CN108333115B - Micro-droplet detection device - Google Patents
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- CN108333115B CN108333115B CN201810172619.9A CN201810172619A CN108333115B CN 108333115 B CN108333115 B CN 108333115B CN 201810172619 A CN201810172619 A CN 201810172619A CN 108333115 B CN108333115 B CN 108333115B
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- 238000001514 detection method Methods 0.000 title claims abstract description 172
- 239000007788 liquid Substances 0.000 claims abstract description 159
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 67
- 230000003287 optical effect Effects 0.000 claims abstract description 62
- 238000001917 fluorescence detection Methods 0.000 claims abstract description 21
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000007924 injection Substances 0.000 claims abstract description 15
- 230000001105 regulatory effect Effects 0.000 claims abstract description 11
- 238000007667 floating Methods 0.000 claims description 72
- 125000006850 spacer group Chemical group 0.000 claims description 32
- 239000002699 waste material Substances 0.000 claims description 17
- 238000011084 recovery Methods 0.000 claims description 15
- 230000001276 controlling effect Effects 0.000 claims description 14
- 238000004458 analytical method Methods 0.000 claims description 10
- 238000011010 flushing procedure Methods 0.000 claims description 3
- 238000007619 statistical method Methods 0.000 claims description 3
- 239000000523 sample Substances 0.000 description 33
- 206010036618 Premenstrual syndrome Diseases 0.000 description 19
- 230000009977 dual effect Effects 0.000 description 18
- 238000000034 method Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
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- 238000000429 assembly Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 2
- 108700026220 vif Genes Proteins 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
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- 238000002073 fluorescence micrograph Methods 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/01—Arrangements or apparatus for facilitating the optical investigation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6402—Atomic fluorescence; Laser induced fluorescence
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Abstract
The invention discloses a micro-droplet detection device, relates to the technical field of micro-droplet detection, and can simultaneously detect micro-droplets in multiple indexes. The micro-droplet detection device comprises a control unit, an air path unit, a chip unit and an optical detection unit, wherein the optical detection unit comprises a double laser module, an optical processing module and a double PMT module, the control unit is respectively connected with the air path unit and the double laser module in a signal manner, and the air path unit is communicated with the chip unit; the chip unit is used for storing a plurality of liquid reagents in a classified manner, and each liquid reagent drives a plurality of discrete micro-droplets by sample injection under the action of corresponding air pressure; the gas path unit is used for providing corresponding gas pressure for each liquid reagent in the chip unit according to the gas path control signals; the double-laser module is used for emitting double-path laser according to the optical detection signal, and obtaining double-path detection light after being regulated and filtered by the optical processing module; the double PMT module is used for receiving double fluorescence detection signals after exciting micro drops by double detection light.
Description
Technical Field
The invention relates to the technical field of micro-droplet detection, in particular to a micro-droplet detection device.
Background
Droplet microfluidic technology is an important component of microfluidic technology. The liquid drop micro-fluidic technology is to send two mutually insoluble fluids, such as most common water and oil, into a micrometer-scale pipeline, and divide the water phase into micro-droplets with stable sizes and micrometer scale by the oil phase under the action of fluid mechanics, wherein each micro-droplet acts as an independent reactor, which is equivalent to a common test tube in biochemical reaction. The micro-droplet is small in volume and large in number, has the advantages of a plurality of conventional test tubes, such as high flux, low reagent consumption and low background noise, and has good industrial prospect.
Usually, one micro-droplet only comprises one target gene, so that the micro-droplet containing the specific target gene is analyzed and detected by using a CCD imaging detection technology, namely, a certain number of micro-droplet fluorescence images are acquired by using a high-speed camera, and then, single micro-droplet fluorescence in the images is automatically identified by using an image processing technology, so that a corresponding diagnosis result is obtained; with the wider and wider use of micro-droplets containing multiple target genes, the demand for realizing multi-index detection of micro-droplets containing multiple target genes increases, and it is obvious that the existing CCD imaging detection technology cannot meet the demand.
Disclosure of Invention
The invention aims to provide a micro-droplet detection device which can simultaneously detect multiple indexes of micro-droplets.
In order to achieve the above object, the present invention provides the following technical solutions:
The micro-droplet detection device comprises a control unit, a gas circuit unit, a chip unit and an optical detection unit, wherein the optical detection unit comprises a double laser module, an optical processing module and a double PMT module, the control unit is respectively connected with the gas circuit unit and the double laser module in a signal manner, and the gas circuit unit is communicated with the chip unit;
The chip unit is used for storing a plurality of liquid reagents in a classified mode, and each liquid reagent drives a plurality of discrete micro-droplets in a sample injection mode under the action of corresponding air pressure;
The gas path unit is used for providing corresponding gas pressure for each liquid reagent in the chip unit according to the gas path control signal;
The double-laser module is used for emitting double-path laser according to the optical detection signal, and the double-path detection light is obtained after the double-path laser is regulated and filtered by the light processing module;
the double PMT module is used for receiving a double fluorescence detection signal after the micro liquid drop is excited by the double detection light;
the control unit is used for sending out a gas path control signal and an optical detection signal according to the control instruction.
