CN202854093U - DNA (deoxyribonucleic acid) sequencing device based on graphene nanopore-micro cavity-solid nanopore structure - Google Patents
DNA (deoxyribonucleic acid) sequencing device based on graphene nanopore-micro cavity-solid nanopore structure Download PDFInfo
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- CN202854093U CN202854093U CN201220486772.7U CN201220486772U CN202854093U CN 202854093 U CN202854093 U CN 202854093U CN 201220486772 U CN201220486772 U CN 201220486772U CN 202854093 U CN202854093 U CN 202854093U
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Abstract
The utility model discloses a DNA (deoxyribonucleic acid) sequencing device based on a graphene nanopore-micro cavity-solid nanopore structure. The device mainly comprises a graphene micro-strip with a graphene nanopore, an inverted-pyramid-shaped micro cavity in a silicon base substrate and a solid nanopore on the top of the micro cavity. When the device is used for sequencing, a sequencing reaction cavity is divided into two by the graphene nanopore-micro cavity-solid nanopore structure, single-strand DNA molecules pass through the graphene nanopore in a line under the action of a static electric field, enter into the inverted-pyramid-shaped micro cavity, and at last go through the solid nanopore; and a weak current measurement device is used for simultaneously measuring a longitudinal ion current block in the nanopore caused by passing activity of the DNA molecules and a transverse conductivity change surrounding the nanopore in the graphene micro-strip, so that a synchronous data record and processing system is used for analytically calculating bi-directional data, and sequence analysis of the single-strand DNA molecules is achieved.
Description
Technical field
The utility model belongs to dna molecular sequencing technologies field, is specifically related to a kind of dna sequencing device based on grapheme nano-pore-microcavity-solid nano pore structure.
Background technology
DNA (deoxyribonucleic acid) (DNA) sequencing technologies is one of core technology of modern life science research.For realizing thousand dollars of human genomes (TDG), hundred dollars of human genomes (HDG) target, advance individuation medical diagnosis on disease and treatment, in the urgent need to a kind of novel low-cost, high-throughout direct Sequencing method.The gordian technique that is considered to be hopeful most to realize above-mentioned target based on the single-molecule sequencing of nano-pore.
Up to now, in the various dna single molecule sequence measurements based on nano-pore of having reported, the gas current Blocking Method proposes the earliest, studies also extensive.The ultimate principle of this method is as follows, the sequencing reaction chamber is divided into two by the film with nano-pore, single strand dna is added into one side of film, under the attraction of film another side positive potential electrode, polymeric chain with negative charge enters nano-pore, and slide into the another side of film from one side of film, when polymeric chain passes through nano-pore, meeting is resulted in blockage to original nano-pore ion current, electric current can drop sharply to about 10% of primary current, and the researchist is by the crossing time (t) to polynucleotide chain crossing process, block the gap (Δ t) of generation and the quantitative detection of blocking current (IB) and realize the dna molecular order-checking.
Yet this nano-pore gas current Blocking Method faces the problem of some essence in actual applications.(its Typical Representative is that alpha hemolysin protein molecular (protein α-hemolysin) consist of nano-pore) poor stability, life-span are short to the early stage biomolecule nano-pore that adopts, extremely responsive to environmental factor, and the aperture of biomolecule nano-pore is difficult to manual control, inner aperture only is about 1.5nm, is unsuitable for the detection of different IPs acid molecule.The solid nano hole (Solid-state nanopore) of generally adopting at present is although overcome the shortcoming of above-mentioned biomolecule nano-pore, but also there are the following problems: at first, solid nano hole path length is generally more than the 5nm, can hold more than ten base, this size is long for the curent change that the single base of the needed resolution of order-checking causes; Secondly, when occupying nano-pore, the single core thuja acid only have about 100 ions to pass nano-pore, and 4 bases structurally only have the difference of several atoms, and the gas current that this trickle structuring difference causes changes very faint, to such an extent as to the researchist is difficult to distinguish each base; The 3rd, still can not effectively control at present DNA by the speed of nano-pore based on the sequence measurement in solid nano hole, because speed is too fast, caused base to detect discrimination not high.These problems have seriously restricted the practical application of sort sequencer method.
Various nano-pore sequence measurements by means of other supplementary meanss, such as fluorescence labeling aided nano hole sequencing, hybridization aided nano hole sequencing, tunnel current aided nano hole sequencing and probe modification nano-pore sequencing etc., still belong in itself indirect sequence measurement, have equipment complexity, low speed, the problem such as expensive.So, realize thousand dollars of human genome (TDG) targets even hundred dollars of human genomes (HDG) target, advance the development of individuation medical diagnosis on disease and treatment, need novel direct, efficient, low-cost sequence measurement.
