pads of chip 702 can be surrounded.The size of given I/O pads 716 can be about 80 microns × about 70 microns, and the spacing between I/O pads 716 can be about 150 microns.Sensor array 704 and most connect Interval between near I/O pads 716 can not be shorter than about 400 microns, and the outermost edge of I/O pads 716 and chip 702 it Between interval can not be shorter than about 177.5 microns.

With reference to figure 8, the example package scheme of chip 702 is shown.Chip 702 with I/O pads 716 is bound to load Body layer 802.Carrier layer 802 can be another Semiconductor substrate of such as silicon substrate.In another example, carrier layer 802 is all Such as the insulator of hard plastic material.It can use such as by using solder or any of joining technique of adhesive, will Chip 702 is bonded to carrier layer 802.

In one embodiment, carrier layer 802 includes multiple through holes filled with conductive material 804.Conductive material 804 It can be any metal of such as, but not limited to tin, copper, aluminium, gold or their any alloy.Conductive material 804 can include position Solder projection or soldered ball at the bottom surface 805 of carrier layer 802.Solder can extend beyond surface 805.

According to embodiment, chip package also includes the first insulating barrier 806 of the side of adjacent chip 702.First insulation Layer 806 can also be the plastic material or resin of filling chip 702 peripheral region, and can help chip 702 being fixed on Suitable opening position.In the exemplary embodiment, the first insulating barrier 806 includes the through hole for being also filled with conductive plunger 808.Lead Electric plug 808 can be and the identical material of conductive material 804.Conductive plunger 808 is above the corresponding region of conductive material 804 Rough alignment, so that forming Ohmic contact between conductive plunger 808 and conductive material 804.

Once chip 702 is fixed into carrier layer 802, and there is the first insulating barrier 806 around it, then can be with Electrical connection 812 is formed between I/O pads 716 and conductive plunger 808.Those skilled in the relevant art will be understood that, can use Wire bond technology forms electrical connection 812.In another example, electrical connection 812 is formed using lithographic patterning techniques, wherein, The lithographic patterning techniques pattern conductive trace is to electrically connect I/O pads 716 and corresponding conductive plunger 808.Once formed Electrical connection 812, then the second insulating barrier 810 can be deposited to protect electrical connection 812 from the damage of environment.Second insulating barrier 810 Can be and the identical material of the first insulating barrier 806.Second insulating barrier 810 can be resin material, and the resin material is being electrically connected The flowing of 812 surroundings and then hardening are connect to form containment vessel.Opening 814 is formed in the second insulating barrier 810, is existed to create direction In the path of the sensor array on chip 702.In also patterning the embodiment of reference electrode on chip 702, then 814 are open It will create towards sensor array and the path of reference electrode.

Final chip package 816 includes being bound to carrier layer 802 and being electrically connected to positioned at the bottom surface of carrier layer 802 The chip 702 of each conductive welding spots or metal pad on 805.Also protected by the first insulating barrier 806 and the second insulating barrier 810 Protect damage of the chip 702 from environment.Chip package 816 can more easily handle and be connected to such as printed circuit board (PCB) (PCB) larger substrate.In certain embodiments, chip package 816 can be connected to one or more radiators, to carry For from chip 702 enter in surrounding air or enter chip package 816 attachment substrate in more effective radiating road Footpath.In other embodiments, chip package 816 can be connected to Peltier devices to provide thermoelectricity heating and/or cooling.

With reference to the illustrative embodiment of figure 9, chip package 816 engages with substrate 902.Substrate 902 can be PCB, should PCB includes conductive contact pads to manufacture the electrical contact with solder or conductive welding disk on the bottom surface of carrier layer 802.It can implement Flip-chip bonding technique is to engage chip package 816 on the surface of substrate 902.In brief, along carrier layer 802 Bottom surface solder or conductive welding disk be aligned with the corresponding conductive welding disk patterned on substrate 902, and be bonded together with Chip package 816 is physically attached to substrate 902, and the I/O pads from chip 702 are electrically connected to and are present in lining Conductive trace on bottom 902.Conductive trace on substrate 902 is terminated in edge connector 908.

One or more edge connectors 908 can be provided to the electrical connection of chip 702.Other one or more edges connect Fitting 908 can be provided to the electrical connection of the reference electrode 906 patterned on the surface of substrate 902.Use reference electrode 906 The needs that reference electrode is provided on chip 702 can be eliminated.Figure can be carried out using the metal of such as, but not limited to copper, gold or aluminium It is each in case one or more edge connector 908.It can use discussed above electric with reference that is being used on chip 702 Pole 706 identical technology manufactures reference electrode 906.

