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WO2003089157A1 - Procede et appareil de tri de particules - Google Patents

Procede et appareil de tri de particules Download PDF

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Publication number
WO2003089157A1
WO2003089157A1 PCT/US2003/012359 US0312359W WO03089157A1 WO 2003089157 A1 WO2003089157 A1 WO 2003089157A1 US 0312359 W US0312359 W US 0312359W WO 03089157 A1 WO03089157 A1 WO 03089157A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
predetermined characteristic
particle
actuator
duct
Prior art date
Application number
PCT/US2003/012359
Other languages
English (en)
Inventor
Sebastian Bohm
John Richard Gilbert
Manish Deshpande
Original Assignee
Cytonome, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/179,488 external-priority patent/US6808075B2/en
Priority claimed from US10/179,586 external-priority patent/US6877528B2/en
Application filed by Cytonome, Inc. filed Critical Cytonome, Inc.
Priority to AU2003231021A priority Critical patent/AU2003231021A1/en
Publication of WO2003089157A1 publication Critical patent/WO2003089157A1/fr

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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B07—SEPARATING SOLIDS FROM SOLIDS; SORTING
    • B07C—POSTAL SORTING; SORTING INDIVIDUAL ARTICLES, OR BULK MATERIAL FIT TO BE SORTED PIECE-MEAL, e.g. BY PICKING
    • B07C5/00—Sorting according to a characteristic or feature of the articles or material being sorted, e.g. by control effected by devices which detect or measure such characteristic or feature; Sorting by manually actuated devices, e.g. switches
    • B07C5/34—Sorting according to other particular properties
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F15—FLUID-PRESSURE ACTUATORS; HYDRAULICS OR PNEUMATICS IN GENERAL
    • F15C—FLUID-CIRCUIT ELEMENTS PREDOMINANTLY USED FOR COMPUTING OR CONTROL PURPOSES
    • F15C5/00—Manufacture of fluid circuit elements; Manufacture of assemblages of such elements integrated circuits
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0028—Valves having multiple inlets or outlets
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0042—Electric operating means therefor
    • F16K99/0046—Electric operating means therefor using magnets
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0042—Electric operating means therefor
    • F16K99/0048—Electric operating means therefor using piezoelectric means
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0055—Operating means specially adapted for microvalves actuated by fluids
    • F16K99/0061—Operating means specially adapted for microvalves actuated by fluids actuated by an expanding gas or liquid volume
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0082—Microvalves adapted for a particular use
    • F16K2099/0084—Chemistry or biology, e.g. "lab-on-a-chip" technology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/149—Optical investigation techniques, e.g. flow cytometry specially adapted for sorting particles, e.g. by their size or optical properties

Definitions

  • the invention relates to a method and apparatus for the sorting of particles in a suspension, where the input flow path of a sorting module can be split into several output channels. More particular, the invention relates to a particle sorting system in which a plurality of sorting modules are interconnected as to yield an increased particle throughput.
  • particles that require sorting are various types of cells, such as blood platelets, white blood cells, tumorous cells, embryonic cells and the like. These particles are especially of interest in the field of cytology. Other particles are (macro) molecular species such as proteins, enzymes and poly-nucleotides. This family of particles is of particular interest in the field of drug screening during the development of new drugs.
  • Typical sorting rates for sorters employing flows of particle suspension in closed channels are in the range from a few hundred particles per second to thousands of particles per second, for a single sorting unit.
  • a deflector When the detector detects a particle possessing a predetermined characteristic in the decision phase, a deflector is activated for deflecting the particle in a deflection phase.
  • the deflector comprises an electrode pair, positioned in the branch of the channel where the particles normally flow through in the inactivated state of the deflector.
  • the described device is effective for sorting particles, however one serious drawback is that gas bubbles are created which potentially can accumulate at certain points of the fluidic network or clog flow channels, yielding erroneous sorting. Another drawback is that the generated gasses (mostly oxygen and hydrogen) and ionic species (mostly OH " and FT 1" ) influence the particles flowing through the branch with the electrode pair. In addition, cells and delicate proteins such as enzymes are very fragile and can be destroyed by the fouling constituents co-generated with the gas bubble. Another drawback is the complexity of the overall sorting apparatus. In particular, the micro electrode construction is very complex to mount and assemble in the small channels of the system. As a result, the cost of a sorting unit is relatively large.
  • the deflector is inco ⁇ orated within the channel system, resulting in relatively large costs of construction.
  • Another drawback is the deflector principle used.
  • the generated pressure waves are not confined to the branching point, but will propagate upstream into the detector section as well as downstream both branches and influence the overall flow through the channel. This is particularly a drawback if sorters of this type are connected either in series or in parallel as to build a sorter system with increased throughput. Pressure waves generated in one sorter can then influence the flows and deflection of particles in neighboring sorter units.
