CN1735466A - Method and apparatus for sorting particles - Google Patents
Method and apparatus for sorting particles Download PDFInfo
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- CN1735466A CN1735466A CN 03825178 CN03825178A CN1735466A CN 1735466 A CN1735466 A CN 1735466A CN 03825178 CN03825178 CN 03825178 CN 03825178 A CN03825178 A CN 03825178A CN 1735466 A CN1735466 A CN 1735466A
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Abstract
A method and apparatus for sorting particles moving through a closed channel system of capillary size comprises a bubble valve for selectively generating a pressure pulse to separate a particle having a predetermined characteristic from a stream of particles. The particle sorting system may further include a buffer for absorbing the pressure pulse. The particle sorting system may include a plurality of closely coupled sorting modules which are combined to further increase the sorting rate. The particle sorting system may comprise a multi-stage sorting device for serially sorting streams of particles, in order to decrease the error rate.
Description
Related application
The sequence number that the application requires on September 16th, 2002 to submit to is that 60/411143 U.S. Provisional Patent Application and the sequence number submitted on September 16th, 2002 are the priority of 60/411058 U.S. Provisional Patent Application, is incorporated herein its content as a reference.The application also requires the priority of No. 10/329008 U.S. Patent application submitting on December 23rd, 2002 and as its part subsequent application, and this No. 10/329008 patent is the part subsequent application of No. 10/179488 U.S. Patent application submitting on June 24th, 2002, and the content that is incorporated herein these patents as a reference.
Invention field
The present invention relates to be used for the method and apparatus of the particle of sorting suspension, the fluid admission passage of wherein sorting module is divided into several flow pass.The invention particularly relates to a kind of grain sorting system with a plurality of interconnection sorting modules in order to raising particle throughput.
Background of invention
At biological technical field, especially the sorting particle need be come with high throughput in cytology and drug screening field.The particle that needs sorting is various types of cells, as blood platelet, leucocyte, tumour cell, embryonic cell or the like.At these particles of cytology field is that people cherish a special interest.Other particle has (greatly) molecular substance, for example protein, enzyme and polynucleotide.In the drug screening field of the exploitation of novel drugs, this particle family is that people are interested especially.
The method and apparatus that is used for the sorting particle is known, and the major part described in the prior art is worked under following situation, particle is suspended among the liquid of the channel network with at least one downstream branch point of flowing through, and according to the principle work of detection-decision-water conservancy diversion.At first to analyze the particular characteristics of mobile particle, such as absorbance, fluorescence intensity, size or the like.According to the result of this detection-phase, how decision further handles this particle in downstream stages.Again the result who is made a decision is applied, makes of the predetermined branch direction deflection (deflect) of specific particle towards channel network.
The throughput of screening installation, but the quantity of sorting particle in the i.e. unit interval is crucial factor.For every single separation unit, the typical sorting speed that adopts the sorter of the particle suspension liquid stream in the close passage is that hundreds of particle per second is to several thousand particle per seconds.
Described the example of sorting unit in the U.S. Patent No. 4175662, be incorporated herein its content and (hereinafter be called ' 662 patents) as a reference.In ' 662 patents, grain flow is a cell herein, the central authorities of the straight type passage of flowing through, and straight type passage is divided into two vertical channels (T type branch) in downstream branch point place trouble.Flow into particle and surrounded, make this particle be limited in the central authorities of passage by the skin that compatible fluid constitutes.Under normal conditions, can regulate flow-rate ratio, make particle automatically flow through one of them by two branches.The detector of available for example optical system detects the characteristic (detection-phase) of particle in a zone of passage.In the decision stage, when detector detected the particle with predetermined properties, detector just sent signal.In the water conservancy diversion stage, in case detect particle, air deflector just is activated this particle is deflected.In this example, air deflector comprises the electrode pair that is installed in the channel branch place, and flowing through usually at this bifurcation particle is in the air deflector of unactivated state.By the applied current pulse, the aqueous solution is discharged the bubble that is produced by electrolysis between electrode pair.Along with the increase of bubble size, the flow velocity by this branch reduces in the release stage.After having applied current impulse, bubble has stopped increase, and is being carried by fluid.As a result, the fluid by specific branch temporarily reduces, and target particles has changed the downstream that stream flows to another branch.
Device in ' 662 patents is effective for the sorting particle.Yet there is a serious defective to be that the bubble that produces may be in certain some gathering of Flow Control network.The generation of this bubble may be blocked flow channel, and sorting makes the mistake.Another shortcoming is that the gas (mainly being oxygen and hydrogen) and the ionic species that are produced (are mainly OH
-And H
+) influenced grain flow through having the branch of electrode pair.In addition, the protein of cell and easy damaged is very fragile as enzyme, can be destroyed with the common pollutant component that produces of bubble.Another shortcoming is that whole sorting unit is very complicated.It is very complicated particularly installing in the small size tunnel of system and assemble the microelectrode structure.Therefore, the cost of separation unit is higher relatively.
Described another example of the grain sorting system of prior art in the United States Patent (USP) 3984307, be incorporated herein its content and (hereinafter be called ' 307 patents) as a reference.In ' 307 patents, the grain flow of the outer liquid restriction of being flowed is through the central authorities of passage.Through after the detector region, acutangulate two passages (for example, y-branch) between this passage trouble is divided into.The branch point of passage slightly before the place, a transducer that electricity activates has been installed, be used for the specific particle that deflection has suitable predetermined properties.Described transducer is piezo-activator or ultrasonic transducer, and electricity activates the back and produce pressure wave in passage.The pressure wave that is produced can temporarily disturb flowing in the branch, thereby target particles is deflected in another branch.
In the device of ' 307 patents, the device of discussing as the front is added to air deflector in the channel system and can causes higher cost.Another shortcoming of this device is employed air deflector principle.The pressure wave that is produced is not confined to branch point, but upstream the district propagates into detector region, and propagates into two branches downwards.This can have influence on all fluids by passage.If with the sorter serial or parallel connection of this type, institute did during as structure high throughput separation system, this shortcoming was just particularly outstanding.The pressure wave that is produced in sorter may then influence flowing and water conservancy diversion of particle in the contiguous sorter unit.
