WO2002029400A2 - Appareils et procedes pour le fractionnement en continu de particules a l'aide de forces acoustiques et autres forces - Google Patents

Appareils et procedes pour le fractionnement en continu de particules a l'aide de forces acoustiques et autres forces Download PDF

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Publication number
WO2002029400A2
WO2002029400A2 PCT/US2001/042280 US0142280W WO0229400A2 WO 2002029400 A2 WO2002029400 A2 WO 2002029400A2 US 0142280 W US0142280 W US 0142280W WO 0229400 A2 WO0229400 A2 WO 0229400A2
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WO
WIPO (PCT)
Prior art keywords
chamber
carrier medium
matter
acoustic
electrical signal
Prior art date
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PCT/US2001/042280
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English (en)
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WO2002029400A3 (fr
Inventor
Xiao-Bo Wang
Jing Cheng
Lei Wu
Junquan Xu
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Aviva Biosciences Corporation
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Publication date
Priority claimed from CN 00130562 external-priority patent/CN1221309C/zh
Priority claimed from US09/679,023 external-priority patent/US6881314B1/en
Application filed by Aviva Biosciences Corporation filed Critical Aviva Biosciences Corporation
Priority to AU2002213426A priority Critical patent/AU2002213426A1/en
Priority to EP01981809A priority patent/EP1322953A2/fr
Priority to CA 2422837 priority patent/CA2422837A1/fr
Publication of WO2002029400A2 publication Critical patent/WO2002029400A2/fr
Publication of WO2002029400A3 publication Critical patent/WO2002029400A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/0005—Field flow fractionation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3678—Separation of cells using wave pressure; Manipulation of individual corpuscles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3693—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/0005—Field flow fractionation
    • G01N2030/004—Field flow fractionation characterised by opposing force
    • G01N2030/0055—Field flow fractionation characterised by opposing force hyperlayer, i.e. different particle populations in hyperlayers elevated above wall
    • G01N2030/006—Field flow fractionation characterised by opposing force hyperlayer, i.e. different particle populations in hyperlayers elevated above wall lift hyperlayer, i.e. hydrodynamic lift forces dominate steric effect
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/0005—Field flow fractionation
    • G01N2030/004—Field flow fractionation characterised by opposing force
    • G01N2030/0065—Dielectric FFF, i.e. opposing forces dominate hydrodynamic lift forces and steric effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Definitions

  • E-FFF electro-field-flow-fractionation
  • DEP-FFF dielectrophoretic-field-flow- fractionation
  • U.S. Patent No. 5,240,618 discloses an electrical field-flow-fractionation method
  • U.S. Patent Nos. 5,888,370, 5,993,630 and 5,993,632 disclose methods and apparatuses for fractionation using conventional and generalized dielectrophoresis and field flow fractionation.
  • electrophoretic forces are used to balance sedimentation forces
  • DEP-FFF Human et al, 1997, Markx et al, 1997, Wang et al, 1998)
  • DEP force components in the vertical direction are used to balance sedimentation forces and control particle equilibrium positions in a fluid flow profile.
  • Particles of different dielectric properties are positioned at different heights in the flow profile and are thereby transported at different velocities.
  • Particles e.g., cells
  • properties such as size, density, dielectric parameters, electrical charges, as well as their acoustic impedance - a new parameter for particle discrimination and separation.
  • Positive DEP forces may also be exploited for particle separation - a new dimension to the DEP-FFF method where only negative DEP forces are used.
  • the present invention provides methods and apparatuses for the discrimination of particulate matter and solubilized matter of different types.
  • This discrimination may include, for example, separation, characterization, differentiation and manipulation of the particulate matter.
  • the particulate matter may be placed in liquid suspension before input into the apparatus.
  • the discrimination occurs in the apparatus, which may be a thin, enclosed chamber.
  • Particles may be distinguished, for example, by differences in their density, size, dielectric permitivity, electrical conductivity, surface charge, surface configuration, and/or acoustic impedance.
  • the apparatuses and methods of the present invention maybe used to discriminate different types of matter simultaneously.
  • the apparatuses and methods are applicable to any particle separation problems, in particular cell separations in biomedical setting.
  • particle separation include, but not limited to, separation of cancer cells from normal cells, metastatic cancer cells from blood, fetal nucleated cells from maternal erythrocytes/nucleated cells, virus-infected cells from normal counterpart cells, red blood cells from white blood cells, bacteria from blood or urine or other body fluid, etc.
  • the present invention allows cells to be separated without the need to alter them with ligands, stains, antibodies or other means. Non-biological applications similarly require no such alteration. It is recognized however, that the apparatuses and methods according to the present invention are equally suitable for separating such biological matter even if they have been so altered.
  • the separation process in the present invention introduces little or non-stress on the matter to be separated. Living cells remain undamaged, unaltered and viable during and following separation using the present invention. Or, the stress on the cells is small enough so that the separated cells are still applicable for further characterization, assay or analysis, or growth following separation using the present invention.
  • the two side walls may be parallel to each other, or substantially parallel to each other, and the distance between the two side walls of the chamber that are parallel to each other is referred to as chamber width.
  • the two side walls may be parts of a gasket or a spacer between the top wall and bottom wall.
  • the gasket or spacer may be cut in the middle to form a rectangular thin channel with taper ends.
  • the gasket or spacer may be cut in the middle to form thin channels of other shapes such as ellipse, circle, or any other shape.
