CN110684640B - Microfluidic device and gene sequencer - Google Patents
Microfluidic device and gene sequencer Download PDFInfo
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- CN110684640B CN110684640B CN201910976112.3A CN201910976112A CN110684640B CN 110684640 B CN110684640 B CN 110684640B CN 201910976112 A CN201910976112 A CN 201910976112A CN 110684640 B CN110684640 B CN 110684640B
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- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 73
- 239000007788 liquid Substances 0.000 claims abstract description 189
- 238000012360 testing method Methods 0.000 claims abstract description 30
- 238000012163 sequencing technique Methods 0.000 claims abstract description 14
- 239000010410 layer Substances 0.000 claims description 152
- 239000000758 substrate Substances 0.000 claims description 35
- 239000003153 chemical reaction reagent Substances 0.000 claims description 28
- 238000004140 cleaning Methods 0.000 claims description 14
- 238000004891 communication Methods 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000007599 discharging Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000002699 waste material Substances 0.000 claims description 7
- 230000002572 peristaltic effect Effects 0.000 claims description 6
- 239000012790 adhesive layer Substances 0.000 claims description 4
- 238000003860 storage Methods 0.000 claims description 2
- 239000012530 fluid Substances 0.000 abstract description 21
- 239000000243 solution Substances 0.000 description 40
- 238000001514 detection method Methods 0.000 description 16
- 239000002390 adhesive tape Substances 0.000 description 8
- 239000003570 air Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 230000004907 flux Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003475 lamination Methods 0.000 description 3
- 238000001712 DNA sequencing Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000012536 packaging technology Methods 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010146 3D printing Methods 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
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- 230000004927 fusion Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
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- 229920001296 polysiloxane Polymers 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6869—Methods for sequencing
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Abstract
The invention relates to the technical field of microfluidics and discloses a microfluidic device and a gene sequencer. The microfluidic channel comprises a liquid inlet channel and a liquid outlet channel, wherein the liquid inlet channel and the liquid outlet channel comprise a transverse channel extending along the transverse direction and a longitudinal channel extending along the longitudinal direction. The liquid inlet channel and the liquid outlet channel of the micro-fluid channel in the micro-fluid device are communicated with the solution cavity for testing, so that liquid can be fed through the liquid inlet channel and the liquid outlet channel of the micro-fluid channel, and liquid can be discharged through the liquid outlet channel. The combination arrangement of the transverse flow channel and the longitudinal flow channel can form a three-dimensional micro-fluid channel, and compared with a two-dimensional micro-fluid channel, the liquid inlet efficiency can be improved, so that the device is suitable for the high-flux high-efficiency test requirement. The gene sequencer with the microfluidic device can meet the high-flux and high-efficiency gene sequencing requirements.
Description
Technical Field
The invention relates to the technical field of microfluidics, in particular to a microfluidic device and a gene sequencer.
Background
Microfluidic devices are capable of integrating a range of operations such as sample pretreatment, separation, reaction, detection, and data analysis on a single substrate. The microfluidic technology has been developed rapidly due to its greatly reduced cost and shortened time for microfluidic analysis, and has been widely used in the fields of DNA sequencing, protein analysis, single cell analysis, drug detection, food safety, etc.
The structure of the current microfluidic device is generally simpler, and the microfluidic channel is generally realized only on a two-dimensional plane, so that the current high-flux analysis instrument has a plurality of limitations in use, and the high-flux high-efficiency test requirement is difficult to meet.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides a microfluidic device which is provided with a three-dimensional microfluidic channel and can meet the test requirements of high flux and high efficiency.
The invention also provides a gene sequencer with the microfluidic device.
In a first aspect, an embodiment of the present invention provides a microfluidic device comprising a substrate having disposed thereon:
A microfluidic channel comprising a liquid inlet channel and a liquid outlet channel, both comprising a transverse channel extending in a transverse direction and a longitudinal channel extending in a longitudinal direction;
a first inlet in communication with the liquid inlet channel;
a second inlet in communication with the liquid inlet channel;
And the liquid outlet is communicated with the liquid outlet flow channel and is used for discharging liquid.
The microfluidic device of the embodiment of the invention has at least the following beneficial effects: the transverse flow channel and the longitudinal flow channel form a three-dimensional micro-fluid channel, and compared with the two-dimensional micro-fluid channel adopted at present, the three-dimensional micro-fluid channel can meet the test requirement of high flux and high efficiency.
According to further embodiments of the present invention, the liquid outlet channel comprises a buffer channel and an outlet channel, the outlet channel being in communication with the liquid outlet; one end of the buffer flow channel is used for being communicated with the solution cavity, and the other end of the buffer flow channel is communicated with the outlet channel.
According to other embodiments of the present invention, a third inlet is connected to the liquid outlet channel, the third inlet is connected to the buffer channel, and a third valve hole is connected to the outlet channel.
According to other embodiments of the present invention, the first inlet includes a plurality of liquid inlets, and the liquid inlet channel includes inlet channels respectively connected to the liquid inlets, and each of the inlet channels is independent from each other and is respectively connected to a first valve hole.
According to further embodiments of the present invention, a second valve hole is in communication between the second inlet and the fluid inlet channel.