The size of Exemplary cores chip package 816 can be between 1 to 2 centimetre of about 1 to 2 cm x or smaller, and serves as a contrast The size at bottom 902 can be between 3 to 4 centimetres of 3 to 4 cm x or smaller.

Opening 814 is shown located at the top of chip 702, at least exposes the sensor array of chip 702.In exemplary implementation In example, opening 814 is along X or Y-direction and the rough alignment of reference electrode 906, so that fluid channel can be placed on opening 814 With both tops of reference electrode 906.

Fluid design

With reference to figure 10, there is provided the schematic diagram of exemplary fluid box 1000.Schematic diagram shows the regarding from up to down of box 1000 Figure, and it should be noted that all elements shown in not are all on identical horizontal plane.In addition, in order to improve visualization, there is mesh Ground be not drawn on scale the specific dimensions and ratio of each fluid channel.Box 1000 includes housing 1002.Can use injection, Casting or 3-D printing technologies (only lifting several examples) are formed by any plastic material of such as polymethyl methacrylate (PMMA) Housing 1002.Can be by forming housing 1002 mechanically or by the more than one section to be linked together using adhesive. In one embodiment, each fluid channel and room can be moulded in the one or more assemblies of housing 1002.In another reality Apply in example, each fluid channel and room are formed by the different molded polymeric materials of such as dimethyl silicone polymer (PDMS). The overall dimension of housing 1002 can be between about 4 centimetres between about 4 centimetres to about 7 centimetres of about 7 cm x.With entering for technology Step, housing 1002 can become smaller.In one embodiment, the substrate with encapsulation chip 802 is set in housing 1002 902.In an example, only being partially encapsulated in substrate 902 in housing 1002, and edge connector 908 is exposed to housing 1002 outside.

The fluid design of exemplary shell 1002 includes at least the first raceway groove 1004, the second raceway groove 1006 and triple channel 1008.First raceway groove 1004 and the second raceway groove 1006 respectively include corresponding fluid intake 1010a and 1010b.Fluid intake Fluid is injected into the region in box 1000 by offer from the outside of box 1000.Fluid intake, which also provides, discharges fluid from box 1000 Region to outside box 1000.Triple channel 1008 can be aligned being bonded to above the encapsulation chip 802 of substrate 902.One In individual embodiment, the opening 814 above sensor array is located substantially in triple channel 1008.According to embodiment, in substrate 902 The reference electrode 906 of upper patterning is also aligned in triple channel 1008.

First raceway groove 1004, the second raceway groove 1006 and triple channel 1008 can have between about 1 millimeter and 3 millimeters it Between channel width.Channel height may be about 1 millimeter.In another embodiment, the first raceway groove 1004, the and of the second raceway groove 1006 One or more of triple channel 1008 is the microfluidic channels that width and height dimension are less than 1mm.First raceway groove 1004, Two raceway grooves 1006 and triple channel 1008 can have rectangle, square or semicircular section.

In certain embodiments, one or more of the first raceway groove 1004 and the second raceway groove 1006 and triple channel 1008 Connection.By this way, flowing through the fluid of the first raceway groove 1004 finally will flow through triple channel 1008, and similarly flow through The fluid of two raceway grooves 1006 finally will flow through triple channel 1008.In certain embodiments, triple channel 1008 finally flows into useless Thing room 1016, it collects all fluids for flowing through box 1000.Waste compartment 1016 can include to the exhaust outlet in air (not showing Go out), to avoid the back pressure in fluid system from gathering.

In certain embodiments, entrance 1010a and 1010b respectively includes connector 1012a and 1012b.Connector 1012a/ 1012b can be soft flexible material, and it is closely fitted into entrance 1010a/1010b, by inlet seal so as to anti- Only any fluid leakage.Connector 1012a/1012b can be such as polymeric material of polytetrafluoroethylene (PTFE) (PTFE) or cork. Connector 1012a/1012b can with sealed entry 1010a/1010b, while allow capillary through connector 1012a/1012b without Damage Fluid Sealing.Capillary can be the needle like tube of such as syringe needle.Capillary can include such as metal or duroplasts Hard rigid material.When discussing the connection of box 1000 and analyzer, capillary and box 1000 will be described in further detail later Connection.