  • the chamber may be constructed so that the top wall and bottom wall are of a much greater magnitude than the side walls (e.g., both chamber length and chamber width are substantially greater than the chamber height for a chamber with a rectangular shape), thereby creating a thin chamber.
  • the velocity of the carrier medium in the chamber may follow a parabolic or a near-parabolic profile.
  • the velocity of the carrier medium at the top and bottom walls is zero, and with increasing the distances from the top wall or from the bottom wall, the velocity of the carrier medium increases to a maximum value at the middle position between the top and bottom walls.
  • the apparatus can comprise a single piezoelectric transducer or comprise a plurality of piezoelectric transducers.
  • the plurality of piezoelectric transducers may be energized via common electrical signals or via different electrical signals.
  • the plurality of piezoelectric transducers can be adapted along the interior or exterior surface of the chamber.
  • the plurality of piezoelectric transducers can also be configured on a plane substantially parallel to traveling direction of the carrier medium that is caused to travel through the chamber.
  • the electrical signal generator for energizing the piezoelectric transducer to create the acoustic force is capable of varying magnitude and frequency of said electrical signals.
  • the chamber comprises a top wall, a bottom wall, and two side walls.
  • the electrode element and/or the piezoelectric transducer, or a plurality thereof can be configured on the top wall of the chamber.
  • the electrode element and/or the piezoelectric transducer, or a plurality thereof can be configured on the bottom wall of the chamber.
  • the elecfrode element and/or the piezoelectric transducer, or a plurality thereof can be adapted on opposing surfaces of the chamber.
  • the chamber height between the top and bottom walls is about half wavelength of the standing acoustic wave.
  • the present invention is not intended to be limited to a particular geometric shape and the chamber may be constructed of many different materials, for example, glass, polymeric material, plastics, quartz, coated metal, or the like, provided that the chamber has such structural characteristics that when a carrier medium is caused to travel through the chamber, the velocity of the medium at different positions in the chamber is different.
  • the apparatus can comprise a single piezoelectric transducer or comprise a plurality of piezoelectric transducers.
  • the plurality of piezoelectric transducers may be energized via common electrical signals or via different electrical signals.
  • the plurality of piezoelectric transducers can be adapted along the interior or exterior surface of the chamber.
  • the plurality of piezoelectric transducers can also be configured on a plane substantially parallel to traveling direction of the carrier medium that is caused to travel through the chamber.
  • the present invention provides a "continuous-mode" method of discriminating a matter using dielectrophoretic and acoustic forces in field flow fractionation, which method comprises: a) obtaining an apparatus described in the above Section C ; b) introducing a carrier medium containing a matter to be discriminated into the apparatus via its inlet port, wherein said introducing causes the carrier medium to travel through the chamber of the apparatus according to a velocity profile; c) applying at least one electrical signal provided by an electrical signal generator to the electrode element, wherein said energized elecfrode element creates a non-uniform electrical field, thereby causing at least one dielecfrophoretic force on said matter having components normal to the traveling direction of said carrier medium travelling through said chamber; and d) applying at least another electrical signal provided by an electrical signal generator to the piezoelectric fransducer, wherein said energized piezoelectric transducer creates an acoustic wave, thereby causing at least one acoustic force
  • step f prior to the infroducing of carrier medium into the chamber that causes the carrier medium to travel through the chamber according to a velocity profile (step f), applying electrical signal to the electrode element to cause dielecfrophoretic force on said matter and applying electrical signal to the piezoelectric fransducer to cause acoustic force on said matter result in the matter being displaced into an equilibrium position along a direction normal to the traveling direction of the carrier medium fraveling through the chamber.
  • V m (flow rate)/(chamber width X chamber height (or thickness)).
  • V m (flow rate)/(chamber width X chamber height (or thickness)).
  • the structural characteristics of the chamber that influence the velocity profile of the fluid flow in a rectangular chamber include: chamber width, chamber height (or chamber thickness) and chamber length. Chamber of different size and different geometrical shape will result in different velocity profile when a fluid is caused to travel through the chamber.
  • Discriminatable molecules can be inorganic molecules such as ions, organic molecules or a complex thereof.
  • discriminatable ions include sodium, potassium, magnesium, calcium, chlorine, iron, copper, zinc, manganese, cobalt, iodine, molybdenum, vanadium, nickel, chromium, fluorine, silicon, tin, boron or arsenic ions.
  • discriminatable organic molecules include amino acids, peptides, proteins, nucleosides, nucleotides, oligonucleotides, nucleic acids, vitamins, monosaccharides, oligosaccharides, carbohydrates, lipids or a complex thereof.
  • the matters to be discriminated can be of any size. Preferably, the dimension of the matter to be discriminated is from about 0.01 micron to about 1000 micron.
  • Figure 1 Schematic diagram of an acoustic-FFF chamber with a rectangular channel cut in the middle. Also shown is the operation principle of the acoustic-FFF.
  • Figure 2. Schematic diagram of an acoustic-FFF chamber with an ellipse-shaped channel cut in the middle.
  • Figure 3 Schematic diagram of an ellipse-shaped acoustic-FFF chamber with a channel cut in the middle.
  • Figure 4 Schematic diagram of an acoustic-FFF chamber with multiple outlet ports at the outlet end of the chamber.
  • FIG. 6 Schematic diagrams for elecfrode arrays that may be used for acoustic-E- FFF apparatus.
  • A The interdigitated elecfrode array.
  • B The interdigitated castellated electrode array.