According to further embodiments of the present invention, the microfluidic device further comprises a cleaning flow channel, wherein the cleaning flow channel is respectively communicated with the second inlet and the liquid outlet, and a fourth valve hole is further arranged on the cleaning flow channel.
According to further embodiments of the present invention, the substrate comprises a first substrate, a second substrate, a third substrate, and a fourth substrate, which are sequentially laminated, wherein: a transverse groove is formed in the surface, facing the first base layer, of the second base layer, and the transverse runner is defined by the surface, facing the second base layer, of the first base layer and the transverse groove; the second base layer is provided with the longitudinal flow channels, and the longitudinal flow channels extend along the stacking direction; the third base layer is provided with a slotted hole extending along the transverse direction, and the slotted hole is correspondingly communicated with the longitudinal flow channel; the fourth base layer is provided with a through hole which is communicated with the slotted hole of the third base layer; the surfaces of the second base layer and the fourth base layer facing the third base layer and the slotted holes jointly enclose the transverse flow channel.
According to the microfluidic device of other embodiments of the present invention, the first base layer, the second base layer, the third base layer and the fourth base layer are bonded by an adhesive layer, and a yielding gap is formed on the adhesive layer at a position corresponding to the groove, the slot hole and the through hole.
According to further embodiments of the present invention, the microfluidic device further comprises a fifth base layer, a sixth base layer, and a chip sub-board, wherein the fifth base layer is connected to the bottom of the fourth base layer, the sixth base layer and the fifth base layer are stacked and connected, and the chip sub-board is provided with a test chip, wherein: a solution cavity is formed between the sixth base layer and the test chip, and openings for communicating the through holes of the fourth base layer are formed in the fifth base layer and the sixth base layer; the opening is communicated with the solution cavity; the fourth base layer and the sixth base layer are provided with printed circuits and are connected and conducted through a conductive component, and one end of the conductive component is located at the upper part of the solution cavity.
According to other embodiments of the present invention, the test chip is packaged with a circuit board by COB packaging technology to form the chip daughter board.
According to further embodiments of the present invention, the conductive assembly includes a first conductive post that conducts the printed circuits on the sixth substrate and the fourth substrate and a second conductive post that conducts the printed circuits on the fourth substrate and the chip sub-board, forming a conductive path that can transfer the electrical signals in the solution chamber to the chip sub-board.
In a second aspect, an embodiment of the present invention provides a gene sequencer comprising a microfluidic device according to any one of the above aspects.
The gene sequencer of the embodiment of the invention has at least the following beneficial effects: the gene sequencer with the microfluidic device can meet the high-flux and high-efficiency gene sequencing requirement through the arrangement of the three-dimensional microfluidic channel.
Drawings
FIG. 1 is a top view (perspective) of a first embodiment;
Fig. 2 is a perspective view of the first embodiment;
FIG. 3 is a schematic view of another angle of FIG. 2;
FIG. 4 is an exploded view of the first embodiment;
FIG. 5 is a schematic diagram of the structure of a second base layer according to the first embodiment;
FIG. 6 is a perspective view of FIG. 5;
FIG. 7 is a schematic diagram of the structure of a third base layer according to the first embodiment;
FIG. 8 is a top view (perspective) of a second embodiment;
Fig. 9 is a perspective view of a second embodiment;
FIG. 10 is an exploded view of a second embodiment;
Fig. 11 is a schematic view (perspective) showing a combined structure of a chip sub-board, a fifth base layer, and a sixth base layer according to a second embodiment;
fig. 12 is a schematic perspective view of a second embodiment.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
In the description of the embodiments of the present invention, if an orientation description such as "upper", "lower", etc. is referred to, it is merely for convenience of description and simplification of the description, and it is not indicated or implied that the apparatus or element referred to must have a specific orientation, be configured and operated in a specific orientation, and thus should not be construed as limiting the invention.
In the description of the embodiments of the present invention, if a feature is referred to as being "disposed" or "connected" to another feature, it can be directly disposed or connected to the other feature or be indirectly disposed or connected to the other feature. In the description of the embodiments of the present invention, if "several" is referred to, it means more than one, if "multiple" is referred to, it is understood that the number is not included, and if "first", "second" … … "sixth" and "seventh" are referred to, it is understood that the technical features are used for distinguishing the technical features, and it is not understood that the relative importance or implicit indication of the number of the technical features indicated or the precedence of the technical features indicated is indicated.
The microfluidic device comprises a substrate, wherein a microfluidic channel, a first inlet, a second inlet and a liquid outlet are arranged on the substrate. The microfluidic channel comprises a liquid inlet channel and a liquid outlet channel, wherein the liquid inlet channel and the liquid outlet channel comprise a transverse channel extending along the transverse direction and a longitudinal channel extending along the longitudinal direction. The liquid inlet channel and the liquid outlet channel of the micro-fluid channel in the micro-fluid device are communicated with the solution cavity for testing, so that liquid can be fed through the liquid inlet channel and the liquid outlet channel of the micro-fluid channel, and liquid can be discharged through the liquid outlet channel. The combination arrangement of the transverse flow channel and the longitudinal flow channel can form a three-dimensional micro-fluid channel, and compared with a two-dimensional micro-fluid channel, the liquid inlet efficiency can be improved, so that the device is suitable for the high-flux high-efficiency test requirement. In addition, from the aspect of the overall structural design, on the premise of meeting the test requirement of high flux and high efficiency, the three-dimensional microfluidic channel is further arranged, so that the structural space can be fully utilized, the overall structure of the microfluidic device is smaller than that of a conventional two-dimensional microfluidic device, and the miniaturized development of the microfluidic device in the technical field of microfluidics is facilitated.
