WO2017209780A1 - Appareil, système, et procédé de collecte de matière cible - Google Patents

Appareil, système, et procédé de collecte de matière cible Download PDF

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Publication number
WO2017209780A1
WO2017209780A1 PCT/US2016/051544 US2016051544W WO2017209780A1 WO 2017209780 A1 WO2017209780 A1 WO 2017209780A1 US 2016051544 W US2016051544 W US 2016051544W WO 2017209780 A1 WO2017209780 A1 WO 2017209780A1
Authority
WO
WIPO (PCT)
Prior art keywords
tube
target material
processing vessel
cavity
density
Prior art date
Application number
PCT/US2016/051544
Other languages
English (en)
Inventor
Ronald Seubert
Lance U'REN
Original Assignee
Rarecyte, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rarecyte, Inc. filed Critical Rarecyte, Inc.
Priority to EP16904228.0A priority Critical patent/EP3463659A4/fr
Priority to CN201680086993.6A priority patent/CN109414694A/zh
Publication of WO2017209780A1 publication Critical patent/WO2017209780A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5021—Test tubes specially adapted for centrifugation purposes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D12/00—Displacing liquid, e.g. from wet solids or from dispersions of liquids or from solids in liquids, by means of another liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5021—Test tubes specially adapted for centrifugation purposes
    • B01L3/50215—Test tubes specially adapted for centrifugation purposes using a float to separate phases
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/042—Caps; Plugs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0672—Integrated piercing tool
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0469—Buoyancy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components

Definitions

  • This disclosure relates generally to density-based fluid separation and, in particular, to retrieving target material from a suspension.
  • Suspensions often include materials of interests that are difficult to detect, extract and isolate for analysis.
  • whole blood is a suspension of materials in a fluid.
  • the materials include billions of red and white blood cells and platelets in a proteinaceous fluid called plasma.
  • Whole blood is routinely examined for the presence of abnormal organisms or cells, such as ova, fetal cells, endothelial cells, parasites, bacteria, and inflammatory cells, and viruses, including HIV, cytomegalovirus, hepatitis C virus, and Epstein-Barr virus.
  • Typical techniques used to analyze a blood sample include the steps of smearing a film of blood on a slide and staining the film in a way that enables certain components to be examined by bright field or fluorescence microscopy.
  • Figures 1 A- IB show an example tube.
  • FIGS 2A-2C show an example tube-processing vessel system.
  • Figures 3 A-3B show an example sealing ring.
  • Figures 3C-3D show an example sealing ring.
  • Figures 3E-3F show an example sealing ring.
  • Figure 3G shows an example sealing ring.
  • Figures 5A-5F show an example system retrieving target material.
  • Figures 6A-6E show an example system retrieving target material.
  • a system includes a processing vessel, a displacement fluid, and a tube.
  • the tube includes a funnel, a cannula, and a cavity.
  • the cannula allows for fluid communication between the funnel and the cavity, such that the processing vessel is inserted into the cavity, and the cannula extends into the processing vessel.
  • Figure 1A shows an isometric view of a tube 100.
  • Figure IB shows a cross-sectional view of the tube 100 taken along the line I-I shown in Figure 1A.
  • the tube 100 may be any appropriate size or cross-sectional shape (e.g. cylindrical, elliptical, triangular, square, rectangular, or the like.
  • the cannula 112 such as a tube or a needle, including, but not limited to a non-coring needle, extends from the apex of the concave opening 114 and into the cavity 114.
  • the cavity 114 is a concave opening extending from an aperture 120 in the second end 118 towards the first end 104.
  • the cavity 14 may accept and support a processing vessel (not shown).
  • the cavity 114 may be any appropriate depth to accept and support the processing vessel (not shown).
  • the cavity 114 may be threaded to engage a threaded portion of the processing vessel (not shown).
  • the cannula 112 may extend any appropriate distance into the cavity 114 in order to extend into, to puncture the base of, or be inserted into, the processing vessel (not shown).
  • the clip may be a two-piece ring, a one piece ring wrapping around the full circumference of the tube 100, or a one piece ring wrapping around less than the full circumference of the tube 100, such as one-half (1/2), five-eighths (5/8), two-thirds (2/3), three-quarters (3/4), seven-eighths (7/8), or the like.
  • the cap 108 may be temporarily or permanently affixed to the main body 102 of the tube 100 via the first end 104, such as by welding (e.g. ultrasonic welding), adherence (e.g. an adhesive), clamping (e.g. a sealing ring, crimper, clamp, or the like), or any other appropriate manner for temporarily or permanently affixing two pieces.
  • the tube 100 may also include a plug 116 to be inserted into the cavity 114 to inhibit fluid from escaping from the cannula 112 when the cannula 112 is pointed downward.
  • the plug 1 16 may be composed of re-sealable rubber or other suitable re- sealable material that can be repeatedly punctured with the cannula 112 and re-seals when the cannula 1 12 is removed.
