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Title:
CONTACTLESS CONCENTRATION AND MIXING OF MAGNETIC MATERIAL IN LIQUID
Document Type and Number:
WIPO Patent Application WO/2018/031232
Kind Code:
A1
Abstract:
Methods are provided for concentrating magnetic material, such as magnetic affinity beads, in liquid samples in sample containers such as wells of multiwell sample processing plates or sample tubes. Methods are also provided for dispersing magnetic material in liquid samples to effect mixing of the liquid. The disclosed methods include movement of magnets, such as magnetic rods or pins, to concentrate or disperse magnetic material, such as movement of magnets in interwell spaces of a multiwell plates or in spaces between sample tubes in a tube rack.

Inventors:
LAPHAM, Kyle (180 Kimball Way, South San Francisco, California, 94080, US)
Application Number:
US2017/043810
Publication Date:
February 15, 2018
Filing Date:
July 25, 2017
Export Citation:
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Assignee:
COUNSYL, INC. (180 Kimball Way, South San Francisco, California, 94080, US)
International Classes:
B03C1/01; B03C1/24
Foreign References:
US20130118965A12013-05-16
US20110147294A12011-06-23
Attorney, Agent or Firm:
BOYD, Victoria L. (FisherBroyles, LLP555 Bryant St., #37, Palo Alto California, 94301, US)
Download PDF:
Claims:
CLAIMS

I claim: . A method for concentrating magnetic material in liquid in a well of a sample processing plate that comprises a plurality of wells or in a sample tube in a tube rack that comprises a plurality of sample tubes,

wherein the sample processing plate or tube rack comprises a top and a bottom,

wherein the plate or tube rack comprises open spaces between the wells on the bottom of the plate or between the sample tubes on the bottom of the tube rack, said method comprising moving magnets up and down from beneath and within the spaces between wells or sample tubes,

wherein the magnetic material in the liquid is attracted to the magnets when they are in proximity of the magnetic material, thereby concentrating the magnetic material in the liquid.

2. A method according to claim 1 , wherein the magnets comprise magnetic rods or pins.

3. A method according to claim 1 , wherein the sample processing plate or tube rack is configured above a platform that comprises a plurality of said magnets configured to fit between the wells of the sample processing plate or between the sample tubes in the tube rack.

4. A method according to claim 1 , wherein the magnetic material comprises magnetic affinity beads.

5. A method according to claim 1 , wherein movement of the magnets is controlled by a control system that controls the magnets to concentrate the magnetic material in the wells or sample tubes.

6. A method according to claim 1 , wherein the liquid comprises one or more of biomolecules, nucleic acids, proteins, peptides, antibodies, antibody fragments, antibody-small molecule conjugates, enzymes, metabolites, structural proteins, tissues, seeds, cells, organelles, membranes, blood, plasma, saliva, urine, semen, oocytes, skin, hair, feces, cheek swabs, pap smear lysate, organic molecules, pharmaceutical compounds, bacteria, viruses, and nanoparticles.

7. A method according to claim 4, wherein the magnetic affinity beads comprise an affinity ligand or moiety that binds to a component or compound in the liquid, said method further comprising aspirating liquid from the well or sample tube, thereby separating the bound component or compound from other components in the liquid.

8. A method according to claim 1 , wherein said magnets comprise neodymium iron boron, samarium cobalt, alnico, ceramic, and/or ferrite.

9. A method according to claim 1 , wherein said magnetic material in said liquid comprises a ferromagnetic material selected from iron, cobalt, nickel, a rare earth metal, or an alloy thereof.

10. A method for mixing liquid in a well of a sample processing plate that comprises a plurality of wells or in a sample tube in a tube rack that comprises a plurality of sample tubes,

wherein the sample processing plate or tube rack comprises a top and a bottom,

wherein the plate or tube rack comprises open spaces between the wells on the bottom of the plate or between the sample tubes on the bottom of the tube rack, said method comprising moving magnets up and down from beneath and within the spaces between wells or sample tubes,

wherein the magnetic material in the liquid is attracted to the magnets when they are in proximity of the magnetic material, thereby dispersing the magnetic material and mixing the liquid.

1 1. A method according to claim 10, wherein the magnets comprise magnetic rods or pins.