Describe another kind of sorter in the U.S. Patent No. 4756427, be incorporated herein its content as a reference.This sorter is similar to the sorter in ' 662 patents.But in this example, the resistance by a branch of temporary transient change disturbs flowing in this branch.The change of resistance is the height that changes branched bottom by external actuator.In preferred embodiments, this external actuator is the piezoelectricity disk that is bonded in channel roof, makes it to move down after activation.
Although the structure of the sorter described in ' 427 patents is more simple in structure than previously described sorter, when a plurality of sorter modules of described type connected together with raising sorting speed, it still had problems.As the sorter described in ' 307 patents, this is because the pressure wave that it produced can cause the interference to other sorter module.
Describe another kind of grain sorting device in No. the 5837200th, the United States Patent (USP), be incorporated herein its content as a reference.' 200 patents have been described a kind of magnetic conductance flow module that utilizes, the sorting unit of classifying or selecting according to the magnetic characteristic of particle.' 200 patents have also further described processing in parallel and the process of separating the sub-thread grain flow.
The invention summary
This law is bright to be provided and has been used for the method and apparatus of particle that the closed channel system of capillary dimensions is flow through in sorting.Grain sorting of the present invention system provides a kind of sorting module, and it can assemble and be provided in the time per unit the accurately means of a large amount of particles of sorting at low cost.This grain sorting system can comprise a plurality of close-connected sorting modules, and it combines with the further sorting speed that improved.In order to reduce error rate, this grain sorting system can comprise that the multistep sorting unit is used for sorting grain flow continuously.
According to the present invention, the grain sorting system has realized method that improved Flow Control particle turns to and the device that turns to.This grain sorting system comprises the closed channel system of the capillary dimensions that is used for the sorting particle.This channel system comprises that being used to introduce first of grain flow supplies pipe and be used to provide second of carrier fluid to supply pipe.First mouth of pipe that supplies pipe to form is introduced grain flow in the carrier fluid.First supplies pipe and second to be communicated with the measuring tube fluid for pipe, and measuring tube is divided into first branch road and second branch road in branch point place trouble.Measured zone is limited in the measuring tube, and unites to detect the predetermined properties of the particle in the measured zone with detector.Two relative bubble valve are communicated with placement and spaced relative to each other with measuring tube.Bubble valve is communicated with measuring tube by a pair of relative wing passage.Thereby liquid can form meniscus by partially filled these wing passages therein, as the interface of carrier fluid and bubble valve liquid storage tank.Also provide an external actuator to be used to regulate one of them bubble valve.After external actuator was activated, the liquid storage tank pressure of the bubble valve that is activated increased, and meniscus is deflected and caused in measuring tube and flow to disturb so that fluid wherein deflects.
When the sensor that is positioned at measured zone detected the predetermined properties of particle of the measured zone of flowing through, this sensor just sent signal to respond detected characteristic.External actuator responds sensor, produces pressure pulse in the pressurised chamber of first bubble valve, and the particle with predetermined properties is deflected, and causes selected particle to flow to the second branched pipe downstream.
On the one hand, the present invention includes the method for sorting particle, step comprises: the measuring tube with inlet and branch point is provided, this pipe is divided into two laterals in branch point place trouble, the inlet of the fluid stream ingress pipe of suspended particulate stream will wherein be had, this particle flows through first lateral usually like this, and provides two relative wing passages to be used to make ducted liquid stream temporarily to deflect in the upstream of branch point.First wing passage fluid pressure type ground links to each other with the pressurised chamber of first bubble valve, and the pressure external actuator activates this bubble valve by being used to change wherein.Second wing passage is connected with the buffer chamber fluid pressure type of second bubble valve and is used for the absorption pressure variable quantity.This method further comprises along the measuring tube of wing passage upstream provides measuring station, is used for detecting the predetermined properties of liquid stream particle, and produces signal when detecting predetermined characteristics.This method further may further comprise the steps: in response to the detection to predetermined properties, activate external actuator and disturb, thereby the particle with predetermined properties is deflected and make the downstream of selected grain flow to second lateral in order to produce in the pipeline between the wing passage to flow.
Other aspects of the present invention by a plurality of sorting modules in parallel respectively or with a plurality of sorting modules of binary tree structure series connection, have increased the sorting speed of particle respectively or have increased by the type of sorting particle.
According to an aspect of the present invention, provide a kind of grain sorting system.This grain sorting system comprises first pipeline that is used for transporting the suspended particulate stream that is limited in carrier fluid, it comprises inlet, first outlet and second outlet, be used to detect the sensor of the predetermined properties of particle, the wing passage that is connected with first pipeline, be positioned near the sealing chamber the wing passage, wherein carrier fluid forms meniscus will seal chamber and carrier fluid separates in the wing passage; And actuator.When sensor detected described predetermined properties, actuator changes the indoor pressure of enclosed cavity deflected meniscus.The deflection of meniscus makes the grain flow with predetermined properties to second outlet, and the grain flow that does not have a predetermined properties is to first outlet.
Estimate that the present invention will be very valuable in the screening of high throughput; For example at anti-when one or more cell activity are screened a large amount of candidate compound.It is for for example, especially has value when reactive compound in the synthetic or natural products storehouse of screening or biochemical characteristic.
Also estimating the present invention a plurality of such as the such branch period of the day from 11 p.m. to 1 a.m of biomolecule in high throughput ground screening sample in addition, will be very valuable.The present invention can be used for screening sample, to confirm whether existing of large number of biological molecule, for example activator of polypeptide, receptors ligand, zymolyte, enzyme or receptor active or antagonist, perhaps nucleic acid.
The accompanying drawing summary
Fig. 1 is the schematic diagram according to the grain sorting system of the bright illustrative embodiment of this law.
Fig. 2 to Fig. 4 has represented the course of work of the grain sorting system among Fig. 1.
Fig. 5 represents to have the grain sorting system of the alternate location that is used for actuator chamber and buffer chamber.
Fig. 6 represents the grain sorting system according to another embodiment of the invention.
Fig. 7 represents to be applicable to the bubble valve of grain sorting of the present invention system.