  • the plug 1 16 may be a screw cap with threads to engage complementary threads within the cavity 114 or outside or on the second end 118.
  • a clip may be placed over the plug 1 16 and the first end 104 of the tube 100 to increase the pressure exerted by the plug 116 on the first end 104 to provide a more secure fit.
  • the clip may be a two-piece ring, a one piece ring wrapping around the full circumference of the tube 100, or a one piece ring wrapping around less than the full circumference of the tube 100, such as one-half (1/2), five-eighths (5/8), two-thirds (2/3), three-quarters (3/4), seven-eighths (7/8), or the like.
  • the tube 100 can be composed of a variety of different materials including, but not limited to, a ceramic; metals; organic or inorganic materials; and plastic materials, such as polyoxymethylene ("Delrin ® "), polystyrene, acrylonitrile butadiene styrene (“ABS”) copolymers, aromatic polycarbonates, aromatic polyesters, carboxymethylcellulose, ethyl cellulose, ethylene vinyl acetate copolymers, nylon, polyacetals, polyacetates, polyacrylonitrile and other nitrile resins, polyacrylonitrile-vinyl chloride copolymer, polyamides, aromatic poly amides (“aramids”), polyamide-imide, polyarylates, polyarylene oxides, polyarylene sulfides, polyarylsulfones, polybenzimidazole, polybutylene terephthalate, polycarbonates, polyester, polyester imides, polyether sulfones, polyetherimides, polyetherketone
  • Figure 2 A shows an exploded view of the example tube 100 and processing vessel 202.
  • Figure 2B shows an isometric view of the processing vessel 202 inserted into the cavity 114 at the collection segment 106 of the tube 100 to form a tube- processing vessel system 200.
  • Figure 2C shows a cross-sectional view of the processing vessel 202 inserted into the cavity 1 14 at the collection segment 106 of the tube 100 taken along the line II-II shown in Figure 2B.
  • the tube 100 and processing vessel 202 form a tube-processing vessel system 200.
  • the processing vessel 202 may be an eppendorf tube, a syringe, or a test tube, and has a closed end 204 and an open end 206.
  • the open end 206 is sized to receive a cap 208.
  • the cap 208 may be composed of re-sealable rubber or other suitable re-sealable material that can be repeatedly punctured with a needle or other sharp implement to access the contents stored in the processing vessel 202 interior and re- seals when the needle or implement is removed.
  • the processing vessel 202 may also have two open ends that are sized to receive caps.
  • the processing vessel 202 may have a tapered geometry that widens or narrows toward the open end 206; the processing vessel 202 may have a generally cylindrical geometry; or, the processing vessel 202 may have a generally cylindrical geometry in a first segment and a cone- shaped geometry in a second segment, where the first and second segments are connected and continuous with each other.
  • the processing vessel 202 can be composed of a transparent, semitransparent, opaque, or translucent material, such as plastic or another suitable material.
  • the processing vessel includes a central axis 214, which when inserted into the cavity 114 is coaxial with a central axis of the tube 100.
  • the processing vessel 202 may also include a plug 210 at the closed end 204 to permit the introduction of the target material or to exchange the target material with a displacement fluid 212.
  • the closed end 204 may be threaded to provide for a threaded connection with a threaded cavity (not shown) of the tube 100.
  • the processing vessel 202 may be composed of glass, plastic, or other suitable material.
  • the plug 210 may be composed of re-sealable rubber or other suitable re- sealable material that can be repeatedly punctured with a needle or other sharp implement to access the contents of the processing vessel 202 interior or permit introduction of contents into the processing vessel 202 and re-seals when the needle or implement is removed.
  • the plug 210 may be inserted into the processing vessel 202 such that a seal is maintained between the plug 210 and the processing vessel 202, such as by an interference fit.
  • the plug 210 can be formed in the closed end 204 of the processing vessel 202 using heated liquid rubber that can be shaped while warm or hot and hardens as the rubber cools.
  • An adhesive may be used to attach a plug 210 to the inner wall of the processing vessel can be a polymer-based adhesive, an epoxy, a contact adhesive or any other suitable material for bonding or creating a thermal bond.
  • the plug 210 may be injected into the processing vessel 202.
  • the plug 210 may be thermally bonded to the processing vessel 202.
  • the processing vessel 202 may also include a processing solution (not shown) to effect a transformation on the target material when the target material enters the processing vessel 202.
  • the processing solution (not shown) may be a preservative, a cell adhesion solution, a dye, or the like. Unlike the displacement fluid 212, most, if not all, of the processing solution (not shown) remains within the processing vessel 202 upon centrifugation, thereby effecting the transformation on the target material in one manner or another (i.e. preserving, increasing adhesion properties, or the like).
  • the processing solution (not shown) may be introduced as a liquid or as a liquid contained in a casing.
  • the casing may be dissolvable in an aqueous solution but not in the displacement fluid 212 (such as gel cap); or, the casing may be breakable, such that the casing breaks when the processing vessel 202 is shaken in a vortex mixer. Additionally, more than one processing solution may be used.