12. A method according to claim 10, wherein the sample processing plate or tube rack is configured above a platform that comprises a plurality of said magnets configured to fit between the wells of the sample processing plate or between the sample tubes in the tube rack.

13. A method according to claim 10, wherein the magnetic material comprises magnetic affinity beads.

14. A method according to claim 10, wherein movement of the magnets is controlled by a control system that controls the magnets to disperse the magnetic material, thereby mixing the liquid in the wells or sample tubes.

15. A method according to claim 10, wherein the liquid comprises one or more of biomolecules, nucleic acids, proteins, peptides, antibodies, antibody fragments, antibody-small molecule conjugates, enzymes, metabolites, structural proteins, tissues, seeds, cells, organelles, membranes, blood, plasma, saliva, urine, semen, oocytes, skin, hair, feces, cheek swabs, pap smear lysate, organic molecules, pharmaceutical compounds, bacteria, viruses, and nanoparticles.

16. A method according to claim 10, wherein said magnets comprise

neodymium iron boron, samarium cobalt, alnico, ceramic, and/or ferrite.

17. A method according to claim 10, wherein said magnetic material in said liquid comprises a ferromagnetic material selected from iron, cobalt, nickel, a rare earth metal, or an alloy thereof.

Description:
CONTACTLESS CONCENTRATION AND MIXING

OF MAGNETIC MATERIAL IN LIQUID

CROSS-REFERENCE TO RELATED APPLICATIONS

[01 ] This application claims priority to U.S. Pat. App. No. 62/371 ,752 filed August 6, 2016, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

[02] The invention relates to methods for concentrating magnetic material in liquid and/or dispersing magnetic material in liquid to effect mixing of the liquid.

BACKGROUND

[03] Magnetic affinity beads are used for a number of applications, such as isolation of biomolecules or diagnostic assays. Placing magnets underneath sample tubes or wells of a multiwell plate is a common way to concentrate the beads at the bottom of the tube or well to facilitate removal of excess fluid and washing of the beads. Since magnetic field strength is limited by distance, the closer the magnet is to the beads, the better it works. The problem with this is that in larger or tall sample tubes or wells, pulling magnetic material down to the bottom is less efficient, and positioning the magnet at the top results in the beads collecting at the top of the sample liquid rather than the bottom of the tube or well. An improved method for concentrating magnetic material such as magnetic beads in liquid samples is needed.

[04] Mixing of liquid in sample tubes or wells of a multiwell plate may be performed by a number of methods, including pipetting up and down, shaking, agitating, or inverting. Pipetting contacts the liquid, which may introduce contamination, uses consumables (pipet tips), and may remove small amounts of liquid, reducing the liquid volume and potentially removing sample substances. Shaking, inverting, or other mechanical mixing methods may result in splashing and/or cross-contamination between adjacent or nearby sample tubes or wells. An improved method for mixing liquid in sample tubes or wells of a multiwell plate is needed.

BRIEF SUMMARY OF THE INVENTION

[05] Methods, devices, and systems for concentrating magnetic material in liquid and/or dispersing magnetic material in liquid to mix the liquid are provided herein.

[06] In one aspect, a method is provided for concentrating magnetic material in liquid in a well of a sample processing plate that includes a plurality of wells or in a sample tube in a tube rack that includes a plurality of sample tubes, wherein the sample processing plate or tube rack includes a top and a bottom, wherein the plate or tube rack includes open spaces between the wells on the bottom of the plate or between the sample tubes on the bottom of the tube rack. The method includes moving magnets up and down from beneath and within the spaces between wells or sample tubes, wherein the magnetic material in the liquid is attracted to the magnets when they are in proximity of the magnetic material, thereby concentrating the magnetic material in the liquid. In some embodiments, the magnets are in the form of the magnetic rods or pins. In some embodiments, the magnetic material is in the form of magnetic affinity beads.

[07] In some embodiments, the sample processing plate or tube rack is configured above a platform that includes a plurality of the magnets configured to fit between the wells of the sample processing plate or between the sample tubes in the tube rack.

[08] In some embodiments, movement of the magnets is controlled by a control system that controls the magnets to concentrate the magnetic material in the wells or sample tubes.