  • sorter described in the '427 patent is less complex as the previous sorter structures, it is still problematic to couple multiple sorter modules of the described type together to increase the sorting rate. This is, as in the sorter described in '307 because of the generated pressure waves causing interference with other sorter modules.
  • the present invention provides a method and apparatus for sorting particles moving through a closed channel system of capillary size.
  • the particle sorting system of the invention provides a sorting module that can be assembled at low cost while providing an accurate means of sorting large amounts of particles per unit of time.
  • 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.
  • the particle sorting system implements an improved fluidic particle switching method and switching device according to the current invention.
  • the particle sorting system comprises a closed channel system of capillary size for sorting particles.
  • the channel system comprises a first supply duct for introducing a stream of particles and a second supply duct for supplying a carrier liquid.
  • the first supply duct forms a nozzle to introduce a stream of particles into the flow of carrier liquid.
  • the first supply duct and the second supply duct enter a measurement duct, which branches into a first branch and a second branch at a branch point.
  • a measurement region is defined in the measurement duct and is associated with a detector to sense a predetermined characteristic of particles in the measurement region.
  • Two opposed bubble valves are positioned in communication with the measurement duct and are spaced opposite each other.
  • the bubble valves communicate with the measurement duct through a pair of opposed side passages. Liquid is allowed to partly fill these side passages to form a meniscus therein which interfaces the carrier liquid with the reservoir of the bubble valves.
  • An external actuator is also provided for actuating one of the bubble valves. When the external actuator is activated, the pressure in the reservoir of the activated bubble valve increases, deflecting the meniscus and causing a flow disturbance in the measurement duct to deflect the flow therein.
  • the sensing means When a sensing means in the measuring region senses a predetermined characteristic in a particle flowing through the measurement region, the sensing means produces a signal in response to the sensed characteristic.
  • the external actuator is responsive to the sensing means to cause a pressure pulse in a compression chamber of a first bubble valve to deflect the particle with the predetermined characteristic, causing the selected particle to flow down the second branch duct.
  • the invention comprises a method of sorting particles including the steps of providing a measurement duct having an inlet and a branching point at which the duct separates into two branch ducts, conducting a stream of fluid into the duct inlet with a stream of particles suspended therein, such that the particles normally flow through a first one of the branch ducts and providing upstream from the branching point two opposing side passages for momentarily deflecting the stream in the duct.
  • a first one of the side passages is hydraulically connected to a compression chamber of a first bubble valve, which is acted upon by an external actuator for varying the pressure therein.
  • a second of the side passages is hydraulically connected with a buffer chamber of a second bubble valve for absorbing pressure variations.
  • the method further comprises providing a measurement station along the measurement duct upstream of the side passages for sensing a predetermined characteristic of particles in the stream and for producing a signal when the predetermined characteristic is sensed.
  • the method further comprises the step of, in response to sensing the predetermined characteristic, activating the external actuator for creating a flow disturbance in the duct between the side passages, thereby deflecting the particle having the predetermined characteristics and causing the selected particle to flow down the second branch duct.
  • the particle sort rate is respectively increased or the type of particles sorted being increased, by respectively connecting a plurality of sorting modules in parallel or serially connecting a plurality of sorting modules in a binary tree like configuration.
  • a particle sorting system comprises a first duct for conveying a stream of suspended particles confined in a carrier liquid, comprising an inlet, a first outlet and a second outlet, a sensor for sensing a predetermined characteristic in a particle, a side channel in communication with the first duct, a sealed chamber positioned adjacent to the side channel, wherein the carrier fluid forms a meniscus in the side channel to separate the sealed chamber from the carrier fluid; and an actuator.
  • the actuator modifies the pressure in the sealed chamber to deflect the meniscus when the sensor senses the predetermined characteristic. The deflection of the meniscus causes the particle having the predetermined characteristic to flow into the second outlet while particles that do not have the predetermined characteristic flow into the first outlet.
  • a particle sorting system comprises a first duct for conveying a stream of suspended particles confined in a carrier liquid, a sensor for sensing a predetermined characteristic in a particle and a first side channel in communication with the first duct.
  • the first duct comprises an inlet, a first outlet and a second outlet.
  • the particle sorting system further comprises a sealed actuator chamber positioned adjacent to the first side channel, wherein the carrier fluid forms a meniscus in the first side channel to separate the sealed chamber from the carrier fluid, an actuator for modifying the pressure in the sealed actuator chamber to deflect the meniscus when the sensor senses said predetermined characteristic and a buffer.