  • the processing vessel 202 may include a flexible cap that can be pushed to dispense a pre-determined volume therefrom and onto a substrate, such as a slide or a well plate.
  • the cap 208 may be flexible or the cap 208 may be removed and the flexible cap inserted into the open end 206.
  • the processing vessel 202 may be attached to (i.e. after accumulating the target material) or may include a dispenser, which is capable of dispensing a pre-determined volume of target material from the processing vessel 202 onto another substrate, such as a microscope slide.
  • the dispenser may repeatedly puncture the re-sealable cap 208 or compress the material within the processing vessel 202 to withdraw and dispense the pre-determined volume of target material onto the substrate.
  • the cap 208 may be removed and the dispenser (not shown) may be inserted directly into the processing vessel 202 to dispense the buffy coat-processing solution mixture.
  • Figure 3 A shows an isometric view of a tube 300.
  • Figure 3B shows a cross-sectional view of the tube 300 taken alone the line III-III.
  • the tube 300 is similar to the tube 100 except that the tube 300 includes a valve 302 instead of a cannula 1 12 to provide a passageway between the funnel 110 and the cavity 114.
  • the valve 302 opens to permit fluid flow between the funnel 110 and the cavity 114.
  • the valve 302 is closed to inhibit fluid flow between the funnel 110 and the cavity 114.
  • the collection end 106 may include a break-point 304 where to permit the cavity 1 14 and the valve 302 to be separated from the funnel 110 so that the target material may be removed and retained in a single vessel for subsequent processing.
  • the break-point 304 may include threads, a tongue and groove joint, a dovetail joint, or any appropriate connection method.
  • Figure 4A shows an isometric view of a tube 400.
  • Figure 4B shows a cross-sectional view of the tube 400 taken alone the line IV-IV.
  • the tube 400 is similar to the tube 100 except that the tube 400 includes a hole 402 instead of a cannula 112 to provide a passageway between the funnel 110 and the cavity 1 14.
  • the hole 402 has a diameter that is sized to inhibit fluid communication between the funnel 1 10 and the cavity 1 14 before and after centrifugation and to allow fluid communication between the funnel 10 and the cavity 114 during centrifugation.
  • the diameter for example, may be based on the respective surface tensions of the displacement fluid 212 and the target material.
  • Figure 3A shows an isometric view of a sealing ring 300.
  • Figure 3B shows a top down view of the sealing ring 300.
  • Dot-dashed line 302 represents the central or highest-symmetry axis of the sealing ring 300.
  • the sealing ring 300 includes an inner wall 304, an outer wall 306, and a cavity 308.
  • R m represents the radial distance from the center of the sealing ring 300 to the inner wall 304
  • Row represents the radial distance from the center of the sealing ring 300 to the outer wall 306.
  • the sealing ring 300 is configured to fit around a primary vessel, such as a tube.
  • the cavity 308 is sized and shaped to receive the primary vessel.
  • the sealing ring may be any shape, including, but not limited to, circular, triangular, or polyhedral.
  • Figure 3C shows an isometric view of a sealing ring 310.
  • Figure 3D shows a top down view of the sealing ring 310.
  • Sealing ring 310 is similar to sealing ring 300, except sealing ring 310 is polyhedral.
  • Dot-dashed line 312 represents the central or highest-symmetry axis of the sealing ring 310.
  • the sealing ring 310 includes an inner wall 314, an outer wall 316, and a cavity 318.
  • the sealing ring may be composed of a metal, such as brass, a polymer, or combinations thereof.
  • a sealing ring 320 may be composed of a piezoelectric material.
  • Figure 3F shows a top down view of the sealing ring 320. Dot-dashed line 322 represents the central or highest-symmetry axis of the sealing ring 320.
  • the sealing ring 320 may be connected to an electric potential source 328, such as a battery, via a first lead 324 and a second lead 326.
  • the electric potential source 328 creates a mechanical strain that causes the sealing ring 320 to tighten (i.e. sealing ring 320 radii decrease).
  • the sealing ring 320 includes an inner wall 330, an outer wall 332, and a cavity 334.
  • R / w represents the radial distance from the center of the sealing ring 320 to the inner wall 330
  • R 0 w represents the radial distance from the center of the sealing ring 320 to the outer wall 332.
  • the sealing ring 320 may be in a naturally tightened stated. When applying the electric potential the sealing ring 320 expands.
  • a portion of the sealing ring may be composed of the piezoelectric material, such that the piezoelectric portion acts as an actuator to cause the other portion of the sealing ring to tighten and apply the substantially uniform circumferential pressure on the primary vessel, thereby constricting the primary vessel to form the seal.
  • a sample suspension can be urine, blood, bone marrow, cystic fluid, ascites fluid, stool, semen, cerebrospinal fluid, nipple aspirate fluid, saliva, amniotic fluid, vaginal secretions, mucus membrane secretions, aqueous humor, vitreous humor, vomit, and any other physiological fluid or semi-solid.