Fig. 8 is the schematic diagram of the grain sorting system of the bright illustrative embodiment of this law.
Fig. 9 represents an embodiment of the grain sorting system that is used for the parallel grain flow of sorting of instruction according to the present invention.
Figure 10 represents an embodiment of the grain sorting system that the binary tree type that the is configured to sorting of the instruction according to the present invention is constructed.
Figure 11 represents to be used for another embodiment with the multistage grain sorting system of the parallel grain flow of a plurality of stage sortings.
Figure 12 represents the grain sorting in parallel system according to alternative embodiment of the present invention.
Figure 13 represents grain sorting in parallel system according to another embodiment of the invention.
Figure 14 a and 14b represent grain sorting system according to another embodiment of the invention, comprise the photomask that is used for measuring particle size and/or speed.
Figure 15 represents the separation system in parallel with changeable channel according to another embodiment of the invention.
Figure 16 represents the Variable Array design of separation system in parallel according to another embodiment of the invention.
Figure 17 represents separation system in parallel according to another embodiment of the invention.
Figure 18 represents to be used to implement the medicament sifting motion system of grain sorting of the present invention system.
Detailed Description Of The Invention
The invention provides a kind of grain sorting system that is used for the particle that sorting floats on a liquid.This grain sorting system has the high throughput of predetermined properties particle and low wrong degree of sorting.Describe the present invention in detail below with reference to illustrative embodiment.Those skilled in the art should understand that the present invention can have multiple application mode and embodiment, are not confined to especially be applied in the particular described herein.
Refer to permission fluid that in medium, forms or pass medium formation such as the path that liquids and gases move at this used term " pipeline " " passage " and " flow channel ".The cross sectional dimensions of passage is preferably about 1.0 μ m to about 500 μ m in microfluidic system, is preferably about 25 μ m to about 250 μ m, most preferably is about 50 μ m to about 150 μ m.A those of ordinary skill in the art can determine the volume and the length of this flow channel.This scope is intended to comprise that above-mentioned value is as the upper limit or lower limit.Flow channel can have any selected shape or arrangement mode, for example comprises linear or nonlinear structure and U type structure.
Term " particle " refers to the discrete unit of material, includes but not limited to cell.
Refer at this used term " sensor " and to be used for the measurement target material, for example the device of the characteristic of particle.
Refer at this used term " bubble valve " and can produce the device that pressure pulse flows with the fluid of control by passage.
Refer at this used term " carrier fluid " and to be used to deliver the circumgranular compatible liquid skin of one or more particles by pipeline or passage.
Fig. 1 is the illustrative of the grain sorting system 10 of instruction according to the present invention.According to an application of the present invention, grain sorting system 10 comprises the closed channel system of the capillary dimensions that is used for the sorting particle.This channel system comprises that being used to introduce first of grain flow 18 supplies pipe 12 and be used to provide second of carrier fluid to supply pipe 14.First for pipe 12 formation mouth of pipe 12a, and grain flow is introduced in the carrier fluid stream.First is communicated with measuring tube 16 fluids for pipe 14 for pipe 12 and second, is used for transporting the particle that is suspended in carrier fluid.Measuring tube is divided into the first bypass passage 22a and the second bypass passage 22b in branch point 21 places trouble.Measured zone 20 is limited in the measuring tube 16, and unites to detect the predetermined properties by the particle of measured zone 20 with detector 19.Two relative bubble valve 100a and 100b place with respect to measuring tube and are communicated with its fluid.These valves separate relative to one another, and certainly should understand can also be with other make for those of ordinary skill.Bubble valve 100a is communicated with measuring tube 16 respectively by a pair of relative wing passage 24a and 24b with 100b.Thereby liquid can partially filled these wing passage 24a and 24b form meniscus 25 therein.Meniscus has been determined other fluid in the liquid storage tank of carrier fluid and relevant bubble valve 100, such as the interface of gas.Also provide an actuator 26 to be used to start one of them bubble valve, after it is activated by actuator 26, can in pipeline, temporarily cause to flow to disturb fluid is wherein deflected.As shown in the figure, actuator and bubble valve 100b are coupled.The pressure pulse that the second bubble valve 100a is produced by the first bubble valve 100b with absorption as buffer.
First wing passage 24b links to each other with pressurised chamber 70b fluid pressure type ground among first bubble valve 100b, if the pressure of this pressurised chamber raises like this, flowing near the measuring tube the wing passage just to intrinsic displacement, the flow direction of routine in being basically perpendicular to and managing.The second wing passage 24a that is oppositely arranged with the first wing passage 24b is connected with the buffer chamber 70a fluid pressure type in the second bubble valve 100a, is used to absorb instantaneous pressure.Thereby the first wing passage 24b and second wing passage 24a synergy have been controlled the liquid displacement by causing to pressurised chamber 70b pressurization noted earlier, and this displacement just has the perpendicular component of direction that flows with the conventional granulates of passing through measuring tube like this.
By to pressurised chamber 70b pressurization, a lot of liquid moment emits from the first wing passage 24b.In case when pressurization discharged, the elasticity of the second wing passage 24a just caused the ducted moment liquid stream inflow second wing passage 24a.The signal that sends in response to checkout gear 19 by external actuator 26 and to pressurised chamber 70b pressurization and decompression, the Flow Control of the synergy of two wing passages and their mutual commissures structure make the fluid moment by measuring tube 16 move in the branch road to and fro.This moment liquid displacement have with pipeline in the conventional perpendicular component that flows, can be used to make particle to deflect, so that the remainder particulate in they and the mixture is separated with predetermined properties.
As shown in the figure, measuring tube 16 is divided into two branch road 22a in branch point 21 troubles, and 22b makes particle flow through second branch road 22b in two branch roads usually after the fluid-flow rate adjustment in these branch roads.Angle between branch road 22a and the 22b is 0 to 180 degree, is preferably 10 to 45 degree.Yet, this angle even can be 0 degree, this is corresponding to two parallelpipeds that have straight type next door to each other.
