CN101693239A - Method and apparatus for sorting particles - Google Patents
Method and apparatus for sorting particles Download PDFInfo
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- CN101693239A CN101693239A CN200910168699A CN200910168699A CN101693239A CN 101693239 A CN101693239 A CN 101693239A CN 200910168699 A CN200910168699 A CN 200910168699A CN 200910168699 A CN200910168699 A CN 200910168699A CN 101693239 A CN101693239 A CN 101693239A
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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
The application is for enjoying April 17 2003 applying date and being called the dividing an application of application number 03814212.0 of " method and apparatus of sorting particles ".
Related application
The application requires the priority of following application, the U.S. Provisional Patent Application 60/373256 of application on April 17th, 2002, the U.S. Patent application 10/179586 of application on June 24th, 2002, the U.S. Provisional Patent Application 60/411058 of application on September 16th, 2002, the U.S. Patent application 10/329008 of application on December 23rd, 2002, and the application is the part continuity of the U.S. Patent application 10/179488 of application on June 24th, 2002, and its content is incorporated by reference.
Technical field
The present invention relates to method and apparatus that the particle in the suspension is classified, wherein the inlet flow path of classification component can be divided into several output channels, more specifically, the present invention relates to a kind of particle categorizing system, wherein a plurality of classification component are connected to each other so that the particle throughput that obtains to increase.
Background technology
At technical field of bioengineering, particularly cytology and medicine screening field needs the high throughput classification of particle.Needing the example of the particle of classification is various types of cells, for example blood platelet, white blood cell, tumour cell, blastocyte or the like, and people are interested in especially these particles in the cytology field.Other particle is (greatly) branch subclass, for example protein, enzyme and polynucleotides, and during new medicine development, people are interested in especially this particle family in medicine screening field.
The method and apparatus of particle classification is known, great majority described in the prior are all worked under a kind of like this condition, be that particle is suspended in the liquid that flows through channel network and according to the principle work that detects the decision skew, described channel network has at least one branch point in the downstream.At first analyze the particular characteristics of mobile particle, for example light absorption, fluorescence intensity, size or the like, according to the result of this detection-phase, how decision is further handled particle in the downstream, then, the result who uses decision is with the predetermined branch skew towards channel network of the direction of specific particle.
The throughput of sorting device importantly, that is, and time per unit how many particles of classifying.For independent taxon, in closed channel, utilize the common classification speed of the grader of particle suspension flow to be in a per second hundreds of particle in the scope of several thousand particles of per second.
Described a kind of example of sorting device in United States Patent (USP) 4175662, its content is incorporated herein by reference (being called ' 662 patents hereinafter) at this.In ' 662 patents, be the central authorities that the grain flow of cell flows through straight channels in this case, the branch point of straight channels in a downstream is branched off into two vertical channels (T-branch), the particle that enters by the compatible liquid sheath around, make particle keep being closed in the central authorities of passage.Under normal circumstances, to regulating by the flow-rate ratio of two branches so that particle flows through one of branch automatically, in a part of passage, determine particle characteristics with detector, detector can be optical system (detection-phase).In the decision stage, when detector detected the particle that has predetermined properties, detector produced a signal.In the skew stage,, just activate a deviator so that the particle skew in case particle is detected.In this example, deviator comprises the electrode pair that is arranged in channel branch, and particle flows through described passage usually in the non-actuated condition of deviator.By the application of current impulse, aqueous liquid is created in the bubble of emitting between the electrode pair by electrolysis.Because bubble size increases, the flow by this branch during emitting the bubble stage reduces.After the applied current pulse, bubble increases and to stop, and bubble is carried with liquid stream, the result, and the liquid stream moment by specific branch reduces, and interested particle changes the path and along another diverted flow.
The device of ' 662 patents is effectively for sorting particles, yet an important disadvantages is the bubble that has produced some some place that may be deposited in fluid network, and this bubble generates may block flow channel, produces wrong classification.Another shortcoming is that the gas (mainly being oxygen and hydrogen) and the ionic species that produce (mainly are OH
-And H
+) influenced the particle that flows through branch with electrode pair.In addition, the trickle protein of cell and for example enzyme is very fragile, may be destroyed by the dirt composition that produces with bubble.Another shortcoming is the complexity of whole sorting device, and specifically, the microelectrode structure is very complicated for installing in the thin channel of system and assembling, the result, and the cost of taxon is relatively large.
Disclosed another example of the particle categorizing system of prior art in US3984307, its content is incorporated herein by reference (being called ' 307 patents hereinafter) at this.In ' 307 patents, particle is flowing through passage central authorities, the sheath liquid sealing of being flowed.After the process detector portion, channel branch becomes two passages (for example Y shape branch) that form acute angle therebetween, just before branch point, the transducer of an electric actuation is arranged in passage and is used for being offset and has specific particle suitable, predetermined properties, the transducer of describing is piezo actuator or ultrasonic transducer, it produces pressure wave in passage when electric excitation, the pressure wave of generation is upset flowing in the branch at once, thereby interested particle is displaced in another branch.
In the device of ' 307 patents, in aforementioned means, deviator is attached in the channel system, causes big relatively constructions cost.Another shortcoming of this device is used deviator principle, the pressure wave that produces is not limited to branch point, but upstream propagate in the detector portion, and propagate into downwards in two branches, this influence is flowed by the whole of passage, if the grader of the type is connected in series or is connected in parallel, these two kinds of connections are used the categorizing system with the structure high throughput usually, this shortcoming especially then, at that time, the pressure wave energy that produces in a grader influences the skew of flowing with particle in adjacent grader unit.
Disclosed another kind of grader in United States Patent (USP) 4756427, its content is incorporated herein by reference at this.Grader in this grader and ' 662 patents is similar, yet in this example, the liquid stream in branch is because moment changes branch's resistance is interfered, and resistance is owing to the height of external actuator change branched bottom is changed.In a preferred embodiment, this external actuator is the piezoceramic disk that is bonded on the channel roof, and it makes passage move down when triggering.
Though the grader of describing in ' 427 patents structure does not have aforementioned grader complex structure, but the classifier component of a plurality of described types combined to be increased classification speed and is still problematic, in the described grader of ' 307 patents, this is because the pressure wave that produces causes interference to other classifier component.