Preferably, the chip unit comprises a liquid storage module, a micro-droplet driving module and an EP tube assembly for storing sample reagents;
The liquid storage module comprises a liquid storage part, an EP pipe assembly part and a waste liquid recovery part, wherein the EP pipe assembly part is used for installing an EP pipe assembly in an aligned mode, the liquid storage part comprises a plurality of groups of upper floating oil liquid storage tanks and interval oil liquid storage tanks which are arranged in parallel, and the gas circuit unit is respectively communicated with liquid inlets of the upper floating oil liquid storage tanks and liquid inlets of the interval oil liquid storage tanks;
The micro-droplet driving module comprises a detection sample output part and a micro-droplet driving part, wherein the detection sample output part comprises a plurality of EP pipe liquid inlet holes and a plurality of EP pipe liquid outlet holes which are respectively communicated with each EP pipe in a corresponding manner, the EP pipe liquid inlet holes are communicated with the liquid outlets of the upper floating oil liquid storage tanks in a one-to-one correspondence manner, the EP pipe liquid outlet holes are communicated with the micro-droplet driving part in a one-to-one correspondence manner, the EP pipe liquid inlet holes are used for flushing upper floating oil, and the EP pipe liquid outlet holes are used for floating out sample reagents;
The micro-droplet driving part is also communicated with a liquid outlet of the spacer oil liquid storage groove, and is used for generating a plurality of micro-droplets by pouring sample reagents and spacer oil reagents.
Further, the micro-droplet driving part comprises a cross port, the cross port comprises a sample reagent input port and a micro-droplet output port which are oppositely arranged, and 2 spacer oil ports which are oppositely arranged, the liquid outlet hole of the EP pipe is communicated with the sample reagent input port, the liquid outlet of the spacer oil liquid storage tank is respectively communicated with the 2 spacer oil ports, and the micro-droplet output port is communicated with the waste liquid recovery part through a micro-pipeline;
the cross port is used for converging a sample reagent and a spacer oil reagent and generating a plurality of mutually discrete micro-droplets under the cooperation of corresponding air pressure.
Preferably, the micro-droplet driving part further comprises a detection window arranged between the micro-droplet output port and the waste liquid recovery part, wherein the detection window is used for providing a positioning mark and assisting the optical detection unit to position and detect the micro-droplet.
Preferably, the air path unit comprises an air supply module, an air cavity module and an air pressure adjusting module, wherein the air supply module is communicated with the air pressure adjusting module through the air cavity module, and the air pressure adjusting module is respectively communicated with each upper oil slick liquid storage tank and each spacer oil liquid storage tank;
the air supply module is used for supplying air to the air cavity module according to the air supply signal;
the air cavity module is used for compressing the air supply and adjusting injection air pressure according to an air pressure adjusting signal;
The air pressure adjusting module is used for correspondingly controlling the air supply conduction state of the oil floating storage tank according to the oil floating electromagnetic on-off signal and correspondingly controlling the air supply conduction state of the oil separating storage tank according to the oil separating electromagnetic on-off signal;
The gas circuit control signal comprises the gas supply signal, the gas pressure adjusting signal, the oil floating electromagnetic on-off signal and the interval oil electromagnetic on-off signal.
Further, the air cavity module comprises a first air cavity, a first air pressure sensor, a second air cavity and a second air pressure sensor, the air supply module is communicated with the first air cavity through a first air path pipeline and is communicated with the second air cavity through a second air path pipeline, the first air cavity and the second air cavity are respectively communicated with the air pressure adjusting module, wherein the first air pressure sensor is arranged on the first air path pipeline, and the second air pressure sensor is arranged on the second air path pipeline;
The first air pressure sensor is used for sensing the current air pressure value of the first air path pipeline and feeding back a first air pressure value signal;
The second air pressure sensor is used for sensing the current air pressure value of the second air path pipeline and feeding back a second air pressure value signal.
Preferably, the air pressure adjusting module comprises a plurality of oil floating electromagnetic valves and a plurality of oil spacing electromagnetic valves, the first air cavities are communicated with the oil floating liquid storage tanks in a one-to-one correspondence manner through the oil floating electromagnetic valves, and the second air cavities are communicated with the oil spacing liquid storage tanks in a one-to-one correspondence manner through the oil spacing electromagnetic valves;
the upper oil floating electromagnetic valve is used for correspondingly controlling the conduction state of the upper oil floating electromagnetic valve according to the on-off signal of the upper oil floating electromagnetic valve, and when the upper oil floating electromagnetic valve is in the conduction state, the injection air pressure is continuously injected into the upper oil floating liquid storage tank;
the oil separating electromagnetic valve is used for correspondingly controlling the conduction state of the oil separating electromagnetic valve according to the on-off signal of the oil separating electromagnetic valve, and when the oil separating electromagnetic valve is in the conduction state, the injection air pressure is continuously injected into the oil separating liquid storage tank.
Preferably, the optical detection unit further comprises a positioning module and a detection lens;
The detection lens is used for emitting the two-way detection light to the micro-pipeline;
the positioning module is used for locking a window to be detected from the detection window according to a positioning signal, carrying the chip unit to move to a specific position according to a positioning mark in the window to be detected, and completing the positioning of the micro-pipeline in the window to be detected by the detection lens;
the control unit is also used for sending out the positioning signal according to a control instruction.