The utility model content
The utility model proposes a kind of dna sequencing device based on grapheme nano-pore-microcavity-solid nano pore structure, can realize dna molecular accurately, efficiently, cheaply the order-checking.
To achieve these goals, the utility model adopts following technical scheme:
Dna sequencing device based on grapheme nano-pore-microcavity-solid nano pore structure, this dna sequencing device is to assemble take grapheme nano-pore-microcavity-solid nano pore structure as core, specifically comprise the silicon-based substrate 1 that places electrolytic solution 11, be etched with reverse pyramid microcavity 2 at silicon-based substrate 1 first half, Lower Half be etched with diameter greater than reverse pyramid microcavity 2 towers at the bottom of the cylinder hole of diameter, the cat head of reverse pyramid microcavity 2 is solid nano hole 3, insulation course 6 is coated on silicon-based substrate 1 outside, have on silicon-based substrate 1 top and to be fixed in by built-in electrode 8 that Graphene on the insulation course 6 is little is with 4, little being with of Graphene is etched with grapheme nano-pore 5 on 4, grapheme nano-pore 5 and solid nano hole 3 are coaxial, described grapheme nano-pore-microcavity-solid nano pore structure is divided into up and down two parts with the sequencing reaction chamber, place the external electrode 7 on reaction chamber top to connect negative potential, place the external electrode 7 of reaction chamber bottom to connect positive potential, external electrode 7 and vertical weak current measuring equipment 9 and power supply 12 consist of vertical weak current measuring circuit, and built-in electrode 8 and horizontal weak current measuring equipment 10 and power supply 14 consist of horizontal weak current measuring circuit.
The diameter in described solid nano hole 3 is 1.5-10nm.
The diameter of described grapheme nano-pore 5 is 1.5-7nm.
Described Graphene is little is with 4 to be the single or multiple lift Graphene.
Described vertical weak current measuring equipment 9 is skin peace level current measuring instrument.
Described horizontal weak current measuring equipment 10 is submicron level current measuring instrument.
The electrostatic field that passes through grapheme nano-pore-microcavity-solid nano pore structure for generation of driving single strand dna 13 is provided by power supply 12, the bias voltage of described power supply 12 should be 0.05-0.2V, near the one on negative potential of grapheme nano-pore 5 one sides in grapheme nano-pore-microcavity-solid nano pore structure, the electrode of close solid nano hole 3 one sides connects positive potential.
Described electrolytic solution 11 is KCl, NaCl or LiCl, and its concentration is 0.8～1.5mol/L, and pH is 8.0.
The utility model is compared with existing technology, and has following advantage:
The first, in grapheme nano-pore-microcavity that the utility model adopts-solid nano pore structure, the solid nano hole has overcome the wayward property of instability and aperture of biomolecule nano-pore; The employing of grapheme nano-pore has solved the problem that the oversize resolution that causes checking order of conventional solid nano hole path is difficult to reach single base.In addition, by around grapheme nano-pore-microcavity-solid nano pore structure, increasing ring electric field, change the electrolyte solution component, control temperature, changing grapheme nano-pore-microcavity-methods such as solid nano pore structure volume, can regulate even quantitatively control single strand dna by the speed of nano-pore, for the time has been won in detection.These advantages are laid a good foundation for realizing single base resolution, direct nano-pore order-checking.
The second, when the utility model had adopted dna molecular to pass through grapheme nano-pore-microcavity-solid nano hole pore structure, the Double Data that vertically gas current blocks and laterally electricity is led variation around the nano-pore in the little band of Graphene was resolved the new thought of order-checking.Adopt this bi-directional data that order-checking more information can provide single strand dna to pass through grapheme nano-pore-microcavity-solid nano pore structure the time is provided, improved traditional nano-pore gas current Blocking Method signal to noise ratio (S/N ratio) low, be subject to the problems such as external environmental interference, thereby improve the order-checking precision, be expected to fundamentally solve the root problem that present dna sequencing of new generation faces.
Description of drawings
Accompanying drawing is that the utility model is based on the dna sequencing device schematic diagram of grapheme nano-pore-microcavity-solid nano pore structure.
Embodiment
Below in conjunction with the drawings and specific embodiments the utility model is described further.