Box 1000 includes sample entrance port 1014, and it is arranged as sample introducing the first raceway groove 1004 (as shown in Figure 10) or the Two raceway grooves 1006.In an example, blood sample can be placed into fluid system by sample entrance port 1014.Once Through introducing sample, lid or any other similar sealing structure sample entrance port 1014 can be used, with sample entrance port 1014 weeks Offer leakproof seal is provided.In the raceway groove arrangement shown in Figure 10, the fluid that the first raceway groove 1004 is flowed through from entrance 1010a will be with leading to The sample mixing of the introducing of sample entrance port 1014 is crossed, and mixture is by the opening 814 and reference electrode in triple channel 1008 Flow 906 tops.Once sample to be sent to the sensor array exposed by opening 814, then biomolecule may occur Between interaction, and FET Sensor sensors can be used for detection sample in specific analyte presence or measurement sample The concentration of middle specific analyte.Several examples are only lifted, pressure driven flow can be used to make fluid along each raceway groove and each Moved between individual raceway groove.Pressure is probably as caused by syringe forces liquid or air by box 1000, or by pushing liquid Caused by the forced air of body.Other examples of technology for conveying liquid by box 1000 include electrowetting or use chip Upper peristaltic pump.In certain embodiments, any one of mixed method on each chip known in the art can be used to exist Fluid mixing is carried out in box 1000.The size of the fluid channel of box 1000 can be with sufficiently large so that because liquid is moved through ditch The turbulent flow of liquid carries out some fluid mixing during road.It should be appreciated that the position of sample entrance port 1014 can change.For example, sample Entrance 1014 can above opening 814 so that the sample being incorporated into sample entrance port 1014 be also incorporated into it is logical Cross above the sensor array of the exposure of opening 814.

Once substrate 902 is already integrated into housing 1002, according to embodiment, various capture agent functionalization can be utilized The sensor array accessed by opening 814.The technique may relate to include capture agent by what triple channel 1008 flowed Liquid buffer so that capture agent has an opportunity to be bound to each FET sensor in sensor array.In another reality In example, when sample entrance port 1014 is located at 814 top of opening, capture agent is directly set in the top of opening 814.It is solid After determining capture agent, sample entrance port 1014 can be sealed, so that Storage Box 1000 implements biology until being ready to Sensing test.Capture agent can be retained in its initial cushioning liquid, or can introduce new cushioning liquid to preserve Capture agent, while box 1000 etc. is to be tested.Implement test there is provided herein different capture agents and using capture agent Example.

With reference to figure 11, another design in each fluid thorough cut road for box 1000 is shown.In this design, have first Entrance 1102a the first raceway groove 1104 and the second raceway groove 1106 with entrance 1102b are focused at sample entrance port 1110 At region.Triple channel 1108 with opening 814 of alignment in it at sample entrance port 1110 with the first raceway groove 1104 and Second raceway groove 1106 connects.Opening 814 provides one downwards to the path of chip, so that the sensor array on major general's chip Fluid in triple channel 1108.The fluid of triple channel 1108 is flowed through from the first raceway groove 1104 or the second raceway groove 1106 It is finally collected in waste compartment 1112.Geometry that can be based on each raceway groove or by using valve close specific raceway groove come Fluid is guided towards waste compartment 1112.Sample entrance port 1110 may be located on the top of opening 814.

One or more of first raceway groove 1104, the second raceway groove 1106 and triple channel 1108 can include bubble trap 1114.Bubble trap 1114 can represent the region of the fluid channel with section (or higher " ceiling ") bigger suddenly, So that any air to exist in solution can be risen at bubble trap 1114 in the additional space created.It is related Field it is to be understood by the skilled artisans that can use other bubble traps design.Sensor array below solution reaches opening 814 Bubble is removed for ensuring that accurate sensing result is extremely important from solution before row.

With reference to figure 12, box 1000 is shown connected to analyzer 1200, so as to for implementing biological sensing.Example can be passed through Such as box 1000 is set to be physically contacted with analyzer 1200 towards the receiving port pressing box 1000 of analyzer 1200.Analyzer 1200 Receiving port can include being used to form the electrical bonding pads with some or all of Ohmic contact of edge connector 908.Substrate 902 edge can be closely fitted into the receiving port of analyzer 1200 so that edge connector 908 close to The corresponding conductive welding disk of (press against) analyzer 1200.In addition, assembling box 1000 and its other party of analyzer 1200 Method includes clipping together them, and one is inserted in another.Analyzer 1200 can be small enough in carry and can To be suitable for adult palm.