The first inlet and the second inlet are communicated with the liquid inlet channel and are used for liquid inlet. The first inlet comprises a plurality of liquid inlets which can be used for manually adding the sample and the reagent, and the liquid inlet channel comprises inlet channels which are respectively communicated with the liquid inlets, so that different reagents can be respectively sent into the liquid inlet channel for mixing detection. The liquid outlet is communicated with the liquid outlet channel and is used for discharging waste liquid, and after the test is finished, the waste liquid can be discharged through the liquid outlet channel and the liquid outlet.
First embodiment
Referring to fig. 1 to 3, a top view (perspective) and a perspective view, respectively, of a first embodiment of a microfluidic device are shown. The substrate of the microfluidic device of this embodiment is provided with a microfluidic channel, a first inlet, a second inlet and a liquid outlet. In the reference frame, a direction z perpendicular to the surface of the substrate is defined as a longitudinal direction, and directions x and y perpendicular to the longitudinal direction are defined as transverse directions. When the upper surface of the matrix is parallel to the horizontal plane, the transverse flow channels can convey the solution along the horizontal direction, and the longitudinal flow channels can convey the solution along the vertical direction. The liquid inlet flow channel and the liquid outlet flow channel comprise a transverse flow channel extending along the transverse direction and a longitudinal flow channel extending along the longitudinal direction, and the transverse direction and the longitudinal direction are opposite to the matrix, so that the transverse flow channel and the longitudinal flow channel form a three-dimensional micro-fluid channel, and the solution can be conveyed along the transverse direction and the longitudinal direction.
The microfluidic channel comprises a liquid inlet channel 100 and a liquid outlet channel 200, wherein the first inlet and the second inlet are communicated with the liquid inlet channel and are used for liquid inlet. The first inlet of this embodiment includes three liquid inlets 31, 32, 33 provided at the side of the base body and communicating with the liquid inlet flow passage 100 through one first inlet passage 51, 52, 53, respectively. According to specific detection requirements, the three liquid inlets 31, 32, 33 can be respectively added with a sample or a reagent, and the sample or the reagent enters a liquid containing cavity (a solution cavity is not arranged in the embodiment) for detection through the liquid inlet channel 100 for mixing and corresponding detection. The first inlet passages 51, 52, 53 are independent of each other and are respectively communicated with the first valve holes 61, 62, 63 through the first longitudinal valve passages 34, 35, 36, and the corresponding liquid inlet passage 100 comprises three liquid inlet transverse passages 47, 48, 49 and one liquid inlet longitudinal passage 44, one ends of the three liquid inlet transverse passages 47, 48, 49 are respectively communicated with the first valve holes 61, 62, 63, and the other ends are respectively communicated with the liquid inlet longitudinal passage 44. The solutions fed from the respective liquid inlets 31, 32, 33 pass through the respective first inlet passages 51, 52, 53, the first longitudinal valve passages 34, 35, 36, the first valve holes 61, 62, 63 reach the respective liquid inlet lateral flow passages 47, 48, 49, and then merge into the liquid inlet longitudinal flow passage 44, so as to be introduced into the solution chamber for detection for mixing and testing. The opening and closing of the first valve holes 61, 62, 63 are controlled to adjust the amounts of the sample or reagent entering the liquid inlet channel 100 through the liquid inlets 31, 32, 33, and to adjust the amounts of the various solutions.
A second valve opening 69 is in communication between the second inlet 68 and the inlet flow path 100 for automatic fluid inlet, and the inlet flow path is further provided with a second transverse inlet flow path 50 in communication with the second valve opening 69 and the longitudinal inlet flow path 44. In actual use, the second inlet 68 is connected to the solution bottle, and the liquid is introduced and controlled by opening and closing the second valve hole 69. In this embodiment, the second inlet 68 is disposed on the upper surface of the substrate, the second inlet 68 is connected to the second inlet channel 54 through the second longitudinal channel 41, the second inlet channel 54 is connected to the second valve hole 69 through the second longitudinal valve channel 37, the second valve hole 69 is in communication with the lateral liquid inlet channel 50, and the lateral liquid inlet channel 50 is in communication with the longitudinal liquid inlet channel 44. The solution sequentially passes through the second inlet 68, the second longitudinal channel 41, the second inlet channel 54, the second longitudinal valve channel 37, the second valve hole 69, the second lateral liquid inlet channel 50 and the longitudinal flow channel 44 to enter the solution cavity for detection.