Preferably will be provided on the measuring position of central fluid stream by the sorting particle, be the liquid skin that does not contain particle around it.The method of restriction grain flow is known, is commonly referred to " outer laminar flow " configuration.Usually, by suspended particulate stream is expelled in the carrier fluid that does not contain particle that flows through narrow outlet nozzle, can obtain limiting configuration in pipeline 16.By regulating the flow velocity of suspension and carrier fluid, just can adjust radially restriction configuration and internal particle distance in the pipe.The carrier fluid of big flow velocity can cause more restricted grain flow, has bigger distance between its particle.
In by first suspension of introducing for pipe 12, can distinguish two types particle, plain particles 18a and target particles 18b.Once the particle 18b that detects in the measured zone 20 has predetermined properties, detector 19 just sends signal.Receive the signal that sends in response to the predetermined properties that is detected by detector 19 when external actuator 26, just activate the first actuator bubble valve 100b, produce to flow in the measuring tube 16 between the 24b and disturb at wing passage 24a.Should flow disturb the particle 18b with predetermined properties was deflected, and make it to flow to the first bypass line 22a and be not the downstream of the second bypass line 22b.Detector is connected with actuator 26, makes that actuator just activates the first bubble valve 100b when detector 19 detects the predetermined properties of particle, changes to produce pressure in the liquid storage tank 70b of first bubble valve.The activation of first bubble valve deflects the meniscus 25b in the first bubble valve 100b and causes instantaneous pressure to change in the first wing passage 24b.The instantaneous pressure that is caused by actuator 26 in the second wing passage 24a and the second bubble valve 100a absorptiometry pipe 16 changes.Main, the liquid storage tank 70a of the second bubble valve 100a has elastic wall or compressible fluid is housed such as the buffer chamber of gas.This elastic characteristic makes liquid stream enter the second wing passage 24a from measuring tube, pressure pulse is absorbed and prevents that the mobile of non-selected particle in the grain flow is interfered.
In measured zone 20, utilize suitable sensor 19 to detect the particular characteristics of individual particle, for example size, form, fluorescence intensity and other conspicuous for a person skilled in the art characteristic.Available sensor various types of optical detection for example well known in the art system, microscope for example, NI Vision Builder for Automated Inspection and being used to are measured the electronic installation of the characteristic electron of particle.The system that is used to measure the fluorescence intensity of particle is a particularly system known per of this area.These systems comprise having the light source of suitable wavelength in order to initiation fluorescence, and the detection system that is used to measure the fluorescence intensity that is caused.This method usually is used in combination with particle with the fluorescence labeling substance markers, and fluorescent marker can produce the attachment molecules of another kind of special wavelength light (fluorescence) when being those with specific first wavelength light irradiation.If detect the light of this second wavelength, just sense described characteristic and send signal.
Other example comprises the flowed through light of particle scattering of measured zone of measurement.Analyze the information that scattered light can obtain relevant particle size and form, these information can be used to priming signal when detecting predetermined properties.
Be used for can comprising external actuator to the actuator 26 that the pressurised chamber of first bubble valve is pressurizeed, its signal that can have predetermined properties to the particle that sensor sends produces response.The external actuator that is suitable for pressurizeing has two kinds.First kind of direct liquid in the first wing passage 24b provides air pressure.For example, actuator comprises gas-pressurized for the source, and it is connected with the switching valve of fluid column in the wing passage 24b.The activation of converter is connected with gas-pressurized passage for the source, make that the meniscus in the liquid deflects.In case after stopping to activate, converter connects back passage 24b conventional operating pressure again.
Perhaps, displacement actuator can be used in combination with the pressurised chamber with removable wall.When displacement actuator made the wall of pressurised chamber that inside displacement take place, its pressure inside just raise.If removable wall is displaced to initial position backward, then pressure falls again and is back to conventional operating pressure.The electromagnetic actuators that suitable displacement actuator for example is subjected to displacement piston by magnet exciting coil.Another example is to use piezoelectric, for example with the form of column or lamination disk, produces linear displacement by applying voltage.Two types actuator all can drive the removable wall of pressurised chamber 70, and pressure is wherein changed.
The conversion operations situation of the converter 40 in the grain sorting system 10 of Fig. 2-4 presentation graphs 1.Among Fig. 2, detector 19 detects the predetermined properties in the particle and sends signal activation actuator 26.In case actuator is activated, the pressure in the liquid storage tank 70b of the first bubble valve 100b raises, and meniscus 25b deflects and liquid moment is discharged from the first wing passage 24b, as shown by arrows.Because the elastic performance of the liquid storage tank of the second bubble valve 100a, the unexpected increase of this place's pressure makes liquid flow to the second wing passage 24a in the pipe.Arrow has been expressed the moving process that liquid enters the second wing passage 24a.As a result, as shown in the figure, the fluid in the measuring tube 16 flows and deflects, and makes at the selected target particles 18b between the first wing passage 24b and the second wing passage 24a and shifts towards the perpendicular direction that flows under the state conventional with it.Selection is to the flow resistance of measuring tube 16, the first branch road 22a and the second branch road 22b, make arrive or from the preferred direction of flow of the first wing passage 24b and the fluid of the second wing passage 24a have significantly with measuring tube 16 in the vertical component of conventional flow direction.This target can reach by for example first branch road 22a and the second branch road 22b, makes that the resistance ratios first wing passage 24b of their convection cells and the second wing passage 24a's is big.
Fig. 3 represents that the liquid storage tank of first bubble valve is in the grain sorting system 10 in the decompression process, and this moment, target particles 18b left the volume between the first wing passage 24b and the second wing passage 24a.Actuator 26 makes liquid storage tank 70a after stopping to activate, and the pressure in the 70b is got back under the conventional pressure.At this decompression phase, there is Negative Pressure Difference in two liquid storage tank 70a of bubble valve between the 70b, make among the liquid flow path direction that passes through between the first wing passage 24b and the second wing passage 24a and the preceding width of cloth figure liquid flow path direction shown in the arrow opposite.
Fig. 4 has represented to finish the grain sorting system 10 of conversion sequence.Pressure in the liquid storage tank of bubble valve equates, makes by the fluid of measuring tube 16 is mobile to be tending towards normal.Because radial displacement has taken place target particles 18b, it will flow into the first branch road 22a, and other particle then continues to flow into the second branch road 22b, thereby according to predetermined character particle separation be opened.
