WO2024121562A1 - Particle sorter - Google Patents

Particle sorter Download PDF

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Publication number
WO2024121562A1
WO2024121562A1 PCT/GB2023/053154 GB2023053154W WO2024121562A1 WO 2024121562 A1 WO2024121562 A1 WO 2024121562A1 GB 2023053154 W GB2023053154 W GB 2023053154W WO 2024121562 A1 WO2024121562 A1 WO 2024121562A1
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WO
WIPO (PCT)
Prior art keywords
chamber
port
ports
particle sorter
sorter according
Prior art date
Application number
PCT/GB2023/053154
Other languages
French (fr)
Inventor
Prashant Agrawal
Hamdi Torun
Original Assignee
University Of Northumbria At Newcastle
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
Application filed by University Of Northumbria At Newcastle filed Critical University Of Northumbria At Newcastle
Publication of WO2024121562A1 publication Critical patent/WO2024121562A1/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502761Containers 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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01DSEPARATION
    • B01D21/00Separation of suspended solid particles from liquids by sedimentation
    • B01D21/28Mechanical auxiliary equipment for acceleration of sedimentation, e.g. by vibrators or the like
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01DSEPARATION
    • B01D43/00Separating particles from liquids, or liquids from solids, otherwise than by sedimentation or filtration
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B03SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03BSEPARATING SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS
    • B03B5/00Washing granular, powdered or lumpy materials; Wet separating
    • B03B5/02Washing granular, powdered or lumpy materials; Wet separating using shaken, pulsated or stirred beds as the principal means of separation
    • B03B5/10Washing granular, powdered or lumpy materials; Wet separating using shaken, pulsated or stirred beds as the principal means of separation on jigs
    • B03B5/22Washing granular, powdered or lumpy materials; Wet separating using shaken, pulsated or stirred beds as the principal means of separation on jigs using pulses generated by liquid injection
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06Fluid handling related problems
    • B01L2200/0647Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652Sorting or classification of particles or molecules
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0475Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics

Definitions

  • the present application relates to devices for sorting particles, for example particles with a mean average particle size of 100nm to 1mm, and more particularly, but not exclusively, to sorting the particles by one or more of size, density and visco-elastic properties.
  • Sorting particles from liquids in which they are carried is important in several technical fields, and may be used to separate substantially all particles, or just a selected sub-group of particles with particular properties, from the liquid. Accordingly, from an initial supply of liquid carrying particles, particle sorting is used to produce a first output with a greater concentration of particles, or with a greater concentration of a sub-group of particles with selected properties, and a complementary second output.
  • Technical fields in which particles may be sorted from liquids include chemical and pharmaceutical manufacturing, for example for separating-out particles (e.g. particles within a range of physical properties), enriching emulsions, concentrating particle suspensions, water filtration and use in bio-analytical devices for biosensing.
  • Microscale methods are known, using electric, magnetic and optic fields. Whilst these methods can have a high particle resolution, they have low processing volumes and require complex and expensive fabrication procedures and equipment.
  • High frequency vibrations have been used for particle separation in channels, using high frequency vibrations ranging from 10 kHz to MHz frequencies. Limitations of these methods include: high shear forces that damage delicate emulsions or biological cells, reducing particulate yield; high cost due to complex microscale fabrication; low scalability, especially for sub-micron particulates, due to microscale device requirements; and high power requirements due to significant energy dissipation via heating.
  • Low frequency vibrations have also been used for particle separation in open-topped channels, in which the channel is vibrated to create standing capillary waves at the water-air interface creating a periodic first order velocity field, which causes the accumulation of particles underneath the capillary wave nodes.
  • the wavelength of the capillary waves and the driving frequency cannot be decoupled, limiting the design, operational yield and throughput.
  • a particle sorter comprising: a closed chamber having a plurality of ports; and a first pump coupled to at least one port and configured to provide oscillations to the at least one port in a first mode of operation with an oscillation frequency of 0.1 Hz to 50 Hz, in use.
  • a method of sorting particles with a particle sorter comprising: providing a port of the chamber with a supply of liquid carrying particles; and providing oscillations to the liquid in the chamber.
  • the first pump may provide oscillations in a first mode of operation with an oscillation frequency of 0.1 Hz to 20 Hz, in use.
  • the first pump may be configured to switch between the first mode of operation and a second mode of operation to flush accumulated particulate from the chamber.
  • a second pump may be coupled to a port to flush accumulated particulate from the chamber.
  • the second pump may be coupled to two ports of the chamber to provide an input flushing liquid to a first port of the chamber and to receive an output flushing fluid from a further port of the chamber.
  • a pump may be configured to provide an input supply of liquid to the chamber during the first mode of operation.
  • a gas supply is configured to supply one or more bubbles into the chamber.
  • the first pump may be configured to be selectable to provide one or more of a plurality of different frequency oscillations to the same port of the chamber or different ports of the chamber.
  • the first pump may be coupled to provide first oscillations to a first port and second oscillations to either the first port or a second port, wherein the first and second oscillations have a different oscillation frequency.
  • the chamber may have an inlet flushing port and a plurality of opposed outlet flushing ports, and oscillation ports are each intermediate the inlet flushing port and an outlet flushing port, wherein the first pump is coupled to opposed oscillation ports and a second pump is coupled to an inlet flushing port to supply a flushing flow through the chamber to the outlet flushing ports.
  • the second pump may be coupled to opposed outlet flushing ports comprising a central outlet flushing port between lateral outlet flushing ports, and the first pump may be coupled to opposed oscillation ports that are each intermediate the inlet flushing port and a respective lateral outlet flushing port.
  • the first pump may be coupled to provide first oscillations to a first port and second oscillations to a second port, wherein the first and second oscillations have a common oscillation frequency and a relative phase difference.
  • the chamber may have a base and a roof, and one or more pillars extending between the base and the roof.
  • the chamber may have a base and a roof, and one or both of the base and roof may be provided with a periodically repeating surface profile.
  • the periodically repeating surface profile may be a wave pattern.
  • the periodically repeating surface profile may be an array of dimples.
  • the chamber may have a base, a roof and side walls and two or more ports may be provided in the side walls.
  • the oscillations may be coupled to one or more ports in one or more side walls.
  • the chamber may have a base, a roof and side walls and one or more ports may be provided in one or both of the base and the roof of the chamber.
  • the chamber Adjacent a port provided in the base or roof of the chamber, the respective base or roof may be inclined towards the port.
  • the chamber may have a length, a width and a depth provided by one or more side walls, and ports in the side walls may have a diameter of up to 30% of the lesser of the length and the width, up to 30% of the length or up to 30% of the width.
  • the chamber may have a length of 3mm to 50mm, a width of 3mm to 50mm, and a depth of equal to or less than 3mm, e.g. a depth of equal to or less than 1 mm.
  • the chamber may have a depth of at least 50 pm.
  • the chamber may have a length and the cross-sectional area of the chamber may vary along the length of the chamber.
  • the chamber may have a length and the width of the chamber may vary along the length of the chamber.
  • the chamber may have a length and the depth of the chamber may vary along the length of the chamber.
  • the chamber may have a length, a width and a depth, and the depth may be equal to or less than one third of the lesser of the length and the width.
  • the chamber may have a base that is diamond-shaped, square, rectangular, triangular, pentagonal, hexagonal, n-sided polygons having up to 20 sides, circular or elliptical.
  • the particle sorter may comprise a plurality of serially coupled chambers.
