CN107297334A - Cell sorting device and method based on micro spark cavitation - Google Patents
Cell sorting device and method based on micro spark cavitation Download PDFInfo
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- CN107297334A CN107297334A CN201710400821.8A CN201710400821A CN107297334A CN 107297334 A CN107297334 A CN 107297334A CN 201710400821 A CN201710400821 A CN 201710400821A CN 107297334 A CN107297334 A CN 107297334A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B07—SEPARATING SOLIDS FROM SOLIDS; SORTING
- B07C—POSTAL SORTING; SORTING INDIVIDUAL ARTICLES, OR BULK MATERIAL FIT TO BE SORTED PIECE-MEAL, e.g. BY PICKING
- B07C3/00—Sorting according to destination
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B07—SEPARATING SOLIDS FROM SOLIDS; SORTING
- B07C—POSTAL SORTING; SORTING INDIVIDUAL ARTICLES, OR BULK MATERIAL FIT TO BE SORTED PIECE-MEAL, e.g. BY PICKING
- B07C3/00—Sorting according to destination
- B07C3/02—Apparatus characterised by the means used for distribution
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B07—SEPARATING SOLIDS FROM SOLIDS; SORTING
- B07C—POSTAL SORTING; SORTING INDIVIDUAL ARTICLES, OR BULK MATERIAL FIT TO BE SORTED PIECE-MEAL, e.g. BY PICKING
- B07C3/00—Sorting according to destination
- B07C3/10—Apparatus characterised by the means used for detection ofthe destination
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Abstract
The invention discloses the cell sorting system based on micro spark cavitation and the method for carrying out cell sorting.The cell sorting system includes：Fluidic device, the fluidic device has liquid flow inlet and multiple sortings outlet；And cell sorting device, the cell sorting device include sorting electrode pair, the sorting electrode pair be arranged on the liquid flow inlet and it is multiple it is described sorting outlet between, the electrode pair be configured to using pulse voltage produce sorting power.Thus, the volume of the cell sorting system reduces, and security is improved, and high speed, high flux, high-precision unicellular sorting can be achieved.
Description
Technical field
The present invention relates to analysis technical field, in particular it relates to cell sorting system and the method for carrying out cell sorting,
More particularly, to the micro spark cavitation method for separating for flow cytometer.
Background technology
Flow cytometer can be to the biophysics and biochemistry of each cell (or biological particle) in cell colony
Information is used for quickly detecting.In view of this, it is widely used in scientific research, clinical detection and production activity.Streaming is thin
Born of the same parents' instrument can be divided into two kinds of analytic type and sorting type.Wherein, sorting type flow cytometer can not only detect and analyze cell, also
Specific cells can be sorted out according to analysis result, thus its function more horn of plenty, using also more extensive.
However, current cell sorting system and the method for progress cell sorting still have much room for improvement.
The content of the invention
The present invention is based on inventor couple on the fact that being made with the discovery of problem and understanding：
Inventor has found that current selected by flow cytometry apoptosis generally uses electrostatic field separating method.This sorting mode
There are problems that volume is big, electrostatic potential is high, be also easy to produce Aerosol Pollution, when cell is collected to the mechanical impact force of cell.
Inventor has found that this is needed mainly due to using the flow cytometer of electrostatic field separating method by further investigation and many experiments
The plate electrode of a pair bulky (more than ten centimeters long) is set, to form the electrostatic field for sorting.Above-mentioned electrostatic field
Need to apply positive and negative several kilovoltages on plate electrode, therefore be unfavorable for the miniaturization of instrument, it is hidden with more higher safety
Suffer from.
It is contemplated that alleviating at least to some extent or solving above-mentioned to refer at least one in problem.
In view of this, in one aspect of the invention, the present invention proposes a kind of cell sorting system.The cell sorting system
System includes：Fluidic device, the fluidic device has liquid flow inlet and multiple sortings outlet；And cell sorting device, institute
Stating cell sorting device includes sorting electrode pair, and the sorting electrode pair is arranged on the liquid flow inlet and multiple sortings
Between outlet, the electrode pair is configured to produce sorting power using pulse voltage.Thus, the body of the cell sorting system
Product reduces, and security is improved, and high speed, high flux, high-precision unicellular sorting can be achieved.
Embodiments in accordance with the present invention, the fluidic device further comprises flow chamber, and the flow chamber includes：Main flow
Road, one end of the sprue is connected with the liquid flow inlet, and the other end is connected with multiple sorting outlets.Thus, it is possible to
Further improve the performance sorted using the cell sorting system.
Embodiments in accordance with the present invention, the sorting electrode pair includes anode and negative electrode, the negative electrode and the sun
Pole is located at the homonymy of the sprue.Thus, it is possible to further improve the performance sorted using the cell sorting system.
Embodiments in accordance with the present invention, the flow that the cell liquid to be sorted is acted on by the sorting power is micro- for 10-500
Rice.Thus, it is possible to limit the space of sorting momentum effect, and then spatial resolution is improved, realize high speed, high flux sorting.
Embodiments in accordance with the present invention, the fluidic device includes micro-fluid chip, and the micro-fluid chip includes：Chip
The flow chamber is provided with substrate, the chip substrate；Sample flow fluid channel, the sample flow fluid channel is arranged on the core
It is connected on plate base and with the flow chamber；Sheath fluid stream fluid channel, the sheath flow liquid fluid channel is arranged on the chip substrate
And be connected with the flow chamber；Multiple sorting runners, the multiple sorting runner is connected with the flow chamber respectively, wherein, institute
It is face electrode to state sorting electrode pair, and the sorting electrode pair is arranged on the chip substrate.The micro-fluid chip has next
At least one of advantage：Small volume, it is easy to integrated, security to improve, with high time resolution and high spatial resolution, so that
High speed, high flux, high-precision unicellular sorting can be realized.