This process that detects and optionally particle is deflected can repeat repeatedly each second, thus sorting particle at high speed.When adopting described fluid transfer process, conversion operations can be carried out approximately several thousand times more than each second, and the sorting speed that reaches is about 1,000,000 particles of sorting per hour.
According to another embodiment of the invention, actuator bubble valve 100a can be placed into different positions with buffer bubble valve 100b.For example, as shown in Figure 5, the actuator bubble valve 100a and the first wing passage 24a and/or buffer bubble valve 100b and the second wing passage 24b can be arranged on the upstream of branch point 21.These elements can be arranged on any suitable position, so that the flow resistance between actuator chamber 70a and the buffer chamber 70b is less than the assembly of any of these back and the flow resistance between other pressure confession source.More particularly, actuator chamber 70a and buffer chamber 70b can be provided with to such an extent that make flow resistance between them less than selected particle in grain flow and the flow resistance between the follow-up particle.These assemblies are placed by this way, thus prevented by above-mentioned make pressure wave that method that single selected particle deflects produces upstream or the downstream propagate, and avoid influencing flowing of all the other particles in the grain flow.Bigger difference makes that the flow behavior of remainder is separated with higher level in Flow Control conversion operations with relevant instantaneous pressure and the system between the flow resistance.In addition, the on-the-spot pressure pulse that is used for sorting that suppresses to be produced allows to implement to comprise the sorting network of a plurality of converters 40, and hydraulic pressure and air pressure ground keep apart between each converter and other the converter.
According to another embodiment, as shown in Figure 6, grain sorting of the present invention system can be with any suitable pressure wave generator (replacement bubble valve) and one or more bubble valve as buffer, and for example valve 100b is used in combination.For example, pressure wave generator 260 can comprise such as piezo column or the such actuator of stepper motor, the piston that it has directly or by the deflection of channel system working fluid is worked is in order to optionally to make particle deflect at actuator during by signal activation.Other suitable pressure wave generator comprises electromagnetic actuators, heating power pneumatic actuator and thermal pulse generator, by applying thermal pulse in order to produce vapor bubbles in working fluid.Buffer bubble valve 100b is arranged to absorb the pressure wave that produced by pressure wave generator 260 to prevent the interference to other particle in the grain flow.By changing the volume of buffer chamber 70b, the rigidity or the thickness of the elastic membrane (Reference numeral 72 among Fig. 7) of the cross-sectional area of wing passage 24b and/or formation buffer chamber 70b can make the elastic constant of buffer 100b change according to specific needs.
Fig. 7 represents according to instruction of the present invention, is applicable to that producing pressure pulse will separate and/or play the embodiment of buffer work in order to the valve 100 of absorption pressure pulse in target particles other particle from grain flow.As shown in the figure, the wing passage 24a or the 24b that lead to measuring tube 16 that forms on valve 100 and the substrate is adjoining.Wing passage 24a comprises the fluid interface mouth 17 that is formed by the opening on the channel side wall.The pressurised chamber 70 of sealing is positioned near the wing passage 24a and by the fluid interface mouth and is connected with the wing passage.Shown in chamber 70 constitute by sealed wall 71 and elastic membrane 72.The interface of carrier current among the wing passage 24a between wing passage and chamber forms meniscus 25.Actuator 26 is depressed elastic membrane raises the pressure in the chamber, meniscus is deflected and forms pressure pulse in carrier fluid.
Fig. 8 represents sorting module 50, and it has suitable to pipe 52 grain flows that are used to provide by sorting, and first outlet 54 and 56, two outlets of second outlet all can deliver in sorting module 50 by the particle of sorting.Sorting module 50 comprises detection system 19, is used to detect by entering the particle of sorting module 50 for pipe 52, operationally is connected with converter 40 in order to provide required conversion performance to come the sorting particle for pipe 52.The first branch road 22b among Fig. 1 can be arranged to be connected with outlet 54 second outlets 56 Flow Controls with the second branch road 22a.
Fig. 9 represents the grain sorting system 500 of another alternative embodiment according to the present invention, comprises a plurality of sorting modules 50 that can link together with any structure.For example, 50 one-tenth parallel forms of module in this embodiment.The outlet 54 of sorting module 50 and first is united outlet 58 and is connected, and second outlet 56 and second is united outlet 60 and is connected.Sorting module 50 systems that the arrangement form in parallel of this sorting module obtains uniting, the N that its total sorting speed that has is single sorting module 50 sorting speed times, wherein N is the number of sorting module 50 in parallel.
Figure 10 represents the grain sorting system 550 according to another embodiment, comprises the first sorting module 50a that connects with the second sorting module 50b.The second sorting module 50b is used for the particle that sorting has predetermined properties, and this character is identical or different with the predetermined properties of the first sorting module 50a institute sorting particle.Grain flow can contain at least two types particle by entering the first sorting module 50a for pipe 52.The particle of the first kind sub-elects in the first sorting module 50a, and flows out by the first outlet 54a.Remaining particle flows out the first sorting module 50a by the second outlet 56a, and enters the second sorting module 50b by second for pipe 52b.Particle with other predetermined properties sorts out and passes through the second outlet 54b from this grain flow and flows out.The particle that two kinds of predetermined properties do not possess flows out the second sorting module 50b by the second outlet 56b.Those skilled in the art learn easily, according to needed result, can use the sorting module 50 of any suitable type, and be connected in every way.
Figure 11 represents the hierarchy construction of high throughput-low error assorting room according to another embodiment of the invention.This illustrative embodiment is a two-stage grain sorting system 800, and the first step is used for a plurality of parallel grain flows of sorting, compiles the outflow result of the first step, implements second level assorting room then on first step outflow result's basis.Be among N the independent sort channel 81a-81n particle that each passage each second can the sorting predetermined number from the inflow grain flow in the suspension 80 of particle input chamber 88.Each passage 81 comprises surveyed area 84, is used to detect particle and discerns particle with predetermined properties, and transition region 82, be used for coming with having the particle of predetermined properties and other particle separation of fluid, as described above.Transition region 82 forms the outflow stream of two strands of particles at this transition region 82 according to the particle characteristics of being surveyed at surveyed area 84: " selecting " stream and " discarding " stream.Accumulate a plume from each passage " selecting " stream in collection region 86, so as in secondary sort channel 810 once more by sorting.As shown in the figure, secondary sort channel 810 is according to the assorting room of predetermined characteristics duplicate detection and sorting.