The liquid outlet 67 is communicated with the liquid outlet channel 200 and is used for discharging liquid. After detection or washing, the solution can be discharged through the liquid outlet channel 200 and the liquid outlet 67. The liquid outlet flow channel 200 of the present embodiment includes a buffer flow channel 58, a buffer zone channel 57, a first liquid outlet lateral channel 45, and a first lateral outlet channel 56. One end of the buffer flow channel 58 is communicated with the solution cavity for testing through the first liquid outlet transverse channel 45, the other end of the buffer flow channel is communicated with the buffer area channel 57, and the buffer area channel 57 can be communicated with the first transverse outlet channel 56 through a plurality of sections of micro-fluid channels which are transversely and longitudinally communicated. The buffer flow channel 58 and the buffer area channel 57 can temporarily store the solution, and have the function of preventing the solution in the original solution cavity from being directly discharged from the liquid outlet when the solution is added under the condition that the solution to be tested exists in the test solution cavity and the solution needs to be continuously added. After the solution is added, the solution in the buffer flow channel is only required to be conveyed back to the liquid containing cavity, and the test is not interrupted due to the fact that the solution is added again, so that the complexity of the test step is avoided. Air is pumped into the third inlet 66 by peristaltic pump and is re-pumped into the liquid chamber through the third inlet longitudinal channel 43 and the third inlet channel 46 by the mixed liquid temporarily stored in the buffer flow channel 58 and the buffer zone channel 57.
The liquid outlet channel 200 is communicated with a third inlet 66, the third inlet 66 is communicated with the buffer channel 58, and a peristaltic pump can be adopted to introduce air from the third inlet 66, so that the temporarily stored solution in the buffer channel 58 is returned to the liquid containing cavity. A third valve hole 65 is communicated with the flow passage between the outlet passage and the third inlet 66, and the buffer flow passage 58 and the liquid outlet 42 are opened and closed by opening and closing the third valve hole 65. The solution in the solution chamber is discharged through the liquid outlet longitudinal channel 70, the first liquid outlet transverse channel 45, the buffer channel 58, the third inlet channel 46, the buffer zone channel 57, the third valve hole 65, the third valve longitudinal channel 39, the second transverse outlet channel 73, the outlet valve pipeline 40, the first transverse outlet channel 56, the liquid outlet channel 42 and the liquid outlet 67 in sequence. The first liquid outlet transverse channel 45, the buffer area channel 57 and the second transverse outlet channel 73 are channels arranged above, the buffer channel 58, the third inlet channel 46 and the first transverse outlet channel 56 are channels arranged below, and the communicating parts of the channels arranged above and below are communicated through longitudinally extending channels to form a liquid outlet channel 200 with micro-fluid channels which are longitudinally and longitudinally communicated.
The microfluidic device further includes a cleaning flow channel 300, where the cleaning flow channel 300 is respectively connected to the second inlet 68 and the liquid outlet 42, and the cleaning flow channel 200 is further provided with a fourth valve hole 64. The fourth valve hole 64 is opened and closed to realize the on-off of the cleaning flow passage and the liquid outlet. The cleaning liquid is discharged through the second inlet 68, the second longitudinal channel 41, the second inlet channel 54, the third inlet channel 55, the fourth valve opening channel 38, the fourth valve opening 64, the third lateral liquid outlet channel 71, the fourth lateral outlet channel 72, the first lateral outlet channel 56, the liquid outlet channel 42, the liquid outlet 67.
Referring to fig. 4 to 7, there are shown an exploded view of the first embodiment, a structural view of the second base layer, a perspective view of the second base layer, and a structural view of the third base layer, respectively; in this embodiment, the substrate includes a first base layer 5, a second base layer 7, a third base layer 9 and a fourth base layer 11 which are sequentially laminated and connected, and the grooves, the holes and other structures are formed on each base layer, and then the micro-fluidic channels are formed in a laminated manner, so that the processing and the assembly are simple and convenient.
Referring to fig. 4, 5 and 6, the surface of the second base layer 7 facing the first base layer 5 is provided with a transverse groove 7-1, and the surface of the first base layer 5 facing the second base layer 7 and the transverse groove 7-1 enclose a transverse flow channel; the second base layer 7 is provided with a longitudinal through hole 7-2, and the longitudinal through hole 7-2 extends in the lamination direction to form a longitudinal flow passage.
Referring to fig. 4 and 7, the third base layer 9 is provided with a slot hole 9-1 extending in the transverse direction and a through hole 9-2 penetrating the third base layer, the slot hole 9-1 and the through hole 9-2 being respectively communicated with the longitudinal through hole 7-2 of the second base layer 7; the fourth base layer 11 is provided with a through hole 11-1, and the through hole 11-1 is communicated with the slotted hole 9-1 of the third base layer 9; the surfaces of the second base layer 7 and the fourth base layer 11 facing the third base layer 9 enclose a transverse flow path together with the slot holes. The longitudinal through holes 7-2, 9-2 and 11-1 are correspondingly communicated to form a longitudinal flow passage.
The first base layer 5, the second base layer 7, the third base layer 9 and the fourth base layer 11 are respectively bonded through bonding layers, the bonding layers of the embodiment are double faced adhesive tapes 6, 8 and 10, and abdication gaps are formed on positions, corresponding to the holes and groove structures of the microfluidic channels, the inlets, the outlets and the valve holes, on the base layers, of the double faced adhesive tapes 6, 8 and 10 so as to facilitate solution circulation.