  • Figures 1A to 1C show views of a particle sorting chamber
  • Figure 1 D shows a schematic view of a particle sorter comprising the particle sorting chamber of Figure 1A;
  • Figure 1 E shows a schematic view of an alternative particle sorter comprising the particle sorting chamber of Figure 1A;
  • Figure 2A shows a schematic view of a particle sorter having a single particle sorting chamber
  • Figure 2B shows a schematic view of a particle sorter having two serially coupled particle sorting chambers
  • Figure 2C shows a schematic view of a further particle sorter having two serially coupled particle sorting chambers
  • Figure 2D shows a schematic view of a further particle sorter having a two-dimensional arrange of serially-coupled and parallel-coupled particle sorting chambers
  • Figure 2E shows a schematic view of a further particle sorter having a single particle sorting chamber
  • Figures 3A and 3B show schematic plan views of further particle sorting chambers
  • Figure 4A shows a schematic view of a further particle sorting chamber, and Figure 4B shows particle motion within the chamber of Figure 4A;
  • Figure 5A shows a schematic view of a further particle sorting chamber, and Figure 5B shows particle motion within the chamber of Figure 5A;
  • Figure 6A shows a schematic view of a particle sorting chamber for continuous particle sorting use, and Figure 6B shows a plurality of serially coupled particle sorting chambers of Figure 6A;
  • Figure 7 shows a schematic view of a hexagonal chamber
  • Figure 8 shows a schematic view of a cut-away view of a chamber with a patterned base.
  • Figure 1A shows a perspective view of a closed particle sorting chamber 100 of a particle sorter, within a housing 120 and having inlet/outlet conduits leading coupling through the housing to chamber ports 140.
  • Figures 1 B and 1C show cut-away views of the chamber 100 and housing 120, respectively along the width W and length L of the chamber.
  • Figure 1 D shows a particle sorter 190 in a cut-away view through the chamber 100 (parallel to the length and width of the chamber).
  • the chamber 100 is shallow, being much thinner in one dimension (e.g. Z-axis) than in the perpendicular plane (e.g. the X-Y plane), forming a generally shallow box-shaped void within the housing 120, having side walls 106 with a depth D extending between a base 102 and a roof 104 of the chamber.
  • Figure 1 D shows a view that is cut-away in-plane (e.g. cut parallel to the X-Y plane).
  • a “closed” particle sorting chamber is a chamber 100 that only has openings at the chamber ports 140.
  • the chamber ports 140 are located within faces of the chamber or at corners between faces 106 of the chamber, being within or adjacent the side walls 106, base 102 or roof 104.
  • the chamber ports are much smaller in area than the face of the chamber within which they are provided, or adjacent which they are provided (e.g. being provided where two faces meet, or connecting between two faces).
  • the use of a closed chamber enables the wavelength of the velocity field of the liquid within chamber, which determines the locations of the accumulation regions A, to be decoupled from the oscillation frequency, instead of being defined by the geometry of the chamber.
  • Figure 1 D shows a particle sorter 190, in which a pump 142 is coupled in a closed loop to two opposed ports 140 of the particle sorting chamber 100 of Figure 1A and adapted to provide oscillations V, V’ to respective ports 140 of the chamber (in an oscillation generation mode of operation).
  • the oscillations may be coupled to one or more ports in one or more side walls 106.
  • the particle sorting chamber 100 is filled with a liquid carrying particulate (e.g. having a mean average particle size of 100nm to 1mm).
  • the liquid may be introduced through one of the ports 140 coupled to the pump 142, e.g. being supplied by activation of the first pump.
  • the liquid within the chamber 100 is subjected to oscillations V, V’ produced by the first pump 142 with an oscillation frequency of 0.1 Hz to 50 Hz, which enables relatively rapid collection of particles.
  • the oscillation frequency may be 0.1 Hz to 20 Hz, which may further enable rapid collection of particles.
  • the oscillation V through one port 140 of the chamber 100 is in anti-phase with the oscillation V’ through the opposed port 140 (i.e.
  • FIG. 1 D shows accumulation regions A for oscillations V, V’ through the illustrated particle sorting chamber 100.
  • Oscillations may be provided to chamber with a plurality of different frequencies, e.g. with the same plurality of frequencies being provided to the same one or more ports, or with different frequencies being provided to different ports. Oscillations at different frequencies may have the same or different amplitudes (e.g. measured by displacement volume).
  • one or more bubbles of gas may be provided in the particle sorting chamber 100, e.g. being injected through a port 140 (or directly into the particle sorting chamber 100 through a separate gas injection port).
  • the size (diameter) of the bubble(s) may be controllable to enhance accumulation of particles, e.g. particles may accumulate at the surface of the bubble(s).
  • the supplied bubbles may have a diameter that is up to half the lesser of the length or width of the chamber.
  • the bubbles may remain attached to the base, roof or side walls, in use, e.g. being trapped adjacent a bubble injection port. Differently sized bubbles may be used with the same particle sorting chamber to provide variations in particle accumulatio performance.
  • the properties upon which the selection of particles for accumulation in the accumulation regions A is based may be one or more of the size, density and visco-elastic properties of the particles (e.g. a combination of size, density and visco-elastic properties). For example, with all other properties remaining equal, smaller particles may be more likely to remain dispersed and larger particles may be more likely to accumulate at the accumulations regions A.
  • Each period of oscillation V, V’ may transfer a volume of 0.1 to 50 pL into and back out of the chamber, for example transferring a volume of 2 to 10 pL.
  • the volume transfer rate of the oscillation V, V’ may be 1 pL/min to 10,000 pL/min.
  • liquid is flushed through the chamber 100 to remove the accumulated particles from the chamber, for example by providing a high intensity flow F through the chamber.
  • the chamber 100 may be flushed through one of the ports 140 coupled to the pump 142.
  • the pump 142 may be switched from operation producing oscillations V, V’ to operation for flushing F the chamber 100.
  • the liquid and accumulated particulate that is flushed F from the chamber may be collected, and the chamber may be refilled to repeat the accumulation of particles with the oscillations V, V’.
  • the particulate may be flushed from the chamber with an external fluid supply, e.g. coupled through one or more valves 150 from an inlet 143 to an outlet 145 (the valves may be solenoid switching valves; the valves may be controlled via a micro-controller).
  • the particulate may be removed from the chamber through an extraction port at one or more accumulation regions A, as discussed below, e.g. being removed during on-going particle accumulation, during a flushing step, or both.
  • the chamber 100 may be openable to facilitate the removal of particles from the chamber. Each of the approaches for particle removal may similarly be applied to the other designs of chambers discussed.
  • the liquid carrying particulate may be provided to the chamber 100 and continuously replenished by a gentle flow (e.g. sufficiently gentle not to significantly disturb the accumulation of particles within the chamber), before accumulated particles are removed by periodic flushing (e.g. high intensity flow) or emptying of the chamber.
  • a gentle flow e.g. sufficiently gentle not to significantly disturb the accumulation of particles within the chamber
  • periodic flushing e.g. high intensity flow
  • Potential applications for the particle sorter include separating particles (e.g. particles with physical properties within a particular range), isolating and enriching emulsions, suspensions of cells (i.e. biological particles), and nanoparticle solutions, water filtration and use in bio- analytical devices for bio-sensing.
  • particles e.g. particles with physical properties within a particular range
  • isolating and enriching emulsions e.g. particles with physical properties within a particular range
  • suspensions of cells i.e. biological particles
  • nanoparticle solutions e.g. water filtration and use in bio- analytical devices for bio-sensing.
  • oscillations V, V’ with relatively low frequencies applies low shear forces upon the particles enabling enhanced throughput of accumulated particles, using a mechanically simple chamber that enables particle sorting based upon physical properties of the particulates (e.g. sorting particles with mean average sizes in the range 100nm to 1mm), with low energy consumption due to the low shear forces, and with independent control over selection precision and throughput, e.g. being controlled by the choice of chamber dimensions and oscillation frequency.
  • the particle sorting chamber 100 of Figure 1A is a single empty chamber with a flat floor and ceiling, and ports provided only in the side walls of the chamber.
  • at least one of: a plurality of chambers may be coupled together to provide enhanced particle selection performance; the chamber may be provided with an extraction port in the base or roof of the chamber, e.g. aligned with a particle accumulation region A of the chamber; and the chamber may be provided with one or more pillars, which changes the velocity field within the chamber, and may increase the rate of particle accumulation and the number of particle accumulation regions A.
  • the particle selection properties of a particle sorting chamber are subject to several parameters, including the shape and size of the chamber, and the oscillation driving arrangement of the chamber.
  • the closed chamber may be a simple convex polygonal shape.