Preferably, the control unit comprises a gas circuit control module, a detection control module and a command output module, wherein the command output module is respectively connected with the gas circuit control module and the detection control module, the gas circuit control module is respectively connected with the gas supply module, the first gas cavity, the second gas cavity, the first gas pressure sensor, the second gas pressure sensor, the oil floating electromagnetic valve and the oil interval electromagnetic valve in a signal manner, and the detection control module is respectively connected with the positioning module, the double laser module and the double PMT module in a signal manner;
the gas circuit control module is used for correspondingly outputting a gas supply signal, a gas pressure adjusting signal, an oil floating electromagnetic on-off signal, a spacer oil electromagnetic on-off signal and receiving a first gas pressure value signal and a second gas pressure value signal which are fed back according to a gas circuit control instruction;
The detection control module is used for outputting a positioning signal and an optical detection signal according to the detection control instruction;
The instruction output module is used for adjusting the output of the air circuit control instruction according to the user instruction, the first air pressure value signal and the second air pressure value signal, so that a plurality of mutually discrete micro-droplets are generated through corresponding cross ports; and
And the optical detection module is used for outputting a detection control instruction according to the user instruction, so that the positioning module can be used for carrying out optical detection on the micro liquid drops in the micro pipeline after the positioning is finished.
Preferably, the optical detection unit further comprises a fluorescence signal analysis module connected with the output end of the double PMT module, and the fluorescence signal analysis module is used for obtaining the fluorescence detection result according to the double fluorescence detection signal through statistical analysis.
Compared with the prior art, the micro-droplet detection device provided by the invention has the following beneficial effects:
the micro-droplet detection device provided by the invention consists of a control unit, an air path unit, a chip unit and an optical detection unit, wherein the optical detection unit comprises a double laser module, an optical processing module and a PMT module; the control unit is respectively connected with the gas path unit and the double laser module in a signal manner, the gas path unit is correspondingly communicated with the chip unit, specifically, liquid reagents required for detection are firstly classified and stored in the chip unit, the gas path unit correspondingly provides air pressure for each liquid reagent storage area in the chip unit after receiving a gas path control signal sent by the control unit, so that the liquid reagents are respectively sampled under the action of the corresponding air pressure to generate a plurality of discrete micro-droplets, at the moment, the control unit sends out optical detection signals, the double laser module emits double-path laser according to the optical detection signals, and the double-path laser is regulated and filtered by the optical path processing module to obtain double-path detection light, so that the plurality of mutually discrete micro-droplets sequentially pass through the irradiation area of the double-path detection light, simultaneously, two PMT probes in the double PMT module correspondingly receive each path detection light to form double fluorescent signals, fluorescent detection results are obtained through analysis of the double fluorescent signals, and multi-index detection of the micro-droplets is further realized. In addition, by controlling the air inlet rate of the air path unit, the accurate control of the fluorescence detection rate of the micro liquid drops can be realized, so that the fluorescence signal detection rate of the micro liquid drops is fast and controllable.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention and do not constitute a limitation on the invention. In the drawings:
FIG. 1 is a schematic diagram showing the connection of a micro-droplet detection device according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of the chip unit in FIG. 1;
FIG. 3 is a top view of the chip unit of FIG. 1;
FIG. 4 is a cross-sectional view of the chip unit of FIG. 1;
FIG. 5 is a schematic diagram of the connection of the air circuit unit of FIG. 1 to a chip unit;
FIG. 6 is a schematic diagram showing the connection of the optical detection unit in FIG. 1;
fig. 7 is a schematic diagram showing a state in which the optical detection unit performs fluorescence detection on the microdroplet.
Reference numerals:
1-a control unit and 2-a gas circuit unit;
3-chip units; 4-an optical detection unit;
11-an instruction output module and 12-an air path control module;
13-a detection control module, 21-a gas supply module;
22-an air cavity module, 23-an air pressure regulating module;
221-a first air pressure sensor, 222-a first air cavity;
223-a second air pressure sensor, 224-a second air chamber;
231-floating oil solenoid valve, 232-interval oil solenoid valve;
31-a liquid storage module, 32-a micro-droplet driving module;
33-EP tube assembly, 311-reservoir
312-EP tube fitting portion, 313-waste liquid recovery portion;
3111-floating oil reservoirs, 3112-spacer oil reservoirs;
321-a detection sample output part, 322-a micro-droplet driving part;
3211-EP pipe liquid inlet holes, 3212-EP pipe liquid outlet holes;
3221-cross port, 3222-detection window;
331-EP tube, 41-dual laser module;
42-an optical processing module, 43-a dual PMT module;
44-detection lens.
Detailed Description
In order to make the above objects, features and advantages of the present invention more comprehensible, the following description of the embodiments accompanied with the accompanying drawings will be given in detail. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1-2, the micro-droplet detection device provided in this embodiment includes a control unit 1, an air path unit 2, a chip unit 3 and an optical detection unit 4, where the optical detection unit 4 includes a dual laser module 41, an optical processing module 42 and a dual PMT module 43, the control unit 1 is respectively connected with the air path unit 2 and the dual laser module 41 by signals, and the air path unit 2 is communicated with the chip unit 3;
The chip unit 3 is used for storing a plurality of liquid reagents in a classified manner, and each liquid reagent drives a plurality of discrete micro-droplets by sample injection under the action of corresponding air pressure;
the gas path unit 2 is used for providing corresponding gas pressure for each liquid reagent in the chip unit 3 according to the gas path control signal;
the dual laser module 41 is used for emitting dual-path laser according to the optical detection signal, and the dual-path detection light is obtained after the dual-path laser is regulated and filtered by the light processing module 42;
The double PMT module 43 is configured to receive a double fluorescence detection signal after exciting the micro droplet with the double detection light;
the control unit 1 is used for sending out gas path control signals and optical detection signals according to control instructions.