  • FIG. 7 Schematic diagram of a acoustic-DEP-FFF chamber with a rectangular channel cut in the middle. Also shown is the operation principle of the acoustic-DEP-FFF.
  • FIG. 8 Schematic diagrams for electrode arrays that may be used for acoustic
  • FIG. 9 Schematic diagram showing the "batch mode operation principle" for using acoustic-FFF, acoustic-E-FFF and acoustic-DEP-FFF apparatuses.
  • A Different types of particles are displaced to different equilibrium height positions under the influence of the applied forces during the "relaxation" process.
  • B The particles that have been displaced to different equilibrium positions move along the chamber at different velocities under influence of an established fluid flow in the chamber.
  • atter refers to particulate matter, solubilized matter, or any combination thereof.
  • highly electrically-conductive material refers to the material whose electrical conductivity is substantially larger than that of carrier medium used for the fractionation (e.g., the conductivity of the conductive material is twice or more than twice of that of the carrier medium). It is to be understood that these terms include all of the electrode configurations described in the present specification and claims.
  • electrode array refers to a collection of more than one elecfrode elements. In an electrode array, each individual element may be displaced in a well- defined geometrical relationship with respect to one another.
  • piezoelectric fransducer refers a structure of "piezoelectric material” that can produce an electrical field when exposed to a change in dimension caused by an imposed mechanical force, and that can be energized by an applied electrical signal to produce mechanical stress in the materials.
  • AC electrical signals to the piezoelectric transducer and produce alternating mechanical stress in the material, that is coupled as an acoustic wave into the carrier medium used for fractionation and discrimination of matter.
  • atter is displaced to a position along a direction means that the matter is caused to move to a position along a direction of interest under the influence of forces exerting on matter.
  • the positions are identified as locations or points along the direction.
  • a carrier medium containing the matter to be discriminated is caused to move along the channel length direction. Electrode elements and piezoelectric transducers are adapted on the chamber top and/or bottom walls.
  • acoustic forces and dielecfrophoretic forces are produced on the matter that is placed in the carrier medium. These forces have components along the vertical direction, which are normal to the fraveling direction of the chamber. These force components will cause the matter to move to various positions along the vertical direction. For example, the matter may be initially located close to the chamber bottom wall and may be caused to move to certain heights from the chamber bottom wall when the electrical signals are applied to energize electrode elements and piezoelectric transducers.
  • the forces that influence the positions of "matter” include acoustic forces, elecfrophoretic forces, dielectrophoretic forces, gravitational forces, hydrodynamic lifting forces, thermal diffusion forces.
  • the positions of "matter” along a direction refer to a distribution profile or a concentration profile of the matter along the . direction.
  • the positions of "matter” along a direction refer to the locations of "matter” along the direction.
  • displacement within the velocity profile refers to the displacement of matter within the velocity profile of the carrier medium traveling through the chamber.
  • the displacement of the matter is identified within the frame of the velocity profile.
  • the matter displaced to the fast-moving part of the velocity profile may be caused to move faster than the matter displaced to the slow-moving part of the velocity profile.
  • the displacement of "matter” within the velocity profile refers to a re-distribution profile of the matter within the reference frame of the velocity profile.
  • the displacement of "matter" within the velocity profile refers to the displacement of "matter” within the reference frame of the velocity profile.
  • particles 150 and 160 maybe discriminated according to the height positions h, and h 2 along a vertical direction that is normal to the fraveling direction of the carrier medium. Furthermore, because of the velocity profile, the particles 150 and 160 may be further discriminated according to the vertical positions within the velocity profile. Even furthermore, the particles 150 and 160 are caused to fravel across the chamber at different velocities V x and V 2 . If the particles 150 and 160 are introduced into the chamber at similar time, the particles 150 and 160 will exit the chamber at different times because they are transported through the chamber at different velocities.
  • the velocity profile in the rectangular chamber shown in Figure 1 depends on the structural characteristics of the chamber.
  • a parabolic or a near-parabolic velocity profile along the vertical direction exits in the chamber.
  • the reason for being "near-parabolic” is that the velocity profile at the positions close to the gasket walls does not follow the "parabolic profile”.
  • the chamber width and the chamber height are of similar sizes, the velocity of the carrier medium in the chamber will follow other velocity profile than the "parabolic velocity profile" discussed above.
  • the top and the bottom walls have been considered as flat and parallel to each other during the above discussions.
  • the inlet and outlet port may be a slot (from about micron(s) to about mm in width) drilled across the chamber outlet end.
  • Multiple tubing, arranged in a ribbon form, can be interfaced with such slots.
  • a single inlet port - a hole - is located at the bottom wall of the chamber.
  • the two outlet ports 180 and 190, positioned at both the top and the bottom walls, are the thin slots cut at the walls.
  • a plurality of tubing arranged in a ribbon form is used to connect to the thin slots as the outletports.
  • the two outlet ports arranged at the bottom and top walls correspond to the split-configuration employed in many field- flow-fractionation devices (Springston et al, 1987; Lee et al, 1989; Levin and Giddings,
  • FIG. 5 shows an embodiment of acoustic-E-FFF chamber and the operational principle of acoustic-E-FFF.
  • the chamber has a top wall 210 and a bottom wall 220.
  • the top wall and bottom wall are separated by a gasket or spacer 230 that has a rectangular channel 240 cut in it.
  • the channel 240 has tapered ends.
  • the top wall 210, the gasket 230 and the bottom wall 220 are shown separated from each other. In use, these components are bound to each other to form an acoustic-E-FFF chamber.