Disclosed another particle sorting device in United States Patent (USP) 5837200, its content is incorporated herein by reference at this.' 200 patents have been described a kind of sorting device, and it is based on the magnetic property of particle, classify or select particle with the magnetic deflection assembly, and ' 200 patents have also been described parallel processing and separated single grain flow.
Summary of the invention
The invention provides a kind of method and apparatus of classifying to the particle of the closed channel system that moves through capillary dimensions, particle categorizing system of the present invention provides a kind of classification component, it can assemble with low cost, provides a kind of in the classify accurate means of a large amount of particles of per time unit simultaneously.The particle categorizing system can comprise a plurality of classification component of combining closely, and they are combined with further increase classification speed.In order to reduce error rate, the particle categorizing system can comprise that multiclass classification equipment is to classify to grain flow continuously.
The particle categorizing system is implemented according to improved fluid particle method of switching of the present invention and switching device, the particle categorizing system comprises the closed channel system of capillary dimensions of sorting particles of being used for, channel system comprises second service that is used for introducing first service of grain flow and is used for supplying carrier fluid, first service forms a nozzle grain flow is introduced in the flowing of carrier fluid, first service and second service are communicated with the measuring channel fluid, measuring channel is branched off into first branch and second branch at a branch point, measured zone is limited in the measuring channel and is associated to detect the predetermined properties of particle in measured zone with detector, two relative bubble valve are positioned to and measuring channel and spaced relative to each other, bubble valve is communicated with measuring channel by a pair of relative side path, allow liquid partly to fill these side paths to form meniscus therein, this meniscus is as the boundary of the reservoir of carrier fluid and bubble valve.In external actuator so that the moving bubble valve one also is provided, and when external actuator activated, the pressure in the reservoir of the bubble valve of actuating increased, and made the meniscus skew, caused that in measuring channel flow disturbance is with skew liquid stream wherein.
When the sensor that is arranged in measured zone when the particle that flows through measured zone perceives predetermined properties, sensor responds detected characteristic and produces a signal, external actuator causes a pressure pulse in response to sensor in the discharge chambe of first bubble valve, skew has the particle of predetermined properties, makes the particle of selecting flow along second lateral.
In one aspect, the present invention includes a kind of method of sorting particles, it comprises the following steps: to provide the measuring channel with inlet and branch point, measuring channel is punished into two laterals at branch point, the fluid stream of the grain flow that wherein suspending is directed in the described entrance, so that particle flows through in the lateral first usually, and upstream provide two relative side paths from branch point, be used for the ducted described stream of moment offset measurement.In the side path first hydraulically is connected to the discharge chambe of first bubble valve, and external actuator works changing pressure wherein to it, and in the side path second hydraulically is connected with absorption pressure with the surge chamber of second bubble valve and changes.Method also comprises along the measuring channel of side path upstream provides measuring station, be used for particle in the test fluid stream predetermined properties and when detecting predetermined properties, produce a signal.Method also comprises the following steps: to respond detected predetermined properties, activates external actuator to cause flow disturbance in the measuring channel between the side path, flows along second lateral thereby skew has the particle and the feasible particle of selecting of predetermined properties.
In another aspect of the present invention, by respectively a plurality of classification component being connected in parallel or a plurality of classification component are connected continuously with the tree-shaped configuration of y-bend, the grain type increase that the particle classification speed increases respectively or is classified.
According to an aspect of the present invention, provide a kind of particle categorizing system.The particle categorizing system comprises first pipeline that is used for transmitting the suspended particulate stream that is limited in the carrier fluid, it comprises inlet, first outlet and second outlet, be used for the sensor of predetermined properties in the perception particle, the wing passage that is communicated with first pipeline, the closed chamber of adjacent side channel location, wherein carrier fluid forms meniscus so that closed chamber and carrier fluid are separated in wing passage; And actuator, when sensor senses arrived predetermined properties, the pressure in the actuator change closed chamber was with the skew meniscus, and the skew of meniscus makes the particle with predetermined properties flow into second and exports that the particle that the while does not have predetermined properties flows into first outlet.
Description of drawings
Fig. 1 is the schematic diagram according to the particle categorizing system of illustrative embodiment of the present invention;
The operation of the particle categorizing system of Fig. 2 to 4 presentation graphs 1;
Fig. 5 represents the particle categorizing system, but it shows the chosen position of actuation chamber and surge chamber;
Fig. 6 represents the particle categorizing system of another embodiment according to the present invention;
Fig. 7 represents to be suitable for the bubble valve in the particle categorizing system of the present invention;
Fig. 8 is the schematic of the particle categorizing system of illustrative embodiment of the present invention;
Fig. 9 represents according to the present invention the embodiment to the particle categorizing system of parallel grain flow classification of being used for of instruction;
Figure 10 represents an embodiment of the particle categorizing system that the classification component with the tree-shaped configuration of y-bend of the instruction according to the present invention is configured to;
Figure 11 represents to be used for multistage mode another embodiment to the multistage particle categorizing system of parallel grain flow classification;
Figure 12 represents the particle categorizing system in parallel of another embodiment according to the present invention;
Figure 13 represents the particle categorizing system in parallel of another embodiment according to the present invention;
Figure 14 a and 14b represent the particle categorizing system of another embodiment according to the present invention, and it comprises that optical mask is to allow to measure particle size and/or speed;
Figure 15 represents the categorizing system in parallel with changeable channel of another embodiment according to the present invention;
Figure 16 represents the Variable Array design of the categorizing system in parallel of another embodiment according to the present invention;
Figure 17 represents the categorizing system in parallel of another embodiment according to the present invention.
The specific embodiment
The invention provides a kind of particle categorizing system, be used for the particle that floats on a liquid is classified, the particle categorizing system provides high throughput, low wrong particle classification based on predetermined properties.To describe the present invention with respect to illustrative embodiment below, it should be appreciated by those skilled in the art that the present invention can implement, and is not confined to specific implementations described here especially in its application facet in a large amount of different application and embodiment.