In the micro-droplet detection device provided in this embodiment, the micro-droplet detection device is composed of four parts including a control unit 1, a gas circuit unit 2, a chip unit 3 and an optical detection unit 4, wherein the optical detection unit 4 includes a dual laser module 41, an optical processing module 42 and a dual PMT module 43; the control unit 1 in this embodiment is respectively connected with the gas circuit unit 2 and the dual laser module 41 in a signal manner, the gas circuit unit 2 is correspondingly communicated with the chip unit 3, specifically, the liquid reagents required for detection are firstly classified and stored in the chip unit 3, the gas circuit unit 2 correspondingly provides air pressure for each liquid reagent storage area in the chip unit 3 after receiving the gas circuit control signal sent by the control unit 1, so that the liquid reagents are respectively sampled under the action of the corresponding air pressure to generate a plurality of discrete micro-droplets, at this time, the control unit 1 sends out an optical detection signal, the dual laser module 41 emits dual-path laser according to the optical detection signal, and the dual laser module 42 adjusts and filters the dual-path detection light to obtain the dual-path detection light, so that the plurality of mutually discrete micro-droplets sequentially pass through the irradiation area of the dual-path detection light, and simultaneously, two PMT probes in the dual PMT module 43 correspondingly receive each path of detection light to form dual fluorescent signals, and obtain fluorescent detection results through analysis of the dual fluorescent signals, thereby realizing multi-index detection of the micro-droplets. In addition, by controlling the air inlet rhythm of the air circuit unit 2, the accurate control of the fluorescence detection rate of the micro liquid drops can be realized, so that the fluorescence signal detection rate of the micro liquid drops is fast and controllable.
Referring specifically to fig. 2-4, the chip unit 3 in this embodiment includes a reservoir module 31, a micro-droplet driving module 32, and an EP tube assembly 33 for storing sample reagents; the liquid storage module 31 comprises a liquid storage part 311, an EP pipe assembly part 312 and a waste liquid recovery part 313, wherein the EP pipe assembly part 312 is used for installing the EP pipe assembly 33 in an aligned manner, the liquid storage part 311 comprises a plurality of groups of upper floating oil liquid storage tanks 3111 and interval oil liquid storage tanks 3112 which are arranged in parallel, and the gas circuit unit 2 is respectively communicated with liquid inlets of the upper floating oil liquid storage tanks 3111 and liquid inlets of the interval oil liquid storage tanks 3112; the micro-droplet driving module 32 comprises a detection sample output portion 321 and a micro-droplet driving portion 322, wherein the detection sample output portion 321 comprises a plurality of EP tube liquid inlet holes 3211 and a plurality of EP tube liquid outlet holes 3212 which are respectively communicated with the EP tubes 331 in a corresponding manner, the EP tube liquid inlet holes 3211 are communicated with the liquid outlets of the upper floating oil liquid storage tank 3111 in a one-to-one correspondence manner, the EP tube liquid outlet holes 3212 are communicated with the micro-droplet driving portion 322 in a one-to-one correspondence manner, the EP tube liquid inlet holes 3211 are used for flushing up floating oil, and the EP tube liquid outlet holes 3212 are used for floating out sample reagents; the micro-droplet driving part 322 is also communicated with the liquid outlet of the spacer oil liquid tank 3112, and the micro-droplet driving part 322 is used for generating a plurality of micro-droplets by pouring sample reagent and spacer oil reagent.
As can be appreciated, referring to fig. 3, the micro-droplet driving part 322 includes a cross port 3221, specifically, the cross port 3221 includes a sample reagent input port and a micro-droplet output port which are disposed opposite to each other, and 2 spacer oil ports disposed opposite to each other, the EP tube outlet 3212 is communicated with the sample reagent input port, the outlet of the spacer oil reservoir 3112 is respectively communicated with the 2 spacer oil ports, and the micro-droplet output port is communicated with the waste liquid recovery part 313 through a micro-pipe; the cross port 3221 is used for converging the sample reagent and the spacer oil reagent, and generating a plurality of mutually discrete micro droplets under the cooperation of corresponding air pressures. In addition, the micro-droplet driving section 322 in the above embodiment further includes a detection window 3222 provided between the micro-droplet output port and the waste liquid recovery section 313, the detection window 3222 being for providing a positioning mark, and assisting the optical detection unit 4 in positioning detection of the micro-droplet.
In specific implementation, the number of the upper oil-floating liquid storage tanks 3111 and the number of the interval oil liquid storage tanks 3112 in the liquid storage portion 311 are in one-to-one correspondence, and are respectively used for adding an upper oil-floating reagent in each upper oil-floating liquid storage tank 3111 and adding an upper oil-floating reagent in each interval oil liquid storage tank 3112, wherein the EP tube assemblies 33 include EP tubes 331 with the same number as the upper oil-floating liquid storage tanks 3111, and because the EP tube assemblies 33 are of an integral sealing structure storing sample reagents, during the assembly process, the EP tube assemblies 331 need to be penetrated through the EP tube 331 in each EP tube assembly 33 by using the EP tube cap puncture in the EP tube assembly portion 312 to complete the clamping alignment; next, the air supply unit is respectively connected to each floating oil storage tank 3111 and each spacer oil storage tank 3112, and in order to ensure better air tightness, an air-tight pad corresponding to each storage tank is usually provided on the liquid storage portion 311; in addition, the detection sample output portion 321 is composed of a plurality of paired EP tube liquid inlet holes 3211 and EP tube liquid outlet holes 3212, and when the EP tube assembly 33 is assembled, the liquid outlet of the oil-floating liquid storage tank is communicated with the EP tube liquid inlet holes 3211 through a micro-pipe, so that the oil-floating liquid can be flushed into the micro-pipe from the liquid outlet of the oil-floating liquid storage tank 3111 under the action of air pressure, and enter the EP tube 331 from the EP tube liquid inlet holes 3211, and the sample reagent can always float on the oil-floating liquid and flow out from the EP tube liquid outlet holes 3212 because the density of the sample reagent is smaller than that of the oil-floating reagent.