As shown in drawings, a kind of dna sequencing device based on grapheme nano-pore-microcavity-solid nano pore structure of the utility model, this device is to assemble take grapheme nano-pore-microcavity-solid nano pore structure as core, specifically comprise the silicon-based substrate 1 that places electrolytic solution 11, be etched with reverse pyramid microcavity 2 at silicon-based substrate 1 first half, Lower Half be etched with diameter greater than reverse pyramid microcavity 2 towers at the bottom of the cylinder hole of diameter, the cat head of reverse pyramid microcavity 2 is solid nano hole 3, insulation course 6 is coated on silicon-based substrate 1 outside, have on silicon-based substrate 1 top and to be fixed in by built-in electrode 8 that Graphene on the insulation course 6 is little is with 4, little being with of Graphene is etched with grapheme nano-pore 5 on 4, grapheme nano-pore 5 and solid nano hole 3 are coaxial, described grapheme nano-pore-microcavity-solid nano pore structure is divided into up and down two parts with the sequencing reaction chamber, place the external electrode 7 on reaction chamber top to connect negative potential, place the external electrode 7 of reaction chamber bottom to connect positive potential, external electrode 7 and vertical weak current measuring equipment 9 and power supply 12 consist of vertical weak current measuring circuit, vertically weak current measuring equipment 9 is used for measuring vertical gas current obstruction, built-in electrode 8 and horizontal weak current measuring equipment 10 and power supply 14 consist of horizontal weak current measuring circuit, and laterally weak current measuring equipment 10 is little with the electric variation of leading around 4 grapheme nano-pores 5 for measuring horizontal Graphene.
The diameter in preferred solid nano hole 3 is 1.5-10nm.
The diameter of preferred grapheme nano-pore 5 is 1.5-7nm.
Preferred Graphene is little is with 4 to be the single or multiple lift Graphene.
Preferred vertically weak current measuring equipment 9 is skin peace level current measuring instrument.
Preferred laterally weak current measuring equipment 10 is submicron level current measuring instrument.
The electrostatic field that passes through grapheme nano-pore-microcavity-solid nano pore structure for generation of driving single strand dna 13 is provided by power supply 12, the bias voltage of optimization power supply 12 should be 0.05-0.2V, near the one on negative potential of grapheme nano-pore 5 one sides in grapheme nano-pore-microcavity-solid nano pore structure, the electrode of close solid nano hole 3 one sides connects positive potential.
Preferred electrolytic solution 11 is KCl, NaCl or LiCl, and its concentration is 0.8～1.5mol/L, and pH is 8.0.Principle of work of the present utility model is: at first single strand dna 13 is joined the top, sequencing reaction chamber that fills electrolytic solution 11, under the driving effect of electrostatic field, 13 one-tenth wire of single strand dna are by grapheme nano-pore 5, enter reverse pyramid microcavity 2, and finally arrive the bottom in sequencing reaction chamber by solid nano hole 3; When single strand dna 13 passes through grapheme nano-pore-microcavity-solid nano pore structure, on the one hand the electrolyte ion electric current by grapheme nano-pore-microcavity-solid nano pore structure is resulted in blockage, cause vertical gas current sharply to change, on the other hand, impact is given birth in 5 peripheral electric artificial deliveries on grapheme nano-pore, cause that Graphene is little is with that lateral current density changes in 4, because the Different Alkali based structures is different in the single strand dna 13, it is also different that the electric current that causes at above-mentioned vertical and horizontal both direction when passing through grapheme nano-pore-microcavity-solid nano pore structure and electricity are led change, adopt 9 pairs of single strand dnas 13 of vertical weak current measuring equipment to pass through crossing time t in grapheme nano-pore-microcavity-solid nano pore structure process, vertically the time interval Δ t that blocks occurs in gas current
1, block the big or small IB of gas current
1Quantitatively detect, adopt simultaneously the little time interval Δ t that changes with current density in 4 of 10 pairs of horizontal Graphenes of horizontal weak current measuring equipment
2, electric current big or small IB
2Quantitatively detect, again by measured bi-directional data is carried out analytical Calculation: dna molecular sequence Sequence=f (t, Δ t
1, IB
1, Δ t
2, IB
2), can obtain the sequence of the dna molecular of surveying.