Embodiments in accordance with the present invention, the cell sorting system further comprises：Detection means, the detection means and institute
State cell sorting device to be connected, the detection means is configured to judge the cell by the cell sorting device one by one
Whether it is target cell.Thus, it is possible to further improve the performance of the cell sorting system.
In another aspect of the present invention, the present invention proposes a kind of by foregoing cell sorting system progress cell
The method of sorting, this method includes：Cell liquid to be sorted is supplied into fluidic device；Sorting is produced using cell sorting device
Power, and the cell liquid to be sorted is acted on, to realize cell sorting.Thus, the method for the cell sorting has and above retouched
Whole features and advantage that the cell sorting system stated has, will not be repeated here.
Embodiments in accordance with the present invention, the cell sorting through the following steps that realize：Applied in sorting electrode pair
Plus pulse voltage carries out the medium between micro spark electric discharge, sorting electrode pair described in micro spark discharge breakdown, to produce
The sorting power, makes the sorting power act on the target cell, to change the flow direction of the target cell.By
This, can improve sorting response speed, can both change the direction of motion of target cell, realize the sorting to target cell,
The direction of motion of the cell (untargeted cells) in addition to target cell can be changed, so as to realize the sorting of untargeted cells.
Embodiments in accordance with the present invention, the amplitude of the pulse voltage is that 100-1000V, pulse duration are 100ns-100 μ
s.Thus, it is possible to which by adjusting pulse voltage and pulse duration, the size of sorting impulse force or suction can be changed, so that real
Existing multichannel sorting.
Brief description of the drawings
Fig. 1 shows the structural representation of cell sorting system according to an embodiment of the invention；
Fig. 2 shows the part-structure schematic diagram of cell sorting system according to an embodiment of the invention；
Fig. 3 shows the part-structure schematic diagram of cell sorting system in accordance with another embodiment of the present invention；
Fig. 4 shows the structural representation of cell sorting system according to an embodiment of the invention；
Fig. 5 shows the principle schematic according to an embodiment of the invention sorted based on micro spark cavitation；
Fig. 6 shows that utilization impulse force according to an embodiment of the invention realizes the principle schematic of cell sorting；
Fig. 7 shows that utilization suction according to an embodiment of the invention realizes the principle schematic of cell sorting；
Fig. 8 shows that utilization impulse force according to an embodiment of the invention and suction realize cell multichannel point in a dimension
The principle schematic of choosing；
Fig. 9 shows that utilization impulse force according to an embodiment of the invention realizes that what cell multichannel in a dimension sorted shows
It is intended to；
It is thin in one or two dimension that Figure 10 shows that utilization impulse force according to an embodiment of the invention and suction are realized
The schematic diagram of born of the same parents' multichannel sorting；
Figure 11 shows that utilization impulse force according to an embodiment of the invention realizes cell multichannel in one or two dimension
The schematic diagram of sorting；
Figure 12 shows the structural representation of micro-fluid chip according to an embodiment of the invention；
Figure 13 shows that utilization micro-fluid chip according to an embodiment of the invention realizes the principle signal of cell sorting
Figure；
Figure 14 shows the schematic diagram of the flow of cell sorting method according to an embodiment of the invention；
Figure 15 shows micro-fluid chip pictorial diagram according to an embodiment of the invention；
Figure 16 shows the light micrograph for realizing assorting room according to embodiments of the present invention 2 using impulse force；And
Figure 17 shows that the optical microphotograph for realizing assorting room using impulse force or suction according to embodiments of the present invention 2 shines
Piece.
Description of reference numerals：
100：Fluidic device；110：Liquid flow inlet；120：Flow chamber；121：Sample inflow entrance；122：Sprue；123：Sheath
Liquid flow inlet；130：Sorting outlet；200：Cell sorting device；210：Sort electrode pair；211：Anode；212：Negative electrode；220：
Sorting region；300：Detection means；310：Detection zone；400：Micro-fluid chip；410：Chip substrate；420：Sample flow
Fluid channel；430：Sheath fluid fluid channel；440：Sort runner.
Embodiment
Embodiments of the invention are described below in detail, the example of the embodiment is shown in the drawings.Below with reference to
The embodiment of accompanying drawing description is exemplary, it is intended to for explaining the present invention, and be not considered as limiting the invention.
In one aspect of the invention, the present invention proposes a kind of cell sorting system.Embodiments in accordance with the present invention, ginseng
Fig. 1 is examined, the cell sorting system includes：Fluidic device 100 and cell sorting device 200.Embodiments in accordance with the present invention, should
Fluidic device 100 has liquid flow inlet 110 and multiple sorting outlets 130, and the fluidic device 100 is used to be cell to be sorted
Liquid provides flow passage and synchronization is only had the active region that a cell passes through sorting unit in tandem, as far as possible in cell
Domain, forms single celled sample flow, so as to which in cell liquid flow process, the sorting to target cell is realized exactly.According to
Embodiments of the invention, cell sorting device 200 includes sorting electrode pair 210, and sorting electrode pair 210 is configured to utilize
Pulse voltage carries out micro spark electric discharge and then produces cavitation bubble, and the sorting power produced during with crumbling and fall is expanded using cavitation bubble
(sorting suction when sorting impulse force or cavitation bubble when cavitation bubble is expanded are crumbled and fall) is treated sorting cell liquid and sorted.Should
The volume of cell sorting system reduces, and security is improved, and high speed, high flux, high-precision unicellular sorting can be achieved.