Because the sample reagent input port of the cross port 3221 is communicated with the sample reagent output port 3212 through one micro-channel, the liquid output port of the oil-separating liquid tank 3112 is respectively communicated with 2 oil-separating ports through two micro-channels, so that the air-channel unit 2 is used for respectively supplying air to the oil-separating liquid tank 3111 and the oil-separating liquid tank 3112, the corresponding air pressure can respectively press the sample reagent and the oil-separating reagent to flush the cross port 3221 along the micro-channels, when the two incompatible reagents are combined in the cross port 3221, the oil-phase reagents at the two ends and the water-phase reagent in the middle are cut into discrete micro-droplets in a water-in-oil mode under the matching action of the corresponding air pressure and the liquid surface tension difference, and the discrete micro-droplets flow to the waste liquid recovery 313 in sequence, and in the process of flowing to the waste liquid recovery 313, the micro-droplets communicated with the output port and the waste liquid recovery 313 penetrate through the detection window 3222, so that the fluorescence detection of the micro-droplets can be realized through the detection window 3222 by the optical detection unit 4, and the fluorescence detection result is obtained.
Preferably, the micro-pipe in the liquid storage module 31 is a first micro-pipe, the micro-pipe of the micro-droplet driving module 32 is a second micro-pipe, and the altitude of the second micro-pipe is greater than that of the first micro-pipe, so that the situation that the sample reagent accidentally flows out due to the fact that the floating oil liquid storage tank 3111 erroneously flows into the EP tube 331 can be avoided under the condition that the liquid storage module is not inflated.
As can be seen from the above implementation process, in this embodiment, through the upper oil floating liquid tank 3111 and the spacer oil liquid tank 3112, the EP tube 331, the cross port 3221, the detection window 3222 and the waste liquid recovery portion 313, the two liquid tanks are used to store the upper oil floating reagent and the spacer oil reagent, the air supply of the upper oil floating test liquid tank 3111 and the spacer oil liquid tank 3112 corresponding to the air path unit 2 is performed, the sample injection process of the sample reagent in the EP tube 331 and the spacer oil in the spacer oil liquid tank 3112 in the cross port 3221 is controlled respectively, so that the spacer oil reagent at two ends and the intermediate upper oil floating reagent cooperate with corresponding air pressure in the cross port 3221 to form uniform and continuous stable discrete micro-droplets, through the setting of the detection window 3222, the positioning mark provided by the detection window 3222 can be utilized, the auxiliary optical detection unit 4 accurately positions the micro-channels in the detection window 3222, so as to realize the observation and analysis of the discrete micro-droplet by the optical detection unit 4, and the experimenter can grasp the fluorescence signal of the micro-droplet in real time.
It should be emphasized that, since the air supply rhythm of the air supply module 21 is precisely adjustable, the rate of discrete micro-droplet generation can be adjusted by the air supply rhythm, so as to realize rapid and controllable micro-droplet detection rate; in addition, since the reservoir, the EP tube 331, the cross port 3221 and the detection window 3222 are arranged in parallel, a plurality of groups of discrete micro droplets can be generated in parallel by using the chip unit 3 provided in the present embodiment, so as to realize parallel detection of the discrete micro droplets.
Further, since the EP tube assembly 33 is an integral sealing structure for storing the sample reagent, compared with the conventional open EP tube 331, the integral sealing EP tube assembly 33 can be hermetically connected with the EP tube assembly 312, so that the possibility of cross contamination of the sample reagent is reduced, and in the same way, the waste liquid recovery portion 313 is also an integral sealing structure, so that the detected waste liquid can be recovered in a concentrated manner, and the waste liquid pollution is prevented.
Specifically, referring to fig. 5, the air path unit 2 in the above embodiment includes an air supply module 21, an air cavity module 22, and an air pressure adjusting module 23, where the air supply module 21 is communicated with the air pressure adjusting module 23 through the air cavity module 22, and the air pressure adjusting module 23 is respectively communicated with each oil-up liquid storage tank 3111 and each oil-separating liquid storage tank 3112; the air supply module 21 is used for supplying air to the air cavity module 22 according to the air supply signal; the air cavity module 22 is used for compressing air supply and adjusting injection air pressure according to the air pressure adjusting signal; the air pressure adjusting module 23 is used for correspondingly controlling the air supply conducting state of the oil floating liquid storage tank 3111 according to the oil floating electromagnetic on-off signal, and correspondingly controlling the air supply conducting state of the oil separating liquid storage tank 3112 according to the oil separating electromagnetic on-off signal; the gas circuit control signal comprises a gas supply signal, a gas pressure adjusting signal, an oil floating electromagnetic on-off signal and a spacer oil electromagnetic on-off signal.