  • An inlet port 250 and an outlet port 260 are located on the top wall and bottom wall, at the inlet end and outlet end of the chamber, respectively.
  • the total acoustic wave field may have two components, i.e., standing- wave component and traveling wave component.
  • the ratio of the magnitude of the standing- wave component to the magnitude of the fraveling- wave component is determined by the chamber height (i.e., the distance between the top wall and bottom wall), the wavelength of the acoustic wave, the acoustic properties of the top wall 210 and the bottom wall 220, the decaying factor for the acoustic wave in the carrier medium, hi one embodiment, the chamber height is half wavelength of the standing acoustic wave, and a standing acoustic wave is established in the chamber. An acoustic pressure node exists at the center plane of the chamber.
  • V m is the velocity of the medium at a height z from the chamber bottom wall
  • V m is the average velocity of the medium
  • H is the chamber height.
  • a near-parabolic velocity profile is established along the vertical direction for the carrier medium in such a chamber.
  • particles 350 and 360 may be discriminated according to the height positions (h ⁇ versus h 2 ) along a vertical direction that is normal to the traveling direction of the carrier medium. Furthermore, because of the velocity profile, the particles 350 and
  • particles of different properties may be fractionated into subpopulations.
  • particles displaced to different heights may be fractionated into sub-populations as they exit the chamber through different outlet ports if the different outlet ports are arranged vertically along the outlet end of the chamber.
  • the chamber has been considered as being disposed horizontally. However, the chamber may be disposed along any direction or having any angle with respect to the horizontal plane. In these cases, we would still consider forces acting on the matter to be discriminated primarily along the direction normal to the traveling direction of the carrier medium. The difference between these cases and the above case where the chamber is disposed horizontally is that the effect of the gravitational force may be different. In the above case, the gravitational force acts in a direction perpendicular to the traveling direction of the carrier medium. In the cases where the chamber is not disposed horizontally, the gravitational force may act in a direction not perpendicular to the traveling direction of the carrier medium. Thus, only a component of the gravitational force should be considered for analyzing the forces exerting on the matter to be discriminated along a direction perpendicular to the traveling direction of the carrier medium.
  • the velocity profile of the carrier medium will be different from the "near-parabolic velocity profile" described above.
  • the gasket 230 between the top wall 210 and the bottom wall 220 may be cut in the middle to form channels of other shapes.
  • the channel in the acoustic-E-FFF chamber may have an ellipse shape, similar to that shown in Figure 2 for an acoustic-FFF chamber.
  • the chamber may have one or more outlet ports through which the discriminated matter and the carrier medium may exit the chamber.
  • the inlet and outlet ports may be located on the top or/and bottom walls of the chamber.
  • the inlet and outlet ports may be holes (as small as from about several microns or as large as about several mm in diameter) drilled on the chamber top and/or bottom walls.
  • PEEK or plastic, or metal tubing may be inserted into the holes and serve as the fluid connection between the chamber and the external fluid-circuits such as infusion devices or collection devices.
  • the inlet and outlet port maybe a slot (from about micron(s) to about mm in width) drilled across the chamber outlet end. Multiple tubing, arranged in a ribbon form, can be interfaced with such slots.
  • FIG. 7 shows an embodiment of acoustic-DEP-FFF chamber and the operational principle of acoustic-DEP-FFF.
  • the chamber has a top wall 510 and a bottom wall 520.
  • the top wall and bottom wall are separated by a gasket or spacer 530 that has a rectangular channel 540 cut in it.
  • the channel 540 has tapered ends.
  • Under the bottom wall there is a piezoelectric transducer 525.
  • the top wall 510, the gasket 530, the bottom wall 520, and the piezoelectric fransducer 525 are shown separated from each other. In use, these components are bound to each other to form an acoustic-DEP-FFF chamber.
  • a piezoelectric transducer 525 is bound to the chamber bottom wall 520.
  • the piezoelectric fransducers may be adapted on the top and/or the bottom walls.
  • the transducer may be bound to a solid plate from the top side so that the solid plate forms the top wall of the chamber.
  • the acoustic wave may be generated from the piezoelectric transducer and be coupled into the carrier medium placed in the chamber through the solid plate.
  • the piezoelectric transducer may be used directly as the top wall.
  • the fransducer may be used directly as the chamber bottom wall.
  • the microelecfrode elements or arrays may be fabricated directly on the top surface of such piezoelectric fransducers.
  • the acoustic-DEP-FFF chamber shown in Figure 7 comprises one piezoelectric fransducer in the chamber. Multiple piezoelectric fransducers may be employed in one chamber. These fransducers may be adapted on the top wall in series, or on bottom wall in series, or on both top and bottom walls to form a piezoelectric transducer array. The multiple piezoelectric fransducers may be energized by same or different electrical signals to produce acoustic waves in the chamber.
  • the elecfrode elements may be adapted substantially latitudinally (as shown in Figure 6A or 6B, or as shown in Figure 7 for the electrode elements in the array 545) or longitudinally (i.e., the electrode elements in Figure 6A are turned by 90 degree, or the elecfrode elements in the array 545 of Figure 7 are turned by 90 degree) along a portion of the chamber.
  • the interdigitated elecfrode a ⁇ ays with periodic triangular (700) or arc-like electrode tips (710) shown in Figures 8 may also be used.
  • Electrode array 545 is supported on the chamber bottom wall 520 and the piezoelectric fransducer 525 is bound to the bottom wall 520.