Below according to the specific embodiment of the present invention, each device of the cell sorting system is described in detail：
Embodiments in accordance with the present invention, with reference to Fig. 2, fluidic device 100 further comprises flow chamber 120, and flow chamber 120 is wrapped
Include：Sprue 122.Embodiments in accordance with the present invention, liquid flow inlet 110 and it is multiple sorting outlet 130 separately with stream
Dynamic room 120 is connected, and one end of sprue 122 is connected with liquid flow inlet 110, and the other end is connected with multiple sorting outlets 130.Need
Illustrate, in the present invention, the concrete structure of fluidic device 100 is not particularly limited, as long as can be implemented as cell liquid
Flowing and sorting provide flow passage, and those skilled in the art can be according to actual conditions, to the tool of fluidic device 100
Body structure is designed.Or, the conventional fluidic device that current flow cytometer can be selected to have is formed according to this
The fluidic device 100 of inventive embodiments.
Embodiments in accordance with the present invention, flow chamber 120 may further include：Sample inflow entrance 121 and sheath fluid are flowed into
Mouth 123.Embodiments in accordance with the present invention, when only sample flow (containing needing to be sorted the cell liquid of cell) is flowed into, it is only necessary to one
Individual entrance is used as sample inflow entrance 121.When sample flow needs Hydrodynamic focus, it is necessary to it is possible to additionally incorporate one or more entrances
Flowed into for sheath fluid stream.In other words, flow chamber 120 can also include multiple sheath liquid flow inlets 123.According to the implementation of the present invention
Example, wraps celliferous sample flow and is flowed into by sample inflow entrance 121 in flow chamber 120, and sheath fluid is flowed into from sheath liquid flow inlet 123 to be flowed
In room 120, sheath fluid stream will wrap celliferous sample flow parcel, and sheath fluid stream and sample flow are together flowed into sprue 122, while
Sample flow is focused on the center of sprue 122 by sheath fluid stream in the presence of Hydrodynamic focus, forms unicellular axle stream.
I other words, cell in sprue 122 one by one in tandem.One end of sprue 122 is connected with flow chamber 120, another
End is connected with multiple sorting outlets 130.Thus, it is possible to further improve the performance sorted using the cell sorting system.
Embodiments in accordance with the present invention, with reference to Fig. 3, cell sorting device 200 includes：Sort electrode pair 210.Sort electrode
It is arranged on to 210 between the sprue 122 of the end of flow chamber 120 and multiple sorting outlets 130.According to the implementation of the present invention
Example, sorting electrode pair 210 further comprises：Anode 211 and negative electrode 212.Embodiments in accordance with the present invention, sort electrode pair
210 particular number is not particularly limited, and those skilled in the art can be selected according to actual conditions, for example, can be
A pair (referring to Fig. 1), or two to (referring to Fig. 3).Sorting electrode pair 210 is configured to utilize pulse voltage, right
Sorting power (can be impulse force, or suction) is produced by the cell liquid to be sorted of cell sorting device 200.Thus, should
Cell sorting device can realize high speed, high flux, high-precision unicellular sorting.
It will be appreciated to those of skill in the art that the identification in order to realize target cell, with reference to Fig. 4, the system this can
To further comprise detection means 300.Whether the cell that detection means 300 is used to judge one by one in sample flow is as target cell.
Specifically, supplied by cell liquid to be sorted to before fluidic device 100, in advance using fluorescent marker etc., to cell
It is marked, when the sample flow by mark flows through detection zone, laser 1 and laser 2 send laser, irradiate sample flow
In the particulate such as cell to be sorted and produce optical signal.Optical signal is through filter and dichroscope (reception side scattered light), transmission
Tested and analyzed into detection means 300 (parts such as fluoroscopic examination and PC sections can be entered oneself for the examination), so as to identify target cell.
The modes such as impedance bioelectrical measurement, identification target cell and non-mesh can also be used in embodiments in accordance with the present invention, detection means 300
Mark cell.When it is target cell to detect the cell flowed through in sorting electrode pair 210 zone of action, using sorting electrode pair
210 produce sorting power (impulse force or suction), and target cell is changed the direction of motion by sorting power effect, so as to drop into collecting pipe
In, untargeted cells is not by the effect for sorting power so as to drop into waste product pipe.Thus, it is possible to realize target cell with it is non-
The sorting of target cell.
Understand for convenience, first below to being briefly described using the principle for sorting the generation sorting power of electrode pair 210：
With reference to Fig. 5, when the electric-field intensity between sorting electrode pair 210 (including anode 211 and negative electrode 212) is more than medium
During disruptive field intensity, the electronics 16 overflowed from negative electrode is accelerated, and impacts 17 to anode, that is to say, that sorting electrode punctures
Sort the medium between electrode pair 210.During electronics is moved to anode 211, due to electronics and the neutral molecule of medium
Shock can form more electronics 16 and cation 15 so that interelectrode charged particle avalanche type increase, and in electricity
Interpolar formation conductive channel 18.During medium is breakdown, between particle, particle and it is interelectrode hit produce heat make
Obtain in conductive channel and corresponding electrode area and the confined space on their peripheries and form localized hyperthermia, the medium of surrounding them
And electrode material by transient evaporation, volumetric expansion so as to produce cavitation bubble 19, outwards expansion sends shock wave to cavitation bubble, both
Sort impulse force 20.The sorting impulse force can change between electrode biological particle (such as other biological particles such as cell, albumen, virus)
The direction of motion.Stop after being powered, because cavitation bubble lacks energy input simultaneous cavitation bubble self-energy to surrounding
The rapid dissipation of environment, the internal pressure of cavitation bubble 19 is less than environmental pressure, so as to crumble and fall rapidly and trigger surrounding liquid
Body Filled Dielectrics cavitation bubble space vacant after crumbling and fall, and the sorting suction 21 of a moment is externally produced, utilize this suction
Power can vary in the direction of motion of biological particle between electrode.It is situated between during cavitation bubble is crumbled and fall along with interelectrode
Matter deionization is simultaneously insulated again, and then is ready for sorting next time.Compared with traditional electrostatic field sorting, pulse electricity is utilized
Magnitude of voltage required for pressing the impulse force produced is smaller, and without persistently applying voltage to sorting battery lead plate, it is only necessary to needing to carry out
Apply pulse voltage during sorting to electrode, generation is enough to change cell or the impulse force or suction in Particles Moving direction.Thus,
Can be greatly reduced sorting electrode pair electrode length (electrostatic field to form long range, generally up to more than ten centimetres) and
Magnitude of voltage (conventional electrostatic sorting needs to provide the voltage of thousands of volts) needed for sorting, the sorting system is utilized so as to improve
The security performance of system, it is possible to the volume of the system is greatly reduced.