  • the deflection of the meniscus creates a transient flow in the first duct which deflects particle having said predetermined characteristic to flow into the second outlet while particles that do not have said predetermined characteristic flow into the first outlet.
  • the buffer absorbs a transient flow in the first duct.
  • a particle sorting system comprises a duct for conveying a stream of particles in a carrier fluid, a sensor for sensing a predetermined characteristic in a particle and an actuator.
  • the duct comprises an inlet, a first outlet and a second outlet, wherein the particles normally flow from the inlet into the first outlet.
  • the actuator selectively applies a pressure pulse to the suspension to deflect a particle in the stream of particles into the second outlet when said predetermined characteristic is detected.
  • the particle sorting system further comprises a buffer for absorbing the pressure pulse.
  • a particle sorting system comprises a duct for conveying a stream of suspended particles confined in a carrier fluid, comprising an inlet, a first outlet and a second outlet, wherein the particles normally flow from the inlet into the first outlet, a sensor for sensing a predetermined characteristic in a particle, an actuator for selectively applying a pressure pulse to the stream of suspended particles to deflect a particle in the stream of particles when said predetermined characteristic is detected, causing it to flow into the second outlet and a buffer for absorbing the pressure pulse.
  • the buffer comprises a side channel in communication with the duct, a sealed buffer chamber adjacent to the side channel and a meniscus formed by the carrier fluid at an interface between the sealed chamber and the side channel.
  • a particle sorting system comprises a first duct for conveying a stream of suspended particles confined in a carrier liquid, comprising an inlet, a first outlet and a second outlet, a sensor for sensing a predetermined characteristic in a particle, a side channel in communication with the first duct, a sealed chamber positioned adjacent to the side channel, wherein the carrier fluid forms a first meniscus in the side channel to separate the sealed chamber from the sealed chamber an actuator for modifying the pressure in the sealed chamber to deflect the first meniscus when the sensor senses said predetermined characteristic, whereby the deflection of the meniscus causes a particle having said predetermined characteristic to flow into the second outlet while particles that do not have said predetermined characteristic flow into the first outlet and a buffer for absorbing the pressure pulse.
  • the buffer comprises a side channel in communication with the duct, a sealed chamber adjacent to the side channel and a first meniscus formed by the carrier fluid at an interface between the sealed chamber and the side channel.
  • a particle sorting system for sorting particles suspended in a liquid.
  • the particle sorting system comprises an inlet duct through which flows a liquid containing particles having a predetermined characteristic and particles not having a predetermined characteristic.
  • the inlet duct branches into a plurality of measurement channels which are operated in parallel and simultaneously fed with the liquid, each measurement channel having a sorting module and two outlet channels, and each sorting module having a switch unit for distribution of particles having a predetermined characteristic and particles not having a predetermined characteristic to said two different outlet channel.
  • Each switch unit comprises at least one sensor which detects and classifies the particles having the predetermined characteristic, a side passage in communication with the inlet duct, a sealed chamber adjacent to and separated from the side passage by a meniscus formed by the liquid and an actuator controlled by each said sensor arranged on each said switch unit for selectively deflecting the meniscus to deflect a particle having the predetermined characteristic into one of said outlet channel.
  • Each of the two outlet channels on each measurement channel is connected to a separate summing channel for the particles having a predetennined characteristic and particles not having a predetennined characteristic selectively distributed to it.
  • a particle sorting system for sorting particles suspended in a liquid comprising an inlet duct through which flows a liquid containing particles having a predetermined characteristic and particles not having a predetermined characteristic.
  • the inlet duct branches into a plurality of channels which are operated in parallel and simultaneously fed with the liquid, each channel having a sorting module and two outlet channels, and each sorting module having a switch unit for distribution of particles having a first predetermined characteristic and particles not having the first predetermined characteristic between said two different outlet channels.
  • Each sorting module comprises at least one sensor which detects and classifies the particles having the first predetermined characteristic, and an actuator controlled by each of said sensor ananged on each said switch unit for selectively deflecting a particle having the first predetermined characteristic into one of said outlet channels.
  • Each of said two outlet channels on each sorting module is connected to a separate summing chamiel for the particles having the first predetermined characteristic and particles not having the first predetermined characteristic selectively distributed to it.
  • the system further comprises at least one secondary sorting module connected to the summing channel for the particles having the first predetermined characteristic, each of said secondary sorting modules having a first outlet channel and a second outlet channel, a detector for sensing particles and a switch unit for selectively deflecting a particle having a second predetermined characteristic into one of said outlet channels based on a second predetermined characteristic.
  • a particle sorting system comprising a plurality of parallel primary sorting channels through which flows a stream of suspended particles confined in a carrier liquid.