If the assorting room of each individual passage produces certain and falsely drops error (y) rate (y is that particle is by the probability of wrong choice, less than 1) of selecting, then hierarchy construction produces lower error rate y concerning 2 step classification processes as shown in the figure
2, perhaps producing error rate concerning n step classification process is y
nFor example, if the error rate of single passage is 1%, then the error rates in 2 steps are 0.01%, perhaps 10
4/ one.
Perhaps, this structure is that each secondary passage has M cover primary device, and every cover primary device comprises N sort channel.Suppose in this application, to need to be captured in that to have probability in the inlet flow be the particle of Z, and the per second the largest particles sorting index of single passage sorter is x.The throughput of system is a M*N*x particle per second.It is N*x*z that per second accumulates in N the numbers of particles in the passage, and N*z must be less than 1 so that all particles of assembling from N passage can come sorting by single secondary passage like this.In order to make throughput be higher than N=1/z, must increase N in parallel elementary+1 secondary passage.Total throughput is just from M*N*x and have M secondary passage like this.
Figure 12 represents multiple-series grain sorting system 160 according to another embodiment of the invention.This multiple-series grain sorting system 160 comprises the first sorting module 161 in parallel and the second sorting module 162 in parallel.The first sorting module 161 in parallel is used for the particle of sorting multiple labelling, and sub-elects the particle with two kinds of labels and be transported to exit passageway 165.
Figure 13 represents another kind of multiple-series grain sorting system 170.The first sorting module 171 in parallel is separated the particle with first label, collects these and comes from the particle of different passages and transport these particles with first label by first exit passageway 175.All other particle is introduced into second sorter 172 in parallel then, has the particle of second label in order to sorting.Collection has the particle of second label and transports by second exit passageway 176.Neither having the particle that first label do not have second label yet is transported by the 3rd exit passageway 177.
According to one embodiment of the invention, as shown in Figure 14 a and 14b, the grain sorting system can comprise the sensor that is used to measure particle speed, position and/or size.To the measurement of speed, position and/or size can with the classification of sorting particle is carried out simultaneously or is not carried out simultaneously.As shown in figure 11, in the system based on parallel port, different passages can have different flow resistances, makes the speed difference of particle in each passage or cell.In the system that detection zone 84 and transition region 82 separate with distance L, the speed of particle in the necessary known passage 81 is so that set switching hysteresis time T (i.e. the actuating conversion time that lags behind with respect to the moment of detecting target particles).
In the most of optical systems that are used for detecting cell or particle, cell causes that the luminous zone of photoelectric detector in the detection zone has the size more much bigger than cell dia therein.Like this, when detecting the light time at surveyed area, cell can be in any position in this zone, the feasible definite position that is difficult to locate cell.For more accurate detection is provided, can makes a plurality of pixels of fluorescence detector cover detection zone, but will cause very high expense like this and need complicated support electronic equipment.
According to illustrated embodiment of the invention, photomask 140 can be added to surveyed area, so that, provide accurate detection to speed by on the sorting chip, directly depositing " mask pattern ".Deposition mask pattern like this, the edge that makes mask pattern with respect to cell sorting actuator zone 82 location accurately (prior art is accurate to＜1um).When cell during not by mask, the single fluorescence detector that is used for the light that Acquisition Detection district 84 inner cells send just can be seen light.A lucifuge that is produced in the opaque coupling assembling " bar " of the mask by known length continues period, can measure speed.
Having some, to be of a size of 10um be that the mask pattern of the bar 141 of 1um causes having only size can minimize the signal that comes from cell greater than the bar of cell to 30um, amplitude of variation.Therefore, such pattern also can be used to measure the cell size, and the signal of dependent cells not.A kind of like this " gradient mask " also can produce pattern on fluorescence detector, its can be used for repeatedly analyzing with measuring speed to reduce the deviation of velocity estimation value.The light pattern that is caused by mask 140 also makes detector can discern every edge of mask 140.If all bars 141 are all identical, then the optical signal to each bar is also identical, and people have only by just distinguishing them in proper order.Therefore, the gradient mask pattern will make single detector monitor the zone of relative broad range (cell size several times), thereby measure the speed of cell, measuring surveyed area 84 interior positional precisions is 1um, it is relevant with the position of actuator on channel design and the chip accurately, and the identification cell size, its precision is determined by gradient pattern.Gradient mask 140 makes these parameters of detector energy measurement, and has nothing to do with the enlargement ratio of optical system or the character of fluorescence detector itself.
It will be understood by those skilled in the art that in accordance with the teachings of the present invention separation system also can utilize and be used to measure particle size, position and or other device of speed.These devices that are fit to are easy to for those of ordinary skills obtain and are known.
According to another embodiment of being invented, as shown in figure 15, the grain sorting system comprises the array 8000 of sort channel inequality.With regard to space, luminous intensity utilization and and the suitability of optimal external actuator, use the parallel connected array that comprises a series of sorter passage 810a-810n inequality more efficient.Because the speed of sensing particles exactly, therefore in the Performance Detection process with make between the conversion activation that particle with predetermined properties deflects, passage does not just need the hysteresis section of fixing.So just can change some parameters of passage, the passage shape between for example distance L between detector 84 and the converter 82, or detector 84 and the converter 82.
As perpendicular to single wavelength light source of chip direction the time, need the area limiting of this laser illumination to be: (number of active lanes) * ((surveyed area place width of channel)+(inner passage is C at interval)) (seeing Figure 15) in single laser instrument.Yet, only be aisle spare thereby can absorb the active region that light produces fluorescence: (number of active lanes) * (channel width), it obtains fill factor, curve factor and is: (channel width)/(channel width+C).Preferably near 100% fill factor, curve factor with effective incident light that avoids waste.