The double-sided adhesive 6 between the first base layer 5 and the second base layer 7 is provided with yielding notches with the same positions and the same shapes corresponding to the holes and the groove structures of the surface of the second base layer 7 facing the first base layer 5; the double faced adhesive tape 8 between the second base layer 7 and the third base layer 9 is provided with yielding gaps with the same positions and the same shapes corresponding to the hole and the groove structure on the third base layer 9; the double faced adhesive tape 10 between the third base layer 9 and the fourth base layer 11 is provided with yielding notches with the same positions and the same shapes corresponding to the hole and the groove structure on the third base layer 9.
The microfluidic device of the present embodiment forms a three-dimensional microfluidic channel by combining holes and grooves on the first base layer 5, the second base layer 7, the third base layer 9 and the fourth base layer 11 and yielding notches on the double-sided tapes 6, 8 and 10, and is suitable for detecting liquid phase materials. The materials of the first base layer 5, the second base layer 7, the third base layer 9 and the fourth base layer 11 can be PC materials, the sources of the materials are wide, the processability and the stability are excellent, and the cost is low. The thickness of each basic unit can be set up rationally according to actual demand.
In other embodiments, the substrate may be integrally formed by 3D printing or the like.
Second embodiment
The present embodiment is further optimized based on the first embodiment, and referring to fig. 8 to 12, a top view, a perspective view, an exploded view, a partial structure perspective view, and a perspective view of the microfluidic device of the present embodiment are shown, respectively.
Referring to fig. 10 and 12, in this embodiment, the substrate includes a first base layer 5, a second base layer 7, a third base layer 9, a fourth base layer 11, a fifth base layer 14, a sixth base layer 16, a seventh base layer 20, a chip sub-board, a double sided adhesive tape, a first conductive pillar 12, and a second conductive pillar 18, which are sequentially stacked and connected, and each base layer is bonded by the double sided adhesive tape. The first base layer 5, the second base layer 7, the third base layer 9 and the fourth base layer 11 may be configured in the same manner as the first embodiment, and a silicone valve, a sealing ring and a lamination sheet may be further disposed at each opening on the upper surface of the first base layer 5. Wherein:
the silica gel valve 1 can open or close a corresponding inlet or outlet and is used for controlling the inlet and outlet of a sample, a reagent, air or waste liquid;
The sealing ring 2 is used for sealing the gap between the microfluidic device and the liquid inlet needle A, the air inlet needle B or the outlet needle C;
The lamination sheet 3 is used for fixedly laminating the double faced adhesive tape 4 used for the silica gel valve 1 so as to prevent the silica gel valve from leaking liquid or air leakage, and simultaneously covers the micro-fluid channel in the horizontal direction formed by the first base layer 5;
The first base layer 5 is used for fixing the positions of the silica gel valve 1 and the sealing ring 2 on the substrate and preventing leakage caused by displacement;
The second base layer 7 is used for forming a first transverse microfluidic channel (transverse flow channel) and a microfluidic channel along the longitudinal direction (longitudinal flow channel);
the third base layer 9 is used to form a second microfluidic channel in the lateral direction (lateral flow channel);
The fourth base layer 11 is used for covering the transverse flow channel formed by the third base layer 9 and bearing a printed conducting circuit;
The fifth base layer 14 is used to form a liquid chamber together with the sixth base layer 16 and the chip to be tested;
the sixth substrate 16 is used for forming a liquid containing cavity together with the fifth substrate 14 and the chip to be tested, and carrying a printed circuit;
the seventh base layer 20 is supported between the fourth base layer 11 of the microfluidic device and the chip sub-board to form a gap;
the first conductive post 12 and the second conductive post 18 are used to connect the printed conductive circuits of different layers;
the chip sub-board 21 is used for bearing a chip to be tested;
The double faced adhesive tape 3, 6, 8, 10, 13, 15 and 19 are used for attaching a silica gel valve, a sealing ring, each layer of base layer and a chip daughter board.
According to the above, the three-dimensional microfluidic channel is mainly constituted by the first base layer 5, the second base layer 7, the third base layer 9, and the fourth base layer 11. The liquid containing cavity is formed by the fifth base layer 14, the sixth base layer 16 and the tested chip on the chip sub-board 21 and is used for mixing the sample and various reagents; conductive paths between the liquid containing cavities and the chip sub-boards are also formed between the fifth base layer 14, the sixth base layer 16 and the chip sub-boards so as to detect the transmission of signals. The hollowed-out part in the middle of the seventh base layer 20 corresponds to the position of the tested chip on the chip sub-board, and is used for forming a gap between the fourth base layer and the chip sub-board.
Fig. 11 shows a schematic structural diagram of the fifth base layer 14 and a schematic structural diagram of an electronic sub-board, the fifth base layer 14, and the sixth base layer 16, and referring to fig. 8, 9, and 11, the fifth base layer 14 is connected to the bottom of the fourth base layer 11, and the sixth base layer 16 and the fifth base layer 14 are stacked and connected, and a chip is disposed on the sub-board. The chip under test can be packaged with the circuit board by COB packaging technology to form a chip sub-board, and then glued with the sixth base layer 16 by double sided tape. A solution cavity 24 is formed between the sixth base layer 16 and the chip to be tested, the fifth base layer 14 and the sixth base layer 16 are provided with openings for communicating through holes of the fourth base layer 11, and the openings are communicated with the solution cavity 24, so that the longitudinal flow channel can be communicated with the liquid containing cavity.