  • Each primary sorting channel has a detection region for detecting a predetermined characteristic in a particle and a switching region for separating particles having the predetermined characteristic into a first receiving channel from particles that do not have the predetermined characteristic, which flow into a second receiving channel.
  • the system further comprises an aggregation region for aggregating the particles having the predetermined characteristic from the first receiving channels, and at least one secondary sorting channel in series with the plurality of parallel primary sorting channels for collecting the selected particles from the plurality of first outlet channels and separating particles in the secondary sorting channel having the predetermined characteristic from other particles in the secondary sorting channel.
  • a method of sorting small particles comprises the steps of providing a closed duct having an inlet and a fork at which the duct separates into two branch ducts, conducting a stream of liquid into the duct inlet with a stream of particles suspended therein, the particle stream normally flowing through a first one of the branch ducts surrounding the stream of liquid with a particle free enveloping current of liquid to produce substantially laminar flow and providing a measurement station along the closed duct upstream of the fork for sensing a predetermined property of particles in the stream and for producing a signal when the property is sensed.
  • the method further comprises providing an actuator for applying a pressure on the liquid and providing means for buffering pressure variations in the liquid.
  • the pressure buffering means cooperates with the pressure applying means to result in a momentary deflection of the liquid streaming through the duct substantially pe ⁇ endicular to the normal direction of flow from the point where the pressure is applied towards the point where the pressure is buffered, causing the specific particle having the predetermined property to flow into the second branch duct without eliminating the laminar flow.
  • FIG. 1 is a schematic view of a particle sorting system according to an illustrative embodiment of the invention.
  • FIGS. 2 through 4 illustrate the operation of the particle sorting system of FIG 1.
  • FIG. 5 illustrates a particle sorting system showing alternate positions for the actuator chamber and the buffer chamber.
  • FIG. 6 illustrates the particle sorting system according to another embodiment of the invention.
  • FIG. 7 illustrates a bubble valve suitable for use in the particle sorting system of the invention.
  • FIG. 8 is a schematic diagram of the particle sorting system of an illustrative embodiment of the invention.
  • FIG. 9 shows a particle sorting system for sorting parallel streams of particles.
  • FIG. 10 shows a particle sorting system binary tree-like configuration of sorting modules.
  • FIG. 11 illustrates a multi-stage particle sorting system for sorting parallel streams of particles in two stages.
  • FIG. 12 illustrates a parallel particle sorting system according to an alternate embodiment of the invention.
  • FIG. 13 illustrates a parallel particle sorting system according to another embodiment of the invention.
  • the present invention provides a particle sorting system for sorting particles suspended in a liquid.
  • the particle sorting system provides high-throughput, low error sorting of particles based on a predetermined characteristic.
  • the present invention will be described below relative to illustrative embodiments. Those skilled in the art will appreciate that the present invention may be implemented in a number of different applications and embodiments and is not specifically limited in its application to the particular embodiments depicted herein.
  • a particle sorting system 10 comprises a closed channel system of capillary size for sorting particles.
  • the channel system comprises a first supply duct 12 for introducing a stream of particles 18 and a second supply duct 14 for supplying a carrier liquid.
  • the first supply duct 12 forms a nozzle 12a, and a stream of particles is introduced into the flow of carrier liquid.
  • the first supply duct 12 and the second supply duct 14 enter a measurement duct 16 for conveying the particles suspended in the carrier liquid, which branches into a first branch 22a and a second branch 22b at a branch point 21.
  • a measurement region 20 is defined in the measurement duct 16 and is associated with a detector 19 to sense a predetermined characteristic of particles in the measurement region 20.
  • Two opposed of bubble valves 100a and 100b are positioned in communication with the measurement duct 16 and are spaced opposite each other.
  • the bubble valves 100a, 100b communicate with the measurement duct 16 through a pair of opposed side passages 24a and 24b, respectively. Liquid is allowed to partly fill these side passages 24a and 24b to form a meniscus 25 therein.
  • the meniscus defines an interface between the carrier liquid and a gas in the reservoir of the associated bubble valve 100.
  • An external actuator 26 is also provided for actuating the first bubble valves 100a, which momentarily causes a flow disturbance in the duct to deflect the flow therein when activated by the actuator 26.
  • the second bubble valve 100b serves as a buffer for absorbing the pressure pulse created by the first bubble valve 100a.
  • the first side passage 24a is hydraulically connected to a compression chamber 70a in the first bubble valve 100a, so that if the pressure in this chamber is increased, the flow in the measurement duct near the side passage is displaced inwards, substantially pe ⁇ endicular to the normal flow in the duct.