Claims (8)
1. based on the dna sequencing device of grapheme nano-pore-microcavity-solid nano pore structure, it is characterized in that: this dna sequencing device is to assemble take grapheme nano-pore-microcavity-solid nano pore structure as core, specifically comprise the silicon-based substrate (1) that places electrolytic solution (11), be etched with reverse pyramid microcavity (2) at silicon-based substrate (1) first half, Lower Half be etched with diameter greater than reverse pyramid microcavity (2) tower at the bottom of the cylinder hole of diameter, the cat head of reverse pyramid microcavity (2) is solid nano hole (3), insulation course (6) is coated on silicon-based substrate (1) outside, have on silicon-based substrate (1) top by built-in electrode (8) and be fixed in the little band of Graphene (4) on the insulation course (6), be etched with grapheme nano-pore (5) on the little band of Graphene (4), grapheme nano-pore (5) and solid nano hole (3) are coaxial, described grapheme nano-pore-microcavity-solid nano pore structure is divided into up and down two parts with the sequencing reaction chamber, place the external electrode (7) on reaction chamber top to connect negative potential, place the external electrode (7) of reaction chamber bottom to connect positive potential, external electrode (7) and vertical weak current measuring equipment (9) and power supply (12) consist of vertical weak current measuring circuit, and built-in electrode (8) and horizontal weak current measuring equipment (10) and power supply (14) consist of horizontal weak current measuring circuit.
2. dna sequencing device according to claim 1, it is characterized in that: the diameter in described solid nano hole (3) is 1.5-10nm.
3. dna sequencing device according to claim 1, it is characterized in that: the diameter of described grapheme nano-pore (5) is 1.5-7nm.
4. dna sequencing device according to claim 1, it is characterized in that: the little band of described Graphene (4) is the single or multiple lift Graphene.
5. dna sequencing device according to claim 1 is characterized in that: described vertical weak current measuring equipment (9) is a skin peace level current measuring instrument.
6. dna sequencing device according to claim 1, it is characterized in that: described horizontal weak current measuring equipment (10) is submicron level current measuring instrument.
7. dna sequencing device according to claim 1, it is characterized in that: the electrostatic field that passes through grapheme nano-pore-microcavity-solid nano pore structure for generation of driving single strand dna (13) is provided by power supply (12), the bias voltage of described power supply (12) should be 0.05-0.2V, near the one on negative potential of grapheme nano-pore (5) one sides in grapheme nano-pore-microcavity-solid nano pore structure, the electrode of close solid nano hole (3) one sides connects positive potential.
8. dna sequencing device according to claim 1, it is characterized in that: described electrolytic solution (11) is KCl, NaCl or LiCl, and its concentration is 0.8～1.5mol/L, and pH is 8.0.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102899243A (en) * | 2012-09-21 | 2013-01-30 | 清华大学 | Graphene nanopore-microcavity-solid-state nanopore structure based DNA sequencing device and method |
| CN103224232A (en) * | 2013-04-23 | 2013-07-31 | 北京大学 | Preparation method of graphite nanometer hole |
| CN104897728A (en) * | 2015-06-01 | 2015-09-09 | 中国科学院重庆绿色智能技术研究院 | Nano hole detection system based on micro/nano hole net integrated structure and preparation method of nano hole detection system |
| EP3060918A4 (en) * | 2013-10-23 | 2017-06-07 | Genia Technologies, Inc. | High speed molecular sensing with nanopores |
| CN113957132A (en) * | 2021-10-25 | 2022-01-21 | 浙江大学 | Non-via-hole DNA sequencing method and system based on solid-state nanopore |
-
2012
- 2012-09-21 CN CN201220486772.7U patent/CN202854093U/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102899243A (en) * | 2012-09-21 | 2013-01-30 | 清华大学 | Graphene nanopore-microcavity-solid-state nanopore structure based DNA sequencing device and method |
| CN103224232A (en) * | 2013-04-23 | 2013-07-31 | 北京大学 | Preparation method of graphite nanometer hole |
| CN103224232B (en) * | 2013-04-23 | 2015-02-11 | 北京大学 | Preparation method of graphite nanometer hole |
| EP3060918A4 (en) * | 2013-10-23 | 2017-06-07 | Genia Technologies, Inc. | High speed molecular sensing with nanopores |
| US10421995B2 (en) | 2013-10-23 | 2019-09-24 | Genia Technologies, Inc. | High speed molecular sensing with nanopores |
| CN104897728A (en) * | 2015-06-01 | 2015-09-09 | 中国科学院重庆绿色智能技术研究院 | Nano hole detection system based on micro/nano hole net integrated structure and preparation method of nano hole detection system |
| CN104897728B (en) * | 2015-06-01 | 2017-10-03 | 中国科学院重庆绿色智能技术研究院 | Nano-pore detecting system based on micro-nano hole pattern integrated morphology and preparation method thereof |
| CN113957132A (en) * | 2021-10-25 | 2022-01-21 | 浙江大学 | Non-via-hole DNA sequencing method and system based on solid-state nanopore |
| CN113957132B (en) * | 2021-10-25 | 2023-12-29 | 浙江大学 | Non-via DNA sequencing method and system based on solid nano-pores |
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Granted publication date: 20130403 |