  • the chamber may have a base that is diamond-shaped, square, triangular, pentagonal, hexagonal, or n- sided polygons having up to 20 sides (which may have sides of equal or unequal lengths).
  • the chamber may have a base that is circular or elliptical (oval).
  • Figure 1 E shows an alternative particle sorter 190’ with an in-plane cut-away view through the closed particle sorting chamber 100 of Figure 1A.
  • the pump 142 is configured to produce oscillations V and is coupled to one port 140 of the particle sorting chamber 100 and to an inlet 143.
  • An opposed chamber port 140 is coupled to an outlet 145 that may optionally be closable with a valve 150.
  • the particle sorting chamber 100 is filled (or continuously replenished) with a liquid carrying particulate (e.g. having a mean average particle size of 100nm to 1mm), for example through the port 140 coupled to the pump 142 (e.g. the other port 140 remains open, e.g. the chamber is filled through the pump 142 from inlet 143).
  • the liquid within the chamber 100 is subjected to oscillations V with an oscillation frequency of 0.1 Hz to 50 Hz (e.g. 0.1 Hz to 20 Hz), causing particles either to remain dispersed within the liquid or to accumulate in one or more accumulation regions A’ of the chamber.
  • liquid is flushed through the chamber 100 to remove the accumulated particles, for example by flushing liquid F through the port 140 that is coupled to the pump 142 (e.g. replenishing with further liquid carrying particulate for further accumulation).
  • the oscillation V may be halted, the pump 142 may be switched to produce a flushing flow F to flush the accumulated particulate from the chamber 100 with a vigorous fluid flow (e.g.: out through valve 150 and outlet 145; the valve may be a solenoid switching valve; and the pump 142 may be connected to a fluid supply).
  • a vigorous fluid flow e.g.: out through valve 150 and outlet 145; the valve may be a solenoid switching valve; and the pump 142 may be connected to a fluid supply.
  • flushing F accumulated particulate swept from the chamber may be separated from the flushed fluid by filtration.
  • the particulate may be removed from the chamber through an extraction port at the accumulation regions A’, as discussed below.
  • the chamber 100 may be openable and the particles
  • Flushing flow F and oscillation V may be provided through the same ports 140, for example with the pump 142 switching between the two operations.
  • the pump 142 may provide both oscillations V and a continuous replenishment flow of replenishing particulate carrying liquid.
  • the chamber may be periodically filled and emptied, e.g. by a syringe.
  • the particle sorter may be provided with a pump that may be periodically switched between an oscillation generation mode of operation and a flushing mode of operation.
  • FIG. 2A shows a further particle sorter 190, in which a first pump 142 is coupled to a port 140A of the chamber 100 to provide oscillations V, and a second pump 144 is coupled in a closed loop to two different, opposed ports 140B, 140C of the chamber to provide both a continuous gentle replenishment of liquid carrying the particulate during particle sorting, and for use in flushing F with a vigorous fluid flow (when required to remove accumulated particulate, e.g. out through valve 150 and outlet 145; the valve may be a solenoid switching valve).
  • the liquid and accumulated particulate is swept from the chamber, and may be separated from the closed loop by filtration.
  • the particulate may be removed from the chamber through an extraction port at one or more of the accumulation regions A (e.g. during on-going particle sorting), as discussed below.
  • the particle sorting chamber 100 is supplied with liquid carrying particulate, either in a single filling operation or by continuous replenishment.
  • the liquid within the chamber 100 is subjected to oscillations V, from the first pump 142 through port 140A with an oscillation frequency of 0.1 Hz to 50 Hz (e.g. 0.1 Hz to 20 Hz), generating complementary oscillations through the other ports 140B, 140C, each with approximately half the amplitude, and causing the selection of particles within the chamber, with the selected particles accumulating in the accumulation region A, shown in Figure 3A.
  • the second pump 144 is coupled in a closed loop.
  • the liquid carrying the particulate may only be supplied to the chamber 100 from the pump to provide a liquid supply to an inlet port of the chamber, and an outlet port of the chamber may be configured for discharge from the particle sorter.
  • the particle sorters may be easily scaled, by the connection of chambers in parallel, in series, or both in parallel and in series.
  • Each of the described chamber designs may be connected in parallel, in series, or both in parallel and in series.
  • Figure 2B shows a plurality of chambers 100A, 100B coupled in series.
  • Series coupled chambers 100A, 100B may be operated similarly, to enhance particle selection on the basis of a common criteria. For example, series coupled chambers may preferentially accumulate particles with a mean average particle size above the same threshold.
  • the series coupled chambers 100A, 100B may be operated with different particle selection criteria, enabling the combined chambers to select particles falling within a narrow range of properties.
  • the first chamber 100A may preferentially select the accumulation of particles falling above a first threshold mean average size to accumulate in the first chamber
  • the second chamber 100B may preferentially select particles falling above a lower second threshold mean average size to remain in dispersion. Accordingly, particles falling between the two thresholds may be preferentially accumulated in the second chamber 100B.
  • the plurality of chambers are coupled together by a conduit extending between respective ports 140.
  • the chambers 100A’, 100B’, 100C’ may be directly coupled together, in series, without an intervening conduit, with the port 140 one chamber forming the port of the adjacently coupled chamber, as shown in Figure 2C.
  • the side walls of each chamber may be flat, concave, or a combination of both.
  • chambers may additionally, or alternatively, be coupled together in parallel, with or without intervening conduits.
  • chambers 100 may be coupled together in a two-dimensional array, as shown in Figure 2D.
  • the ports that open at the chamber are small in area relative to the size of chamber (e.g. up to 30% of the lesser of the length and the width, no more than 30% of the length, or 30% of the width of the chamber), so that the wavelength of the velocity field of the liquid within the chamber, which determines the locations of the accumulation regions, is governed by the chamber size.
  • the depth of the chamber may be less than each of the length and the width.
  • the particle sorting chambers may be shallow, e.g. having a depth D that is equal to, or less than, one third of the lesser of the length L and the width W of the chamber. Being shallow improves particle sorting performance, and in particular may enhance the collection of smaller particles.
  • the length of the chamber may be from 0.1x to 10x the width of the chamber.
  • the chamber may have a length of 3mm to 50mm (e.g. 3mm to 15mm), a width of 10pm to 50mm or 3mm to 50mm (e.g. 3mm to 15mm), and a depth of up to 3mm (e.g. a depth of up to 2mm, up to 1 mm or up to 500pm).
  • the chamber may have a depth of at least 250nm.
  • the chamber may have a depth of at least 50pm, or at least 100pm.
  • the cross-sectional area of the chamber may vary along the length of the chamber. For example, one or both of the width and the depth of the chamber may vary along the length of the chamber.
  • the chamber may have a depth of at least three times (or at least five times) the mean average particle diameter (e.g. threshold diameter of particles being accumulated). For example, for sorting particles having a mean average particle diameter of up to 66pm, the chamber may have a depth of 200pm or more.
  • Figure 2A shows a further particle sorter 190, in which a first pump 142 is coupled to one port 140A of the chamber 100 to provide oscillations V.
  • the first pump 142 may be coupled to two (or more) ports 140 of the chamber 100, for example being coupled in a closed loop as shown in Figure 2D, e.g. being coupled to two opposed ports of the chamber.
  • the arrangement of the ports through which the oscillations V, V’, and optionally any continuous replenishment flow (of liquid carrying particulate) through the chamber, are provided determines where the particle accumulation region(s) A arise, and the particle selection criteria applied.
  • Figure 3A shows the location of the accumulation region A with oscillation V provided perpendicularly through a port 140 on only one side (similarly to Figure 2A), whereas Figure 3B shows a differently located accumulation region A with both antiphase oscillation V’ additionally being provided through an opposed port to that of the oscillation V in Figure 3A (e.g. similarly to Figure 2D).
  • a pump is configured to provide a flushing flow F when the chamber is periodically emptied of accumulated particulate (and optionally a gentle replenishment flow), through a pair of opposed ports that are perpendicular to the orientation of the oscillation.