In certain embodiments, analyzer 1200 comprises at least the first syringe 1202a and the second syringe 1202b.The One syringe 1202a and the second syringe 1202b may each comprise the buffer solution or other used during the operation of box 1000 Fluid.Syringe 1202a/1202b includes the pin 1204a/1204b of alignment, to extend to the residue away from analyzer 1200 In partial interval.In certain embodiments, can be with alignment pins 1204a/1204b, so that connecing towards analyzer 1200 Receiving end mouth pressing box 1000 can cause pin 1204a/1204b to pass through corresponding connector 1012a/1012b and enter entrance 1010a/ In 1010b.In this embodiment, pin 1204a/1204b is a reality through corresponding connector 1012a/1012b capillary Example.Therefore, leakproof seal is created so that solution to be transferred to the corresponding entrance of box 1000 from each syringe 1202a/1202b In 1010a/1010b.It will be appreciated that though specification only describes two syringes being aligned with two input ports, still Any amount of syringe and fluid inlet port, including the reality being connected using only a syringe with single entrance can be used Example.Each syringe 1202a/1202b can be pre-loaded with the solution for each test.In another embodiment, user Easily each syringe 1202a/1202b can be removed and replace with different syringes.

Each syringe 1202a/1202b can have by corresponding actuator 1206a/1206b controls and its phase The piston of pass.Actuator 1206a/1206b example includes stepper motor or induction machine.Actuator 1206a/1206b is pressed The speed of syringe 1202a/1202b piston is by the flow velocity of solution in the fluid channel for directly affecting box 1000.It can pass through Motor control module 1208a/1208b controls actuator 1206a/1206b.Those skilled in the relevant art will be understood that, motor Control module 1208a/1208b includes generation and is used for needed for the voltage for the speed and operation for controlling actuator 1206a/1206b Circuit.

All electrically connect of the edge connector 908 with box 1000 of manufacture can be routed to sensing electronic equipment 1210. Sensing electronic equipment 1210 can include any amount of discrete circuit, integrated circuit and discrete artificial circuit component, and it is designed Many different electric signals are provided and receive between sensing electronic equipment 1210 and edge connector 908.For example, sensing electricity Sub- equipment 1210 is configurable to provide power supply signal, ground signalling and clock signal to edge connector 908, subsequently can be used for Other electronic equipments in power supply and operation sensor array and chip 702.Sensing electronic equipment 1210 can be provided for Activate the various voltage offset levels of the grid of the specific FET sensor in sensor array.Sensing electronic equipment 1210 can be with The signal for representing the drain current from the measurement of specific FET sensor is received, and is represented from the temperature sensor on chip 702 The signal of output.Sensing electronic equipment 1210 can be by data storage that this is received in memory, or can use institute The data of reception change voltage offset level, or change the heat as caused by the heater on chip 702.Generally, sensing electricity The sub- control of the equipment 1210 all signalings related to the biological sensing of the sensor array implementation by box 1000.

In certain embodiments, analyzer 1200 also includes processor 1212, and it controls such as motor of analyzer 1200 The function of other each modules of control module 1208a/1208b and sensing electronic equipment 1210 and timing.Processor 1212 can To be any kind of CPU (CPU) or microcontroller, and can be implemented and analyzer by user program The specific function of 1200 operation correlation.Processor 1212 is configurable to the letter that analysis receives from sensing electronic equipment 1210 Number, to determine the concentration level of the given analyte of the sample in box 1000.The data related to the concentration level of determination It can be stored in the memory of analyzer 1200.In another embodiment, electronic equipment 1210 is sensed to determine to come from box 1000 In sample given analyte concentration level, and be additionally configured to the data storage related to identified concentration level In the memory of analyzer 1200.

In certain embodiments, analyzer 1200 includes being designed as the communication module for making data communicate with external treatment device 1214.Processor 1212 can be electrically connected with communication module 1214 and transmitted with control data.Communication can be wired or wireless. The example of wire communication includes the data transfer by network cable or universal serial bus (USB) cable.Radio communication can be with Including wireless RF transmission, bluetooth, WiFi, 3G or 4G.Communication module 1214 is also designed to receive number from external treatment device According to.For example, can by for how the program of each component of Operations Analyst instrument 1200 be sent to communication module 1214 and by Reason device 1212 performs.Communication module 1214 can include any amount of known hardware element with promote analogue data and/or Digital data transfer and reception.