  • electrode arrays of various geometrical types may also be fabricated directly on piezoelectric transducers.
  • PZT is a type of piezoelectric material and could be used as a piezoelectric fransducer. After its surface being polished to sufficient smoothness, microfabrication methods could be used to fabricate microelecfrodes on such piezoelectric substrate.
  • the piezoelectric fransducer with microelecfrodes on the top surface and a planner electrode on the bottom surface may be used as bottom wall of the acoustic-DEP-FFF chamber.
  • the electrical signals could be applied to microelecfrode array on the top surface of the piezoelectric fransducer to produce dielectrophoresis forces.
  • electrical signals could be applied to the top array (e.g. through one of the common electrical conductor buses 705 or 708) and the bottom planer electrodes for producing acoustic field and forces.
  • the advantage of this approach is that the elecfrode array for producing dielectrophoresis forces is integrated onto the surface of the piezoelectric transducer.
  • Such an integration of the elecfrode array with the piezoelectric transducer is similar to that of the acoustic-E-FFF chamber shown in Figure 5, where the electrode element for producing electrophoresis force is on the top surface of the piezoelectric transducer.
  • Acoustic radiation force F acous tic 620 in the vertical direction pointing towards or away from the top (or bottom) wall, depending on a factor which relates to the densities of the particles and the suspending medium, and to the acoustic impedance of the of the particles and the medium.
  • the force F ac ou t i c 620 may be a component of total acoustic force acting on the particle.
  • Dielectrophoretic force F DEP 625 in the vertical direction on the polarized particles. Depending on whether the particles are more or less polarizable than the surrounding medium, this force points downwards to the elecfrode elements or upwards away from the elecfrode elements.
  • the dielecfrophoretic force F D E P 625 may be a component of the total dielecfrophoretic force acting on particles.
  • V m is the velocity of the medium at a height z from the chamber bottom wall
  • (V m ) is the average velocity of the medium
  • H is the chamber height.
  • a near-parabolic velocity profile is established along the vertical direction for the carrier medium in such a chamber.
  • particles 550 and 560 may be discriminated according to the height positions (h, versus h 2 ) along a vertical direction that is normal to the fraveling direction of the carrier medium.
  • the particles 550 and 560 may be further discriminated according to the vertical positions within the velocity profile. Even furthermore, the particles 550 and 560 are caused to travel across the chamber at different velocities Pj and V 2 . If the particles 550 and 560 are infroduced into the chamber at similar time, the particles 550 and 560 will exit the chamber at different times because they are transported through the chamber at different velocities ( V, versus
  • the particles of different properties may be displaced to different positions along the vertical direction; may be discriminated according to their displacement positions along the vertical direction or within the velocity profile (h x versus h 2 ); maybe discriminated according to the velocities at which the particles travel through the chamber ( V, versus V 2 ) or according to the exit times of the particles leaving the chamber.
  • Particles of different properties maybe fractionated into subpopulations.
  • particles displaced to different heights may be fractionated into sub-populations as they exit the chamber through different outlet ports if the different outlet ports are arranged vertically along the outlet end of the chamber.
  • the chamber has been considered as being disposed horizontally. However, the chamber may be disposed along any direction or having any angle with respect to the horizontal plane. In these cases, we would still consider forces acting on the matter to be discriminated primarily along the direction normal to the traveling direction of the carrier medium. The difference between these cases and the above case where the chamber is disposed horizontally is that the effect of the gravitational force may be different. In the above case, the gravitational force acts in a direction perpendicular to the traveling direction of the carrier medium. In the cases where the chamber is not disposed horizontally, the gravitational force may act in a direction not perpendicular to the fraveling direction of the carrier medium. Thus, only a component of the gravitational force should be considered for analyzing the forces exerting on the matter to be discriminated along a direction perpendicular to the traveling direction of the carrier medium.
  • the gasket 530 between the top wall 510 and the bottom wall 520 may be cut in the middle to form channels of other shapes.
  • the channel in the acoustic-DEP-FFF chamber may have an ellipse shape, similar to that shown in Figure 2 for an acoustic-FFF chamber.
  • the velocity profile of the carrier medium will be different from that for the chamber shown in Figure 7.
  • the channel for the acoustic-FFF chamber shown in Figure 3 may be used for an acoustic- DEP-FFF chamber.
  • Such a chamber will result in a unique velocity profile for the carrier medium when it is caused to travel through the channel.
  • the acoustic-DEP-FFF chamber may have one or more inlet ports through which the matter to be discriminated and the carrier medium are infroduced.
  • the chamber may have one or more outlet ports through which the discriminated matter and the carrier medium may exit the chamber.
  • the inlet and outlet ports may be located on the top or/and bottom walls of the chamber.
  • the inlet and outlet ports may be holes (as small as from about several microns or as large as about several mm in diameter) drilled on the chamber top and/or bottom walls.
  • PEEK or plastic, or metal tubing may be inserted into the holes and serve as the fluid connection between the chamber and the external fluid-circuits such as infusion devices or collection devices.
  • acoustic-FFF For acoustic-FFF, appropriate acoustic field condition is applied so that particles are given a specified time to reach their equilibrium positions under the influence of the acoustic force and other forces (e.g., gravitational force, hydrodynamic lifting force).
  • the acoustic field conditions in the chamber(s) are applied through energizing the piezoelectric transducer(s) with appropriate electrical signals.