  • a chamber 100 may be provided with oscillations through each port in a mirror symmetric arrangement, with the oscillations V through two opposed ports 140 being in phase and having the same amplitude, but in anti-phase with the oscillations V’ through perpendicular ports.
  • oscillations provided to different ports may have a different phase relationship from being in-phase or anti-phase, and may have the same or different amplitudes.
  • Figure 4A shows an arrangement in which a first pair of opposed ports are driven in phase with each other (i.e. simultaneous in-flow at both ports) with oscillation V, and driven with anti-phase oscillations V’ at a perpendicular second pair of opposed ports (the arrangements of a flushing flow and an optional replenishing flow are not shown).
  • This driving pattern causes particle accumulation in four accumulation regions A spaced apart around the square chamber symmetrically between the ports 140 (e.g. the chamber has two-fold mirror symmetry, and the accumulation regions A are arranged with corresponding symmetry).
  • the accumulation regions A are the regions of slowest velocity field.
  • Figure 4B shows the corresponding streaming field and the motion of particles 180 subject to accumulation, within the chamber of Figure 4A.
  • a pillar 148 may be provided within the chamber, e.g. centrally, e.g. extending between the floor and roof of the chamber, to change the way in which the particles move in response to oscillations V.
  • the provision of a pillar (or more than one pillar) may change the particle selection criteria of the chamber, e.g. may enhance the collection of smaller particles, and may reduce the collection size threshold.
  • the provision of the pillar(s) may increase particle collection rates and may increase the number of particle accumulation regions A (which may facilitate bio-sampling and analysis).
  • Figure 5B shows the streaming field and particle motion in a square chamber, with the same pattern of oscillations V, V’ as shown in Figure 4B, but with the chamber of Figure 5A, which has an additional central pillar 148.
  • the addition of the pillar 148 may enhance the speed of particle collection.
  • the addition of the pillar 148 may enhance the collection of smaller sized particles.
  • the addition of the pillar 148 may increase the number of particle accumulation regions A.
  • Each of the described chamber designs may be provided with one or more pillars.
  • the one or more pillars may be provided centrally within the chamber, away from the centre of the chamber, or at a combination of both.
  • an extraction port 146 may optionally be provided in the base 102 (or roof) of the chamber 100 for the extraction of the particles that accumulate in a corresponding accumulation region A (or for the outlet of liquid from which at least some of the particulate has been removed).
  • the accumulated particles may fall into the extraction port 146 under gravity, or may be extracted by a liquid flow drawn out of the extraction port 146 (e.g. by a pump).
  • the inclination may be by less than 30° relative to the surrounding base (or roof).
  • Each of the other described chamber designs may be provided with one or more extraction ports at their accumulation region(s).
  • the one or more extraction ports may be provided centrally within the chamber, away from the centre of the chamber, or at a combination of both.
  • the ports may all be in the side walls 106 of each chamber 100 (e.g. in faces of the chamber extending parallel to the height of the chamber). Alternatively, some of the ports may be provided in the base 102 or roof 104 of the chamber.
  • oscillations V may be provided through a central port provided in the base 102 or roof 104 of the chamber 100 (e.g. in addition to, or instead of, oscillations provided through one or more ports 140 provided in side walls 106 of the chamber).
  • Figure 6A shows an alternative chamber for continuous in-plane particle sorting 100T.
  • the chamber 100T is triangular, fanning out from an input supply port 140S to a plurality of outlet ports in the opposite end of the chamber 100T, being a central outlet port 140C between lateral outlet ports 140L.
  • opposed ports 140V are provided with complementary oscillations V, V’, causing spatial sorting of particles carried in the liquid flow F passing through the chamber from the input supply port 140S, providing a different distribution of particles in the outlet flows through the central outlet port 140C and the lateral outlet ports 140L.
  • the inlet flow F contains equal percentages of particles having a smaller and larger mean average particle size (e.g.
  • the chamber 100T may be used to produce an outlet flow with an enriched concentration of particles.
  • Figure 6B shows an arrangement of serially coupled chambers for continuous in-plane particle sorting 100T, as shown in Figure 6A.
  • the inlet ports 140S of the second stage of chambers 100T2 are coupled to the lateral outlet ports 140L of first stage chamber 100T1 , and as shown in the distribution graphs, the second stage of particle sorting further enhances the concentration of larger particles in the outlet from the second stage lateral outlet ports 140L. Oscillations at the same frequency but with different phases may be provided to different ports of the chamber.
  • pairs of adjacent ports are driven with oscillations in antiphase (e.g. VO, VO’), with a phase shift between successive pairs of ports around the side wall of the chamber.
  • oscillations in antiphase e.g. VO, VO’
  • phase shift between successive pairs of ports around the side wall of the chamber may enable the simultaneous collection of a plurality of different particles in different particle accumulation regions.
  • Oscillations at one or more different frequencies may be provided to the same port or different ports of the chamber, by the pump.
  • the use of more than two different frequencies of driving oscillations may enable the simultaneous collection of a plurality of different particles in different particle accumulation regions.
  • the chambers may be provided with a two or more different frequencies of oscillations, which may cause different types of particles to accumulate at different accumulations regions of the chamber (which may be provided with corresponding extraction ports).
  • the base 102 or roof 104 of the chamber 100 may be patterned to modify the movement of particles within the chamber under the action of the provided oscillations.
  • the patterning may be a wave pattern or a two-dimensional array of dimples.
  • Figure 8 shows a chamber with a wave pattern 102P provided on the base 102 of the chamber.
  • the provision of a patterned base or roof may simply fabrication of the chamber.
  • the provision of a patterned base or roof may enable more efficient particle sorting and so the use of more compact particle sorting chambers, which may assist with the construction of multiple devices in a limited footprint.

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Abstract

A particle sorter comprising: a closed chamber having a plurality of ports; and a first pump coupled to at least one port and configured to provide oscillations to liquid in the chamber with an oscillation frequency of 0.1 Hz to 50 Hz, in use, and a method of sorting particles.

Description

PARTICLE SORTER
TECHNICAL FIELD
The present application relates to devices for sorting particles, for example particles with a mean average particle size of 100nm to 1mm, and more particularly, but not exclusively, to sorting the particles by one or more of size, density and visco-elastic properties.
BACKGROUND
Sorting particles from liquids in which they are carried is important in several technical fields, and may be used to separate substantially all particles, or just a selected sub-group of particles with particular properties, from the liquid. Accordingly, from an initial supply of liquid carrying particles, particle sorting is used to produce a first output with a greater concentration of particles, or with a greater concentration of a sub-group of particles with selected properties, and a complementary second output. Technical fields in which particles may be sorted from liquids include chemical and pharmaceutical manufacturing, for example for separating-out particles (e.g. particles within a range of physical properties), enriching emulsions, concentrating particle suspensions, water filtration and use in bio-analytical devices for biosensing.
Bulk industrial particle separation is commonly performed by filtration and centrifugation. However, yield is low, requiring high processing volumes. Commercial application is restricted by low particle resolution (discrimination, e.g. by size).
Microscale methods are known, using electric, magnetic and optic fields. Whilst these methods can have a high particle resolution, they have low processing volumes and require complex and expensive fabrication procedures and equipment.
High frequency vibrations have been used for particle separation in channels, using high frequency vibrations ranging from 10 kHz to MHz frequencies. Limitations of these methods include: high shear forces that damage delicate emulsions or biological cells, reducing particulate yield; high cost due to complex microscale fabrication; low scalability, especially for sub-micron particulates, due to microscale device requirements; and high power requirements due to significant energy dissipation via heating.
Low frequency vibrations have also been used for particle separation in open-topped channels, in which the channel is vibrated to create standing capillary waves at the water-air interface creating a periodic first order velocity field, which causes the accumulation of particles underneath the capillary wave nodes. However, in such devices, the wavelength of the capillary waves and the driving frequency cannot be decoupled, limiting the design, operational yield and throughput.
SUMMARY OF THE DISCLOSURE
According to a first aspect, there is provided a particle sorter comprising: a closed chamber having a plurality of ports; and a first pump coupled to at least one port and configured to provide oscillations to the at least one port in a first mode of operation with an oscillation frequency of 0.1 Hz to 50 Hz, in use.