  • na ' ive or memory B cells or na ' ive or memory T cells a vesicle, a liposome, a protein, a nucleic acid, a biological molecule, a naturally occurring or artificially prepared microscopic unit having an enclosed membrane, parasites (e.g. spirochetes, such as Borrelia burgdorferi which cause Lyme disease; malaria-inducing agents), microorganisms, viruses, or inflammatory cells.
  • the sample may be a biological solid, such as tissue, that has been broken down, such as by collagenase, prior to or after being added to the primary vessel.
  • centrifugation such as 2g, 5g, lOg, lOOg, lOOOg, 1250g, 1500g, 2000g, 2500g, 3000g, 5000g, or lOOOOg, where g is the force of gravity.
  • centrifugation may not be used, and gravity (i.e. l ) may be used to permit the exchange of fluids and/or the separation of fluids.
  • gravity i.e. l
  • the densities of the fluids described below may be so great or the differentiation between the densities of the fluids may be so great that the separation and/or exchange of fluids occur without centrifugation.
  • the methods, even without centrifugation, may be performed in any appropriate amount of time, including, but not limited to, less than one hour (i.e. 1 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, etc.), one hour (i.e. 60 min) or more than one hour (i.e. 90 min, 2 hours, 4 hours, 8 hours, 24 hours, etc.).
  • a filling device may be inserted into the cavity 1 14 of the tube 100 prior to the processing vessel 202 being inserted into the cavity 1 14.
  • the filling device such as a pump or syringe, includes a layering fluid having a density which may be less than or greater than the target material.
  • the cannula 112 extends into the filling device (not shown) to access an inner volume at least partially filled with the layering fluid.
  • the filling device (not shown) is used to displace or remove or substitute air within the tube with the layering fluid, such as by undergoing centrifugation or by providing a pressure gradient.
  • the layering may have a density greater than or less than the target material.
  • suitable layering fluids include, but are not limited to, solution of colloidal silica particles coated with polyvinylpyrrolidone (e.g. Percoll), polysaccharide solution (e.g. Ficoll), iodixanol (e.g.
  • polyvinylpyrrolidone e.g. Percoll
  • polysaccharide solution e.g. Ficoll
  • iodixanol e.g.
  • an organic solvent such as ,4-Dioxane, acetonitrile, ethyl acetate, tert-butanol, cyclohexanone, methylene chloride, tert-Amyl alcohol, tert-Butyl methyl ether, butyl acetate, hexanol, nitrobenzene, toluene, octanol, octane, propylene carbonate, tetramethylene sulfones, and ionic liquids; polymer-based solutions; surfactants; perfluoroketones, such as per
  • the number of support members, support member spacing, and support member thickness can each be independently varied.
  • the support members can also be broken or segmented.
  • the main body is sized to have an outer diameter that is less than the inner diameter of the tube 100, thereby defining fluid retention channels between the outer surface of the main body and the inner wall of the tube 100.
  • the surfaces of the main body between the support members can be flat, curved or have another suitable geometry.
  • the support members and the main body may be a singular structure or may be separate structures.
  • Embodiments include other types of geometric shapes for float end caps.
  • the top end cap may be teardrop-shaped, dome-shaped, cone-shaped, or any other appropriate shape.
  • the bottom end cap may be teardrop-shaped, dome-shaped, cone- shaped, or any other appropriate shape.
  • the main body of the float 504 can include a variety of different support structures for separating samples, supporting the tube wall, or directing the suspension fluid around the float during centrifugation. Embodiments are not intended to be limited to these examples.
  • the main body may include a number of protrusions that provide support for the tube. In alternative embodiments, the number and pattern of protrusions can be varied.
  • the main body may include a single continuous helical structure or shoulder that spirals around the main body creating a helical channel.
  • the helical shoulder can be rounded or broken or segmented to allow fluid to flow between adjacent turns of the helical shoulder.
  • the helical shoulder spacing and rib thickness can be independently varied.
  • the main body may include a support member extending radially from and circumferentially around the main body.
  • the support members may be tapered.
  • the float 504 can be composed of a variety of different materials including, but not limited to, metals; organic or inorganic materials; ferrous plastics; sintered metal; machined metal; plastic materials and combinations thereof.
  • the tube 100 may have an inner wall and a first diameter.
  • the float 504 can be captured within the tube 100 by an interference fit, such that under centrifugation, an inner wall of the tube 100 expands to permit axial movement of the float 504. When centrifugation stops, the inner wall reduces back to the first diameter to induce the interference fit. Alternatively, the inner wall may not expand and the interference fit may not occur between the float 504 and the tube 100, such that the float moves freely within the tube before, during, or after centrifugation.
  • the end caps of the float may be manufactured as a portion of the main body, thereby being one singular structure, by machining, injection molding, additive techniques, or the like; or, the end caps may be connected to the main body by a press fit, an adhesive, a screw, any other appropriate method by which to hold at least two pieces together, or combinations thereof.