[09] In some embodiments, the liquid in the well or sample tube includes one or more of biomolecules, nucleic acids, proteins, peptides, antibodies, antibody fragments, antibody-small molecule conjugates, enzymes, metabolites, structural proteins, tissues, seeds, cells, organelles, membranes, blood, plasma, saliva, urine, semen, oocytes, skin, hair, feces, cheek swabs, pap smear lysate, organic molecules, pharmaceutical compounds, bacteria, viruses, and nanoparticles. [10] In some embodiments, the magnetic material is in the form of magnetic affinity beads that include an affinity ligand or moiety that binds to a component or compound in the liquid, and the method further includes aspirating liquid from the well or sample tube, thereby separating the bound component or compound from other components in the liquid.

[11 ] In some embodiments, the magnets include neodymium iron boron, samarium cobalt, alnico, ceramic, and/or ferrite.

[12] In some embodiments, the magnetic material in the liquid includes a ferromagnetic material selected from iron, cobalt, nickel, a rare earth metal, or an alloy thereof.

[13] In another aspect, a method is provided for mixing liquid in a well of a sample processing plate that includes a plurality of wells or in a sample tube in a tube rack that includes a plurality of sample tubes, wherein the sample processing plate or tube rack Includes a top and a bottom, wherein the plate or tube rack includes open spaces between the wells on the bottom of the plate or between the sample tubes on the bottom of the tube rack. The method includes moving magnets up and down from beneath and within the spaces between wells or sample tubes, wherein the magnetic material in liquid is attracted to the magnets when they are in proximity of the magnetic material, thereby dispersing the magnetic material and mixing the liquid. In some embodiments, the magnets are in the form of the magnetic rods or pins. In some embodiments, the magnetic material is in the form of magnetic affinity beads.

[14] In some embodiments, the sample processing plate or tube rack is configured above a platform that includes a plurality of the magnets configured to fit between the wells of the sample processing plate or between the sample tubes in the tube rack.

[15] In some embodiments, movement of the magnets is controlled by a control system that controls the magnets to disperse the magnetic material, thereby mixing the liquid in the wells or sample tubes.

[16] In some embodiments, the liquid in the well or sample tube includes one or more of biomolecules, nucleic acids, proteins, peptides, antibodies, antibody fragments, antibody-small molecule conjugates, enzymes, metabolites, structural proteins, tissues, seeds, cells, organelles, membranes, blood, plasma, saliva, urine, semen, oocytes, skin, hair, feces, cheek swabs, pap smear lysate, organic molecules, pharmaceutical compounds, bacteria, viruses, and nanoparticles.

[17] In some embodiments, the magnets include neodymium iron boron, samarium cobalt, alnico, ceramic, and/or ferrite.

[18] In some embodiments, the magnetic material in the liquid includes a ferromagnetic material selected from iron, cobalt, nickel, a rare earth metal, or an alloy thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[19] Figures 1A and 1 B show two embodiments of magnet arrays for concentration of magnetic material in liquid and/or mixing of liquid in wells of a multiwell sample processing plate or in sample tubes in a tube rack.

[20] Figure 2 shows an embodiment of a multiwell sample processing plate configured with a magnet array underneath the plate and configured such that the magnets fit and are movable within the interwell spaces of the plate, concentrating magnetic material in the wells of a multiwell sample processing plate.

[21 ] Figures 3A, 3B, and 3C show an embodiment in which a magnet is moved up and gradually moved down alongside a well of a multiwell sample processing plate or a sample tube to concentrate and pull down magnetic material in liquid in the well or tube.

[22] Figure 4 shows an embodiment in which a magnet is moved up and down alongside a well of a multiwell sample processing plate or a sample tube to disperse magnetic material in liquid in the well, thereby mixing the liquid in the well or tube.

DETAILED DESCRIPTION

[23] Methods, devices, and systems are provided for contactless concentration of magnetic material in liquid and/or for contactless mixing of liquid in sample containers. In some embodiments, the magnetic material is in the form of magnetic beads, e.g., magnetic affinity beads.