According to a second aspect, there is provided a method of sorting particles with a particle sorter according to the first aspect, comprising: providing a port of the chamber with a supply of liquid carrying particles; and providing oscillations to the liquid in the chamber.
The first pump may provide oscillations in a first mode of operation with an oscillation frequency of 0.1 Hz to 20 Hz, in use.
The first pump may be configured to switch between the first mode of operation and a second mode of operation to flush accumulated particulate from the chamber.
A second pump may be coupled to a port to flush accumulated particulate from the chamber.
The second pump may be coupled to two ports of the chamber to provide an input flushing liquid to a first port of the chamber and to receive an output flushing fluid from a further port of the chamber.
A pump may be configured to provide an input supply of liquid to the chamber during the first mode of operation.
A gas supply is configured to supply one or more bubbles into the chamber.
The first pump may be configured to be selectable to provide one or more of a plurality of different frequency oscillations to the same port of the chamber or different ports of the chamber. The first pump may be coupled to provide first oscillations to a first port and second oscillations to either the first port or a second port, wherein the first and second oscillations have a different oscillation frequency.
The chamber may have an inlet flushing port and a plurality of opposed outlet flushing ports, and oscillation ports are each intermediate the inlet flushing port and an outlet flushing port, wherein the first pump is coupled to opposed oscillation ports and a second pump is coupled to an inlet flushing port to supply a flushing flow through the chamber to the outlet flushing ports.
The second pump may be coupled to opposed outlet flushing ports comprising a central outlet flushing port between lateral outlet flushing ports, and the first pump may be coupled to opposed oscillation ports that are each intermediate the inlet flushing port and a respective lateral outlet flushing port.
The first pump may be coupled to provide first oscillations to a first port and second oscillations to a second port, wherein the first and second oscillations have a common oscillation frequency and a relative phase difference.
The chamber may have a base and a roof, and one or more pillars extending between the base and the roof.
The chamber may have a base and a roof, and one or both of the base and roof may be provided with a periodically repeating surface profile. The periodically repeating surface profile may be a wave pattern. The periodically repeating surface profile may be an array of dimples.
The chamber may have a base, a roof and side walls and two or more ports may be provided in the side walls.
The oscillations may be coupled to one or more ports in one or more side walls.
The chamber may have a base, a roof and side walls and one or more ports may be provided in one or both of the base and the roof of the chamber.
Adjacent a port provided in the base or roof of the chamber, the respective base or roof may be inclined towards the port. The chamber may have a length, a width and a depth provided by one or more side walls, and ports in the side walls may have a diameter of up to 30% of the lesser of the length and the width, up to 30% of the length or up to 30% of the width.
The chamber may have a length of 3mm to 50mm, a width of 3mm to 50mm, and a depth of equal to or less than 3mm, e.g. a depth of equal to or less than 1 mm.
The chamber may have a depth of at least 50 pm.
The chamber may have a length and the cross-sectional area of the chamber may vary along the length of the chamber. The chamber may have a length and the width of the chamber may vary along the length of the chamber. The chamber may have a length and the depth of the chamber may vary along the length of the chamber.
The chamber may have a length, a width and a depth, and the depth may be equal to or less than one third of the lesser of the length and the width.
The chamber may have a base that is diamond-shaped, square, rectangular, triangular, pentagonal, hexagonal, n-sided polygons having up to 20 sides, circular or elliptical.
The particle sorter may comprise a plurality of serially coupled chambers.
DESCRIPTION OF THE DRAWINGS
Examples are further described hereinafter with reference to the accompanying drawings, in which:
• Figures 1A to 1C show views of a particle sorting chamber;
• Figure 1 D shows a schematic view of a particle sorter comprising the particle sorting chamber of Figure 1A;
• Figure 1 E shows a schematic view of an alternative particle sorter comprising the particle sorting chamber of Figure 1A;
• Figure 2A shows a schematic view of a particle sorter having a single particle sorting chamber;
• Figure 2B shows a schematic view of a particle sorter having two serially coupled particle sorting chambers;
• Figure 2C shows a schematic view of a further particle sorter having two serially coupled particle sorting chambers; • Figure 2D shows a schematic view of a further particle sorter having a two-dimensional arrange of serially-coupled and parallel-coupled particle sorting chambers;
• Figure 2E shows a schematic view of a further particle sorter having a single particle sorting chamber;
• Figures 3A and 3B show schematic plan views of further particle sorting chambers;
• Figure 4A shows a schematic view of a further particle sorting chamber, and Figure 4B shows particle motion within the chamber of Figure 4A;
• Figure 5A shows a schematic view of a further particle sorting chamber, and Figure 5B shows particle motion within the chamber of Figure 5A;
• Figure 6A shows a schematic view of a particle sorting chamber for continuous particle sorting use, and Figure 6B shows a plurality of serially coupled particle sorting chambers of Figure 6A;
• Figure 7 shows a schematic view of a hexagonal chamber; and
• Figure 8 shows a schematic view of a cut-away view of a chamber with a patterned base.
DETAILED DESCRIPTION
In the described examples, like features have been identified with like numerals, albeit in some cases having suffix letters; and typographical marks (e.g. primes). For example, in different figures, 100, 100A, 100B have been used to indicate a particle sorting chamber.
Figure 1A shows a perspective view of a closed particle sorting chamber 100 of a particle sorter, within a housing 120 and having inlet/outlet conduits leading coupling through the housing to chamber ports 140. Figures 1 B and 1C show cut-away views of the chamber 100 and housing 120, respectively along the width W and length L of the chamber. Figure 1 D shows a particle sorter 190 in a cut-away view through the chamber 100 (parallel to the length and width of the chamber).
The chamber 100 is shallow, being much thinner in one dimension (e.g. Z-axis) than in the perpendicular plane (e.g. the X-Y plane), forming a generally shallow box-shaped void within the housing 120, having side walls 106 with a depth D extending between a base 102 and a roof 104 of the chamber. Figure 1 D shows a view that is cut-away in-plane (e.g. cut parallel to the X-Y plane).
The side walls 106 of the chamber are flat, concavely shaped (i.e., concave, facing into the chamber) or a combination of both. A “closed” particle sorting chamber is a chamber 100 that only has openings at the chamber ports 140. The chamber ports 140 are located within faces of the chamber or at corners between faces 106 of the chamber, being within or adjacent the side walls 106, base 102 or roof 104. The chamber ports are much smaller in area than the face of the chamber within which they are provided, or adjacent which they are provided (e.g. being provided where two faces meet, or connecting between two faces).
The use of a closed chamber enables the wavelength of the velocity field of the liquid within chamber, which determines the locations of the accumulation regions A, to be decoupled from the oscillation frequency, instead of being defined by the geometry of the chamber.
Figure 1 D shows a particle sorter 190, in which a pump 142 is coupled in a closed loop to two opposed ports 140 of the particle sorting chamber 100 of Figure 1A and adapted to provide oscillations V, V’ to respective ports 140 of the chamber (in an oscillation generation mode of operation). The oscillations may be coupled to one or more ports in one or more side walls 106.
In use, the particle sorting chamber 100 is filled with a liquid carrying particulate (e.g. having a mean average particle size of 100nm to 1mm). The liquid may be introduced through one of the ports 140 coupled to the pump 142, e.g. being supplied by activation of the first pump. The liquid within the chamber 100 is subjected to oscillations V, V’ produced by the first pump 142 with an oscillation frequency of 0.1 Hz to 50 Hz, which enables relatively rapid collection of particles. For example, the oscillation frequency may be 0.1 Hz to 20 Hz, which may further enable rapid collection of particles. The oscillation V through one port 140 of the chamber 100 is in anti-phase with the oscillation V’ through the opposed port 140 (i.e. the volume of the chamber is constant, and the oscillations through the two ports are complementary). Subject to the selected oscillation frequency, the amplitude of the oscillations, and the shape of the chamber, differing levels of selection will be applied to different particles within the liquid according to their physical properties, causing them either to remain dispersed within the liquid or to accumulate in one or more accumulation regions A of the chamber. Figure 1 D shows accumulation regions A for oscillations V, V’ through the illustrated particle sorting chamber 100.