  • appropriate electric field and acoustic field conditions are applied so that particles are given a specified time to reach their equilibrium positions under the influence of the acoustic force, electrophoretic force and other forces (e.g., gravitational force, hydrodynamic lifting force).
  • acoustic-DEP-FFF For acoustic-DEP-FFF, appropriate dielecfrophoretic field and acoustic field conditions are applied so that particles are given a period of time to reach their equilibrium positions under the influence of the acoustic force, dielectrophoretic force and other forces (e.g., gravitational force, hydrodynamic lifting force).
  • This step is called the "relaxation” in typical field-flow-fractionation (Giddings, 1981 , Giddings, 1993).
  • Figure 9 A particles of different properties are displaced to different equilibrium positions within the chamber under the influence of applied forces.
  • the equilibrium positions of different particle types correspond to the equilibrium concentration profile for different particle types.
  • Figure 9A and 9B show such a batch-mode process in a cross-sectional view of a rectangular, acoustic-FFF (or acoustic-E-FFF, or acoustic-DEP-FFF) chamber.
  • Figure 9 A shows that during the relaxation step, particle types 800 and 850 have been displaced to different heights under the influence of the applied forces.
  • Figure 9B shows that after the fluid flow profile (i.e., a velocity profile 780) is established in the chamber following the relaxation step, particle type 800 has moved ahead of particle type 850 and will exit the chamber earlier at the outlet port 795 The fluid flow is established by infusing a carrier medium into the chamber inlet port 790.
  • This "batch-mode" acoustic-FFF can be used with any acoustic-FFF apparatus described in this invention.
  • the matter to be discriminated is displaced into equilibrium position along a direction normal to the traveling direction of the carrier medium traveling through the chamber by applying electrical signal to the piezoelectric transducer to cause acoustic force on said matter.
  • the "batch-mode" operation of discriminating a matter using elecfrophoretic and acoustic forces in field flow fractionation comprises the following steps: a) obtaining an acoustic-E-FFF apparatus described in the present invention; b) loading a carrier medium into the chamber of apparatus via its inlet port until the chamber is filled with the carrier medium; c) delivering a sample that contains a matter to be discriminated into the carrier medium in the chamber; d) applying at least one electrical signal provided by an electrical signal generator to the electrode element, wherein said energized elecfrode element creates an electrical field, thereby causing at least one electrophoretic force on said matter; e) applying at least another electrical signal provided by an electrical signal generator to the piezoelectric transducer, wherein said energized piezoelectric fransducer creates an acoustic wave, thereby causing at least one acoustic force on said matter; f) introducing the carrier medium into the chamber of the apparatus via its inlet port,
  • the matter to be discriminated is displaced into equilibrium position along a direction normal to the fraveling direction of the carrier medium traveling through the chamber applying by applying electrical signal to the elecfrode element to cause elecfrophoretic force on said matter and applying electrical signal to the piezoelectric transducer to cause acoustic force on said matter.
  • the "batch-mode" operation of discriminating a matter using dielecfrophoretic and acoustic forces in field flow fractionation comprises the following steps: a) obtaining an acoustic-DEP-FFF apparatus described in the present invention; b) loading a carrier medium into the chamber of apparatus via its inlet port until the chamber is filled with the carrier medium; c) delivering a sample that contains a matter to be discriminated into the carrier medium in the chamber; d) applying at least one electrical signal provided by an electrical signal generator to the elecfrode element, wherein said energized electrode element creates a non-uniform electrical field, thereby causing at least one dielectrophoretic force on said matter; e) applying at least another electrical signal provided by an electrical signal generator to the piezoelectric fransducer, wherein said energized piezoelectric fransducer creates an acoustic wave, thereby causing at least one acoustic force on said matter; f) introducing the carrier medium
  • step f prior to the infroducing of carrier medium into the chamber that causes the carrier medium to fravel through the chamber according to a velocity profile (step f), the matter to be discriminated is displaced into equilibrium position along a direction normal to the fraveling direction of the carrier medium fraveling through the chamber by applying electrical signal to the elecfrode element to cause dielectrophoretic force on said matter and applying electrical signal to the piezoelectric fransducer to cause acoustic force on said matter.
  • particle-mixture samples are continuously fed into the acoustic-FFF (or acoustic-E-FFF or acoustic-DEP-FFF) chamber through the inlet port.
  • acoustic-FFF appropriate acoustic field condition is applied so that particles that are continuously fed into the chamber are continuously being driven towards their equilibrium positions under the influence of the acoustic force and other forces (e.g. gravity, hydrodynamic lift force).
  • the acoustic field conditions in the chamber(s) are applied through energizing the piezoelectric transducer(s) with appropriate electrical signals.
  • DEP-FFF appropriate dielecfrophoretic field and acoustic wave conditions are applied so that particles that are continuously fed into the chamber are continuously being driven towards their equilibrium positions under the influence of the acoustic force, dielectrophoretic force and other forces (e.g. gravity, hydrodynamic lift force).
  • acoustic force e.g. gravity, hydrodynamic lift force.
  • dielectrophoretic force e.g. gravity, hydrodynamic lift force.
  • other forces e.g. gravity, hydrodynamic lift force.
  • the subpopulation having higher equilibrium positions in the acoustic-FFF (or acoustic-E-FFF, or acoustic-DEP-FFF) chamber may exit the chamber from an outlet port that is located at higher positions at the outlet end.
  • the subpopulations having lower equilibrium positions may exit the chamber from an outlet port that is located at lower positions at the outlet end.