Refer to the path that is formed in the medium or passes medium at this used term " pipeline " " passage " and " flow channel ", this medium allows the moving of fluid of liquids and gases for example.Preferably, the cross sectional dimensions of passage is in the scope between about 1.0 microns to about 500 microns, preferably between about 25 microns and about 250 microns, most preferably between about 50 microns to about 150 microns in the microfluid system.Those of ordinary skills will determine suitable flow channel volume and length, these scopes are intended for the upper limit or lower limit comprises above-named value, flow channel can have any selected shape or layout, and its example comprises linear or non-linear configuration and U-shaped configuration.
Term " particle " refers to the urstoff of separation, including, but not limited to cell.
Term " sensor " refers to and is used for the device of measurement target characteristic as used herein, and target for example is a particle.
Term " bubble valve " refers to and produces pressure pulse with the device that flow of control by passage as used herein.
Term " carrier fluid " refers to the compatible liquid sheath around particle as used herein, and it is used for carrying one or more particles by pipeline or passage.
Fig. 1 is the schematic diagram of the particle categorizing system 10 of instruction according to the present invention.According to a kind of application of the present invention, particle categorizing system 10 comprises the closed channel system of capillary dimensions of sorting particles of being used for, channel system comprises second service 14 that is used for introducing first service 12 of grain flow 18 and is used for supplying carrier fluid, first service 12 forms a nozzle 12a, and grain flow is introduced in the flowing of carrier fluid.First service 12 and second service 14 are communicated with measuring channel 16 fluids, measuring channel 16 is used for transmitting the particle that is suspended in the carrier fluid, measuring channel is branched off into the first branched bottom 22a and the second branched bottom 22b at a branch point 21, and measured zone 20 is limited in the measuring channel 16 and is associated with detector 19 passes the predetermined properties of the particle of measured zone 20 with detection.Two relative bubble valve 100a and 100b place and are arranged to be communicated with its fluid with respect to measuring channel.Valve separates relative to one another, can use other configuration although those those of ordinary skill should be understood also.Bubble valve 100a is communicated with measuring channel 16 by a pair of relative side path 24a and 24b respectively with 100b, allow liquid partly to fill these side path 24a and 24b to form meniscus 25 therein, this meniscus has been determined the boundary between carrier fluid and the one other fluid, and described one other fluid for example is the gas in the reservoir of the bubble valve 100 that is associated.Also provide actuator 26 activating any bubble valve, when being activated by actuator 26, bubble valve moment in pipeline causes that flow disturbance is with skew flowing wherein.As shown, actuator is attached to bubble valve 100b, the pressure pulse that the second bubble valve 100a is caused by the first bubble valve 100b with absorption as buffer.
The first side path 24b hydraulically is connected to the discharge chambe 70b among the first bubble valve 100b, if so that the pressure in this chamber increases, mobile inwardly displaced near the measuring channel the side path is substantially perpendicular to ducted proper flow.The position second side path 24a relative with the first side path 24b hydraulically is connected to the surge chamber 70a among the second bubble valve 100a, is used for the absorption pressure transition.This first side path 24b and the second side path 24a acting in conjunction are to guide aforementioned liquid displacement by causing for discharge chambe 70b supercharging, so that displacement has the component of crossing measuring channel perpendicular to the particle normal flow.
When giving discharge chambe 70b supercharging, some liquid were discharged from first side path 24b moment, and the elasticity of the second side path 24a causes ducted liquid moment to flow into the second side path 24a when supercharging is discharged.When the acting in conjunction of two side paths and their interconnective fluidic structures make the hydraulic pressure chamber 70b supercharging that causes at the signal that is sent by external actuator 26 response detection devices 19 and step-down, mobile moment by measuring channel 16 moves around to one side, this moment liquid displacement has the component perpendicular to proper flow in the pipeline, it can be applied to make in the particle skew with predetermined properties, so that these particles are separated from all the other particles of mixture.
As shown, measuring channel 16 is branched off into two 22a of branch, 22b at branch point 21, flow in these branches is conditioned so that particle flows through second 22b in two branches usually, angle between the 22a of branch, the 22b is between 0 to 180 degree, preferably 10 to 45 the degree between, yet, angle in addition can be 0 the degree, this angle is corresponding with the pipeline of two parallel connections, has straight partition wall between them.
The particle that is classified is preferably supplied to measuring position in the central fluid stream, its by no particle-liquid sheath around.The processing of sealing grain flow is known, is commonly referred to " sheath stream " configuration, and is common, by a narrow outlet nozzle suspended particulate stream is ejected into and realizes sealing in the no particle carrier fluid that flows in pipeline 16.By regulating the flow-rate ratio of suspension and carrier fluid, can regulate ducted radial-sealing and mutual particle distance, big relatively carrier fluid flow causes having the grain flow of sealing more of very big distance between particle.
In the suspension of introducing by first service 12, can distinguish two types particle, plain particles 18a and particle 18b interested.When the predetermined properties that in measured zone 20, detects among the particle 18b, detector 19 sends a signal, when the detected predetermined properties of detector 19 responses signals, external actuator 26 activates the first actuator bubble valve 100b, produce flow disturbance in the measuring channel 16 between side path 24a, 24b, flow disturbance makes the particle 18b skew with predetermined properties so that it is mobile along the first lateral 22a rather than the second lateral 22b.Detector is communicated by letter with actuator 26, when in particle, detecting predetermined properties with convenient detector 19, actuator activates the first bubble valve 100b to be changed to cause pressure in the reservoir 70b of first bubble valve, and the actuating of first bubble valve makes the meniscus 25b skew among the first bubble valve 100b and causes that in the first side path 24b instantaneous pressure changes.The second side path 24a and the second bubble valve 100a absorb the instantaneous pressure in measuring channel 16 that is caused by actuator 26 to be changed.Basically, the reservoir 70a of the second bubble valve 100a has elastic wall or holds for example surge chamber of compressible fluid such as gas, elastic property allows liquid to flow into the second side path 24a from measuring channel, make pressure pulse be absorbed, and prevent to disturb flowing of non-selected particle in the grain flow.