The air cavity module 22 comprises a first air cavity 222, a first air pressure sensor 221, a second air cavity 224 and a second air pressure sensor 223, the air supply module 21 is communicated with the first air cavity 222 through a first air path pipeline and is communicated with the second air cavity 224 through a second air path pipeline, the first air cavity 222 and the second air cavity 224 are respectively communicated with the air pressure regulating module 23, wherein the first air pressure sensor 221 is arranged on the first air path pipeline, and the second air pressure sensor 223 is arranged on the second air path pipeline; the first air pressure sensor 221 is configured to sense a current air pressure value of the first air path pipe, and feed back a first air pressure value signal; the second air pressure sensor 223 is used for sensing the current air pressure value of the second air path pipeline and feeding back a second air pressure value signal.
Preferably, referring to fig. 2 and 5, the air pressure adjusting module 23 in the above embodiment includes a plurality of oil floating solenoid valves 231 and a plurality of oil separating solenoid valves 232, the first air chambers 222 are in one-to-one correspondence with the oil floating storage tanks 3111 through the oil floating solenoid valves 231, and the second air chambers 224 are in one-to-one correspondence with the oil separating storage tanks 3112 through the oil separating solenoid valves 232; the upper oil float solenoid valve 231 is used for correspondingly controlling the conduction state of the upper oil float solenoid valve 231 according to the on-off signal of the upper oil float solenoid valve 231, and when the upper oil float solenoid valve 231 is in the conduction state, the injection air pressure is continuously injected into the upper oil float liquid storage tank 3111; the spacer solenoid valve 232 is used for controlling the conduction state of the spacer solenoid valve 232 according to the on-off signal of the spacer solenoid valve 232, and when the spacer solenoid valve 232 is in the conduction state, the injection air pressure is continuously injected into the spacer reservoir 3112.
In particular, when the air supply module 21 includes an air pump and an air collecting bottle, the air collecting bottle is used for storing air supply generated by the air pump to form an air pressure source, the air pressure released by the air collecting bottle after receiving the air supply signal is correspondingly stored in the first air cavity 222 and the second air cavity 224 through the air channel pipeline, meanwhile, the current air pressure value of the first air channel pipeline is monitored in real time by using the first air pressure sensor 221 arranged on the first air channel pipeline, similarly, the current air pressure value of the second air channel pipeline is monitored in real time by using the second air pressure sensor 223 arranged on the second air channel pipeline, and the air pressure value signal is fed back to the control unit 1, so that the control unit 1 correspondingly adjusts the air pressure injected by the first air cavity 222 and the second air cavity 224 according to the fed back air pressure value signal, and meanwhile, the conduction states of the floating oil solenoid valve 231 and the spacer solenoid valve 232 are controlled by using the control unit 1 adaptively, so that the floating oil reagents and the spacer oil reagents in the floating oil reservoirs 3111 and the spacer fluid reservoirs 3112 can be continuously and stably injected under the cooperation of the corresponding air pressures, and the discrete and stable optical detection units 4 are formed in the cross ports 3221, and the discrete and stable fluorescent detection units are formed.
As can be seen from the above specific implementation process, in this embodiment, the gas collecting bottle is used to provide the primary air pressure, then the first air pressure sensor 221/the second air pressure sensor 223 is used to feed back the air pressure value signal of the current corresponding air channel pipeline in real time, the control unit 1 adjusts the injection air pressure of the air cavity after receiving the air pressure value signal to form the secondary air pressure, so that the precise air pressure control is performed on the floating oil reagent and the oil separation reagent in the manner of secondary air pressure adjustment, and it is ensured that the reagent can form the discrete micro-droplets meeting the requirements at the cross port 3221.
Further, referring to fig. 6 to 7, the optical detection unit 4 in the above embodiment further includes a positioning module and a detection lens 44; wherein,
The detection lens 44 is used for emitting two-way detection light to the micro-channel;
The positioning module is used for locking a window to be detected from the detection window 3222 according to the positioning signal, and carrying the chip unit 3 to move to a specific position according to the positioning mark in the window to be detected, so as to complete the positioning of the micro-pipeline in the window to be detected by the detection lens 44;
The control unit 1 is also used for sending out positioning signals according to control instructions.
In the embodiment, the accuracy of positioning the micro-channels in the optical detection unit 4 and the detection window 3222 is a precondition of ensuring the reliability of the fluorescence detection result, and because the optical path of the optical detection unit 4 is complex and inconvenient to move, in order to meet the requirement that the optical detection unit 4 can accurately position the micro-channels in each detection window 3222 in sequence, the embodiment adopts the fixation of the optical detection unit 4 and the matching of the chip unit 3 with a displacement mode to realize the requirement of accurate positioning, in particular, the positioning module locks a window to be detected from a plurality of detection windows 3222 according to positioning signals, and carries the chip unit 3 to move to a specific position according to positioning marks in the window to be detected, wherein the specific position refers to the position of the micro-channels in the window to be detected, which can be accurately irradiated by the double-path detection light emitted by the detection lens 44 after horizontally moving the chip unit 3, namely, the micro-channels in the window to be detected are horizontally moved to the position of the micro-channels in the window to be detected under the detection lens 44. It should be noted that the positioning module is a sliding guide rail with a positioning device.
Illustratively, the dual laser module 41 includes 473nm and 532nm lasers, the light processing module 42 includes an exit photon module and a reflection photon module, wherein the exit photon module includes a filter, a mirror, and a dichroic mirror that are sequentially set, the reflection photon module includes a dichroic mirror, a convex lens, a dichroic mirror, and a color filter that are sequentially set, the dual PMT module 43 includes 2 PMTs, and the detection lens 44 module is a 20-fold micro objective lens. In the embodiment, the setting mode of double lasers is adopted to perform double-positive detection on the micro-droplets, so that multi-index detection on the micro-droplets is realized.