  • FIG. 10 shows an example where the chamber has one outlet port 870 on the top wall and two outlet ports 880 and 890 on the bottom wall.
  • the chamber may be an acoustic-FFF chamber, or acoustic-E-FFF chamber, or acoustic-DEP-FFF chamber.
  • a fluid velocity profile (i.e. fluid flow profile) 860 is established in the chamber.
  • the subpopulation 900 that is displaced to the highest positions by the applied forces during the transit time through the chamber may exit the outlet port 870 at the top wall.
  • the "continuous-mode" operation of discriminating a matter using elecfrophoretic and acoustic forces in field flow fractionation comprises the following steps: a) obtaining an acoustic-E-FFF apparatus described in the present invention; b) infroducing a carrier medium containing a matter to be discriminated into the apparatus via its inlet port, wherein said introducing causes the carrier medium to fravel through the chamber according to a velocity profile; c) applying at least one electrical signal provided by an electrical signal generator to the elecfrode elements, wherein said energized electrode elements creates an electrical field, thereby causing at least one elecfrophoretic force on said matter having components normal to the fraveling direction of said carrier medium travelling through said chamber; and d) applying at least another electrical signal provided by an electrical signal generator to the piezoelectric fransducer, wherein said energized piezoelectric transducer creates an acoustic wave, thereby causing at least one acoustic force on said matter having components
  • the "continuous-mode" operation of discriminating a matter using dielecfrophoretic and acoustic forces in field flow fractionation comprises the following steps: a) obtaining an acoustic-DEP-FFF apparatus described in the present invention; b) introducing a carrier medium containing a matter to be discriminated into the apparatus via its inlet port, wherein said introducing causes the carrier medium to fravel through the chamber of the apparatus according to a velocity profile; c) applying at least one electrical signal provided by an electrical signal generator to the elecfrode element, wherein said energized electrode element creates a non-uniform electrical field, thereby causing at least one dielecfrophoretic force on said matter having components normal to the fraveling direction of said carrier medium fravelling through said chamber; and d) applying at least another electrical signal provided by an electrical signal generator to the piezoelectric fransducer, wherein said energized piezoelectric transducer creates an acoustic wave, thereby causing at least one
  • Acoustic radiation force is a non-contact force that can be used for trapping, handling, moving particles in fluid.
  • the use of the acoustic radiation force in a standing ultrasound wave for particle manipulation has been demonstrated for concentrating erythrocytes (Yasuda et al, 1997), focusing micron-size polystyrene beads (0.3 to 10 micron in diameter, Yasuda and Kamakura, 1997), concentrating DNA molecules (Yasuda et al, 1996C), batch and semicontinuous aggregation and sedimentation of cells (Pui, et al, 1995).
  • a standing plane, acoustic wave can be established in an acoustic-FFF chamber, or acoustic-E-FFF or acoustic-DEP-FFF chamber by applying AC signals to the piezoelectric fransducers.
  • an acoustic wave that has a standing-wave component can be established in an acoustic-FFF chamber, or acoustic-E-FFF or acoustic-DEP-FFF chamber by applying AC signals to the piezoelectric transducers.
  • the standing wave is established along a particular direction (e.g., z-axis direction) in a fluid.
  • Facoustic ⁇ r3k E acoustic A SUl(2Az)
  • ⁇ m and ⁇ p are the density of the particle and the medium
  • ⁇ m and ⁇ p are the acoustic impedance of the particle and medium, respectively.
  • A is termed herein as the acoustic-polarization-factor.
  • the particle moves away from the pressure node.
  • particles having different density and acoustic impedance will experience different acoustic-radiation-forces when they are placed into the same standing acoustic wave field.
  • the acoustic radiation force acting on a particle of 10 micron in diameter can vary somewhere between 0.01 and 1000 pN, depending on the established acoustic energy density distribution.
  • the piezoelectric fransducers are made from "piezoelectric materials" that produce an electric field when exposed to a change in dimension caused by an imposed mechanical force (piezoelectric or generator effect). Conversely, an applied electric field will produce a mechanical stress (electrostrictive or motor effect) in the materials. They transform energy from mechanical to electrical and vice- versa.
  • the piezoelectric effect was discovered by Pierre Curie and his brother Jacques in 1880. It is explained by the displacement of ions, causing the electric polarization of the materials' structural units. When an electric field is applied, the ions are displaced by electrostatic forces, resulting in the mechanical deformation of the whole material.
  • an acoustic-FFF or acoustic-E- FFF or acoustic-DEP-FFF apparatus when AC voltages are applied to the piezoelectric fransducers, the vibration occurred to the transducers will be coupled into the fluid in the chamber and result in an acoustic wave in the chamber.
  • Such an acoustic wave may have standing wave and traveling wave components.
  • U.S. Patent No. 4,523,682 which is hereby incorporated by reference in its entirety, discloses a method for separating particles of different sizes, densities and other properties in an acoustic chamber.
  • U.S. Patent No. 4,523,682 describes the spatial separation of particles of different properties in an acoustic wave.
  • the aspect of acoustic-FFF separation in the present invention provides the apparatus and methods for separating particles from a mixture.
  • the purified particle populations may be obtained using the present invention, while the US 4523682 can separate particles only according to the positions the particles occupy in an acoustic chamber.
  • Electrophoretic forces The electrostatic force or elecfrophoretic force F B on a particle in an applied electrical field E z d z is given by
  • E rms the RMS value of the field strength
  • ⁇ m the dielectric permitivity of the medium.