After biological sensing test is had been carried out, box 1000 can be removed and abandoned from analyzer 1200.In addition, note Emitter 1202a/1202b can be removed and abandoned from analyzer 1200.Therefore, all reagents, which retain, is included in box 1000 or note In emitter 1202a/1202b, and the pollution of any other part of analyzer 1200 does not occur.In this way it is possible to weight Any amount of additional box is newly tested using single analyzer 1200, wherein different capture agents individually work(can be used The each box of energyization is tested with implementing different biological sensings.

In another embodiment, syringe 1202a/1202b is integrated on box 1000, and box 1000 and analyzer 1200 Between connection syringe 1202a/1202b associated piston is aligned with the actuator 1206a/1206b on analyzer 1200. In this embodiment, analyzer 1200 carries container without any reagent completely.

In another embodiment, box 1000 includes one or more capillaries through corresponding connector 1012a/1012b. In the embodiment, when being connected between box 1000 and analyzer 1200, capillary and remaining note in analyzer 1200 Emitter 1202a/1202b is connected glibly.After biological sensing test is had been carried out, box 1000 and its capillary can be from Remove and abandon in analyzer 1200.

With reference to figure 13, illustrative methods 1300 are shown.Can be after box 1000 be already attached to analyzer 1200 by dividing The implementation 1300 of analyzer 1200.Can before the shown operation of method 1300, between or implement afterwards in method 1300 Unshowned other operations relevant with fluid processing and electrical measurement.With the different order implementation with a shown order 1300 each operation.In embodiment, the implementation 1300 after capture agent is fixed in box 1000.

At frame 1302, the first solution flows through the first raceway groove of box.First solution can be by being connected to the first raceway groove Entrance enters box.The first solution can be provided by syringe, the syringe has through the porch for being arranged on the first raceway groove The pin of connector.First solution can include cushioning liquid to provide stable pH environment.

At frame 1304, in the double grid dorsal part sensing FET sensor of the first solution alignment sensor array.It can implement Calibrate to measure the noise of each FET sensor or background signal.The measured value can be stored and later in detection biology point The period of the day from 11 p.m. to 1 a.m, the measured value is subtracted from measurement signal to attempt and reduce noise and obtain apparent detection signal.First is molten Liquid is necessarily present in above sensor array and the reference electrode patterned in main detection raceway groove, to implement to calibrate.At some In embodiment, the first solution does not flow during calibration measurement.In certain embodiments, calibration measurement represents FET sensor Reference threshold voltage.

At frame 1306, sample is input in the fluid network of box by sample entrance port.Sample can include blood sample This any liquid sample.In certain embodiments, sample is the semi-solid samples decomposed in the solution.Passing through sample , can be by using lid or other similar sealing structure sample entrance ports after entrance input sample.

At frame 1308, the second solution flows through the second raceway groove of box.Second solution is probably molten with the first solution identical Liquid.Second solution can intersect with sample to be input to the path of fluid system at frame 1306, and be mixed with sample.Then, The mixture of sample and the second solution can flow through the second raceway groove and enter sensor array where main detection raceway groove in.Second Solution can be cushioning liquid.In an example, the second solution is the cushioning liquid decomposed.It can be made using pressure driven flow Second solution moves along each raceway groove and between each raceway groove.Several examples are only lifted, pressure is probably to be forced by syringe Liquid or air are by caused by box, or caused by the forced air by being pushed towards the second solution.For being conveyed by box Other examples of the technology of second liquid include electrowetting or using peristaltic pumps on chip.

At frame 1310, the biomolecule being present in sample is just cultivated on an array of sensors.Culture can continue example As between any given time between 30 seconds to 10 minutes.In the training period, the sample mixed with the second solution can not Flowing, or can be with very slow flow rate.Can be with design current velocity, so that fresh solution appears in sensing with the time Above device array, but flow less strong in order to avoid causing to damage to capture agent or preventing association reaction from occurring.

At frame 1312, after incubation time expires, the 3rd solution flows through the first raceway groove of box and by main detection raceway groove, So that the whole samples mixed with the second solution are pushed into waste compartment substantially.It can be noted in preset time section by main detection raceway groove Enter the 3rd solution, to ensure that sample is removed from main detection raceway groove.Ideally, the 3rd solution used in frame 1312 It is and the first solution identical solution.In another embodiment, the 3rd solution is different from the first solution.3rd solution can be slow Rush solution.