Oscillations may be provided to chamber with a plurality of different frequencies, e.g. with the same plurality of frequencies being provided to the same one or more ports, or with different frequencies being provided to different ports. Oscillations at different frequencies may have the same or different amplitudes (e.g. measured by displacement volume).
During the oscillation generation mode of operation, one or more bubbles of gas (e.g. air) may be provided in the particle sorting chamber 100, e.g. being injected through a port 140 (or directly into the particle sorting chamber 100 through a separate gas injection port). The size (diameter) of the bubble(s) may be controllable to enhance accumulation of particles, e.g. particles may accumulate at the surface of the bubble(s). The supplied bubbles may have a diameter that is up to half the lesser of the length or width of the chamber. The bubbles may remain attached to the base, roof or side walls, in use, e.g. being trapped adjacent a bubble injection port. Differently sized bubbles may be used with the same particle sorting chamber to provide variations in particle accumulatio performance.
The properties upon which the selection of particles for accumulation in the accumulation regions A is based may be one or more of the size, density and visco-elastic properties of the particles (e.g. a combination of size, density and visco-elastic properties). For example, with all other properties remaining equal, smaller particles may be more likely to remain dispersed and larger particles may be more likely to accumulate at the accumulations regions A.
Each period of oscillation V, V’ may transfer a volume of 0.1 to 50 pL into and back out of the chamber, for example transferring a volume of 2 to 10 pL. The volume transfer rate of the oscillation V, V’ may be 1 pL/min to 10,000 pL/min.
After a sufficient period of particle accumulation, liquid is flushed through the chamber 100 to remove the accumulated particles from the chamber, for example by providing a high intensity flow F through the chamber. The chamber 100 may be flushed through one of the ports 140 coupled to the pump 142. For example, the pump 142 may be switched from operation producing oscillations V, V’ to operation for flushing F the chamber 100. The liquid and accumulated particulate that is flushed F from the chamber may be collected, and the chamber may be refilled to repeat the accumulation of particles with the oscillations V, V’.
Alternatively, the particulate may be flushed from the chamber with an external fluid supply, e.g. coupled through one or more valves 150 from an inlet 143 to an outlet 145 (the valves may be solenoid switching valves; the valves may be controlled via a micro-controller). In a further alternative, the particulate may be removed from the chamber through an extraction port at one or more accumulation regions A, as discussed below, e.g. being removed during on-going particle accumulation, during a flushing step, or both. Yet further, the chamber 100 may be openable to facilitate the removal of particles from the chamber. Each of the approaches for particle removal may similarly be applied to the other designs of chambers discussed.
The liquid carrying particulate may be provided to the chamber 100 and continuously replenished by a gentle flow (e.g. sufficiently gentle not to significantly disturb the accumulation of particles within the chamber), before accumulated particles are removed by periodic flushing (e.g. high intensity flow) or emptying of the chamber.
Potential applications for the particle sorter include separating particles (e.g. particles with physical properties within a particular range), isolating and enriching emulsions, suspensions of cells (i.e. biological particles), and nanoparticle solutions, water filtration and use in bio- analytical devices for bio-sensing.
The use of oscillations V, V’ with relatively low frequencies applies low shear forces upon the particles enabling enhanced throughput of accumulated particles, using a mechanically simple chamber that enables particle sorting based upon physical properties of the particulates (e.g. sorting particles with mean average sizes in the range 100nm to 1mm), with low energy consumption due to the low shear forces, and with independent control over selection precision and throughput, e.g. being controlled by the choice of chamber dimensions and oscillation frequency.
The particle sorting chamber 100 of Figure 1A is a single empty chamber with a flat floor and ceiling, and ports provided only in the side walls of the chamber. In alternative arrangements, at least one of: a plurality of chambers may be coupled together to provide enhanced particle selection performance; the chamber may be provided with an extraction port in the base or roof of the chamber, e.g. aligned with a particle accumulation region A of the chamber; and the chamber may be provided with one or more pillars, which changes the velocity field within the chamber, and may increase the rate of particle accumulation and the number of particle accumulation regions A.
The particle selection properties of a particle sorting chamber are subject to several parameters, including the shape and size of the chamber, and the oscillation driving arrangement of the chamber.
The closed chamber may be a simple convex polygonal shape. For example, the chamber may have a base that is diamond-shaped, square, triangular, pentagonal, hexagonal, or n- sided polygons having up to 20 sides (which may have sides of equal or unequal lengths).
The chamber may have a base that is circular or elliptical (oval).
Figure 1 E shows an alternative particle sorter 190’ with an in-plane cut-away view through the closed particle sorting chamber 100 of Figure 1A. The pump 142 is configured to produce oscillations V and is coupled to one port 140 of the particle sorting chamber 100 and to an inlet 143. An opposed chamber port 140 is coupled to an outlet 145 that may optionally be closable with a valve 150.
In use, the particle sorting chamber 100 is filled (or continuously replenished) with a liquid carrying particulate (e.g. having a mean average particle size of 100nm to 1mm), for example through the port 140 coupled to the pump 142 (e.g. the other port 140 remains open, e.g. the chamber is filled through the pump 142 from inlet 143). The liquid within the chamber 100 is subjected to oscillations V with an oscillation frequency of 0.1 Hz to 50 Hz (e.g. 0.1 Hz to 20 Hz), causing particles either to remain dispersed within the liquid or to accumulate in one or more accumulation regions A’ of the chamber.
After a sufficient period of particle accumulation, liquid is flushed through the chamber 100 to remove the accumulated particles, for example by flushing liquid F through the port 140 that is coupled to the pump 142 (e.g. replenishing with further liquid carrying particulate for further accumulation). For example, the oscillation V may be halted, the pump 142 may be switched to produce a flushing flow F to flush the accumulated particulate from the chamber 100 with a vigorous fluid flow (e.g.: out through valve 150 and outlet 145; the valve may be a solenoid switching valve; and the pump 142 may be connected to a fluid supply). During flushing F, accumulated particulate swept from the chamber may be separated from the flushed fluid by filtration. Alternatively, the particulate may be removed from the chamber through an extraction port at the accumulation regions A’, as discussed below. In a further alternative, the chamber 100 may be openable and the particles may be removed by opening the chamber.
Flushing flow F and oscillation V may be provided through the same ports 140, for example with the pump 142 switching between the two operations. The pump 142 may provide both oscillations V and a continuous replenishment flow of replenishing particulate carrying liquid.
In a further alternative, the chamber may be periodically filled and emptied, e.g. by a syringe. In a yet further alternative, the particle sorter may be provided with a pump that may be periodically switched between an oscillation generation mode of operation and a flushing mode of operation.
Figure 2A shows a further particle sorter 190, in which a first pump 142 is coupled to a port 140A of the chamber 100 to provide oscillations V, and a second pump 144 is coupled in a closed loop to two different, opposed ports 140B, 140C of the chamber to provide both a continuous gentle replenishment of liquid carrying the particulate during particle sorting, and for use in flushing F with a vigorous fluid flow (when required to remove accumulated particulate, e.g. out through valve 150 and outlet 145; the valve may be a solenoid switching valve). During flushing F, the liquid and accumulated particulate is swept from the chamber, and may be separated from the closed loop by filtration. Alternatively, the particulate may be removed from the chamber through an extraction port at one or more of the accumulation regions A (e.g. during on-going particle sorting), as discussed below.
In use, the particle sorting chamber 100 is supplied with liquid carrying particulate, either in a single filling operation or by continuous replenishment. The liquid within the chamber 100 is subjected to oscillations V, from the first pump 142 through port 140A with an oscillation frequency of 0.1 Hz to 50 Hz (e.g. 0.1 Hz to 20 Hz), generating complementary oscillations through the other ports 140B, 140C, each with approximately half the amplitude, and causing the selection of particles within the chamber, with the selected particles accumulating in the accumulation region A, shown in Figure 3A.