In measured zone 20, check with the particular characteristics of 19 pairs of individual particles of right sensors, for example size, shape, fluorescence intensity and other is for a conspicuous characteristic of those of ordinary skill.The example of suitable sensor known in the art is various types of optical detection such as microscope system for example, NI Vision Builder for Automated Inspection and the electronic installation that is used for measuring the particle electronic property, system well known in the art is the system that is used for measuring the fluorescence intensity of particle, these systems comprise light source with the suitable wavelength that is used for causing fluorescence and the detection system that is used for measuring the fluorescence intensity that is caused, this method is used in combination with the particle that is marked with fluorescence labelling usually, fluorescence labelling is a kind of accessory molecule, and it produces the light (fluorescence) of another specific second wavelength when being penetrated by the illumination of specific first wavelength.If detect the light of this second wavelength, then detect described characteristic and send signal.
Other example comprises the measurement of the light of the particle scattering of being flow through measured zone, explains about the size and dimension of particle and the generation information of scattering when detecting predetermined properties, can adopt this information to send signal.
Be used for can comprising external actuator to the actuator 26 of the discharge chambe of first bubble valve pressurization, its response has the signal of selected predetermined properties from the expression particle of sensor.There are two classes to be fit to increase the pressure external actuator, the first kind directly offers air pressure the liquid among the first side path 24b, for example, actuator can comprise the high pressurized gas that is connected to the liquid capacity among the side path 24b with switch valve, the actuating of switch is connected to high pressurized gas with path, and this makes the meniscus skew in the liquid.When not activating, switch is connected back to normal operating pressure with path 24b.
According to another program, displacement actuator can be used in combination with the closed compression chamber with removable wall.When displacement actuator made the wall of discharge chambe inwardly displaced, internal pressure increased, if removable wall shift is got back to the home position, pressure just subtracts gets back to service pressure.An example of suitable displacement actuator is an electromagnetic actuators, and it causes the displacement of plunger when coil electricity.Another example is the use of piezoelectric, for example is the form of cylinder or a pile pan, and it produces linear displacement when applying voltage.The removable wall that two types actuator all engages discharge chambe 70 changes to cause pressure wherein.
The switching manipulation of the switch 40 in the particle categorizing system 10 of Fig. 2 to 4 presentation graphs 1.In Fig. 2, the predetermined properties in the detector 19 perception particles also produces signal with actuated actuators 26.When actuator activated, the pressure in the reservoir 70b of the first bubble valve 100b increased, and made meniscus 25b skew and caused liquid to be discharged from first side path 24b moment, as shown by arrows.Because the elastic property of the reservoir of the second bubble valve 100a, so the abrupt pressure increase that takes place at this point in the pipeline makes liquid flow into the second side path 24a, liquid this in the second side path 24a moves with an arrow to be represented.The result, if can see in the drawings, mobile quilt by measuring channel 16 is offset, make the particle 18b selected interested between the first side path 24b and the second side path 24a move perpendicular to the flow direction under its normal condition, have tangible component to flow resistance, first 22a of branch and second 22b of branch of measuring channel 16 are chosen so that commute the preferred direction of flow of the first side path 24b and the second side path 24a, this component is perpendicular to the proper flow by measuring channel 16.For example, the flow resistance by making first 22a of branch and second 22b of branch reaches this target greater than the flow resistance of the first side path 24b and the second side path 24a.
Fig. 3 represents when particle 18b interested leaves volume between the first side path 24b and the second side path 24a, the particle categorizing system 10 during the decompression of the first bubble valve reservoir.Actuator 26 is deactivated, make reservoir 70a, 70b pressure inside turn back to normal pressure, at this decompression phase, between two reservoir 70a, 70b of bubble valve, Negative Pressure Difference is arranged, make the liquid stream shown in liquid and the prior figures flow through the first side path 24b and the second side path 24a on the contrary, as shown by arrows.
Fig. 4 is illustrated in and finishes switching programme particle categorizing system 10 afterwards.Pressure in the bubble valve reservoir equates, make by flowing of measuring channel 16 normally, as particle 18b interested during radial displacement, it will flow into first 22a of branch, other particle continues to flow into second 22b of branch simultaneously, thereby separates particle based on predetermined properties.
In order with high speed particle to be classified, the detection of particle and this processing per second that has selection to be offset can repeat many times.Adopt described fluid switch, can produce the approximately per hour classification speed of sorting particles up to a million to carry out switching manipulation up to the speed of the about hundreds of of per second time switching manipulation.
Another embodiment according to the present invention, actuator bubble valve 100b and buffer bubble valve 100a can be placed in the diverse location, for example, as shown in Figure 5, the actuator bubble valve 100b and the first side path 24b and/or buffer bubble valve 100a and the second side path 24a can upstream place from branch point 21, element can be placed in any suitable position, so that the flow resistance between actuation chamber 70b and the buffer chamber 70a is less than the flow resistance between any and other pressure source in the element of these back.More specifically, actuation chamber 70b and buffer chamber 70a can place like this, and promptly the flow resistance between them is less than the flow resistance between subsequently the particle in selected particle and the grain flow.Thereby after this manner element location has prevented pressure wave that the method by the single selected particle of above-mentioned skew produces upstream or propagates down stream, influence the mobile of all the other particles in the grain flow.If the difference on flow resistance is bigger, the fluid switch operation that then has a related pressure transient is just higher with the degree that the flow behavior in system's remainder is isolated.And the original position damping of the generation pressure pulse that applies for classification allows to comprise the enforcement of the sorter network of a plurality of switches 40, and each switch is all hydraulically isolated with air pressure ground with other switch.
According to another embodiment shown in Fig. 6, particle categorizing system of the present invention can be in conjunction with one or more bubble valve as buffer, and for example valve 100b uses any suitable pressure wave generator (replacement bubble valve).For example, pressure wave generator 260 can comprise an actuator, for example piezo column or stepper motor, its be provided with can be directly or the skew by channel system act on plunger on the working fluid, when actuator is activated by a signal, selectively to be offset particle.Other suitable pressure wave generator comprises electromagnetic actuators, heating power pneumatic actuator and by applying thermal pulse produces steam bubble in working fluid thermal pulse generator.Buffer bubble valve 100b is placed to the pressure wave that absorption is produced by pressure wave generator 260, to prevent the flow disturbance in other particle of grain flow.The spring constant of buffer 100b can be according to specific needs, and the volume by changing buffer chamber 70b, the cross-sectional area of side path 24b and/or the rigidity or the thickness that form the flexible membrane (Reference numeral 72 among Fig. 7) of buffer chamber 70b change.