At frame 1314, the output of measurement sensor array is to determine whether to occur any association reaction.Sensor exports It can be the drain current from the measurement of one or more of sensor array double grid dorsal part sensing FET sensor.The leakage of measurement Compared with the drain current that electrode current can be measured during the calibration of sensor identical with frame 1304.If threshold value is electric Pressure (for example, correspond roughly to turn on FET and cause the voltage needed for drain current flows) has occurred in calibration sensor Change, then can determine there occurs association reaction, and target analytes are present in sample.The amount and symbol of threshold voltage variation Number it is likely to be dependent on following many factors：Such as double grid dorsal part sensing FET sensor is n-channel device or p-channel device, is examined The type of the analyte of survey and the amount of the positive charge related to analyte or negative electrical charge.In another example, from sensor array The measurement output of row be threshold voltage in itself, its threshold value that can be measured during calibration of sensor identical with frame 1304 Voltage is compared.

Chemistry, biology and interface

Devices, systems, and methods of the invention described in this application can be used for detecting and/or monitoring between each entity Interaction.These interactions include biological and chemical reaction to detect the target analytes in test sample.As reality Example, the reaction for including physics, chemistry, biochemistry or bioconversion can be monitored, with detect intermediate, accessory substance, product and The generation of combinations thereof.In addition, the devices, systems, and methods of the present invention can be used in each measure as described herein examining These reactions are surveyed, are included but is not limited to, circulating tumor cell measure and chelatometry for liquid biopsy (chelationassay) to detect the presence of heavy metal and other environmental contaminants.Can in a single format or array format prison Such measure and reaction are surveyed, to detect such as plurality of target analyte.

Bio-sensing example with DGBSS FET sensors

With reference to figure 14, implement exemplary bio sensing test using above-mentioned double grid dorsal part sensing FET sensor.DNA probe 1404 (examples of capture agent) are bonded to boundary layer 508 by connection molecule 1402.Connection molecule 1402, which can have, to be combined To the reactive chemical group of the part of boundary layer 508.The example of connection molecule includes mercaptan.Boundary layer 508 can also be passed through Surface silanization or by the way that the surface of boundary layer 508 is exposed into ammonia (NH₃) plasma to be to form reaction on the surface Property NH₂Group forms connection molecule.As those skilled in the relevant art are generally understood, silanization process is related to interface The surface of layer 508 is exposed to different chemicals successively, to establish covalently bound molecule on the surface of boundary layer 508.Visit Pin DNA 1404 represents single stranded DNA.According to embodiment, before any step of implementation 1300, by connection molecule 1402 It is bonded to boundary layer 508.Before any step of implementation 1300, DNA probe 1404 can also be bound to connection molecule 1402.In another example, DNA probe 1404 is bonded to connection molecule 1402 at the frame 1302 of method 1300.

According to embodiment, the double grid dorsal part sensing FET sensor shown in Figure 14 will be present in such as said chip 702 A FET in sensor array on chip.Cutting include the wafer of chip 702 with by chip 702 and wafer separate it Before, connection molecule 1402 can be bonded to boundary layer 508.

DNA probe 1404 can be fixed on boundary layer 508 before FET sensor is subjected to sample 1401.Sample 1401 can include the single-stranded DNA sequence 1406 for the pairing for being forcefully bound to the DNA probe 1404 matched with it.It is additional DNA the negative electrical charge with reference to present on can increase boundary layer 508, and the combination of the additional DNA located immediately at FET sense The top of channel region 208 of device.

DNA combinations are conceptually illustrated in Figure 15 A.Here the DNA probe with nucleotide sequence TCGA be bound to The chain of nucleotide sequence AGCT its complementary pairing.Any unpaired sequence hybridizes all without with DNA probe sequence.Pairing DNA combination adds negative electrical charge of the accumulation in the interface of boundary layer 508.In the example shown in Figure 15 A, boundary layer 508 It is hafnium oxide.

Figure 15 B show the threshold of the double grid dorsal part sensing FET sensor when the DNA of pairing is bound to the surface of boundary layer 508 Threshold voltage is offset.In brief, voltage is applied to fluid grid 510 until FET sensor " conducting ", and electric current is in drain region Flowed between 206 and source area 204.When due to complementary DNA with reference to and more negative electrical charges be present on boundary layer 508 when, need Voltage that will be higher is with the formation conductive inversion layer in channel region 208.Therefore, according to embodiment, in FET sensor conducting and Before Ids electric current flowings, higher voltage can be applied to fluid grid 510.This species diversity of threshold voltage can be measured, And the presence of the DNA sequence dna for determining target pairing, and determine its concentration.It is it should be appreciated that net just tired at boundary layer 508 Accumulated charge will cause threshold voltage to reduce rather than increase.Additionally, compared with p-channel FET, n-channel FET threshold voltage Change is by with opposite symbol.