According to a particular embodiment of the invention, sorting electrode pair 210 is arranged on the homonymy of sprue 122.With reference to Fig. 6, when
When not applying pulse voltage in sorting electrode pair 210, unicellular stream keeps original flow direction in sprue 122.Work as needs
When producing impulse force 20, apply pulse voltage in sorting electrode pair 210, the cavitation bubble 19 of generation sends out shock wave, both
Impulse force 20.Impulse force 20 acts on the single target cell 31 for now flowing through sprue 122, makes target cell to the side away from electrode
To motion.Thus, it is possible to realize the function of cell sorting.With reference to Fig. 7, when needing to produce suction 21, in sorting electrode pair 210
Upper application pulse voltage, cavitation bubble 19 first expands growth, after cavitation bubble expansion terminate after can moment crumble and fall, now around
Liquid medium fills rapidly vacuole, and produces the reverse impact ripple for pointing to vacuole, both suction 21.Suction 21, which is acted on, now to be flowed through
The single target cell 31 of sprue 122, makes target cell be moved to the direction close to electrode.Thus, it is possible to realize reverse
The function of cell sorting.Two kinds have been utilized respectively impulse force and the process that crumbles and fall afterwards that cavitation bubble is produced in expansion process
The suction of middle generation, realizes the control to sorting direction.It will be appreciated to those of skill in the art that being now to utilize sorting
The impulse force or suction produced between electrode pair 210 realizes cell sorting, accordingly, it would be desirable to so that the impulse force produced between electrode or suction
Power, can act on sprue 122.For example, a correspondence can be set in sprue 122 in the position of sorting electrode pair
Opening.When target cell flows through the opening of sorting unit, apply to electrode pair 210 between pulse voltage, breakdown electrode pair
Medium, produce sorting power (impulse force or suction), the sorting power is delivered in sprue 122, and acts on target cell, makes mesh
The direction of motion for marking cell changes, so as to realize sorting.It will be appreciated to those of skill in the art that formed in breakdown process
The local location that conductive channel is existed only between positive and negative electrode, for example, puncture the liquid medium flowed through between sorting electrode pair,
The electric current produced in breakdown process will not be by the liquid in sprue, including cell stream therein is (because liquid is bad lead
Body, such as distilled water or conventional PBS solution), mechanical force when expanding or crumble and fall only with cavitation bubble is sorted, because
Without producing infringement to cell.Thus, it is possible on the premise of cytoactive is ensured, realize cell sorting.Also, by adjusting
The parameter change singles such as amplitude of pulse voltage that section applies in sorting electrode pair 210 sort the size of cavitation bubble and released
The energy put, can regulate and control the size of the sorting power of generation, by control sorting opportunity with utilize cavitation bubble expand yes
Impulse force or suction when crumbling and fall, it is possible to achieve the regulation and control to sorting force direction.With reference to Fig. 8, sorting electrode is applied to by regulation and control
On the opportunity of parameter and control sorting to the pulse voltage on 210, target cell can be sorted to different positions, entered
And realize and various kinds of cell is sorted simultaneously, such as, can be by setting a pair of sorting electrode pair (anodes 211 shown in Fig. 8
And negative electrode 212) realize that totally 5 tunnels are sorted 131-135).Similarly, can be by setting two pairs of sorting electrode pairs with reference to Fig. 9
(negative electrode and anode of electrode pair 1, the negative electrode and anode of electrode pair 2), cell point in a dimension is realized merely with sorting impulse force
The control in direction is selected, and controls the energy size of impulse force, can equally be realized while being sorted to various kinds of cell (in such as Fig. 9
It is shown to realize 131~135 totally 5 tunnels sortings).
Embodiments in accordance with the present invention, in order to realize the sorting of target cell, it is necessary to control the width of voltage pulse applied
Value and duration.The amplitude of voltage pulse is relevant with the effect of duration and sorting, and the amplitude of voltage pulse is too high, can cause power consumption
Increase and impulsive force are too strong；Amplitude is too low, and medium can be caused breakdown, and then can not realize sorting.Apply voltage arteries and veins
Overlong time is rushed, the generation of a large amount of electrolysis bubbles can be caused, influence separating effect is (after bubble accumulation is excessive with liquid electrolytic
Can occur microburst)；Time is too short, and to impact dynamics inadequate.Embodiments in accordance with the present invention, the amplitude of voltage pulse, when
Length is relevant with the species of liquid between electrode.According to a particular embodiment of the invention, when electrode gap is 200 μm, electric contrasted between solid dielectric
For PBS solution, when cell flow rate is 5m/s in cell liquid, the amplitude for applying voltage pulse can be 100-1000V, and duration can be with
It is 100ns-100 μ s, single sorting (sorts and start to liquid stream to recover stable time span again) used time 0.25ms, thus,
Sorting speed can reach 4000 it is per second.