  • FIG. 5B shows an isometric view of the tube 100, the float 504, and the blood having undergone density-based separation, such as by centrifugation.
  • the centrifuged whole blood includes three fractions.
  • the three fractions include plasma, buffy coat, and red blood cells.
  • the suspension undergoes axial separation into three fractions along the length the tube based on density, with red blood cells 514 located on the bottom, plasma 510 located on top, and buffy coat 512 located in between, as shown in Figure 8.
  • the float 504 may have any appropriate density to settle within one of the fractions.
  • the density of the float 504 can be selected so that the float 504 expands the buffy coat 512 between the main body of the float and the inner wall of the primary vessel.
  • the buffy coat 512 can be trapped within an area between the float 504 and the primary vessel 702.
  • the plasma 510 may be removed from the tube 100, such as by pipetting, suctioning, pouring, or the like.
  • at least one delineation fluid 520 may be added to the tube.
  • the delineation fluid may provide further separation between the target material and any non- target material above and/or below the target material.
  • the at least one delineation fluid 520 may have a density greater than or less than the target material.
  • the delineation fluid may have a density greater than the buffy coat 512 and less than the red blood cells 514.
  • the at least one delineation fluid 520 may be miscible or immiscible with the suspension fluid and inert with respect to the suspension materials.
  • the at least one delineation fluid 520 may also provide an area in which to seal the primary vessel 702, because there is greater delineation and separation between the buffy coat 512 and the red blood cells 514.
  • the at least one delineation fluid 520 may be used whether or not a float is used.
  • suitable delineation fluids include, but are not limited to, solution of colloidal silica particles coated with polyvinylpyrrolidone (e.g. Percoll), polysaccharide solution (e.g. Ficoll), iodixanol (e.g.
  • OptiPrep cesium chloride, sucrose, sugar-based solutions, polymer-based solutions, surfactants, an organic solvent, a liquid wax, an oil, a gas, and combinations thereof; olive oil, mineral oil, silicone oil, immersion oil, mineral oil, paraffin oil, silicon oil, fluoro silicone, perfluorodecalin, perfluoroperhydrophenanthrene, perfluorooctylbromide, and combinations thereof; organic solvents such as 1,4-Dioxane, acetonitrile, ethyl acetate, tert-butanol, cyclohexanone, methylene chloride, tert-Amyl alcohol, tert-Butyl methyl ether, butyl acetate, hexanol, nitrobenzene, toluene, octanol, octane, propylene carbonate, tetramethylene sulfones, and ionic liquids; poly
  • the tube, float, delineation fluid, and remaining fractions undergo re-centrifugation.
  • a sealing ring is applied.
  • Figure 5D shows a two-part seal including an internal pliant part to be inserted into the primary vessel and an external constricting part to constrict and deform at least the primary vessel to seal an upper portion of the primary vessel from a lower portion of the primary vessel.
  • the external constricting part may also constrict and deform the internal pliant part.
  • the two-part seal prevents fluids from moving past the two-part seal within the primary vessel and prevents movement of the internal pliant part.
  • the internal pliant part is described with reference to the float 504 and the external constricting part is described with reference to the sealing ring 300, but the system described is not intended to be so limited and may include any appropriate float and any appropriate external constricting device.
  • the sealing ring 300 exerts circumferential or radial forces on the tube
  • Magnified view 522 shows the sealing ring 300 tightened around the float 504 and the tube 100.
  • the sealing ring 300 having been placed at an interface of the delineation fluid 520 and the red blood cells 514, causes the tube 100 to collapse inwardly until a seal is formed between the tube 100 and the float 504.
  • An outer wall of the sealing ring 300 may sit flush with an outer wall of the tube 100; the outer wall of the sealing ring 300 may extend past the outer wall of the tube 100; or, the outer wall of the tube 100 may extend past the outer wall of the sealing ring 300.
  • the sealing ring 300 remains tightened to maintain the seal, which prevents fluids from moving past the seal in any direction.
  • the sealing ring 300 may also remain in tension.
  • the sealing ring 300 may be overtightened and then the force applied to the sealing ring 300 is removed.
  • the sealing ring 300 may expand slightly, though still remains constricted.
  • a clamp may be used to circumferentially apply a force directed toward the central axis of the tube 100 to the sealing ring 300.
  • the sealing ring 300 is placed around the tube 100 after the tube 100 undergoes density-based separation, such as by centrifugation.
  • the sealing ring 300 and the tube 100 are then placed into the clamp.
  • the clamp may include a shelf to support the sealing ring 300 against the tube 100. Operation of the clamp may be automated or may be performed manually. Alternatively, the clamp may form a seal between the float 504 and tube 100 without the inclusion of the sealing ring 300.
  • a seal may be formed between the float 504 and the tube 100 such as by ultrasonic welding; or by applying heat or a temperature gradient to deform and/or melt the tube 100 to the float 504.