  • the second side passage 24b positioned opposite of the first side passage 24a is hydraulically connected to a buffer chamber 70b in the second bubble valve 100b for absorbing pressure transients. This second side passage 24b co-operates with the first side passage 24a to direct the before mentioned liquid displacement caused by pressurizing the compression chamber 70a, so that the displacement has a component pe ⁇ endicular to the normal flow of the particles through the measurement duct.
  • the measurement duct 16 branches at the branch point 21 into two branches 22a, 22b and the flow rates in these branches are adjusted so that the particles normally stream through the second of the two branches 22b.
  • the angle between the branches 22a, 22b is between 0 and 180 degrees, preferably between 10 and 45 degrees. However, the angle can even be 0 degrees, which corresponds to two parallel ducts with a straight separation wall between them.
  • the particles to be sorted are preferably supplied to a measurement position in a central fluid current, which is surrounded by a particle free liquid sheath.
  • the process of confining a particle stream is known, and often referred to as a 'sheath flow' configuration.
  • Normally confinement is achieved by injecting a stream of suspended particles through a narrow outlet nozzle into a particle free carrier liquid flowing in the duct 16.
  • the ratio of flow rates of the suspension and carrier liquid By adjusting the ratio of flow rates of the suspension and carrier liquid, the radial confinement in the duct as well as the inter particle distance can be adjusted.
  • a relative large flow rate of the carrier liquid results in a more confined particle stream having a large distance between particles.
  • a suspension introduced by the first supply duct 12 two types of particles can be distinguished, normal particles 18a and particles of interest 18b.
  • the detector 19 Upon sensing the predetermined characteristic in a particle 18b in the measurement region 20, the detector 19 raises a signal.
  • the external actuator 26 activates the first actuator bubble valve 100a, when signaled by the detector 19 in response to sensing the predetermined characteristic, to create a flow disturbance in the measurement duct 16 between the side passages 24a, 24b.
  • the flow disturbance deflects the particle 18b having the predetermined characteristic so that it flows down the first branch duct 22a rather than the second branch duct 22b.
  • the detector communicates with the actuator 26, so that when the detector 19 senses a predetermined characteristic in a particle, the actuator activates the first bubble valve 100a to cause pressure variations in the reservoir 70a of the first bubble valve.
  • the activation of the first bubble valves deflects the meniscus 25 a in the first bubble valve 100a and causes a transient pressure variation in the first side passage 24a.
  • the second side passage 24b and the second bubble valve 100b absorb the transient pressure variations in the measurement duct 16 induced via the actuator 26.
  • the reservoir 70b of the second bubble valve 100b is a buffer chamber having a resilient wall or containing a compressible fluid, such as a gas.
  • the resilient properties allow the flow of liquid from the measurement duct into the second side passage 24b, allowing the pressure pulse to be absorbed and preventing disturbance to the flow of the non-selected particles in the stream of particles.
  • a suitable sensor means 19 for a particular characteristic, such as size, form, fluorescent intensity etc.
  • Examples of applicable sensing means known in the art, are various types of optical detection systems such as microscopes, machine vision systems and electronic means for measuring electronic properties of the particles. Particularly well known systems in the field are systems for measuring the fluorescent intensity of particles.
  • These systems comprise a light source having a suitable wavelength for inducing fluorescence and 1 a detection system for measuring the intensity of the induced fluorescent light.
  • This approach is often used in combination with particles that are labelled with a fluorescent marker, i.e. an attached molecule that upon illuminating with light of a particular first wavelength produces light at another particular second wavelength (fluorescence). If this second wavelength light is detected, the characteristic is sensed and a signal is raised.
  • Other examples include the measurement of light scattered by particles flowing through the measurement region. Inte ⁇ reting the scattering yield information on the size and form of particles, which can be adopted to raise a signal when a predetermined characteristic is detected.
  • the actuator 26 for pressurizing the compression chamber of the first bubble valve may comprise an external actuator that responds to a signal from the sensor that a particle has a selected predetermined characteristic.
  • the first class directly provides a gas pressure to the liquid in the first side passage 24a.
  • the actuator may comprise a source of pressurized gas connected with a switching valve to the liquid column in the side passage 24a. Activation of the switch connects the passage to the source of pressurized gas, which deflects the meniscus in the liquid. Upon deactivation, the switch connects the passage 24a back to the normal operating pressure.
  • a displacement actuator may be used in combination with a closed compression chamber having a movable wall.
  • the displacement actuator displaces the wall of the compression chamber inward, the pressure inside increases. If the movable wall is displaced back to the original position, the pressure is reduced back to the normal operating pressure.
  • An example of a suitable displacement actuator is an electromagnetic actuator, which causes displacement of a plunger upon energizing a coil.