In the illustrated particle sorter 190, the second pump 144 is coupled in a closed loop. Alternatively the liquid carrying the particulate may only be supplied to the chamber 100 from the pump to provide a liquid supply to an inlet port of the chamber, and an outlet port of the chamber may be configured for discharge from the particle sorter.
The particle sorters may be easily scaled, by the connection of chambers in parallel, in series, or both in parallel and in series. Each of the described chamber designs may be connected in parallel, in series, or both in parallel and in series.
Figure 2B shows a plurality of chambers 100A, 100B coupled in series. Series coupled chambers 100A, 100B may be operated similarly, to enhance particle selection on the basis of a common criteria. For example, series coupled chambers may preferentially accumulate particles with a mean average particle size above the same threshold. Alternatively, the series coupled chambers 100A, 100B may be operated with different particle selection criteria, enabling the combined chambers to select particles falling within a narrow range of properties. For example, the first chamber 100A may preferentially select the accumulation of particles falling above a first threshold mean average size to accumulate in the first chamber, and the second chamber 100B may preferentially select particles falling above a lower second threshold mean average size to remain in dispersion. Accordingly, particles falling between the two thresholds may be preferentially accumulated in the second chamber 100B.
In Figure 2B, the plurality of chambers are coupled together by a conduit extending between respective ports 140. Alternatively, the chambers 100A’, 100B’, 100C’ may be directly coupled together, in series, without an intervening conduit, with the port 140 one chamber forming the port of the adjacently coupled chamber, as shown in Figure 2C. The side walls of each chamber may be flat, concave, or a combination of both.
Similarly, the chambers may additionally, or alternatively, be coupled together in parallel, with or without intervening conduits. For example, chambers 100” may be coupled together in a two-dimensional array, as shown in Figure 2D.
The ports that open at the chamber are small in area relative to the size of chamber (e.g. up to 30% of the lesser of the length and the width, no more than 30% of the length, or 30% of the width of the chamber), so that the wavelength of the velocity field of the liquid within the chamber, which determines the locations of the accumulation regions, is governed by the chamber size.
The depth of the chamber may be less than each of the length and the width. The particle sorting chambers may be shallow, e.g. having a depth D that is equal to, or less than, one third of the lesser of the length L and the width W of the chamber. Being shallow improves particle sorting performance, and in particular may enhance the collection of smaller particles. The length of the chamber may be from 0.1x to 10x the width of the chamber.
The chamber may have a length of 3mm to 50mm (e.g. 3mm to 15mm), a width of 10pm to 50mm or 3mm to 50mm (e.g. 3mm to 15mm), and a depth of up to 3mm (e.g. a depth of up to 2mm, up to 1 mm or up to 500pm). The chamber may have a depth of at least 250nm. The chamber may have a depth of at least 50pm, or at least 100pm. The cross-sectional area of the chamber may vary along the length of the chamber. For example, one or both of the width and the depth of the chamber may vary along the length of the chamber.
The chamber may have a depth of at least three times (or at least five times) the mean average particle diameter (e.g. threshold diameter of particles being accumulated). For example, for sorting particles having a mean average particle diameter of up to 66pm, the chamber may have a depth of 200pm or more.
Figure 2A shows a further particle sorter 190, in which a first pump 142 is coupled to one port 140A of the chamber 100 to provide oscillations V. Alternatively, the first pump 142 may be coupled to two (or more) ports 140 of the chamber 100, for example being coupled in a closed loop as shown in Figure 2D, e.g. being coupled to two opposed ports of the chamber.
The arrangement of the ports through which the oscillations V, V’, and optionally any continuous replenishment flow (of liquid carrying particulate) through the chamber, are provided determines where the particle accumulation region(s) A arise, and the particle selection criteria applied.
For example, Figure 3A shows the location of the accumulation region A with oscillation V provided perpendicularly through a port 140 on only one side (similarly to Figure 2A), whereas Figure 3B shows a differently located accumulation region A with both antiphase oscillation V’ additionally being provided through an opposed port to that of the oscillation V in Figure 3A (e.g. similarly to Figure 2D). In each case, a pump is configured to provide a flushing flow F when the chamber is periodically emptied of accumulated particulate (and optionally a gentle replenishment flow), through a pair of opposed ports that are perpendicular to the orientation of the oscillation.
A chamber 100 may be provided with oscillations through each port in a mirror symmetric arrangement, with the oscillations V through two opposed ports 140 being in phase and having the same amplitude, but in anti-phase with the oscillations V’ through perpendicular ports. Alternatively, oscillations provided to different ports may have a different phase relationship from being in-phase or anti-phase, and may have the same or different amplitudes.
In a further example, Figure 4A shows an arrangement in which a first pair of opposed ports are driven in phase with each other (i.e. simultaneous in-flow at both ports) with oscillation V, and driven with anti-phase oscillations V’ at a perpendicular second pair of opposed ports (the arrangements of a flushing flow and an optional replenishing flow are not shown). This driving pattern causes particle accumulation in four accumulation regions A spaced apart around the square chamber symmetrically between the ports 140 (e.g. the chamber has two-fold mirror symmetry, and the accumulation regions A are arranged with corresponding symmetry). The accumulation regions A are the regions of slowest velocity field. Figure 4B shows the corresponding streaming field and the motion of particles 180 subject to accumulation, within the chamber of Figure 4A.
As shown in Figure 5A, a pillar 148 may be provided within the chamber, e.g. centrally, e.g. extending between the floor and roof of the chamber, to change the way in which the particles move in response to oscillations V. The provision of a pillar (or more than one pillar) may change the particle selection criteria of the chamber, e.g. may enhance the collection of smaller particles, and may reduce the collection size threshold. The provision of the pillar(s) may increase particle collection rates and may increase the number of particle accumulation regions A (which may facilitate bio-sampling and analysis).
Figure 5B shows the streaming field and particle motion in a square chamber, with the same pattern of oscillations V, V’ as shown in Figure 4B, but with the chamber of Figure 5A, which has an additional central pillar 148. The addition of the pillar 148 may enhance the speed of particle collection. The addition of the pillar 148 may enhance the collection of smaller sized particles. The addition of the pillar 148 may increase the number of particle accumulation regions A.
Each of the described chamber designs may be provided with one or more pillars. The one or more pillars may be provided centrally within the chamber, away from the centre of the chamber, or at a combination of both.
As indicated in Figures 3A and 3B, an extraction port 146 may optionally be provided in the base 102 (or roof) of the chamber 100 for the extraction of the particles that accumulate in a corresponding accumulation region A (or for the outlet of liquid from which at least some of the particulate has been removed). For example, the accumulated particles may fall into the extraction port 146 under gravity, or may be extracted by a liquid flow drawn out of the extraction port 146 (e.g. by a pump).
Adjacent an extraction port 146 provided in the base (or roof) of the chamber the respective base (or roof) is inclined towards the port, relative to the surrounding base (or roof), e.g. the extraction port may have a funnel-shaped opening into the chamber, to enhance flow of accumulated particles from the chamber to the extraction port and into the connecting conduit.
The inclination may be by less than 30° relative to the surrounding base (or roof).
Each of the other described chamber designs may be provided with one or more extraction ports at their accumulation region(s).
The one or more extraction ports may be provided centrally within the chamber, away from the centre of the chamber, or at a combination of both.
The ports may all be in the side walls 106 of each chamber 100 (e.g. in faces of the chamber extending parallel to the height of the chamber). Alternatively, some of the ports may be provided in the base 102 or roof 104 of the chamber.
In an alternative arrangement, oscillations V may be provided through a central port provided in the base 102 or roof 104 of the chamber 100 (e.g. in addition to, or instead of, oscillations provided through one or more ports 140 provided in side walls 106 of the chamber).