  • the methods are described with reference to the sealing ring, but the methods described below are not intended to be so limited in their application and may be performed without the sealing ring.
  • a motor causes translation of either a collet, including collet fingers, or a pressure member to cause compression of the collet fingers.
  • the motor may be connected to the collet or the pressure member by a shaft, such as a cam shaft, and one or more gears.
  • a base engages and holds the object.
  • the collet is driven by the motor, the pressure member remains stationary.
  • the pressure member is driven by the motor, the collet remains stationary.
  • the clamp may include a release, so as to cause the pressure member to slide off of the collet fingers 904, thereby removing the clamping force.
  • the clamp may be, but is not limited to, a collet clamp, an O-ring, a pipe clamp, a hose clamp, a spring clamp, a strap clamp, or a tie, such as a zip tie.
  • the clamp may be used without a sealing ring to provide a seal between a float and a tube.
  • the tube 100 may be inverted, the plug 116 may be removed from the tube 100, the processing vessel 202 may be inserted into the tube 200, and the displacement fluid 212 may be added to the processing vessel 202. It be noted that the displacement fluid 212 may be added to the processing vessel 202 before or after inserting the processing vessel 202 into the tube 200
  • Figure 5F shows the tube 100 and the processing vessel 202 after centrifugation.
  • the displacement fluid 212 having a density greater than the buffy coat 512 but less than the delineation fluid 520, flows from the processing vessel 202 into the tube 100, the buffy coat 512 moves upwards within the tube 100 through the cannula 214, and into the processing vessel 202.
  • the processing vessel 202 including the buffy coat 512 may then be removed from the tube 100 to undergo further processing, analysis, storage, or the like.
  • a processing solution may be added, though the processing solution may have already been in the processing vessel prior to retrieval of the target material.
  • the processing vessel may be shaken, such as by a vortex mixer.
  • the processing solution (not shown), having been added before shaking either in liquid form, in a dissolvable casing, or in a breakable casing, may then mix with the buffy coat to effect a transformation and form a buffy coat-processing solution mixture.
  • the buffy coat-processing solution mixture may then be dispensed onto a substrate, such as a microscope slide.
  • Figure 4B shows a flow diagram for an example method for retrieving target material.
  • a suspension such as anticoagulated whole blood 502
  • the whole blood 502 is added to the tube 100.
  • a stain 606, a negative enrichment reagent 604, and a delineation fluid 602 may be added to the tube 100.
  • the stain 606 is added to the primary vessel to label the target material.
  • the negative enrichment reagent 604 is also added to the primary vessel to change the density of a non-target material, for example, the plasma 10, without changing the density of the target material.
  • the negative enrichment reagent 604 may change the density of a non-target material such that the density of the target material is less than or greater than a changed density of the non-target material.
  • the stain 606 and the negative enrichment reagent 604 may be allowed to incubate for any appropriate amount of time, including, but not limited to, less than one hour (i.e. 1 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, etc.), one hour (i.e. 60 min) or more than one hour (i.e. 90 min, 2 hours, 4 hours, 8 hours, 24 hours, etc.).
  • a stain may be a solution containing a fluorescent probe may be used to stain and thereby label the target material, thereby providing a fluorescent signal for identification and characterization.
  • the solution containing the fluorescent probe may be added to the suspension before the suspension is added to the vessel, after the suspension is added to the vessel but before centrifugation, or after the suspension has undergone centrifugation.
  • the fluorescent probe includes a fluorescent molecule bound to a ligand.
  • the target material may have a number of different types of surface markers.
  • Each type of surface marker is a molecule, such an antigen, capable of attaching a particular ligand, such as an antibody.
  • ligands can be used to classify the target material and determine the specific type of target materials present in the suspension by conjugating ligands that attach to particular surface markers with a particular fluorescent molecule.
  • fluorescent molecules include, but are not limited to, quantum dots; commercially available dyes, such as fluorescein, FITC ("fluorescein isothiocyanate"), R- phycoerythrin ("PE”), Texas Red, allophycocyanin, Cy5, Cy7, cascade blue, Hoechst, DAPI ("4',6-diamidino-2-phenylindole”) and TRITC ("tetramethylrhodamine isothiocyanate”); combinations of dyes, such as CY5PE, CY7APC, and CY7PE; and synthesized molecules, such as self-assembling nucleic acid structures.
  • fluorescent dots such as fluorescein, FITC (“fluorescein isothiocyanate"), R- phycoerythrin (“PE”), Texas Red, allophycocyanin, Cy5, Cy7, cascade blue, Hoechst, DAPI (“4',6-diamidino-2-phenylindole”) and TRITC
  • each solution includes a different type of fluorescent molecule bound to a different ligand.
  • a nucleus of the target material may have a different size than the nucleuses of the non-target material. Determining nuclear size may aid in differentiating between target and non-target material.