  • Another example is the use of piezoelectric material, for example in the form of a cylinder or a stack of disks, which upon the application of a voltage produces a linear displacement. Both types of actuators engage the movable wall of the compression chamber 70 to cause pressure variations therein.
  • FIGs 2-4 illustrate the switching operation of switch 40 in the particle sorting system 10 of Figure 1.
  • the detector 19 senses the predetermined characteristic in a particle and raises a signal to activate the actuator 26.
  • the pressure within the reservoir 70a of the first bubble valve 100a is increased, deflecting the meniscus 25a and causing a transient discharge of liquid from the first side passage 24a, as indicated by the a ⁇ ow.
  • the sudden pressure increase caused at this point in the duct causes liquid to flow into the second side passage 24b, because of the resilient properties of the reservoir of the second bubble valve 100b. This movement of liquid into the second side passage 24b is indicated with an arrow.
  • the flow through the measurement duct 16 is deflected, causing the selected particle of interest 18b located between the first side passage 24a and the second side passage 24b to be shifted pe ⁇ endicular to its flow direction in the normal state.
  • the flow resistances to the measurement duct 16, the first branch 22a and the second branch 22b is chosen so that the preferred direction of the flow to and from the first side passage 24a and the second side passage 24b has an appreciable component pe ⁇ endicular to the normal flow through the measurement duct 16. This goal can for instance be reached by the first branch 22a and the second branch 22b so that their resistances to flow is large in comparison with the flow resistances of the first side passage 24a and the second side passage 24b.
  • Figure 3 shows the particle sorting system 10 during the relief of the first bubble valve reservoir when the particle of interest 18b has left the volume between the first side passage 24a and the second side passage 24b.
  • the actuator 26 is deactivated, causing the pressure inside the reservoirs 70a, 70b to return to the normal pressure.
  • this relief phase there is a negative pressure difference between the two reservoirs 70a, 70b of the bubble valves, causing a liquid flow through the first side passage 24a and the second side passage 24b opposite to the liquid flow shown in the previous figure and as indicated by the arrows.
  • Figure 4 illustrates the particle sorting system 10 after completion of the switching sequence.
  • the pressures inside the reservoirs of the bubble valves are equalized, allowing the flow through the measurement duct 16 to normalize.
  • the particle of interest 18b has been displaced radially, it will flow into the first branch 22a, while the other particle continue to flow into the second branch 22b, thereby separating the particles based on the predetermined characteristic.
  • This process of detecting and selective deflecting of particles maybe repeated many times per second for sorting particles at a high rate.
  • Adopting the fluid switching as described, switching operations may be executed up to around several thousand switching operations per second, yielding sorting rates in the order of million sorted particles per hour.
  • the actuator bubble valve 100a and the buffer bubble valve 100b may be placed in different positions.
  • the actuator bubble valve 100a and the first side passage 24a and or the buffer bubble valve 100b and the second side passage 24b may be place upstream from the branch point 21.
  • the components may be placed in any suitable location, such that the flow resistance between the actuator chamber 70a and the buffer chamber 70b is less than the flow resistance between any of these latter components and other pressure sources. More particularly, the actuator chamber 70a and the buffer chamber 70b may be placed such that the flow resistance between them is less than the flow resistance between a selected particle and a subsequent particle in the stream of particles.
  • the positioning of the components in this manner thus prevents a pressure wave generated by the above described method of deflecting a single selected particle, from travelling upstream or downstream and affecting the flow of the remaining particles in the stream of particles.
  • the larger the difference in flow resistances the larger the level of isolation of the fluidic switching operation with associated pressure transients from the flow characteristics in the rest of the system.
  • the in-situ dampening of generated pressure pulses applied for sorting allows the implementation of sorting networks comprising a plurality of switches 40, each of which is hydraulically and pneumatically isolated from the others.
  • the particle sorting system of the invention may use any suitable pressure wave generator (in place of a bubble valve) in combination with the buffer bubble valve 100b.
  • the pressure wave generator 260 may comprise an actuator such as a piezoelectric column or a stepper motor, provided with a plunger that can act upon the flowing liquid, either directly or via deflection of the channel system, to selectively deflect particles when the actuator is activated by a signal.
  • Other suitable pressure wave generators include electromagnetic actuators, thermopneumatic actuators and a heat pulse generator for generating vapor bubbles in the flowing liquid by applying heat pulses.
  • the buffer bubble valve 100b is positioned to absorb the pressure wave created by the pressure wave generator 260 to prevent flow disturbance in the other particles of the particle stream.
  • the spring constant of the buffer 100b may be varied according to the particular requirements by varying the volume of the buffer chamber 70b, the cross-sectional area of the side passage 24b and/or the stiffness or the thickness of a flexible membrane (reference 72 in Figure 7) forming the buffer chamber 70b.