The fourth and sixth substrates 11 and 16 are provided with printed circuits and are connected by a conductive member, one end of which is located at the upper portion of the solution chamber 24. In this embodiment, the conductive assembly includes a first conductive pillar 12 and a second conductive pillar 18, and the first conductive pillar 12 and the second conductive pillar 18 may be copper pillars. The first conductive posts 12 conduct the printed circuits 22, 23 on the sixth substrate 16 and the fourth substrate 11, the second conductive posts 18 conduct the printed circuits 22 on the fourth substrate 11 and the chip sub-board 21, and form conductive paths, so that electrical signals at the top of the solution cavity 24 can be transmitted to the chip sub-board 21.
In the field of microfluidics, a series of operations such as sample pretreatment, separation, reaction, detection, and data analysis can be integrated on a substrate by using a microfluidic device, as will be described below from the practical point of view. The microfluidic technology has been developed rapidly due to its greatly reduced cost and shortened time for microfluidic analysis, and has been widely used in the fields of DNA sequencing, protein analysis, single cell analysis, drug detection, food safety, etc.
Along with the rapid development of science and technology, the application of medical engineering has become more and more popular, and the demand for medical instruments is also increasing, wherein the development of preventive medicine is most spotlighted, because Chinese people strongly regulate and cure the disease, so that the Chinese people can see the disease early through early screening and intervene early, and the importance of strategic position is improved to the level of the national level.
In preventive medical engineering, the development of gene detection is the most rapid, and the application of light for noninvasive prenatal gene detection is one, which is served for tens of millions of pregnant women within a few years, and other early screening applications such as cancer are not left. However, with the widespread popularity of gene detection, the manual method has been far from demand in laboratory operation detection, so the demand of a gene sequencer with an automatic detection function is also high, and the development of the current gene sequencing technology is focused, wherein the design of combining a microfluidic channel and a gene sequencing chip is a necessary condition of an automatic gene sequencer, so that in order to ensure sufficient fusion and reaction time between a reagent and a chip, and in order to reduce the volume of the gene sequencer, a high-efficiency microfluidic device is very important.
The structural design of current microfluidic devices is generally relatively simple, and microfluidic channels are generally implemented in only two-dimensional planes, with obvious limitations on high-throughput genetic testing applications. In combination with the foregoing structural description of the microfluidic device, the embodiment of the invention provides a microfluidic device with three-dimensional microfluidic channels, which can solve the problems of production and use of multidimensional microfluidics, and has very important practical significance in practical application.
The microfluidic device of this embodiment can be used in conjunction with existing gene sequencers to perform gene sequencing. The gene sequencer can be provided with a pipeline for introducing reagents, a pipeline for discharging solution or air, a valve control device for opening or closing the silica gel valves at the first valve opening, the second valve opening, the third valve opening and the fourth valve opening, a pump for feeding liquid or discharging liquid, a pump for introducing air, a gene sequencing program, an automatic control program for automatically controlling the opening or closing of the silica gel valve and the pump, an automatic tightness testing program, and a tightness degree for detecting the fitting of the liquid feeding device and the microfluidic device of the gene sequencer. Gene sequencing can be performed by the following steps:
1) Placing the device on a gene sequencer, respectively connecting a second inlet, a third inlet and a liquid outlet with corresponding pipelines of the gene sequencer, starting an automatic tightness testing program (preassembling the gene sequencer), and automatically closing all valve ports after testing;
2) Manually adding a sample, a first reagent, a second reagent to the first inlets 31, 32, 33, respectively;
3) Initiating a gene sequencing procedure (pre-installation of a gene sequencer);
5) The gene sequencing program automatically controls the opening of the fourth valve orifice 64 (through valve);
5) Automatically controlling the flow of cleaning fluid from the reagent bottle into the second inlet 68 by the gene sequencing program;
6) The washing liquid is discharged from the second inlet 68, through the second longitudinal channel 41, the second inlet channel 54, the third inlet channel 55, the fourth valve opening channel 38, the fourth valve opening 64, the third lateral liquid outlet channel 71, the fourth lateral outlet channel 72, the first lateral outlet channel 56, the liquid outlet channel 42, the liquid outlet 67, and into a waste liquid bottle communicating with the liquid outlet 67.