With reference to figure 16, implement another exemplary biological sensing using double grid dorsal part sensing FET sensor and test.Probe antibody 1604 (another examples of capture agent) are bound to boundary layer 508 by connection molecule 1602.Connection molecule 1602 can have It is bound to the reactive chemical group of the part of boundary layer 508.Sample solution 1601 can be provided above probe antibody 1604, To determine that the antigen of pairing whether there is in sample solution 1601.According to embodiment, in any step of implementation 1300 Before, connection molecule 1602 is bound to boundary layer 508.Before any step of implementation 1300, probe antibody 1604 It can be combined with to connection molecule 1602.In another example, probe antibody 1604 is bonded at the frame 1302 of method 1300 Binding molecule 1602.

With reference to figure 17, show to match the cohesive process of antigen and probe antibody 1604.Here, the antigen of pairing will be bound to Fixed probe antibody, and unpaired antigen does not combine.Similar with above-mentioned DNA hybridization process, the antigen of pairing will change Stored charge existing at boundary layer 508.By with discussed above with reference to Figure 15 B it is roughly the same in a manner of measure due to come It is self-bonded to the skew of threshold voltage caused by the stored charge of the pairing antibody of probe antibody.

In embodiment, there is provided a kind of fluid box, including：Substrate, including multiple contact pads, are configured to and analyzer Electrical connection, semiconductor chip, has sensor array, and reference electrode；First fluid raceway groove, there is first entrance, and Second fluid raceway groove is connected to, is directed at the second fluid raceway groove so that the sensor array and the reference electrode are arranged on In the second fluid raceway groove；Sample entrance port, for sample to be placed on into the first fluid raceway groove or the second fluid ditch In the path in road；First connector, it is arranged on the first access point and makes stream including being configured to be passed through without by capillary The flexible material that body is leaked by first connector.

In embodiment, fluid box also includes the 3rd fluid channel with second entrance.

In embodiment, the 3rd fluid channel is connected to the second fluid raceway groove.

In embodiment, fluid box also includes the second connector, is arranged at the second entrance, and including be configured to by The capillary passes through without the flexible material for making the fluid be leaked by second connector.

In embodiment, first connector and second connector are configured to and are connected to first mao of the analyzer Tubule and the alignment of the second capillary, and when the fluid box and the analyzer are physically contacted, multiple contact pads and institute State analyzer connection.

In embodiment, when the fluid box and the analyzer are physically contacted, first capillary and described the Two capillaries are each passed through first connector and second connector.

In embodiment, the substrate is printed circuit board (PCB).

In embodiment, fluid box also includes the waste compartment for being connected to the second fluid raceway groove.

In embodiment, one or more of described sensor array sensor includes being configured to be bound to being present in institute State multiple probe molecules of the target molecule in sample.

In embodiment, the sensor array includes double grid dorsal part sensing FET sensor array.

In embodiment, there is provided a kind of fluid box, including：First fluid raceway groove, there is first entrance, and be connected to Second fluid raceway groove, the second fluid raceway groove is directed at so that sensor array and reference electrode are arranged on the second fluid ditch In road；Sample entrance port, for sample to be placed in the path of the first fluid raceway groove or the second fluid raceway groove；First Connector, it is arranged on the first access point and enables flow through described first including being configured to be passed through without by capillary and insert The flexible material of leakage is filled in, wherein, the capillary is connected to analyzer, and when the fluid box and the analyzer physics During contact, the capillary passes through first connector.

In embodiment, the sensor array includes double grid dorsal part sensing FET sensor array.

In embodiment, one or more of described sensor array sensor includes being configured to be bound to being present in institute State multiple probe molecules of the target molecule in sample.

In embodiment, the multiple probe molecule includes the one or more in DNA, RNA and antibody.

In embodiment, fluid box also includes：With the multiple contact pads for being configured to electrically connect with the analyzer, tool There are the semiconductor chip of the sensor array, and reference electrode.