Fig. 7 represents according to the present invention one embodiment of the valve 100 of instruction, and it is fit to produce pressure pulse so that interested particle and other particle in the grain flow are separated and/or serve as the buffer of absorption pressure pulse.As shown, valve 100 forms near side path 24a or 24b ground, and side path 24a or 24b are formed in the substrate that leads to measuring channel 16.Side path 24a comprises the fluid interface 17 that is formed by a slit in the sidewall of path, the discharge chambe 70 adjacent sides path 24a of sealing locate and are communicated with the side path by fluid interface.Illustrative chamber 70 is formed by seal 71 and flexible membrane 72, the interface of carrier fluid among the side path 24a between side path and discharge chambe forms meniscus 25, actuator 26 is depressed flexible membrane to increase the pressure in the discharge chambe, and this makes the meniscus skew and cause pressure pulse in carrier fluid.
Fig. 8 represents to have the classification component 50 of suitable service 52 and first outlet conduit 54 and second outlet conduit 56, service 52 is used to provide the grain flow that is classified, and any in first outlet conduit 54 and second outlet conduit 56 can both be carried at the particle of classification in the classification component 50.Classification component 50 comprises detector system 19, and it is used for detecting the particle that enters classification component 50 by service 52, and detector system can be operatively coupled to and be used to provide the switch 40 of required switching capability with sorting particles.First 22b of branch of Fig. 1 can be arranged to be connected with second outlet conduit, 56 fluid ground with outlet conduit 54 with second 22a of branch.
Fig. 9 represents the particle categorizing system 500 of another embodiment according to the present invention, and it comprises a plurality of classification component 50 that can combine with any suitable configuration, for example, and assembly 50 combination in parallel in this embodiment.The outlet conduit 54 of classification component 50 be attached to first unite 58, the second outlet conduits 56 be attached to second unite the outlet 60.The system that is arranged in parallel the classification component 50 that produces associating of classification component, its classification speed always be single classification component 50 classification speed N doubly, wherein N is the quantity of the classification component 50 that is connected in parallel.
Figure 10 represents the particle categorizing system 550 according to another embodiment, it comprises the first classification component 50a that connects with the second classification component 50b, the second classification component 50b can be equipped with and be used for more such particles are classified, and the predetermined properties of these particles is identical or different with the predetermined properties of the particle of being classified by the first classification component 50a.Grain flow enters the first classification component 50a by service 52, and can comprise at least two types particle, first type particle is classified in the first classification component 50a and is left by the first outlet conduit 54a, remaining particle leaves the first classification component 50a by the second outlet conduit 56a, and introduces the second classification component 50b by the second service 52b.From this grain flow, the particle with another kind of predetermined properties is classified and leaves by the second outlet conduit 54b, and the particle that two kinds of predetermined properties do not have leaves the second classification component 50b by the second outlet conduit 56b.Those those of ordinary skill should be understood easily, can use the classification component 50 of any adequate types, and depend on and they can be combined desirable result in every way.
Figure 11 represents the layered architecture of the low misclassification of high throughput of another embodiment according to the present invention.Illustrative embodiment is two grade particles categorizing systems 800, and it is used for to a plurality of parallel grain flow classification in the first order, and the output of the set first order is carried out secondary classification to the output of the first order then and handled.Assign among N the independent classification passage 81a-81n from the particle inlet flow of particle input chamber 88 is split in the suspension 80, each passage per second can both be classified to the particle of selected quantity.Each passage 81 all comprises surveyed area 84 and switch region 82, and surveyed area 84 is used for checking that particle and identification have the particle of predetermined properties, and switch region 82 is used for separating with other particle in the grain flow having the particle of predetermined properties, as mentioned above.Switch region 82 produces two particle output streams: " selecting " stream and " refusal " stream based on the particle characteristics of measuring in its switch region 82 in surveyed area 84.From each passage " selecting " stream in collection area 86, assemble one will be in the second classification passage 810 stream of subseries again, as shown, the second classification passage 810 is handled based on the classification of predetermined properties duplicate detection and classification.
Suppose that the classification of each individual passage handles (y) rate of makeing mistakes that all produces some wrong choices (y by the particle of wrong " selections " less than one probability), then for 2 grades of drawn layering structures, the error rate y that the layered architecture generation is lower
2, or be y for n level layering structure error rate
nFor example, if single passage error rate is 1%, then 2 grades error rate is 0.01% or 10
4/ one.
According to another program, each second channel can have M first group in the hierarchy, and each first group has N classification passage.Suppose to use to want to catch and be present in particle in the input with ratio z, and the maximum classification rate that single passage grader has is a per second x particle, then system's throughput is a per second M*N*x particle, the amounts of particles that per second is gathered in N passage is N*x*z, so N*z must be less than 1 so that can be by independent second channel classification from all particles of N passage set.Surpass N=1/z in order to increase throughput, must increase the group of the parallel connection of some N first passage+1 second channel,, then, total throughput is the result with M*N*x of M second channel.
Figure 12 represents the multiple-series particle categorizing system 160 of another embodiment according to the present invention.Multiple-series particle categorizing system 160 comprises that first classification component 161 in parallel and second classification component 162, the first classification component 161 in parallel are applicable in the particle of multiple labelling, and the particle with two marks is selected and transmits by exit passageway 165.
Figure 13 represents another multiple-series particle categorizing system 170.First classification component 171 in parallel will have the particle separation of first mark, collecting granules and transmit the particle with first mark by first exit passageway 175 from different passages.Then, all other particles are sent into second grader 172 in parallel, it is used for to the particle classification with second mark.Particle with second mark is collected and transmits by second exit passageway 176, neither has first mark and does not also have the particle of second mark by 177 transmission of the 3rd exit passageway.