  • Fig. 7 illustrates an embodiment of a bubble valve 100 suitable for creating a pressure pulse to separate particles of interest from other particles in a stream of particles and/or acting as a buffer for absorbing a pressure pulse according to the teachings of the present invention.
  • the bubble valve 100 is formed adjacent to a side passage 24a or 24b formed in a substrate which leads to the measurement duct 16.
  • the side passage 24a includes a fluid interface port 17 formed by an aperture in the side wall of the passage.
  • a sealed compression chamber 70 is positioned adjacent to the side passage 24a and communicates with the side passage through the fluid interface port.
  • the illustrative chamber 70 is formed by a seal 71 and a flexible membrane 72.
  • Fig. 8 shows a sorting module 50 having an appropriate supply duct 52 for providing a stream of particles to be sorted as well as an outlet duct 54 and a second outlet duct 56 carrying the particles sorted in the sorting module 50.
  • the sorting module 50 comprises detector system 19 for sensing particles entering the sorting module 50 via the supply duct 52 operationally connected to a switch 40 for providing the required switching capabilities to sort particles.
  • the first branch 22b and second branch 22a are in fluidic connection with the outlet duct 54 and second outlet duct 56.
  • Fig. 9 shows a particle sorting system 500 according to an alternate embodiment of the invention, comprising a plurality of sorting module 50 operating in parallel.
  • the individual outlet duct 54 of the sorting module 50 are forwarded to a first combined outlet 58, the individual second outlet duct 56 are forwarded to a second combined outlet 60.
  • the parallel arrangement of sorting modules yields a system of combined sorting module 50 having an overall sorting rate of N times the sorting rate of an individual sorting module 50, where N is the number of parallel connected sorting module 50.
  • Fig. 10 shows a particle sorting system 550 according to another embodiment, comprising a first sorting module 50a and a second sorting module 50b in series with the first sorting module 50a.
  • the second sorting module 50b may be equipped for sorting out particles having a predetermined characteristic different than the predetermined characteristic of the particles sorted out by the first sorting module 50a.
  • the particle stream enters the first sorting module 50a through the supply duct 52 and may contain at least two types of particles.
  • a first type of particles is sorted out in the first sorting module 50a and leaves through the first outlet duct 54a.
  • the remaining particles leave the first sorting module 50a through second outlet duct 56a and are fed into the second sorting module 50b via the second supply duct 52b. From this stream of particles, particles having the other predetermined characteristic are sorted out and leave through the second outlet duct 54b . Particles that posses neither of the two predetermined characteristics leave the second sorting module 50b via the second outlet duct 56b.
  • FIG. 11 shows a hierarchical architecture for high throughput-low error sorting according to another embodiment of the invention.
  • the embodiment shown is a two- stage particle sorting system 800 for sorting a plurality of parallel particles streams in a first stage, aggregating the outputs of the first stage and then performing a secondary- sorting process on the output of the first stage.
  • An input stream of particles in suspension 80 from a particle input chamber 88 is split among N single sorting channels 81a-81n, each channel being capable of sorting a selected number of particles per second.
  • Each channel 81 includes a detection region 84 for examining the particles and identifying particles that have a predetermined characteristic and a switching region 82 for separating the particles having the predetermined characteristic from the other particles in the stream, as described above.
  • the switching region 82 produces two output streams of particles: a "selected" stream and a "rejected" stream in its switching region 82 based on the measured particle characteristics at the detection region 84.
  • selected streams from each channel are aggregated in an aggregation region 86 into one stream to be sorted again in a secondary sorting channel 810.
  • the secondary sorting channel 810 repeats the sorting process of detecting and sorting based on a predetermined characteristic.
  • the hierarchical architecture Given that each single channel sorting process produces some e ⁇ or (y) rate (y is a probability less than one of a particle being "selected" by mistake) of mistaken selections, the hierarchical architecture produces an lower error rate of y 2 for a 2-stage hierarchy as drawn or y" for an n-stage hierarchy. For example, if the single channel error rate is 1% the 2-stage error rate is 0.01% or one part in 10 4 .
  • the architecture could have M primary sets of N sorting channels per secondary channel.
  • the system throughput is M*N*x in particles per second.
  • the number of particles aggregated in N channels per second is N*x*z and so N*z must be less than 1 so that all particles aggregated from N channels can be sorted by a single secondary channel.
  • Overall throughput then comes from M*N*x with M secondary channels.
  • Figure 12 show a parallel-serial particle sorting system 160 according to another embodiment of the invention.