  • the tube 100 may be inverted, the plug 116 may be removed from the tube 100, the processing vessel 202 may be inserted into the tube 200, and the displacement fluid 212 may be added to the processing vessel 202. It be noted that the displacement fluid 212 may be added to the processing vessel 202 before or after inserting the processing vessel 202 into the tube 200
  • Figure 6E shows the tube 100 and the processing vessel 202 after centrifugation.
  • the displacement fluid 212 having a density greater than the buffy coat 512 but less than the delineation fluid 520, flows from the processing vessel 202 into the rube 100, the buffy coat 512 moves upwards within the tube 100 through the cannula 214, and into the processing vessel 202.
  • the density-alerting fluid 604 having mixed with the plasma 510 to form a high density plasma 608, causes the high density plasma 608 to have a density greater than at least the buffy coat 502 and the delineation fluid 602.
  • the processing vessel 202 including the buffy coat 512 may then be removed from the tube 100 to undergo further processing, analysis, storage, or the like.
  • a processing solution may be added, though the processing solution may have already been in the processing vessel prior to retrieval of the target material.
  • the processing vessel may be shaken, such as by a vortex mixer.
  • the processing solution (not shown), having been added before shaking either in liquid form, in a dissolvable casing, or in a breakable casing, may then mix with the buffy coat to effect a transformation and form a buffy coat-processing solution mixture.
  • the buffy coat-processing solution mixture may then be dispensed onto a substrate, such as a microscope slide.
  • Suitable negative enrichment reagents include, but are not limited to, a solution of colloidal silica particles coated with polyvinylpyrrolidone (e.g. Percoll), polysaccharide solution (e.g. Ficoll), iodixanol (e.g. OptiPrep), a complex, branch glucan (e.g. Dextran), cesium chloride, sucrose, sugar-based solutions, polymer solutions, multi-phase polymer solutions, tetrameric antibody complexes (e.g.
  • polyvinylpyrrolidone e.g. Percoll
  • polysaccharide solution e.g. Ficoll
  • iodixanol e.g. OptiPrep
  • branch glucan e.g. Dextran
  • cesium chloride e.g.
  • RosetteSep or the like; or particles, such as beads (composed of at least one of a metal, silica, glass, a polymer, or the like), nanoparticles, metal-based compounds, metal complexes, lipids, sugars, or the like.
  • the positive enrichment reagent is also added to the primary vessel to change the density of the target material without changing the density of a non-target material.
  • the positive enrichment reagent may change the density of the target material such that the density of the non-target material is less than or greater than a changed density of the target material.
  • the positive enrichment reagent may be allowed to incubate for any appropriate amount of time, including, but not limited to, less than one hour (i.e. 1 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, etc.), one hour (i.e. 60 min) or more than one hour (i.e. 90 min, 2 hours, 4 hours, 8 hours, 24 hours, etc.).
  • Suitable positive enrichment reagents include, but are not limited to, a solution of colloidal silica particles coated with polyvinylpyrrolidone (e.g. Percoll), polysaccharide solution (e.g. Ficoll), iodixanol (e.g. OptiPrep), a complex, branch glucan (e.g. Dextran), cesium chloride, sucrose, sugar-based solutions, polymer solutions, multiphase polymer solutions, tetrameric antibody complexes (e.g.
  • polyvinylpyrrolidone e.g. Percoll
  • polysaccharide solution e.g. Ficoll
  • iodixanol e.g. OptiPrep
  • branch glucan e.g. Dextran
  • cesium chloride e.g.
  • RosetteSep or the like; or particles, such as beads (composed of at least one of a metal, silica, glass, a polymer, or the like), nanoparticles, metal-based compounds, metal complexes, lipids, sugars, or the like.
  • Sequential density fractionation is the division of a sample into fractions or of a fraction of a sample into sub-fractions by a step-wise or sequential process, such that each step or sequence results in the collection or separation of a different fraction or sub-fraction from the preceding and successive steps or sequences.
  • sequential density fractionation provides individual sub-populations of a population or individual sub-sub-populations of a sub-population of a population through a series of steps.
  • buffy coat is a fraction of a whole blood sample.
  • the buffy coat fraction can be further broken down into sub-fractions including, but not limited to, reticulocytes, granulocytes, lymphocytes/monocytes, and platelets.
  • the buffy coat may also contain the desired target material. These sub- fractions may be obtained individually by performing sequential density fractionation.
  • Two or more processing vessels and respective displacement fluids may be used depending on the number of fractions or sub-fractions desired for separation and collection.
  • Each successive displacement fluid is denser than the preceding displacement fluid.
  • the displacement fluid to collect the target material has a density greater than the density of the desired target material; for example, example, the displacement fluid may have a density that is approximately 0.001 to approximately 0.005 g/cm greater than the density of the desired target material.
  • each successive fraction or sub-fraction is denser than the preceding fraction or sub-fraction.
  • the consecutive sub- fractions may be analyzed, such as for diagnostic, prognostic, research purposes, to determine components characteristics (i.e. a complete blood count), how those characteristics change over time, or the like.