Embodiments in accordance with the present invention, with reference to Fig. 3, the flow that cell liquid to be sorted is acted on by sorting power can be 10-
500μm.It should be noted that in the present invention, " flow of sorting power effect " is cell liquid in flow process, can be by
Sort the flow distance of power.Specifically, the flow of sorting power effect can be such as length D (electrode chambers and the sprue in Fig. 3
The length of connection position).Embodiments in accordance with the present invention, length D can be 200 μm.Thus, it is possible to limit the sky of sorting power effect
Between, and then spatial resolution is improved, realize high speed, high flux, high-precision unicellular sorting.It is real with existing utilization electrostatic field
The cell sorting system now sorted is compared, and the voltage of conventional electrostatic sorting is high, and separation is, it is necessary between two electrodes in electrostatic field
Need to reach enough length, generally up to more than ten centimetres with enough distance and electrode.The application uses moment
Impulse force or suction realize cell sorting in unicellular stream, thus, it is only required to ensure it is unicellular stream in certain distance, by point
Select power, you can realize the separation of target cell.Therefore, distance can be shorter.In other words, electrode and the stream of sorting power
Journey can be only the yardstick of hundred microns or even ten microns, meanwhile, voltage is low, and security performance is high, beneficial to integrated.
Embodiments in accordance with the present invention, in order to further improve the efficiency and effect that are sorted using the system, also
Multiple sorting electrode pairs 210 can be set.By it is multiple sorting electrode pairs be arranged on different directions, enable to it is unicellular stream by
To the active force of different directions, so as to realize that multichannel is sorted.With reference to Figure 10, when with a pair of sorting electrode pairs 210, together
Shi Liyong impulse forces and suction are sorted, it is possible to achieve the m roads sorting (as shown in Figure 10, m=5) of a dimension, then will be thin
Born of the same parents are sorted among different collection tubes；When with two pairs of sorting electrode pairs 210, while being divided using impulse force and suction
Choosing, wherein first pair of sorting electrode pair 210 can realize that m roads are sorted in the direction of the x axis, second pair of sorting electrode pair 210 is in y-axis
It can realize that n roads are sorted on direction, when two pairs of sorting electrodes one work, it is possible to achieve m × n roads sorting (as shown in Figure 10, m
=7, n=7), then by among cell sorting to different collection tubes.With reference to Figure 11, when with two pairs of sorting electrode pairs 210
When, only sorted using impulse force, the m roads sorting (as shown in figure 11, m=5) of a dimension can also be realized, then by cell
It is sorted among different collection tubes；When with 4 pairs of sorting electrode pairs 210, only sorted using impulse force, wherein the twoth pair
Sorting electrode pair 210 can realize that m roads are sorted in the direction of the x axis, and two further pairs sorting electrode pair 210 in the y-axis direction can be with
Realize that n roads are sorted, when four pairs of sorting electrodes one work, it is possible to achieve m × n roads sorting (as shown in figure 11, m=7, n=7),
Then by among cell sorting to different collection tubes.
Embodiments in accordance with the present invention, above-mentioned cell sorting system is beneficial to integrated.Therefore, the cell sorting system can be used
In the fluidic device 100 using micro-fluid chip 400.Embodiments in accordance with the present invention, with reference to Figure 12, on micro-fluid chip 400
Flow chamber 120 is provided with, micro-fluid chip 400 includes：Chip substrate 410, sample flow fluid channel 420, sheath fluid stream fluid channel
430th, multiple sorting runners 440.In other words, micro-fluid chip can be used, traditional flow chamber is substituted, thus be conducive into
One step improves the degree of integration of the cell sorting system.According to a particular embodiment of the invention, micro-fluid chip 400 can include
Sample flow fluid channel 420 and multiple sheath fluid stream fluid channels 430, to supply cell liquid to be sorted to the micro-fluid chip 400
And sheath fluid.Sample flow fluid channel 420 is arranged on chip substrate 410 and is connected with flow chamber 120, sample flow fluid channel 420
For providing flow channel for sample flow to be sorted, sheath fluid fluid channel 430 is arranged on chip substrate 410 and and flow chamber
120 are connected, and sheath fluid stream fluid channel 430 provides flow channel for sheath fluid stream.Embodiments in accordance with the present invention, wrap celliferous sample
Stream enters in flow chamber 120 from sample flow fluid channel 420, and sheath fluid enters in flow chamber 120 from sheath fluid fluid channel 430, sheath fluid stream
Sample flow is wrapped up, sheath fluid stream and sample flow are together flowed into sprue 122, while the sample in the presence of Hydrodynamic focus
Stream is focused on the center of sprue 122 by sheath fluid stream, forms unicellular axle stream, and cell can be in all according to flow direction
Straight line and it is single flow through sprue 122, be thus conducive to improving separating effect.Certainly, according to actual conditions, sample
Stream can also be only completed the focusing of a dimension, and both sample flow was only focused on the horizontal centre or vertical centre of sprue 122.
It will be appreciated by persons skilled in the art that the specific species of above-mentioned sheath fluid is not particularly limited, cell sorting only need to be realized
Function.For example, sheath fluid can be distilled water, deionized water, PBS.It should be noted that in the present invention, liquid
The concrete structure of stream device 100 is not particularly limited, and focuses on and formed unicellular to the cell in sample flow as long as can realize
Just can it flow, those skilled in the art can be designed according to actual conditions to the concrete structure of fluidic device 100.According to this
The embodiment of invention, realizes the identification to target cell in detection zone 310, and detection is led to using the optical system of chip exterior
The means for crossing detection fluorescent marker realize that detection zone 310 has the laser facula of irradiating cell.Sorting electrode pair 210 also may be used
To be arranged on chip substrate 410, it is changed for the direction of motion to cell, so as to realize sorting.According to the present invention's
Embodiment, the particular type of sorting electrode is not particularly limited, as long as meeting the function of realizing cell sorting.For example, can
Face electrode is thought, it is possible thereby to beneficial to being integrated on micro-fluid chip, realize the flattening of the micro-fluid chip.According to the present invention
Embodiment, multiple sorting runners 440 are connected with flow chamber 120 respectively, for being carried out to the cell for having changed the direction of motion
Collect, realize sorting.Embodiments in accordance with the present invention, with reference to Figure 13, it is possible to use micro-fluid chip carries out multichannel cell sorting,
On the principle sorted using impulse force or suction, before detailed description has been carried out, will not be repeated here.Microfluid
Chip can realize sorting in completely enclosed runner, it is to avoid Aerosol Pollution, be conducive to protecting the health of operating personnel
Safety.The miniflow body sorting chip of low cost can realize an a piece of use, both every time in detection all with a brand-new chip, energy
It is enough fundamentally to avoid cross pollution, improve the degree of accuracy of detection and sorting.Generally speaking, the micro-fluid chip has next excellent
At least one of point：Small volume, it is easy to integrated, security to improve, with high time resolution and high spatial resolution, so as to
To realize high speed, high flux, high-precision unicellular sorting.