  • the parallel-serial particle sorting system 160 includes a first parallel sorting module 161 and a second parallel sorting module 162.
  • the first sorting module 161 is applied in multiple marked particles and particles having both markers are sorted out and conveyed through the exit channel 165.
  • Figure 13 shows another parallel-serial particle sorting system 170.
  • the first parallel sorting module 171 separates particles having a first marker, collects the particles from the different channels and conveys the particles having the first marker through the first exit channel 175. All other particles are then fed into a second parallel sorter 172 for sorting particles having a second marker. The particles having the second marker are collected and conveyed through a second exit channel 176. Particles having neither the first marker nor the second marker are conveyed through a third exit channel 177.

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  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Computer Hardware Design (AREA)
  • Microelectronics & Electronic Packaging (AREA)
  • Theoretical Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Fluid Mechanics (AREA)
  • Separation Of Solids By Using Liquids Or Pneumatic Power (AREA)

Abstract

L'invention concerne un procédé et un appareil permettant de trier des particules circulant à travers un système de canaux fermé de dimension capillaire, lequel appareil comprend une bulle « à fonction soupape » (25) destinée à produire, de manière sélective, une impulsion de pression pour séparer une particule (18b) d'un flux de particules, laquelle particule présente une caractéristique prédéterminée. Ce système de tri de particules peut également comporter un tampon (100a, 100b), destiné à absorber cette impulsion de pression.
PCT/US2003/012359 2002-04-17 2003-04-17 Procede et appareil de tri de particules WO2003089157A1 (fr)

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AU2003231021A AU2003231021A1 (en) 2002-04-17 2003-04-17 Method and apparatus for sorting particles

Applications Claiming Priority (6)

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US37325602P 2002-04-17 2002-04-17
US60/373,256 2002-04-17
US10/179,488 2002-06-24
US10/179,586 2002-06-24
US10/179,488 US6808075B2 (en) 2002-04-17 2002-06-24 Method and apparatus for sorting particles
US10/179,586 US6877528B2 (en) 2002-04-17 2002-06-24 Microfluidic system including a bubble valve for regulating fluid flow through a microchannel

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EP1566434A2 (fr) * 2004-01-21 2005-08-24 Hewlett-Packard Development Company, L.P. Procédé et dispositif de triage de particules
EP1977830A1 (fr) * 2007-03-30 2008-10-08 Roche Diagnostics GmbH Soupape micro-fluidique commandée par temperature
CN103027009A (zh) * 2011-09-29 2013-04-10 贺陈弘 微小昆虫自动分类系统
WO2012094325A3 (fr) * 2011-01-03 2013-09-06 Cytonome/St. Llc Procédé et appareil de surveillance et d'optimisation de tri de particules
CN110606373A (zh) * 2019-09-29 2019-12-24 中国石油大学(北京) 气力输送系统弯管抗磨损的静电方法及静电调节装置
CN111812329A (zh) * 2020-07-28 2020-10-23 山东圣剑医学研究有限公司 一种定量检测多种肿瘤标志物的抗体芯片试剂盒
CN114292741A (zh) * 2021-12-13 2022-04-08 清华大学 一种基于电火花空化气泡的分选装置及方法
CN114950967A (zh) * 2022-04-14 2022-08-30 北京本草方源（亳州）药业科技有限公司 一种中草药称重筛分投料装置

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EP1566434A3 (fr) * 2004-01-21 2006-11-29 Hewlett-Packard Development Company, L.P. Procédé et dispositif de triage de particules
EP1566434A2 (fr) * 2004-01-21 2005-08-24 Hewlett-Packard Development Company, L.P. Procédé et dispositif de triage de particules
EP1977830A1 (fr) * 2007-03-30 2008-10-08 Roche Diagnostics GmbH Soupape micro-fluidique commandée par temperature
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CN110606373A (zh) * 2019-09-29 2019-12-24 中国石油大学(北京) 气力输送系统弯管抗磨损的静电方法及静电调节装置
CN111812329A (zh) * 2020-07-28 2020-10-23 山东圣剑医学研究有限公司 一种定量检测多种肿瘤标志物的抗体芯片试剂盒
CN114292741A (zh) * 2021-12-13 2022-04-08 清华大学 一种基于电火花空化气泡的分选装置及方法
CN114292741B (zh) * 2021-12-13 2023-01-24 清华大学 一种基于电火花空化气泡的分选装置及方法
CN114950967A (zh) * 2022-04-14 2022-08-30 北京本草方源（亳州）药业科技有限公司 一种中草药称重筛分投料装置
CN114950967B (zh) * 2022-04-14 2024-06-07 湖北广仁药业有限公司 一种中草药称重筛分投料装置

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