According to an embodiment of the invention shown in Figure 14 a and the 14b, the particle categorizing system can comprise the sensor that is used for measuring particle speed, position and/or size, and the measurement of speed, position and/or size can be carried out simultaneously or not carry out simultaneously with the grain sorting that is used for classifying.In the parallel port based on system shown in Figure 11, different passages can have different flow resistances, makes the particle in each passage or the speed difference of cell.In the system of surveyed area 84 and switch region 82 separation distance L,, must know the particle speed in the passage 81 for configuration switch time-delay T (that is, postponing the time of actuation of the switch with respect to the moment that detects target particles).
Detect in the optical system of cell or particle at great majority, the zone that causes light on the photoelectric detector of cell in surveyed area has the size more much bigger than cell dia size, thereby, when in surveyed area, detecting the light time, cell may be in the zone Anywhere, the feasible exact position that is difficult to just determine cell.For more accurate detection is provided, can make many pixels of photodetector fill up surveyed area, but this have very big cost and need complicated supporting electronic equipment.
The illustrative embodiment according to the present invention can be added to optical mask 140 surveyed area to provide accurate speed to detect by directly pile up one " covering pattern " on the classification chip.Covering pattern can so pile up, and promptly makes the edge cover pattern accurately locate (reaching＜1 micron precision with current techniques) with respect to cell classification actuator zone 82.When cell does not have crested, capturing optical independent photodetector will be seen light from the cell in surveyed area 84, be measured by the light duration permissible velocity that one of continuous non-transparent parts " bar " of known length mask disconnects.
Mask pattern have several size ranges in 1 micron grade from 10 microns to 30 microns bar 141, this mask pattern causes size only just will reduce to minimum from the signal of cell greater than the bar of cell, thereby this pattern can also be used for irrespectively measuring cell size with cell signal.This " gradient mask " also produces a pattern in photodetector, can analyze so that speed is measured several times it, reduces the difference of velocity estimation.Pattern in the light that is caused by mask 140 also allows each limit in the detector identification mask 140, if bar 141 all is identical, then the optical signal of each bar will be identical, a people only can distinguish them by order, thereby, the gradient mask pattern allows independent detector to check that wide zone (times over cell size) is to measure cell speed, with respect to channel design with about 1 micron precision measure in surveyed area 84 the exact position and the actuator position on the chip, the precision that provides with gradient pattern identification cell size.Gradient mask 140 allows the detector and the magnifying power of optical system or the character of photodetector itself irrespectively to measure these parameters.
According to instruction of the present invention, those skilled in the art should understand the miscellaneous equipment that is used to measure particle size, position and/or speed in categorizing system, for those those of ordinary skills, are easy to utilize and know suitable device.
According to another embodiment shown in Figure 15, the particle categorizing system comprises the array 8000 of different classification passages.With regard to the coupling of the use of space, luminous energy and optimal external actuator, comprise that the use of the parallel connected array of a series of different classification passage 810a-810n is more effective.Owing to can accurately detect particle speed with aforesaid sensor, so passage need character detect and actuation of the switch between fixed delay not be offset have examine the particle of character, thereby, some parameter of passage, for example the path shape between distance L between detector 84 and the switch 82 or detector 84 and the switch 82 can change.
Penetrate perpendicular to the illumination of each wavelength of chip with single laser travel direction, need area of laser irradiation, this area is following to be determined: (number of channels) * ((channel width of surveyed area)+(interchannel interval C)) (seeing Figure 15).Yet, can absorb light only is the area of passage with the effective area that produces fluorescence: (number of channels) * (channel width), this stays next activity coefficient: (channel width)/(channel width+C), activity coefficient are preferably near 100% input light to avoid waste available.
Thereby in categorizing system in parallel interchannel interval being reduced to minimum is important for photo detection area and optical system efficiency.In the Variable Array design of the present invention shown in Figure 16, the channel spacing in the surveyed area 84 is near width of channel, so that the utilization of light is approximately near 50%.Channel spacing in the zone of action 82 can be bigger, as shown in Figure 16.Actuator 26 also can change along the position of passage, to produce the bigger available radius of external driver device actuator.
Figure 17 represents the particle categorizing system 1700 of another embodiment according to the present invention, and particle categorizing system 1700 comprises the classification component 1701 of a plurality of multiple operations.System 1700 comprises input area 1710 and the surveyed area 1720 that is used for sample is incorporated into each classification component, and surveyed area 1720 is used for measuring the predetermined properties of particle in each classification passage 1702 of surveyed area.System also comprises switch region 1730, and it comprises an actuator in each classification component, is used for having the particle of predetermined properties and not having the particle separation of predetermined properties.As shown, in the embodiment of Figure 17, distance between the classification passage 1702 in the surveyed area 1720 is less than the interchannel distance in the switch region 1730, when detecting particle with laser, tight spacing in the surveyed area can be saved cost, simultaneously the actuator of farther spacing adaptation various sizes in the switch region 1730.
Described being used for forming the appropriate system that concentrates the zone in the attorney No.TGZ-023 that applies for same date with the application, its content is incorporated herein by reference at this.
According to illustrative embodiment, the carrier fluid that is removed can recycle and send back in the inlet of first passage, and recirculation line or miscellaneous equipment can be connected to first passage with concentrating the zone, handles with the classification that allows carrier fluid to be reused for subsequently.According to another program, carrier fluid can be removed from unaccepted particle, and introduces before abandoning unaccepted particle in the first passage inlet.
Invention has been described about illustrative embodiment, because in the case without departing from the scope of the present invention, in above-mentioned structure, can make some and change, thus should think be included in the above-mentioned specification or the full content in the accompanying drawings be illustrative and and nonrestrictive.
Will also be appreciated that following claim has covered all statements of whole general and the specific feature and the invention scope of invention described here,, we can say that invention falls between them according to language.
Claims (21)
1. particle categorizing system, it comprises:
The first classification passage, the suspended particulate stream that is limited in the carrier fluid flows through the first classification passage, the first classification passage all has surveyed area and switch region, surveyed area is used for detecting the predetermined properties in the particle, the switch region is used for separating with the particle that does not have predetermined properties having the particle of predetermined properties, particle with predetermined properties enters first receive path, and the particle that does not have a predetermined properties flows into second receive path;
Collection area is used for gathering the particle with predetermined properties from first receive path,
Concentrate the zone, be used for after the particle set with predetermined properties, adjustable ring is around the volume of the carrier fluid of the particle with predetermined properties; With
The second classification passage that at least one and the first classification passage are contacted is used for from the first receive path collecting granules, and separates having the particle of predetermined properties and other particle in the second classification passage in the second classification passage.