Figure 6A shows an alternative chamber for continuous in-plane particle sorting 100T. The chamber 100T is triangular, fanning out from an input supply port 140S to a plurality of outlet ports in the opposite end of the chamber 100T, being a central outlet port 140C between lateral outlet ports 140L. Part way along each side wall 106, opposed ports 140V are provided with complementary oscillations V, V’, causing spatial sorting of particles carried in the liquid flow F passing through the chamber from the input supply port 140S, providing a different distribution of particles in the outlet flows through the central outlet port 140C and the lateral outlet ports 140L. In the illustrated example, the inlet flow F contains equal percentages of particles having a smaller and larger mean average particle size (e.g. of smaller and larger radius rp), and larger particles are preferentially passed to the lateral outlet ports 140L, and preferentially (e.g. substantially only) smaller particles are passed to the central outlet port 140C, relative to the particle distribution of the inlet flow. Similarly, if the inlet flow F contains only smaller or larger particles, the chamber 100T may be used to produce an outlet flow with an enriched concentration of particles.
Figure 6B shows an arrangement of serially coupled chambers for continuous in-plane particle sorting 100T, as shown in Figure 6A. The inlet ports 140S of the second stage of chambers 100T2 are coupled to the lateral outlet ports 140L of first stage chamber 100T1 , and as shown in the distribution graphs, the second stage of particle sorting further enhances the concentration of larger particles in the outlet from the second stage lateral outlet ports 140L. Oscillations at the same frequency but with different phases may be provided to different ports of the chamber.
In the illustrated example hexagonal chamber 100 of Figure 7, pairs of adjacent ports are driven with oscillations in antiphase (e.g. VO, VO’), with a phase shift between successive pairs of ports around the side wall of the chamber. The use of more than two different phases of driving oscillations may enable the simultaneous collection of a plurality of different particles in different particle accumulation regions.
Oscillations at one or more different frequencies may be provided to the same port or different ports of the chamber, by the pump.
The use of more than two different frequencies of driving oscillations may enable the simultaneous collection of a plurality of different particles in different particle accumulation regions.
The chambers may be provided with a two or more different frequencies of oscillations, which may cause different types of particles to accumulate at different accumulations regions of the chamber (which may be provided with corresponding extraction ports).
The base 102 or roof 104 of the chamber 100 may be patterned to modify the movement of particles within the chamber under the action of the provided oscillations. For example, the patterning may be a wave pattern or a two-dimensional array of dimples. Figure 8 shows a chamber with a wave pattern 102P provided on the base 102 of the chamber. The provision of a patterned base or roof may simply fabrication of the chamber. The provision of a patterned base or roof may enable more efficient particle sorting and so the use of more compact particle sorting chambers, which may assist with the construction of multiple devices in a limited footprint.
The figures provided herein are schematic and not to scale.
Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Claims

1. A particle sorter comprising: a closed chamber having a plurality of ports; and a first pump coupled to at least one port and configured to provide oscillations to the at least one port in a first mode of operation with an oscillation frequency of 0.1 Hz to 50 Hz, in use.
2. The particle sorter according to claim 1, wherein the first pump provides oscillations in a first mode of operation with an oscillation frequency of 0.1 Hz to 20 Hz, in use.
3. The particle sorter according to claim 1 or claim 2, wherein the first pump is configured to switch between the first mode of operation and a second mode of operation to flush accumulated particulate from the chamber.
4. The particle sorter according to claim 1 or claim 2, comprising a second pump coupled to a port to flush accumulated particulate from the chamber.
5. The particle sorter according to claim 4, wherein the second pump is coupled to two ports of the chamber to provide an input flushing liquid to a first port of the chamber and to receive an output flushing fluid from a further port of the chamber.
6. The particle sorter according to any preceding claim, wherein a pump is configured to provide an input supply of liquid to the chamber during the first mode of operation.
7. The particle sorter according to claim 6, wherein a gas supply is configured to supply one or more bubbles into the chamber.
8. The particle sorter according to any preceding claim, wherein the first pump is configured to be selectable to provide one or more of a plurality of different frequency oscillations to the same port of the chamber or different ports of the chamber.
9. The particle sorter according to any preceding claim, wherein the chamber has an inlet flushing port and a plurality of opposed outlet flushing ports, and oscillation ports are each intermediate the inlet flushing port and an outlet flushing port, wherein the first pump is coupled to opposed oscillation ports and a second pump is coupled to an inlet flushing port to supply a flushing flow through the chamber to the outlet flushing ports.
10. The particle sorter according to claim 9, wherein the second pump is coupled to opposed outlet flushing ports comprising a central outlet flushing port between lateral outlet flushing ports, and the first pump is coupled to opposed oscillation ports that are each intermediate the inlet flushing port and a respective lateral outlet flushing port.
11. The particle sorter according to any preceding claim, wherein the first pump is coupled to provide first oscillations to a first port and second oscillations to a second port, wherein the first and second oscillations have a common oscillation frequency and a relative phase difference.
12. The particle sorter according to any preceding claim, wherein the chamber has a base and a roof, and one or more pillars extending between the base and the roof.
13. The particle sorter according to any preceding claim, wherein the chamber has a base and a roof, and one or both of the base and roof are provided with a periodically repeating surface profile.
14. The particle sorter according to any preceding claim, wherein the chamber has a base, a roof and side walls, and two or more ports are provided in the side walls; and
15. The particle sorter according to claim 14, wherein the oscillations are coupled to one or more ports in one or more side walls.
16. The particle sorter according to any preceding claim, wherein the chamber has a base, a roof and side walls, and one or more ports are provided in one or both of the base and the roof of the chamber.
17. The particle sorter according to claim 16, wherein adjacent a port provided in the base or roof of the chamber, the respective base or roof is inclined towards the port.
18. The particle sorter according to any preceding, wherein the chamber has a length, a width and a depth provided by one or more side walls, and ports in the side walls have a diameter of up to 30% of the lesser of the length and the width, up to 30% of the length, or up to 30% of the width.
19. The particle sorter according to any preceding claim, wherein the chamber has a length of 3mm to 50mm, a width of 10pm to 50mm, and a depth of less than 3mm.
20. The particle sorter according to any preceding claim, wherein the chamber has a depth of at least 50 pm.
21. The particle sorter according to any preceding claim, wherein the chamber has a length and the cross-sectional area of the chamber varies along the length of the chamber.
22. The particle sorter according to any preceding claim, wherein the chamber has a length, a width and a depth, and the depth is equal to or less than one third of the lesser of the length and the width.
23. The particle sorter according to any preceding claim, wherein the chamber has a base that is diamond-shaped, square, rectangular, triangular, pentagonal, hexagonal, n-sided polygons having up to 20 sides, circular or elliptical.
24. The particle sorter according to any preceding claim, comprising a plurality of serially coupled chambers.
25. A method of sorting particles with a particle sorter according to any preceding claim, comprising: providing a port of the chamber with a supply of liquid carrying particles; and providing oscillations to the liquid in the chamber.
PCT/GB2023/053154 2022-12-06 2023-12-06 Particle sorter WO2024121562A1 (en)

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Citations (5)

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US20050082204A1 (en) * 1995-04-03 2005-04-21 Schwartz David C. Micro-channel long molecule manipulation system
US20090014360A1 (en) * 2007-04-16 2009-01-15 The General Hospital Corporation D/B/A Massachusetts General Hospital Systems and methods for particle focusing in microchannels
US20110294139A1 (en) * 2009-02-06 2011-12-01 On-Chip Biotechnologies Co., Ltd. Disposable chip-type flow cell and flow cytometer using same
US20210055202A1 (en) * 2017-06-02 2021-02-25 The General Hospital Corporation Oscillatory focusing of particles in channels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050082204A1 (en) * 1995-04-03 2005-04-21 Schwartz David C. Micro-channel long molecule manipulation system
US20020127736A1 (en) * 2000-10-03 2002-09-12 California Institute Of Technology Microfluidic devices and methods of use
US20090014360A1 (en) * 2007-04-16 2009-01-15 The General Hospital Corporation D/B/A Massachusetts General Hospital Systems and methods for particle focusing in microchannels
US20110294139A1 (en) * 2009-02-06 2011-12-01 On-Chip Biotechnologies Co., Ltd. Disposable chip-type flow cell and flow cytometer using same
US20210055202A1 (en) * 2017-06-02 2021-02-25 The General Hospital Corporation Oscillatory focusing of particles in channels

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