  • ⁇ DEP the particle polarization factor
  • a non-uniform electrical field can be established in an acoustic-DEP-FFF chamber by applying AC signals to the microelecfrodes incorporated on the chamber surfaces.
  • the dielectrophoretic forces will follow an approximately exponential decay with the distance from the electrode plane, as shown by Huang et al,
  • DEP forces acting on a particle of 10 micron in diameter can vary somewhere between about 0.01 and about 1000 pN. h previously reported DEP-FFF technology (Huang et al, Biophys. J. Vol. 73, pi 118-1129, 1997; Wang et al., Biophys. J. Vol. 74, p2689-2701, 1998; Yang, J. et al. Anal. Chem. Vol.
  • a fluid flow profile may be established in an acoustic-FFF chamber, or acoustic-E- FFF or acoustic-DEP-FFF chamber for particle separation and analysis.
  • a laminar, parabolic flow profile may be generated for a rectangular chamber with the chamber length and chamber width substantially greater than the chamber height.
  • Such a velocity profile may be described as,
  • V m is the fluid velocity at the height z from the chamber bottom. His the chamber height and (V m is the average fluid-velocity in the chamber.
  • F lift hydrodynamic lifting force acting on the particle in the vertical direction if the particle is placed close to the chamber bottom (or top) wall and if the chamber is disposed horizontally or nearly-horizontally. If the distance between the particle and the chamber bottom wall is very small (e.g. ⁇ 1 micron for a 10 micron particle in a 200 micron height chamber), the hydrodynamic lifting force will direct the particle away from the chamber wall (Williams et al., 1992; 1994; 1996; 1997).
  • This force has been used in the classical, hyperlayer-FFF operation in which the particles are positioned at different height from the chamber wall by balancing the hydrodynamic lifting force and sedimentation force (e.g., Ratanathanawongs S. K. and Giddings, 1992, Williams et al, 1996). It is known that this hydrodynamic lifting force decay rapidly to zero with the distance from the chamber wall, yet its origin remains to be debated.
  • the acoustic-radiation-force has been added into the force equation. Similar force-balance analysis can be performed for an acoustic-E-FFF chamber that is not disposed horizontally. In such a case, the effect of the sedimentation force on the displacement of the particles within the flow velocity profile is different from that shown above. Only a component of the sedimentation force, which is within the velocity profile and is perpendicular to the traveling direction of the carrier medium, contributes to the displacement of the particles in the velocity profile.
  • the zero-net-force position may correspond to an equilibrium height h eq .
  • Such position is dependent on the applied acoustic wave energy density, the applied non-uniform electrical field, and more importantly, particle density, and dielectric property and size.
  • FFF separation and analysis of molecules and small particles and acoustic/elecfrophoretic/ dielectrophoretic effects of particles may readily perform theoretical analyses of applying the acoustic-FFF, or acoustic-E-FFF or acoustic-DEP-FFF methods for separating and analyzing molecules and small particles.

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Abstract

Cette invention concerne le domaine du fractionnement en continu, et notamment des appareils et procédés de discrimination des matières par utilisation d'une force acoustique ou d'une force acoustique alliée à une force électrophorétique ou diélectrophorétique, en fractionnement continu.
PCT/US2001/042280 2000-09-30 2001-09-20 Appareils et procedes pour le fractionnement en continu de particules a l'aide de forces acoustiques et autres forces WO2002029400A2 (fr)

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EP1627675A1 (fr) * 2003-12-17 2006-02-22 Matsushita Electric Industrial Co., Ltd. Dispositif de separation de composants, procede de production de ce dispositif et procede de separation de composants utilisant ce dispositif
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WO2006032703A1 (fr) * 2004-09-24 2006-03-30 Spectronic Ab Procede et dispositif pour la separation de particules
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WO2011161463A3 (fr) * 2010-06-25 2012-05-03 Isis Innovation Limited Séparateurs acoustiques
US9731062B2 (en) 2011-08-29 2017-08-15 The Charles Stark Draper Laboratory, Inc. System and method for blood separation by microfluidic acoustic focusing
RU2607580C2 (ru) * 2011-08-30 2017-01-10 Сентр Насьональ Де Ла Решерш Сьентифик Устройство для манипулирования объектами с использованием акустического силового поля
US9504780B2 (en) 2013-01-30 2016-11-29 The Charles Stark Draper Laboratory, Inc. Extracorporeal clearance of organophosphates from blood on an acoustic separation device
US9974898B2 (en) 2013-01-30 2018-05-22 The Charles Stark Draper Laboratory, Inc. Extracorporeal clearance of organophosphates from blood on an acoustic separation device
WO2014138739A1 (fr) * 2013-03-08 2014-09-12 The Charles Stark Draper Laboratory, Inc. Système et procédé pour séparation du sang par focalisation acoustique microfluidique
US10166323B2 (en) 2013-03-08 2019-01-01 The Charles Stark Draper Laboratories, Inc. Blood separation by microfluidic acoustic focusing
US11617820B2 (en) 2013-03-08 2023-04-04 The Charles Stark Draper Laboratory, Inc. System for blood separation by microfluidic acoustic focusing in separation channels with dimensions defined based on properties of standing waves
US10099002B2 (en) 2014-07-31 2018-10-16 The Charles Stark Draper Laboratory, Inc. Systems and methods for parallel channel microfluidic separation
US10661005B2 (en) 2014-07-31 2020-05-26 The Charles Stark Draper Laboratory, Inc. Systems and methods for parallel channel microfluidic separation
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