2. the system as claimed in claim 1 is characterized in that, concentrates the zone and removes superfluous carrier fluid from the particle with predetermined properties.
3. the system as claimed in claim 1 is characterized in that, the described first classification passage is a plurality of first parallel classification passages.
4. the system as claimed in claim 1 is characterized in that, described concentrated zone comprises:
With the crossing concentration channels of one of described receive path; With
The diaphragm that concentration channels and described receive path are separated.
5. the system as claimed in claim 1 is characterized in that, described concentrated zone comprises:
With the crossing concentration channels of described collection area; With
The diaphragm that concentration channels and collection area are separated.
6. the system as claimed in claim 1 is characterized in that, described concentrated zone comprises:
With the crossing concentration channels of the second classification passage; With
With the concentration channels and second diaphragm that separate of classification passage.
7. the system as claimed in claim 1 is characterized in that, the surveyed area of each first classification passage comprises sensor, is used for measuring the particle speed in the corresponding first passage.
8. the system as claimed in claim 1 is characterized in that, it also is included in and concentrates the regional hydration plant that afterwards second carrier fluid is added on the particle.
9. system as claimed in claim 2 is characterized in that, it also comprises will concentrate the recirculation line that the zone is connected to the first classification passage, is used for the described carrier fluid of removing surplus is incorporated in the first classification passage.
10. the method for a sorting particles, it comprises:
Transmit a plurality of suspended particulate streams that are limited in the carrier fluid by a plurality of first parallel classification passages, each first classification passage all has surveyed area and switch region, surveyed area is used for detecting the predetermined properties in the particle, the switch region is used for separating with the particle that does not have predetermined properties having the particle of predetermined properties, particle with predetermined properties enters first receive path, and the particle that does not have predetermined properties flows into second receive path;
To have the particle of predetermined properties separates with the particle that does not have predetermined properties;
Set is from the particle with predetermined properties of first receive path in collection area;
After the particle set with predetermined properties, adjustable ring is around the volume of the carrier fluid of the particle with predetermined properties;
Transmit selected particle by at least one second classification passage, the second classification passage and a plurality of first parallel classification passage polyphones with predetermined properties; With
Other particle that the particle and second that second classification is had predetermined properties in the passage is classified in the passage separates.
11. a particle categorizing system, it comprises:
Be used for transmitting the pipeline of the grain flow in the carrier fluid, it comprises inlet, first outlet and second outlet, and wherein, particle flows into first outlet from inlet;
Be used for the sensor of predetermined properties of one of them described particle of perception;
Actuator is used for when detecting the described predetermined properties of particle, selectively exerts pressure pulse the described particle with predetermined properties in the grain flow is displaced in second outlet to current-carrying liquid; With
Be used for the buffer of absorption pressure pulse.
12. particle categorizing system as claimed in claim 11 is characterized in that, described actuator comprises and a kind of in piezo column, stepper motor, electromagnetic actuators, heating power pneumatic actuator and the thermal pulse generator is used for producing steam bubble in working fluid.
13. particle categorizing system as claimed in claim 11, it is characterized in that, described actuator comprises the wing passage that is communicated with described pipeline, the closed chamber of adjacent side channel location, wherein carrier fluid forms meniscus so that closed chamber and carrier fluid are separated in wing passage, and actuator, it is used for changing pressure in the closed chamber during to described predetermined properties in sensor senses, so that meniscus skew, the skew of meniscus makes the particle with described predetermined properties flow into second outlet thus, and the particle that does not have described predetermined properties simultaneously flows into first outlet.
14. particle categorizing system as claimed in claim 11 is characterized in that described buffer comprises the surge chamber that is communicated with described pipeline, wherein carrier fluid forms meniscus so that carrier fluid separates with surge chamber.
15. particle categorizing system as claimed in claim 11 is characterized in that described buffer comprises the wing passage that is communicated with described pipeline; With
The surge chamber of adjacent side channel location, wherein carrier fluid forms meniscus so that surge chamber and carrier fluid are separated in wing passage.
16. particle categorizing system as claimed in claim 15 is characterized in that described surge chamber has removable wall.
17. a particle categorizing system that is used for to the classification of the particle that floats on a liquid, it comprises:
Inlet duct comprises the particle with predetermined properties and the liquid that does not have the particle of predetermined properties flow through this inlet duct, wherein,
A) described inlet duct is branched off into a plurality of passages, described passage parallel operation also is provided with described liquid simultaneously, each passage all has classification component and two exit passageways, each classification component all has switch element, and switch element is used for distributing between described two different exit passageways has the particle of first predetermined properties and the particle that does not have first predetermined properties;
B) each classification component comprises at least one sensor and an actuator, sensor detects and classifies has the particle of first predetermined properties, actuator is by being arranged in the described sensor control of on each described switch element each, and the particle that is used for selectively will having first predetermined properties is displaced in one of described exit passageway;
C) each in described two exit passageways on each classification component all is connected to independently synthetic passage, and it is used to the particle that does not have first predetermined properties that has the particle of first predetermined properties and selectively distribute to it: with
D) at least one is connected to second classification component of synthetic passage, it is used to have the particle of first predetermined properties, each described second classification component all has first exit passageway and second exit passageway, be used for detecting the detector of particle, and switch element, the particle that switch element selectively will have second predetermined properties is displaced in one of described exit passageway based on second predetermined properties.
18. particle categorizing system as claimed in claim 17 is characterized in that, described second predetermined properties is identical with first predetermined properties.
19. particle categorizing system as claimed in claim 17 is characterized in that, described second predetermined properties is different with first predetermined properties.