Therefore, make the interchannel of separation system in parallel minimize for the efficient of photo detection area and optical system very important at interval.In Variable Array design of the present invention, as shown in figure 16, the channel spacing in surveyed area 84 has reached width of channel, and light utilization efficiency has reached about 50% like this.Channel spacing in activation region 82 can be bigger, as shown in figure 16.Position along the actuator 26 of passage also can change so that make the external drive actuator have bigger effective radius.
Figure 17 represents grain sorting system 1700 according to another embodiment of the invention.This grain sorting system 1700 comprises the sorting module 1701 of a plurality of parallel operations.Grain sorting system 1700 comprises the injection zone 1710 and the surveyed area 1720 that is used to measure the particle predetermined properties of each sort channel 1702 in the surveyed area that is used for sample is introduced each sorting module.System also contains transition region 1730, is included in the actuator in each sorting module, is used for coming with the particle separation that does not have predetermined properties having the particle of predetermined properties.As shown in the figure, in the embodiment of Figure 17, sort channel in the surveyed area 1720 between each sort channel 1702 distance less than channel pitch in the transition region 1730 from.Cost when close spacing has been saved with the laser detection particle in the surveyed area, and bigger distance can adapt to the actuator of various sizes at interval in the transition region 1730.
Application number is 10/329018, and exercise question is applicable to the system that forms rich region for having described in the United States Patent (USP) of " realization of microfluidic components in the microfluidic system ", is incorporated herein its content as a reference.
According to shown in embodiment, the carrier fluid that removes can utilize and fill in back the inlet of primary channel again.Recovery approach or other device can be connected to primary channel with rich region, make the assorting room of back can utilize above-mentioned carrier fluid again.Perhaps, can be before removing discarded particle from discarded particle, remove in carrier fluid and introduce in the primary channel import.
Grain sorting of the present invention system has multiple application in the microflow control technique field.According to a kind of application, the grain sorting system can be implemented on as shown in figure 18 in the medicament sifting motion system.As shown in figure 18, medicament sifting motion system 140 comprises grain sorting module 10, is used for target cell is discerned and separated from the sample that comprises this target cell.The sample that will contain target cell is introduced screening system by the injection channel, and by the grain sorting module, it makes target cell separate and make target cell through mixing incubation zone 141 with remaining sample.Test compounds is contacted by TCH test channel 142 introducing mixing incubation zones 141 and with the target cell that is provided by grain sorting subsystem 10.Detect the effect that test compounds produces target cell at surveyed area 145 then.
Illustrative medicament sifting motion system 140 with grain sorting device 10 can use polytype label.This medicament sifting motion system can use the label of the activity of energy measurement certain enzyme, thereby can be used for searching the adjuster of the path that enzyme is existed.Medicament sifting motion system can also use the label of the concentration of interior courier/signal of any cell of energy measurement and label, with identification particular cell types, particularly rare (being less than one in each hundred cell) type.For example, the label that is fit to includes but not limited to, the cell surface marker thing, and as antibody and recombinant Display Technique, and luciferase substrate label, signal combination compound such as Ca in the cell
++Binding fluorescent dyes (Fura-3, Indo-1) and bioluminescence zymolyte label.In luciferase substrate label, compound enters cell and is transformed into fluorescent material by specific desmoenzyme.The Bodipy aminoacetaldehyde or the BAAA that for example are used for the ALDH enzyme are used for the MUP (4-methylumbelliferyl phosphate) of phosphatase and are used for the dihydro rhodamine 123 of cellular oxidation reduction system.The example that can be used for other fluorescent dye of the inventive method comprises that in bioluminescence zymolyte label, compound enters cell and directly luminous with specific endocellular enzyme effect.Usually this technology can combine with reporter to observe the activation of gene.Example comprises D-fluorescein and relevant reporter, and DMNPE and relevant reporter.
Shown in application in, can be according to the different compounds that the effect of various chemistry and biochemical system screened any number.For example can screening compounds to blocking-up, slow down or alternate manner suppresses the effect of the critical event relevant with the unpredictable biochemical system of effect.For example, ability that can filler test compounds block system, this system causes, or has caused the outbreak of disease or disease special symptom to occur to small part, for example comprises genetic disease, cancer, bacterium or virus infections or the like.The compound that has shown optimistic result in these Screening test methods can then be used to further test with discriminating disease or disease symptoms are treated effective pharmacological agents.
Perhaps, can be at promotion, raising or alternate manner cause the ability screening compounds of biochemical system, and this biochemical system has the function of expection, for example treats the defective disease that exists among the patient.
The present invention can be used for separating the rare cell various application of (promptly forming less than the 0.1%-1% that injects sample), such as but not limited to: cell is replanted, cell transplantation and cell transfecting or replant or transplant before genetic modification.The present invention also can be used for the tumour cell in the sample separation, to be used to develop the particular treatment method.
The present invention also can be used to screen the compound that acts on blastema, is for example separating (apheresis) acquisition 10 by blood
11Individual cell and screen any subgroup but not clone.The present invention can also be used to screen the compound that acts on incomplete clone, wherein in this screening sequence less than 100% expression of cell lines correct gene.The present invention also can be used to screen the compound that the cell that is in the specific cells phase of the cycles is worked, for example, and the compound that screening is worked to the cell that only is in replicative phase.
The present invention is described by relevant illustrative embodiment.Because under the situation that does not depart from the scope of the invention, above-mentioned structure can be made certain change, and therefore institute comprises or all the elements shown in the drawings only are intended to indicative explaination and there is no restrictive sense in the above-mentioned explanation.
What it is also to be understood that is that following claim will comprise all general and special features of the present invention described herein, and we can say the scope of all requirements of the present invention, as language expression, all drop on wherein.
Illustrated after the present invention, as new invention desired and by patent license protect in have:
Claims (23)
1. microfluidic system comprises:
Substrate
Be formed at the cell sorting system on the described substrate, be used for based on the predetermined characteristics sorting cells; And
Be formed at the screening system that is used to screen cell on the described substrate, described screening system has and is used to mix the cell with predetermined properties and the Mixed Zone of test compounds, and is used to detect the surveyed area of described test compounds to effect with particular characteristics cell.