In embodiment, there is provided a kind of analyzer is configured to be connected with fluid box, and the analyzer includes：

Syringe, be arranged so that when the fluid box is physically connected to the analyzer, the pin of the syringe with The corresponding input port alignment of the fluid box；

Actuator, it is configured to control the operation of the syringe；

Sensing module, be configured to when the fluid box is physically connected to the analyzer, via multiple conductive welding disks to The fluid box sends signal and from the fluid box reception signal, wherein, the multiple conductive welding disk contacts the fluid box On corresponding multiple conductive welding disks；And processor, the sensing module is electrically connected to, and be configured to from the stream The signal that body box receives determines the concentration level of the given analyte of the sample in the fluid box.

In embodiment, analyzer also includes actuator control, is configured to control the operation of the actuator.

In embodiment, the processor is also electrically connected to the actuator control.

In embodiment, analyzer also includes at least one other syringe, is arranged so as to work as the fluid box physics When being connected to the analyzer, the pin of at least one other syringe is aligned with the corresponding input port of the fluid box.

In embodiment, analyzer also includes memory, be configured to storage with by the processor determine to setting analysis The relevant data of the concentration level of thing.

Final remarks

It should be appreciated that the part being described in detail, rather than the summary of open part, it is intended to for explaining claim.It is public The one or more of the invention desired by inventor but the exemplary embodiment being not all of can be illustrated by opening the summary of part, Therefore, it is not intended to limit the invention in any way and accompanying claims.

It should be appreciated that the purpose that this paper words or terms are used to describe rather than limit, so that this specification Term or wording according to teaching and instruct to explain herein by those skilled in the relevant art.

The range and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should only root Limited according to appended claims and its equivalent.

Claims (10)

1. a kind of fluid box, including：

Substrate, including

Multiple contact pads, it is configured to electrically connect with analyzer,

Semiconductor chip, there is sensor array, and

Reference electrode；

First fluid raceway groove, there is first entrance, and be connected to second fluid raceway groove, be directed at the second fluid raceway groove and cause The sensor array and the reference electrode are arranged in the second fluid raceway groove；

Sample entrance port, for sample to be placed in the path of the first fluid raceway groove or the second fluid raceway groove；

First connector, it is arranged on the first access point and enables flow through institute including being configured to be passed through without by capillary State the flexible material of the first connector leakage.

2. fluid box according to claim 1, in addition to the 3rd fluid channel with second entrance.

3. fluid box according to claim 2, wherein, the 3rd fluid channel is connected to the second fluid raceway groove.

4. fluid box according to claim 3, in addition to the second connector, are arranged at the second entrance, and including It is configured to be passed through without the flexible material for making the fluid leak by second connector by the capillary.

5. fluid box according to claim 4, wherein, first connector and second connector are configured to and are connected to First capillary of the analyzer and the alignment of the second capillary, and when the fluid box and the analyzer are physically contacted When, multiple contact pads are connected with the analyzer.

6. fluid box according to claim 5, wherein, it is described when the fluid box and analyzer physical contact First capillary and second capillary are each passed through first connector and second connector.

7. fluid box according to claim 1, wherein, the substrate is printed circuit board (PCB).

8. fluid box according to claim 1, in addition to it is connected to the waste compartment of the second fluid raceway groove.

9. a kind of fluid box, including：

First fluid raceway groove, there is first entrance, and be connected to second fluid raceway groove, be directed at the second fluid raceway groove and cause Sensor array and reference electrode are arranged in the second fluid raceway groove；

Sample entrance port, for sample to be placed in the path of the first fluid raceway groove or the second fluid raceway groove；

First connector, it is arranged on the first access point and enables flow through institute including being configured to be passed through without by capillary The flexible material of the first connector leakage is stated, wherein, the capillary is connected to analyzer, and when the fluid box and described point When analyzer is physically contacted, the capillary passes through first connector.

10. a kind of analyzer, being configured to be connected with fluid box, the analyzer includes：

Syringe, be arranged so that when the fluid box is physically connected to the analyzer, the pin of the syringe with it is described The corresponding input port alignment of fluid box；

Actuator, it is configured to control the operation of the syringe；

Sensing module, it is configured to when the fluid box is physically connected to the analyzer, via multiple conductive welding disks to described Fluid box sends signal and from the fluid box reception signal, wherein, the multiple conductive welding disk is contacted on the fluid box Corresponding multiple conductive welding disks；And

Processor, the sensing module is electrically connected to, and the signal for being configured to receive from the fluid box is next to determine From the concentration level of the given analyte of the sample in the fluid box.