  • Subsequent processing vessels and displacement fluids may be used to collect additional subfractions of the buffy coat 512 until all subfractions are collected or until the desired subtraction is collected.
  • sequential density fractionation is described as being performed with a float and a sealing ring, sequential density fractionation may be performed without a float, a sealing ring, or both.
  • the following is an example method for performing sequential density fractionation after having performed all steps up to insertion of the processing vessel:
  • the target material may be placed on a substrate for imaging and detection (and subsequent storage for archival purposes). At least one portion of the detected target material may then be removed from the substrate, such as by picking, to undergo further analysis.
  • the isolated target material may be deposited into a PCR tube, a well of a well plate, a slide, or any appropriate substrate or vessel for performing the further analysis.
  • the target material may be analyzed using any appropriate analysis method or technique, though more specifically extracellular and intracellular analysis including intracellular protein labeling; chromo genie staining; nucleic acid analysis, including, but not limited to, DNA arrays, expression arrays, protein arrays, and DNA hybridization arrays; in situ hybridization (“ISH”— a tool for analyzing DNA and/or RNA, such as gene copy number changes); polymerase chain reaction (“PCR”); reverse transcription PCR; or branched DNA (“bDNA”— a tool for analyzing DNA and/or RNA, such as mRNA expression levels) analysis.
  • ISH in situ hybridization
  • PCR polymerase chain reaction
  • bDNA branched DNA
  • the isolated nucleated red blood cell may undergo further processing to test for such fetal abnormalities including, but not limited to, chromosomal abnormalities (e.g.
  • fetal aneuploidy Down syndrome, trisomy 13, trisomy 18, or a sex chromosome abnormality, such as Turner syndrome), smaller sub- chromosomal abnormalities, gender testing, mutational analysis, and rhesus blood type testing.
  • intracellular proteins which may be labeled include, but are not limited to, cytokeratin ("CK"), actin, Arp2/3, coronin, dystrophin, FtsZ, myosin, spectrin, tubulin, collagen, cathepsin D, ALDH, PBGD, Aktl, Akt2, c-myc, caspases, survivin, p27 kip , FOXC2, BRAF, Phospho-Aktl and 2, Phospho- Erkl/2, Erkl/2, P38 MAPK, Vimentin, ER, PgR, PI3K, pFAK, KRAS, ALKH1, Twistl, Snaill, ZEBl, Fibronectin, Slug, Ki-67, M30, MAGEA3, phosphorylated receptor kinases, modified histones, chromatin-associated proteins, and MAGE.
  • CK cytokeratin
  • actin actin
  • Arp2/3, coronin coron
  • fixing agents such as formaldehyde, formalin, methanol, acetone, paraformaldehyde, or glutaraldehyde
  • detergents such as saponin, polyoxyethylene, digitonin, octyl ⁇ -glucoside, octyl ⁇ -thioglucoside, l-S-octyl-p-D-thioglucopyranoside, polysorbate-20, CHAPS, CHAPSO, (l,l,3,3-Tetramethylbutyl)phenyl-polyethylene glycol or octylphenol ethylene oxide), or labeling agents (such as fluorescently-labeled antibodies, enzyme-conjugated antibodies, Pap stain, Giemsa stain, or hematoxylin and eosin stain) may be used.
  • the density of the target material may be increased (such as by attaching a weight to the target material or by having the target material absorb or ingest the weight) or may be decreased (such as by attaching a buoy to the target material or by having the target material absorb or ingest the buoy).
  • the weight or the buoy may be bound to a ligand.
  • the target material may have a number of different types of surface markers. Each type of surface marker is a molecule, such as an antigen, capable of attaching a particular ligand, such as an antibody. As a result, ligands can be selected to attached specifically to the target material to alter the density of the target material. Examples of suitable weights and/or buoys include, but are not limited to beads composed of metal, glass, ceramic, plastic, or combinations thereof. Alternatively, the weight or buoy may be attached to a non-target material to change the density of the non-target material to obtain a purer sample of the target material.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Clinical Laboratory Science (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Dispersion Chemistry (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Centrifugal Separators (AREA)

Abstract

La présente invention concerne un appareil, un système et un procédé servant à extraire une matière cible d'une suspension. Un système comprend un récipient de traitement, un fluide de déplacement et un tube. Le tube comprend un entonnoir, une canule et une cavité. La canule permet une communication fluidique entre l'entonnoir et la cavité, de telle sorte que le récipient de traitement est introduit dans la cavité, et la canule s'étend dans le récipient de traitement.
PCT/US2016/051544 2016-06-03 2016-09-13 Appareil, système, et procédé de collecte de matière cible WO2017209780A1 (fr)

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EP16904228.0A EP3463659A4 (fr) 2016-06-03 2016-09-13 Appareil, système, et procédé de collecte de matière cible
CN201680086993.6A CN109414694A (zh) 2016-06-03 2016-09-13 用于收集靶物质的设备、系统和方法

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