It should be noted that said system can be not only used for sorting cell, it can be also used for realizing such as albumen, virus
And the sorting of other biological particulate.In other words, other biological particles such as cell, albumen, virus can be included in sample flow
At least one of.
In another aspect of the present invention, the present invention proposes a kind of by foregoing cell sorting system progress cell
The method of sorting.Embodiments in accordance with the present invention, this method includes：Cell liquid to be sorted is supplied into fluidic device, utilized
Cell sorting device produces sorting power, sorting power is acted on cell liquid to be sorted, and changes the flow direction of target cell, so that
Realize the sorting of cell.Specifically, with reference to Figure 14, this method can include：
S100：Celliferous sample flow will be wrapped to be input in liquid fluid system
In this step, the celliferous sample flow of bag to be sorted is input in fluidic device 100.As it was previously stated,
Sample flow is input to before fluidic device 100, using labels such as fluorescent materials, cell is marked in advance,
In order to recognize target cell by the means of fluoroscopic examination, naturally it is also possible to which by other means recognize target cell, such as electricity
Testing impedance.Embodiments in accordance with the present invention, the particular type of sample flow is not particularly limited, for example can for cell, albumen,
Other biological particles such as virus.
S200：Cell is identified detection means one by one
In this step, cell is identified one by one using detection means 300, the species of cell is differentiated, to determine quilt
Whether the cell of detection is sorted (whether being target cell), if multichannel is sorted, in addition it is also necessary to according to the particular type of cell
Judge that the target cell needs to be sorted into which specific runner.According to the specific implementation of the present invention, in bag to be sorted
Celliferous sample flow is supplied to fluidic device, and unicellular stream is formed in the presence of sheath fluid stream.Unicellular stream is flowed through point
Before screening device, cell liquid is identified in advance, to tell target cell and untargeted cells.According to the present invention's
Embodiment, the specific method for carrying out cell recognition is not particularly limited, for example, can be by the fluorescence of laser irradiating and detecting cell
And scattered light signal, or detect that the identification of target cell and untargeted cells is realized in the impedance of cell.
S300：The impulse force or suction produced using micro spark cavitation realizes cell sorting
In this step, based on testing result above, cell sorting device 200 is made to produce sorting impulse force or suction, and
Cell liquid to be sorted is acted on, to realize cell sorting.On using sorting the principle that impulse force or suction are sorted, before
Detailed description has been carried out, will not be repeated here.Generally speaking, in this step, pulse is applied to sorting electrode pair 210
Voltage, makes the medium between the breakdown electrode pair of sorting electrode pair 210 and produces cavitation bubble, is expanded using moment cavitation bubble
Impulse force or suction when crumbling and fall change the flow direction of particle, so that target cell be sorted out from cell stream.
Specifically, sorting electrode pair to be arranged on to the homonymy of sprue 122, unicellular stream flows in sprue 122, leads to
Cross detection means 300 and identify target cell in unicellular stream.When target cell flows through sorting unit 200, in sorting electrode
210 pairs of upper media applied between pulse voltage, breakdown electrode pair, medium produces cavitation bubble during breakdown between electrode,
Cavitation bubble expansion produces impulsive force in surrounding, and the impulsive force is delivered in sprue 122, and acts on target cell, makes target
Cell is moved to the direction away from electrode, so as to realize sorting；Or just puncture liquid before target cell is by sorting unit
Body produces cavitation bubble, and cavitation bubble is crumbled and fall and produces suction in surrounding while when target cell is by sorting unit, should
Suction is delivered in sprue 122, and acts on target cell, target cell is moved to the direction close to electrode, so that real
Now reversely sorting.
It will be appreciated to those of skill in the art that the conductive channel formed in breakdown process exist only in positive and negative electrode it
Between local location, the electric current produced in breakdown process will not by the liquid in sprue, including cell stream therein (because
Liquid is non-conductor, such as distilled water or conventional PBS solution), machinery when expanding or crumble and fall only with cavitation bubble
Power is sorted, thus will not produce infringement to target cell.Thus, it is possible on the premise of target cell activity is ensured, it is real
Existing cell sorting.Also, by adjusting the parameter change single point such as amplitude of pulse voltage applied in sorting electrode pair 210
The size of cavitation bubble and the energy of release are chosen, the size of the sorting power of generation can be regulated and controled, by the opportunity for controlling sorting
Suction during expanding the impulse force for being using cavitation bubble or crumble and fall, it is possible to achieve the regulation and control to sorting force direction.Pass through regulation and control
Be applied to sorting electrode pair 210 on pulse voltage parameter and control sorting opportunity, target cell can be sorted to
On different positions, and then realize while being sorted to various kinds of cell.Similarly, can be by setting multiple sorting electrode pairs
210, the control to cell sorting direction is realized merely with sorting impulse force, can equally be realized while being divided various kinds of cell
Choosing.
According to a particular embodiment of the invention, above-mentioned cell sorting can with through the following steps that realize：
Sorting electrode pair is arranged on to the homonymy of sprue.The main flow for being provided with the sorting electrode pair is flowed through in target cell
During the corresponding region in road, the liquid medium electrode pair is punctured and cavitation bubble is produced, moment cavitation bubble is utilized
The impulse force of expansion or suction when crumbling and fall realize orientation and the quantitative change to the target cell direction of motion, so as to complete sorting.