20. a particle categorizing system, it comprises:
A plurality of first parallel classification passages, the suspended particulate stream that is limited in the carrier fluid flows through the first classification passage, each first classification passage all has surveyed area and switch region, surveyed area is used for detecting the predetermined properties in the particle, and the switch region is used for separating with the particle that does not have predetermined properties having the particle of predetermined properties, particle with predetermined properties enters first receive path, and the particle that does not have predetermined properties flows into second receive path;
Collection area is used for the particle that has predetermined properties from first receive path is gathered in the collective flow of the particle with predetermined properties; With
At least one and the second classification passage of a plurality of parallel first classification passage polyphones, be used for from the described collective flow of a plurality of first receive paths receptions, and separate having the particle of predetermined properties and other particle in the second classification passage in the second classification passage with particle of predetermined properties.
21. the short grained method of classification, it comprises the following steps:
Closed conduct with inlet and fork is provided, and pipeline is divided into two laterals in the turnoff;
Liquid stream is introduced entrance, and grain flow is suspended in the liquid stream, and grain flow flows through first in the lateral usually;
Use agranular enclosed liquid to flow to produce laminar flow basically around described liquid stream;
Closed conduct along the fork upstream provides measuring station, be used for the particle in the described stream of perception predetermined character and be used for when detecting described character, producing signal;
Actuator is provided, is used for pressure is applied on the liquid; With
Provide and be used for the device that pressure changes in the buffering liquid, this pressure buffer device and pressure applying means acting in conjunction, with point from the point of exerting pressure towards compensator or trimmer pressure, be substantially perpendicular to the moment skew that proper flow direction ground causes the liquid that flows through pipeline, make that under the situation of not cutting off laminar flow the specific particle with predetermined character flows into second lateral.
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37325602P | 2002-04-17 | 2002-04-17 | |
| US60/373256 | 2002-04-17 | ||
| US10/179,586 US6877528B2 (en) | 2002-04-17 | 2002-06-24 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
| US10/179488 | 2002-06-24 | ||
| US10/179586 | 2002-06-24 | ||
| US10/179,488 US6808075B2 (en) | 2002-04-17 | 2002-06-24 | Method and apparatus for sorting particles |
| US41105802P | 2002-09-16 | 2002-09-16 | |
| US60/411058 | 2002-09-16 | ||
| US10/329,008 US6976590B2 (en) | 2002-06-24 | 2002-12-23 | Method and apparatus for sorting particles |
| US10/329008 | 2002-12-23 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN03814212.0A Division CN1662311B (en) | 2002-04-17 | 2003-04-17 | Method and apparatus for sorting particles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101693239A true CN101693239A (en) | 2010-04-14 |
Family
ID=42092265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910168699A Pending CN101693239A (en) | 2002-04-17 | 2003-04-17 | Method and apparatus for sorting particles |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101693239A (en) |
| IL (1) | IL183714A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106537113A (en) * | 2014-04-15 | 2017-03-22 | 斯派超科学股份有限公司 | Particle counter and classification system |
| CN107209198A (en) * | 2015-04-30 | 2017-09-26 | 惠普发展公司，有限责任合伙企业 | Target component is positioned and discharged |
| CN107206433A (en) * | 2014-12-05 | 2017-09-26 | 尔本麦宁有限公司 | Sensor separation equipment and method |
| CN107297334A (en) * | 2017-05-31 | 2017-10-27 | 清华大学 | Cell sorting device and method based on micro spark cavitation |
| CN107532990A (en) * | 2015-05-12 | 2018-01-02 | 芯片生物技术株式会社 | Single particle analytic method and the system for the parsing |
| CN109709003A (en) * | 2017-10-25 | 2019-05-03 | 中国航发商用航空发动机有限责任公司 | Impurity particle detection sensor test device and method |
| CN111571177A (en) * | 2020-04-24 | 2020-08-25 | 博世华域转向系统有限公司 | Selection method for selecting multiple pin grades of driving unit |
-
2003
- 2003-04-17 CN CN200910168699A patent/CN101693239A/en active Pending
-
2007
- 2007-06-06 IL IL183714A patent/IL183714A/en unknown
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106537113A (en) * | 2014-04-15 | 2017-03-22 | 斯派超科学股份有限公司 | Particle counter and classification system |
| CN106537113B (en) * | 2014-04-15 | 2020-06-05 | 斯派超科学股份有限公司 | Particle counter and classification system |
| CN107206433B (en) * | 2014-12-05 | 2020-12-22 | 尔本麦宁有限公司 | Sensor separation apparatus and method |
| CN107206433A (en) * | 2014-12-05 | 2017-09-26 | 尔本麦宁有限公司 | Sensor separation equipment and method |
| US11458508B2 (en) | 2014-12-05 | 2022-10-04 | Urban Mining Corp B.V. | Sensor separation apparatus and method |
| US10562075B2 (en) | 2014-12-05 | 2020-02-18 | Urban Mining Corp B.V. | Sensor separation apparatus and method |
| CN107209198A (en) * | 2015-04-30 | 2017-09-26 | 惠普发展公司，有限责任合伙企业 | Target component is positioned and discharged |
| CN107209198B (en) * | 2015-04-30 | 2019-07-19 | 惠普发展公司，有限责任合伙企业 | Target component positioning and discharge |
| US10828639B2 (en) | 2015-04-30 | 2020-11-10 | Hewlett-Packard Development Company L.P. | Target constituent location and discharge |
| CN107532990A (en) * | 2015-05-12 | 2018-01-02 | 芯片生物技术株式会社 | Single particle analytic method and the system for the parsing |
| CN107532990B (en) * | 2015-05-12 | 2021-11-12 | 芯片生物技术株式会社 | Single particle analysis method and system for the same |
| CN107297334A (en) * | 2017-05-31 | 2017-10-27 | 清华大学 | Cell sorting device and method based on micro spark cavitation |
| CN109709003B (en) * | 2017-10-25 | 2021-07-30 | 中国航发商用航空发动机有限责任公司 | Impurity particle detection sensor testing device and method |
| CN109709003A (en) * | 2017-10-25 | 2019-05-03 | 中国航发商用航空发动机有限责任公司 | Impurity particle detection sensor test device and method |
| CN111571177A (en) * | 2020-04-24 | 2020-08-25 | 博世华域转向系统有限公司 | Selection method for selecting multiple pin grades of driving unit |
Also Published As
| Publication number | Publication date |
|---|---|
| IL183714A (en) | 2010-12-30 |
| IL183714A0 (en) | 2007-09-20 |
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Application publication date: 20100414 |