7) The gene sequencing program automatically controls to close the fourth valve hole 64 (through valve);
8) The gene sequencing program automatically controls and opens the first valve hole 61 (sample valve) and the third valve hole 65 (outlet valve), and opens the vacuum pump to suck the sample from the manual sample and the first inlet 31, and the sample is sucked into the liquid containing cavity 24 through the first inlet channel 51, the first longitudinal valve channel 34, the liquid inlet transverse channel 47 and the liquid inlet longitudinal channel 44;
9) Automatically controlling and closing the first valve hole 61 (sample valve) and the vacuum pump by the gene sequencing program;
10 Automatically controlling and opening a first valve hole 62 (a first reagent valve) and opening a vacuum pump to suck a first reagent from the first inlet 32, and allowing the first reagent to enter the liquid containing cavity 24 through the first inlet channel 52, the first longitudinal valve channel 35, the liquid inlet transverse flow channel 48 and the liquid inlet longitudinal flow channel 44;
11 Automatically controlling and closing the first valve hole 62 (first reagent valve) and the vacuum pump by the gene sequencing program;
12 Automatically controlling and opening a first valve hole 63 (a second reagent valve) and opening a vacuum pump to suck a second reagent from the first inlet 33, and enabling the second reagent to enter the liquid containing cavity 24 through the first inlet channel 53, the first longitudinal valve channel 36, the liquid inlet transverse flow channel 49 and the liquid inlet longitudinal flow channel 44;
13 Automatically controlling and closing the first valve hole 63 (second reagent valve), the third valve hole 65 (outlet valve) and the vacuum pump by the gene sequencing program;
14 Automatically executing coverage rate test of mixed liquid in the liquid containing cavity 24 and the tested chip by the gene sequencing program;
15 If the coverage test is passed (i.e., the solution completely covers the chip under test), then go to step 18;
16 If the coverage test is not passed (i.e. the solution does not completely cover the chip to be tested), the gene sequencing program automatically opens the third valve hole 65 (outlet valve) and the vacuum pump, sucks the mixed solution from the solution chamber 24, then enters the buffer flow passage 58 and the buffer area passage 57 for temporary storage through the first liquid outlet transverse passage 45, then closes the third valve hole 65 (outlet valve) and the vacuum pump, opens the peristaltic pump to drive air into the third inlet 66, and drives the mixed solution temporarily stored in the buffer flow passage 58 and the buffer area passage 57 into the solution containing chamber 24 again through the third inlet longitudinal passage 43 and the third inlet passage 46, and then closes the peristaltic pump;
17 Repeating steps 14) -17);
18 The gene sequencing program automatically executes the gene sequencing work, and after the completion, the third valve hole 65 (outlet valve) and the vacuum pump are opened, the mixed liquid is sucked from the liquid containing cavity 24 and is discharged into the waste liquid bottle sequentially through the first liquid outlet transverse channel 45, the buffer flow channel 58, the buffer area channel 57, the third inlet channel 46, the third valve longitudinal channel 39, the outlet valve pipeline 40, the first transverse outlet channel 56, the liquid outlet channel 42 and the liquid outlet 67.
Compared with the existing two-dimensional microfluidic channel microfluidic device, the microfluidic device of the embodiment can be applied to a high-flux gene detector, can be more suitable for testing requirements of high flux and high efficiency of gene detection, realizes reasonable utilization of space, and is beneficial to miniaturization development of the microfluidic device.
The embodiment of the invention also provides a gene sequencer, which comprises the micro-fluid device of any embodiment, thereby meeting the high-flux and high-efficiency gene sequencing requirement and helping to promote the further development of the gene sequencing technology.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (5)
1. A method of gene sequencing, characterized in that the method of gene sequencing is performed by a gene sequencer comprising a microfluidic device comprising a substrate provided with:
A microfluidic channel comprising a liquid inlet channel and a liquid outlet channel, both comprising a transverse channel extending in a transverse direction and a longitudinal channel extending in a longitudinal direction;
a first inlet in communication with the liquid inlet channel;
a second inlet in communication with the liquid inlet channel;
the liquid outlet is communicated with the liquid outlet flow channel and is used for discharging liquid;
Cleaning the flow channel;
The liquid outlet channel comprises a buffer channel and an outlet channel, and the outlet channel is communicated with the liquid outlet; one end of the buffer flow channel is used for being communicated with the solution cavity, and the other end of the buffer flow channel is communicated with the outlet channel; the liquid outlet channel is communicated with a third inlet, the third inlet is communicated with the buffer channel, and the outlet channel is communicated with a third valve hole; the first inlet comprises a plurality of liquid inlets, the liquid inlet channel comprises inlet channels which are respectively communicated with the liquid inlets, and the inlet channels are mutually independent and are respectively communicated with a first valve hole; the cleaning flow passage is respectively communicated with the second inlet and the liquid outlet, and a fourth valve hole is further formed in the cleaning flow passage;
The gene sequencer is provided with a pipeline for introducing reagents, a pipeline for discharging solution or air, a valve control device for opening or closing the silica gel valves at the first valve opening, the second valve opening, the third valve opening and the fourth valve opening, a pump for feeding liquid or discharging liquid, a pump for introducing air, a gene sequencing program, an automatic tightness test program, and a tightness test program, wherein the tightness test program is used for detecting the bonding tightness of a liquid feeding device and a microfluidic device of the gene sequencer; the gene sequencer performs gene sequencing by the following steps:
1) Placing the device on a gene sequencer, respectively connecting a second inlet, a third inlet and a liquid outlet with corresponding pipelines of the gene sequencer, starting an automatic tightness testing program, and automatically closing all valve ports after testing;