The sorting impulse force or suction change the direction of motion of the target cell in target cell.As it was previously stated, applying pulse every time
Voltage, only changes the flow direction for waiting to sort a cell in unicellular stream, is achieved in unicellular sorting function.It that is to say
Say, when the target cell in containing unicellular stream flows through the region corresponding with sorting electrode pair, apply pulse voltage, breakdown potential
Medium extremely between simultaneously produces cavitation bubble, and cavitation bubble instantaneous expansion produces shock wave, and forms one towards sprue
The impulsive force in direction, the impact force action changes target cell flow direction, so as to realize sorting in target cell；Or
Target cell produces cavitation bubble by just puncturing liquid before sorting unit, while when target cell is by sorting unit
Cavitation bubble is crumbled and fall and produces suction in surrounding, and the suction is delivered in sprue, and acts on target cell, makes target cell
Moved to the direction close to electrode, so as to realize reverse sorting.
Embodiments in accordance with the present invention, the amplitude of pulse voltage is that 100-1000V, pulse duration are 100nm-100 μ s.Root
According to embodiments of the invention, in order to realize the sorting of target cell, it is necessary to control the amplitude and duration of the voltage pulse of application, electricity
The amplitude of pressure pulse is relevant with the effect of duration and sorting, and the amplitude of voltage pulse is too high, and power consumption can be caused to increase and rush
Hit power too strong；Amplitude is too low, and medium can be caused breakdown, and then can not realize sorting.Apply voltage pulse time long,
The generation of a large amount of electrolysis bubbles can be caused with liquid electrolytic, (after bubble accumulation excessively microexplosion can occur for influence separating effect
It is fried)；Time is too short, and to impact dynamics inadequate.Embodiments in accordance with the present invention, between amplitude, duration and the electrode of voltage pulse
The species of liquid is relevant.According to a particular embodiment of the invention, when electrode gap is 200 μm, electric contrasted between solid dielectric is PBS solution,
When cell flow rate is 5m/s in cell liquid, the amplitude for applying voltage pulse can be 100-1000V, and duration can be 100ns-
100 μ s, single sorting (sorting starts to liquid stream to recover stable time span again) used time 0.25ms, thus, sort speed
Can reach 4000 it is per second.
In summary, the method for carrying out cell sorting by foregoing cell sorting system has advantages below at least
One of：Security is improved, and time, spatial resolution are high, and high speed, high flux, high-precision unicellular sorting can be achieved.
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Unreceipted particular technique or bar in embodiment
Part, carried out according to the technology or condition described by document in the art or according to product description.Agents useful for same or instrument
The unreceipted production firm person of device, being can be by the conventional products of acquisition purchased in market.
Embodiment 1
The fluidic device used using the conventional flow cytometer shown in Fig. 2, sprue is located at a pair of sorting electrode pairs
Homonymy, by the medium between breakdown electrode pair and produce cavitation bubble, the impulse force that is expanded using moment cavitation bubble or crumble and fall
When suction realize orientation to the target cell direction of motion and quantitative change, so as to complete sorting.With reference to Figure 10, electrode pair
The 210 and length D (length D as shown in Figure 3) that communicates of sprue 122 is 200 μm, and the waterpower internal diameter of sprue 122 is 200 μ
M, is 5m/s positioned at the speed of the unicellular stream at the center of sprue 122, applies amplitude 100-1000V, the duration of voltage pulse
100ns-100 μ s, the limit separation velocity being theoretically achievable can be 25000 (=flow velocitys/port height=5m/s ÷ per second
200μm).After the classification that cell is determined by flow cytometry detection device 300, by controlling pulse voltage and target cell logical
The opportunity for crossing sorting region carrys out the size and Orientation of regulating force pulse.When with a pair of sorting electrode pairs 210, while sharp
Sorted with impulse force and suction, it is possible to achieve the 5 tunnels sorting of a dimension, can be by each cell sorting to different space bits
131-135 is put, cell is entered in air 46, is eventually fallen into different sampling pipes, so as to realize the multichannel to cell mass
Sorting；When with 2 pairs of sorting electrode pairs 210, while being sorted using impulse force and suction, wherein first pair of sorting electrode pair
210 can realize that 7 tunnels are sorted in the direction of the x axis, and second pair of sorting electrode pair 210 can realize that 7 tunnels are sorted in the y-axis direction,
When two pairs of sorting electrodes one work, it is possible to achieve 7 × 7 tunnels are sorted, then by among cell sorting to different collection tubes.Ginseng
Figure 11 is examined, when with 2 pairs of sorting electrode pairs 210, is only sorted using impulse force, 5 roads point of a dimension can also be realized
Choosing, then by among cell sorting to different collection tubes；When with 4 pairs of sorting electrode pairs 210, only divided using impulse force
Choosing, wherein the twoth pair of sorting electrode pair 210 can realize that 7 tunnels are sorted in the direction of the x axis, two further pairs sort electrode pair 210 in y
It can realize that 7 tunnels are sorted on direction of principal axis, when four pairs of sorting electrodes one work, it is possible to achieve 7 × 7 tunnels are sorted, then by cell
It is sorted among different collection tubes.