It should be noted that, the optical detection unit 4 in this embodiment further includes a fluorescence signal analysis module connected to the output end of the dual PMT module 43, where the fluorescence signal analysis module is configured to obtain the fluorescence detection result according to the fluorescence detection signal by statistical analysis.
In specific implementation, the laser emitted by the 473nm laser is adjusted and filtered by the light processing module 42 to obtain a first detection light, when the first detection light excites the microdrops (positive microdrops) containing the target genes, a first fluorescence detection signal is formed, similarly, the laser emitted by the 532nm laser is adjusted and filtered by the light processing module 42 to obtain a second detection light, when the second detection light excites the microdrops (positive microdrops) containing the other target genes, a second fluorescence detection signal is formed, the first fluorescence detection signal/the second fluorescence detection signal are correspondingly received through the first PMT/the second PMT, and finally, the fluorescence signal analysis module is utilized to obtain the initial copy number or the concentration of the target molecules according to the Poisson distribution principle and the number of the positive microdrops and the proportion of the positive microdrops to the total microdrops, so as to obtain the fluorescence detection result.
Preferably, referring to fig. 1, the control unit 1 in the above embodiment includes an air path control module 12, a detection control module 13 and an instruction output module 11, where the instruction output module 11 is connected to the air path control module 12 and the detection control module 13 respectively, the air path control module 12 is connected to the air supply module 21, the first air cavity 222, the second air cavity 224, the first air pressure sensor 221, the second air pressure sensor 223, the oil floating electromagnetic valve 231 and the oil separating electromagnetic valve 232 respectively, and the detection control module 13 is connected to the positioning module, the dual laser module 41 and the dual PMT module 43 respectively;
the air circuit control module 12 is configured to correspondingly output an air supply signal, an air pressure adjustment signal, an oil floating electromagnetic on-off signal, an oil interval electromagnetic on-off signal, and receive a first air pressure value signal and a second air pressure value signal that are fed back according to an air circuit control instruction;
The detection control module 13 is used for outputting a positioning signal and an optical detection signal according to the detection control instruction;
the instruction output module 11 is configured to adjust output of the air path control instruction according to the user instruction, the first air pressure value signal, and the second air pressure value signal, so that a plurality of mutually discrete micro droplets are generated through the corresponding cross ports 3221; and
And the optical detection module is used for outputting a detection control instruction according to the user instruction, so that the positioning module can be used for carrying out optical detection on the micro liquid drops in the micro pipeline after the positioning is finished.
Those skilled in the art will appreciate that implementing all or part of the above-described methods in accordance with the embodiments may be accomplished by way of a computer program stored on a computer readable storage medium, which when executed may comprise the steps of the embodiments of the methods described above. The storage medium may be a magnetic disk, an optical disk, a Read-Only Memory (ROM), a random-access Memory (Random Access Memory, RAM), or the like.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (6)
1. The micro-droplet detection device is characterized by comprising a control unit, an air path unit, a chip unit and an optical detection unit, wherein the optical detection unit comprises a double laser module, an optical processing module, a double PMT module and a fluorescent signal analysis module connected with the output end of the double PMT module, the control unit is respectively connected with the air path unit and the double laser module in a signal manner, and the air path unit is communicated with the chip unit;
The chip unit is used for storing a plurality of liquid reagents in a classified mode, and each liquid reagent drives a plurality of discrete micro-droplets by sample injection under the action of corresponding air pressure;
The gas path unit is used for providing corresponding gas pressure for each liquid reagent in the chip unit according to the gas path control signal;
The double-laser module is used for emitting double-path laser according to the optical detection signal, and the double-path detection light is obtained after the double-path laser is regulated and filtered by the light processing module;
the double PMT module is used for receiving a double fluorescence detection signal after the micro liquid drop is excited by the double detection light;
the control unit is used for sending out a gas path control signal and an optical detection signal according to the control instruction;
the fluorescence signal analysis module is used for obtaining a fluorescence detection result according to the double fluorescence detection signals through statistical analysis;
Wherein the chip unit comprises a liquid storage module, a micro-droplet driving module and an EP tube assembly for storing sample reagents;
The liquid storage module comprises a liquid storage part, an EP pipe assembly part and a waste liquid recovery part, wherein the EP pipe assembly part is used for installing an EP pipe assembly in an aligned mode, the liquid storage part comprises a plurality of groups of upper floating oil liquid storage tanks and interval oil liquid storage tanks which are arranged in parallel, and the gas circuit unit is respectively communicated with liquid inlets of the upper floating oil liquid storage tanks and liquid inlets of the interval oil liquid storage tanks;
The micro-droplet driving module comprises a detection sample output part and a micro-droplet driving part, wherein the detection sample output part comprises a plurality of EP pipe liquid inlet holes and a plurality of EP pipe liquid outlet holes which are respectively communicated with each EP pipe in a corresponding manner, the EP pipe liquid inlet holes are communicated with the liquid outlets of the floating oil storage tanks in a one-to-one correspondence manner, the EP pipe liquid outlet holes are communicated with the micro-droplet driving part in a one-to-one correspondence manner, the EP pipe liquid inlet holes are used for flushing floating oil, and the EP pipe liquid outlet holes are used for floating sample reagents;
The micro-droplet driving part comprises a cross port, the cross port comprises a sample reagent input port and a micro-droplet output port which are oppositely arranged, and 2 interval oil ports which are oppositely arranged, the liquid outlet hole of the EP pipe is communicated with the sample reagent input port, the liquid outlet of the interval oil liquid storage tank is respectively communicated with the 2 interval oil ports, and the micro-droplet output port is communicated with the waste liquid recovery part through a micro-pipeline; the cross port is used for converging a sample reagent and a spacer oil reagent and generating a plurality of mutually discrete micro-droplets under the cooperation of corresponding air pressure;
The micro-droplet driving part further comprises a detection window arranged between the micro-droplet output port and the waste liquid recovery part, wherein the detection window is used for providing a positioning mark and assisting the optical detection unit to position and detect the micro-droplet.