2. microfluidic system as claimed in claim 1 further is included in the interface channel between cell sorting system and the screening system, is used for selected cell is transported to screening system from cell sorting system.
3. microfluidic system as claimed in claim 1, wherein said cell sorting system comprises:
Be used for transporting first pipeline of the suspension cell stream of carrier fluid, comprise that inlet, first outlet and second export;
Be used to detect the sensor of one of the size of the predetermined properties of particle and particle and speed;
The wing passage that is connected with first pipeline;
Be positioned near the sealing chamber the described wing passage, wherein carrier fluid forms meniscus will seal chamber and carrier fluid separates in the wing passage; And
Actuator, when detector detects described predetermined properties, this actuator changes the indoor pressure of enclosed cavity deflects meniscus, makes the cell with described predetermined properties flow to second outlet by the deflection of meniscus, and the particle that does not have a described predetermined properties flows to first outlet.
4. microfluidic system as claimed in claim 3, wherein said cell sorting system further comprises the buffer that is used for absorbing the first pipeline pressure variety.
5. microfluidic system as claimed in claim 3, wherein said actuator comprises pressurized-gas source.
6. microfluidic system as claimed in claim 3, wherein said sealing chamber comprises removable wall.
7. microfluidic system as claimed in claim 5, wherein said actuator comprises displacement actuator, is used for moving the removable wall of described sealing chamber to change the pressure of described sealing chamber.
8. microfluidic system as claimed in claim 7, wherein said actuator comprise a kind of in electromagnetic actuators and the piezoelectric element.
9. system that is used for the filler test compound comprises:
A kind of being used for target particles from the grain sorting system that the sample that contains described target particles is separated, described grain sorting system comprises:
Be used to transport first pipeline of sample, comprise inlet, first outlet and second outlet;
Be used for detecting the sensor of the predetermined properties of target particles;
The wing passage that is connected with first pipeline;
Be positioned near the sealing chamber of described wing passage, the wherein said first ducted carrier fluid forms meniscus so that described sealing chamber and described carrier fluid are separated in described wing passage; And
Actuator, when sensor detects described predetermined properties, this actuator changes the indoor pressure of enclosed cavity deflects meniscus, makes the particle with described predetermined properties flow to second outlet by the deflection of meniscus, and the particle that does not have a described predetermined properties flows to first outlet
With the described second mixing incubation zone that is connected of outlet, be used for receiving target particle and test compounds and be used for described test compounds is mixed with described target particles; And
Be used to detect the surveyed area of described test compounds to the effect of target particles.
10. a test compounds comprises the method for the effect of target cell:
Based on one group of cell of predetermined characteristics sorting;
The cell that will have described predetermined properties by interface channel is transported to the Mixed Zone; And
Compound is incorporated into described Mixed Zone.
11. a method of screening blastema comprises:
One group of cell of sorting is to separate a cell subsets from this group;
Compound is added in the described cell subsets; And
Analyze described cell subsets to determine of the effect of described compound to described cell subsets.
12. the method for an analysis of compounds side effect comprises:
One group of blastema is provided;
Compound is added in the described blastema;
Measure the activity of described blastema to determine to cause by described compound;
To have active blastema separates with the blastema that does not have activity.
13. the described method of claim 10, wherein said predetermined properties is for existing the label of expection.
14. the described method of claim 13, the label of wherein said expection are antibody, enzyme, substrate, confactor, fluorescent dye or reporter.
15. one kind is used for the method that screening compounds is exchanged the ability of ganglion cell's activity, and described cell is contacted with test compounds, and monitors the response of described cell to described test compounds with the microfluidic system of claim 1.
16. a method of utilizing microfluidic system isolated cell subgroup from cell colony comprises:
From have the phenotypic colony of expection, discern cell; And
Never have and separate described cell in the phenotypic cell of described expection.
17. the described method of claim 16, the blastema culture of wherein said cell colony for separating.
18. the described method of claim 16, wherein said cell colony are cell culture.
19. a separation is used for the method for the cell subsets of cell transplantation, comprising:
Identification has the phenotypic cell of expection;
Utilize micro fluidic device to separate described cell;
Thereby separate the cell subsets that is used to transplant.
20. a separation will be carried out the method for the cell subsets of genetic modification, comprise:
Based on the cell subsets in the phenotype identification cell colony of expection;
Utilize micro fluidic device to separate described cell;
Thereby separate and to carry out the cell subsets of genetic modification.
21. the method for claim 20, the cell that will carry out genetic modification of wherein said separation is replanted in the target.
22. the method for an isolated cell subgroup comprises:
Identification has shown the cell subsets of cell cycle phase particular marker;
Utilize micro fluidic device to separate described cell;
Thereby separate the cell subsets that is in the same cell phase of the cycles.
23. a test compounds comprises the method for enzymatic activity regulating power in the body:
Add compound to cell colony, wherein said compound can send fluorescence when being activated by described cellular enzymes; And
Measure described cell fluorescence to determine that described compound is to regulating the ability of enzymatic activity.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41105802P | 2002-09-16 | 2002-09-16 | |
| US60/411,058 | 2002-09-16 | ||
| US60/411,143 | 2002-09-16 | ||
| US10/329,008 | 2002-12-23 |
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| CN200910166804A Division CN101653768A (en) | 2002-09-16 | 2003-09-16 | Method and apparatus for sorting particles |
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| CN1735466A true CN1735466A (en) | 2006-02-15 |
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| CN 03825178 Pending CN1735466A (en) | 2002-09-16 | 2003-09-16 | Method and apparatus for sorting particles |
| CN200910166804A Pending CN101653768A (en) | 2002-09-16 | 2003-09-16 | Method and apparatus for sorting particles |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200910166804A Pending CN101653768A (en) | 2002-09-16 | 2003-09-16 | Method and apparatus for sorting particles |
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| ZA (1) | ZA200502168B (en) |
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Also Published As
| Publication number | Publication date |
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| ZA200502168B (en) | 2006-06-28 |
| CN101653768A (en) | 2010-02-24 |
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