Embodiment 2
The fluidic device 100 of micro-fluid chip 400, includes with reference to Figure 15 micro-fluid chips 400：Chip substrate 410, sample
Flow fluid channel 420, sheath fluid stream fluid channel 430, it is multiple sorting runner 440, flow chamber 120, sprue 122, detection zone 310,
Sorting unit 200 (sorting electrode pair) and sorting region 220.Flow chamber 120 is provided with chip substrate 410, the stream
Dynamic room 120 is used to provide flow channel for sample flow, and cell is made into synchronization as far as possible in tandem to form unicellular stream
Only one cell is by detection zone and the sorting region 220 of sorting unit, to be realized during being flowed in cell
Sorting to target cell.Wrap celliferous sample flow from sample flow fluid channel 420 to enter in flow chamber 120, sheath fluid is from sheath fluid
Fluid channel 430 enters in flow chamber 120, and sheath fluid stream wraps up sample flow, and sheath fluid stream and sample flow together flow into sprue 122
In, while sample flow is focused on the center of sprue 122 by sheath fluid stream in the presence of Hydrodynamic focus, formed slender
Born of the same parents' axle stream, cell can be in all straight line and single process sorting unit 200 according to flow direction, thus be conducive to
Improve separating effect.Certainly, according to actual conditions, sample flow can also be only completed the focusing of a dimension, both sample flow only by
Focus on the horizontal centre or vertical centre of sprue 122.The negative electrode and anode for sorting 210 pairs of electrode are arranged on sprue
122 homonymies, produce impulse force or suction by puncturing, the flow direction of target cell are changed between medium, electrode.Utilize punching
The light micrograph of power single assorting room is as shown in figure 16.When not sorting, sample flow is focused onto in sprue 122
Heart position, subsequently enters the sorting runner 440 on the right side in downstream；When being applied in a voltage amplitude between anode 211 and negative electrode 212
When value 600V, the μ s of duration 5 electric pulse, the liquid between positive and negative electrode is breakdown and produces cavitation bubble 19, cavitation bubble expansion
A mechanical shock wave is produced, causes local sample flow to change the direction of motion, and enter in the sorting runner 440 in left side；Electricity
After end-of-pulsing, fluid path recovers stable, and sample flow comes back to the center of sprue 122, and it is right to re-enter into downstream
The sorting runner 440 of side.In single assorting room, the fluid path stabilization time of single sorting is 0.25ms, and sorting space is
200 μm, sample flow flow velocity 5m/s, its highest separation velocity can be per second for 4000.Figure 17 illustrates electrode pair cavitation gas
The expansion of bubble and the light micrograph for the process that crumbles and fall, correspondence sample flow is first by impact away from electrode, afterwards under suction
Electrode position is attracted to, last sample flow recovers stable.This explanation can not only utilize the impulse force in cavitation bubble expansion process
Realize sorting, also using cavitation gas crumble and fall it is swollen during suction realize sort.
In the description of the invention, the orientation or position relationship of the instruction such as term " on ", " under " are based on shown in the drawings
Orientation or position relationship, are for only for ease of the description present invention rather than require that the present invention must be with specific azimuth configuration and behaviour
Make, therefore be not considered as limiting the invention.
In the description of this specification, the description of reference term " one embodiment ", " another embodiment " etc. means knot
Specific features, structure, material or the feature for closing embodiment description are contained at least one embodiment of the present invention.At this
In specification, identical embodiment or example are necessarily directed to the schematic representation of above-mentioned term.Moreover, the tool of description
Body characteristicses, structure, material or feature can in an appropriate manner be combined in any one or more embodiments or example.This
Outside, in the case of not conflicting, those skilled in the art by the not be the same as Example described in this specification or can show
Example and the feature of be the same as Example or example is not combined and combined.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (9)
1. a kind of cell sorting system, it is characterised in that including：
Fluidic device, the fluidic device has liquid flow inlet and multiple sortings outlet；And
Cell sorting device, the cell sorting device includes sorting electrode pair, and the sorting electrode pair is arranged on the liquid stream
Between entrance and multiple sorting outlets, the electrode pair is configured to produce sorting power using pulse voltage.
2. cell sorting system according to claim 1, it is characterised in that the fluidic device further comprises flowing
Room, the flow chamber includes：
Sprue, one end of the sprue is connected with the liquid flow inlet, and the other end is connected with multiple sorting outlets.
3. cell sorting system according to claim 2, it is characterised in that the sorting electrode pair includes anode and the moon
Pole, the negative electrode and the anode are located at the homonymy of the sprue.
4. cell sorting system according to claim 1, it is characterised in that the cell liquid to be sorted is by the sorting
The flow of power effect is 10-500 microns.
5. cell sorting system according to claim 2, it is characterised in that the fluidic device includes micro-fluid chip,
The micro-fluid chip includes：
The flow chamber is provided with chip substrate, the chip substrate；
Sample flow fluid channel, the sample flow fluid channel is arranged on the chip substrate and is connected with the flow chamber；
Sheath fluid stream fluid channel, the sheath fluid stream fluid channel is arranged on the chip substrate and is connected with the flow chamber；
Multiple sorting runners, the multiple sorting runner is connected with the flow chamber respectively,
Wherein, the sorting electrode pair is face electrode, and the sorting electrode pair is arranged on the chip substrate.
6. cell sorting system according to claim 1, it is characterised in that further comprise：
Detection means, the detection means is connected with the cell sorting device, and the detection means is configured to one by one
Judge the cell by the cell sorting device whether as target cell.
7. a kind of method that cell sorting system using described in claim any one of 1-6 carries out cell sorting, its feature exists
In, including：
Cell liquid to be sorted is supplied into fluidic device；Sorting power is produced using cell sorting device, and acts on described treat
Cell liquid is sorted, to realize the sorting to target cell.
8. method according to claim 7, it is characterised in that the cell sorting is through the following steps that realize：
Apply pulse voltage in sorting electrode pair and carry out micro spark electric discharge, sort electrode pair described in micro spark discharge breakdown
Between medium, to produce the sorting power, make it is described sorting power act on the target cell, to change the target
The flow direction of cell.
9. method according to claim 8, it is characterised in that when the amplitude of the pulse voltage is 100-1000V, pulse
A length of 100ns-100 μ s.
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