2) Manually adding a sample, a first reagent and a second reagent into the first inlet respectively;
3) Starting a gene sequencing program;
4) The gene sequencing program automatically controls and opens the fourth valve hole;
5) Automatically controlling the cleaning liquid to flow into the second inlet from the reagent bottle by the gene sequencing program;
6) The cleaning liquid is discharged from the second inlet through the second longitudinal channel, the second inlet channel, the third inlet channel, the fourth valve hole, the third liquid outlet transverse channel, the fourth transverse outlet channel, the first transverse outlet channel, the liquid outlet channel and the liquid outlet to a waste liquid bottle communicated with the liquid outlet;
7) The gene sequencing program automatically controls to close the fourth valve hole;
8) The gene sequencing program automatically controls and opens the first valve hole and the third valve hole, and opens the vacuum pump to suck the sample from the manual sample and the first inlet, and the sample enters the liquid containing cavity through the first inlet channel, the first longitudinal valve channel, the liquid inlet transverse channel and the liquid inlet longitudinal channel;
9) The gene sequencing program automatically controls and closes the first valve hole and the vacuum pump;
10 Automatically controlling and opening a first valve hole by a gene sequencing program, opening a vacuum pump, sucking a first reagent from a first inlet, and allowing the first reagent to enter a liquid containing cavity through a first inlet channel, a first longitudinal valve channel, a liquid inlet transverse channel and a liquid inlet longitudinal channel;
11 The gene sequencing program automatically controls and closes the first valve hole and the vacuum pump;
12 Automatically controlling and opening a first valve hole by a gene sequencing program, opening a vacuum pump, sucking a second reagent from a first inlet, and allowing the second reagent to enter a liquid containing cavity through a first inlet channel, a first longitudinal valve channel, a liquid inlet transverse channel and a liquid inlet longitudinal channel;
13 The gene sequencing program automatically controls and closes the first valve hole, the third valve hole and the vacuum pump;
14 The gene sequencing program automatically executes coverage rate test of mixed liquid in the liquid containing cavity and the tested chip;
15 If the coverage test is passed, jump to step 18);
16 If the coverage rate test is not passed, the gene sequencing program automatically opens a third valve hole and a vacuum pump, sucks the mixed liquid from the liquid containing cavity, then enters a buffer flow channel and a buffer area channel from a first liquid outlet transverse channel for temporary storage, then closes the third valve hole and the vacuum pump, opens a peristaltic pump to drive air into a third inlet, drives the mixed liquid temporarily stored in the buffer flow channel and the buffer area channel into the liquid containing cavity again through a third inlet longitudinal channel and a third inlet channel, and then closes the peristaltic pump;
17 Repeating steps 14) -17);
18 The gene sequencing program automatically executes the gene sequencing work, and after the gene sequencing program is completed, the third valve hole and the vacuum pump are opened, the mixed liquid is sucked out from the liquid containing cavity, and the mixed liquid is sequentially discharged into the waste liquid bottle through the first liquid outlet transverse channel, the buffer flow channel, the buffer area channel, the third inlet channel, the third valve longitudinal channel, the outlet valve pipeline, the first transverse outlet channel, the liquid outlet channel and the liquid outlet.
2. The method of claim 1, wherein the substrate comprises a first substrate, a second substrate, a third substrate, and a fourth substrate in a stacked and connected order, wherein:
a transverse groove is formed in the surface, facing the first base layer, of the second base layer, and the transverse runner is defined by the surface, facing the second base layer, of the first base layer and the transverse groove;
The second base layer is provided with the longitudinal flow channels, and the longitudinal flow channels extend along the stacking direction;
The third base layer is provided with a slotted hole extending along the transverse direction, and the slotted hole is correspondingly communicated with the longitudinal flow channel;
the fourth base layer is provided with a through hole which is communicated with the slotted hole of the third base layer;
The surfaces of the second base layer and the fourth base layer facing the third base layer and the slotted holes jointly enclose the transverse flow channel.
3. The method according to claim 2, wherein the first base layer, the second base layer, the third base layer and the fourth base layer are bonded by an adhesive layer, and the adhesive layer is provided with a relief notch at a position corresponding to the groove, the slot hole and the through hole.
4. The method of claim 2, wherein the microfluidic device further comprises a fifth base layer, a sixth base layer, and a chip daughter board, the fifth base layer being attached to the bottom of the fourth base layer, the sixth base layer and the fifth base layer being attached in a stack, the chip daughter board having a test chip disposed thereon, wherein:
A solution cavity is formed between the sixth base layer and the test chip, and openings for communicating the through holes of the fourth base layer are formed in the fifth base layer and the sixth base layer; the opening is communicated with the solution cavity;
the fourth base layer and the sixth base layer are provided with printed circuits and are connected and conducted through a conductive component, and one end of the conductive component is located at the upper part of the solution cavity.
5. The method of claim 4, wherein the conductive assembly comprises a first conductive post and a second conductive post, the first conductive post electrically connects the printed circuit on the sixth substrate and the fourth substrate, the second conductive post electrically connects the printed circuit on the fourth substrate and the chip daughter board, and a conductive path is formed that is capable of transferring the electrical signal in the solution chamber to the chip daughter board.
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| US11167288B2 (en) * | 2017-10-31 | 2021-11-09 | National Technology & Engineering Solutions Of Sandia, Llc | Digital microfluidic systems and methods for droplet manipulation |
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