2. The micro-droplet detection device according to claim 1, wherein the gas path unit comprises a gas supply module, a gas cavity module and a gas pressure regulating module, the gas supply module is communicated with the gas pressure regulating module through the gas cavity module, and the gas pressure regulating module is respectively communicated with each floating oil liquid storage tank and each interval oil liquid storage tank;
the air supply module is used for supplying air to the air cavity module according to the air supply signal;
the air cavity module is used for compressing the air supply and adjusting injection air pressure according to an air pressure adjusting signal;
The air pressure adjusting module is used for correspondingly controlling the air supply conduction state of the oil floating storage tank according to the oil floating electromagnetic on-off signal and correspondingly controlling the air supply conduction state of the oil separating storage tank according to the oil separating electromagnetic on-off signal;
The gas circuit control signal comprises the gas supply signal, the gas pressure adjusting signal, the oil floating electromagnetic on-off signal and the interval oil electromagnetic on-off signal.
3. The micro-droplet detection device according to claim 2, wherein the air cavity module comprises a first air cavity, a first air pressure sensor, a second air cavity and a second air pressure sensor, the air supply module is communicated with the first air cavity through a first air path pipeline and is communicated with the second air cavity through a second air path pipeline, the first air cavity and the second air cavity are respectively communicated with the air pressure regulating module, wherein the first air pressure sensor is arranged on the first air path pipeline, and the second air pressure sensor is arranged on the second air path pipeline;
The first air pressure sensor is used for sensing the current air pressure value of the first air path pipeline and feeding back a first air pressure value signal;
The second air pressure sensor is used for sensing the current air pressure value of the second air path pipeline and feeding back a second air pressure value signal.
4. The micro-droplet detection device according to claim 3, wherein the air pressure adjusting module comprises a plurality of oil floating electromagnetic valves and a plurality of oil spacing electromagnetic valves, the first air cavities are communicated with the oil floating liquid storage tanks in a one-to-one correspondence through the oil floating electromagnetic valves, and the second air cavities are communicated with the oil spacing liquid storage tanks in a one-to-one correspondence through the oil spacing electromagnetic valves;
the upper oil floating electromagnetic valve is used for correspondingly controlling the conduction state of the upper oil floating electromagnetic valve according to the on-off signal of the upper oil floating electromagnetic valve, and when the upper oil floating electromagnetic valve is in the conduction state, the injection air pressure is continuously injected into the upper oil floating liquid storage tank;
the oil separating electromagnetic valve is used for correspondingly controlling the conduction state of the oil separating electromagnetic valve according to the on-off signal of the oil separating electromagnetic valve, and when the oil separating electromagnetic valve is in the conduction state, the injection air pressure is continuously injected into the oil separating liquid storage tank.
5. The micro-droplet detection apparatus according to claim 4, wherein the optical detection unit further comprises a positioning module and a detection lens;
The detection lens is used for emitting the two-way detection light to the micro-pipeline;
the positioning module is used for locking a window to be detected from the detection window according to a positioning signal, carrying the chip unit to move to a specific position according to a positioning mark in the window to be detected, and completing the positioning of the micro-pipeline in the window to be detected by the detection lens;
the control unit is also used for sending out the positioning signal according to a control instruction.
6. The micro-droplet detection device according to claim 5, wherein the control unit comprises a gas path control module, a detection control module and a command output module, the command output module is respectively connected with the gas path control module and the detection control module, and the gas path control module is respectively connected with the gas supply module, the first gas chamber, the second gas chamber, the first gas pressure sensor, the second gas pressure sensor, the oil floating electromagnetic valve and the oil interval electromagnetic valve in a signal manner; the detection control module is respectively connected with the positioning module, the double laser module and the double PMT module in a signal way;
the gas circuit control module is used for correspondingly outputting a gas supply signal, a gas pressure adjusting signal, an oil floating electromagnetic on-off signal, a spacer oil electromagnetic on-off signal and receiving a first gas pressure value signal and a second gas pressure value signal which are fed back according to a gas circuit control instruction;
The detection control module is used for outputting a positioning signal and an optical detection signal according to the detection control instruction;
The instruction output module is used for adjusting the output of the air circuit control instruction according to the user instruction, the first air pressure value signal and the second air pressure value signal, so that a plurality of mutually discrete micro-droplets are emitted through corresponding cross ports; and
And the optical detection module is used for outputting a detection control instruction according to the user instruction, so that the positioning module can be used for carrying out optical detection on the micro liquid drops in the micro pipeline after the positioning is finished.
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| CN111044819A (en) * | 2019-12-13 | 2020-04-21 | 歌尔股份有限公司 | Early warning system and method for tiny droplet release device |
| CN114887674B (en) * | 2022-04-26 | 2024-03-08 | 北京百迈客生物科技有限公司 | Micro-droplet generation device |
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