[24] The magnets may be used to concentrate magnetic material, e.g., magnetic beads, at a specific location within the container, e.g., well or sample tube, facilitating removal of excess fluid and washing of the magnetic material. Further, since magnetic field strength is limited by distance, the closer the magnet is to the magnetic material, the better the attraction. The magnetic field may be adjusted inside the container, e.g., well or sample tube, in real time by dynamically moving the magnets in relation to the top and bottom of the container, thereby mixing the magnetic material, e.g., magnetic beads, and consequently the liquid within the container, e.g., well or tube. This may be used as an alternative to shaking or inverting, for example the container or, for example a multiwell sample processing plate or sample tube rack, which can result in splashing and cross-contamination between wells or tubes, or pipetting liquid up and down, which contacts the liquid, potentially resulting in contamination, and uses consumables (pipet tips). Mixing of the liquid by movement of magnets up and down alongside the container, e.g., between wells of a multiwell plate or between sample tubes in a tube rack, as described herein, is a contactless mixing method that involves movement of the magnetic material in the container, e.g., wells or tubes, rather than the liquid.

[25] In some embodiments, magnetic material in liquid in a sample container, such as, but not limited to, a well of a multiwell plate or a sample tube, may be concentrated by movement of one or more magnet alongside the container, such as between adjacent wells of a multiwell plate (e.g., from beneath the plate and up and down in the interwell space between adjacent wells) or between adjacent sample tubes in a tube rack (e.g., from beneath the tube rack and up and down between adjacent sample tubes), thereby concentrating the magnetic material in the liquid by attraction to the external magnet(s).

[26] In some embodiments, liquid containing magnetic material therein in a sample container, such as, but not limited to, a well of a multiwell plate or a sample tube, may be mixed by movement of one or more magnet alongside the container, such as between adjacent wells of a multiwell plate (e.g., from beneath the plate and up and down in the interwell space between adjacent wells) or between adjacent sample tubes in a tube rack (e.g., from beneath the tube rack and up and down between adjacent sample tubes), thereby dispersing the magnetic material in the liquid by attraction to the external magnet(s) and mixing the liquid.

[27] "Magnets" (e.g, rods or pins that fit alongside a container for liquid, such as within interwell spaces of sample plates or between sample tubes in a tube rack) may be composed entirely of magnetic material, or one or more portion(s), for example, a terminal portion, may be composed of magnetic material. Suitable materials for this purpose include, but are not limited to, Neodymium Iron Boron, Samarium Cobalt, Alnico (e.g., iron alloys, which in addition to iron are composed primarily of aluminum, nickel, and cobalt, and also including copper and sometimes titanium), Ceramic or Ferrite magnets.

[28] "Magnetic material" in liquid in a container, such as wells of a sample plate or sample tubes, may be moved by attraction to the magnets, for example magnets that fit within the interwell spaces of a multiwell sample processing plate or between sample tubes in a tube rack, may be, for example, in the form of magnetic beads, optionally coupled to functional groups, affinity ligands, antibodies or fragments thereof, or other reagents for binding or reaction with one or more compound(s) or component(s) in a liquid sample. Suitable materials for this purpose include, but are not limited to, ferromagnetic materials such as iron, cobalt, nickel, some rare earth metals and various alloys of these materials.

[29] In some embodiments, magnetic affinity beads can bind to a target molecule within a liquid sample, i.e., the liquid contains a target molecule to which an affinity moiety on the magnetic beads binds. Magnetic affinity beads may be added to the container, for example, wells or a multiwell sample processing plate or sample tubes, prior to, simultaneously with, or after addition of samples for analysis. For example, the affinity beads may be coated in antibodies, streptavidin, or cationic or anionic moieties. In some embodiments, the magnetic affinity beads are capable of separating one or more molecule(s) or component(s) of a sample from other components of the sample.

[30] In some embodiments, the magnetic material, e.g. , magnetic beads, may contain an affinity reagent, ligand, or substance that may bind to or immobilize one or more components or moieties in a sample. Magnetic material, e.g., magnetic affinity beads, may contain one or more affinity moiety that is capable of binding to a target molecule when present in a liquid sample.

[31 ] In some embodiments, a plurality of liquid samples is analyzed or one or more target molecule(s) extracted from each liquid sample. In some embodiments, the plurality of samples includes blood or saliva. In some embodiments, method includes extraction of DNA from the plurality of samples using magnetic beads. In some embodiments, a sample input may include, but is not limited to, biomolecules, nucleic acids (including DNA or RNA), proteins, peptides, antibodies, antibody fragments, antibody-small molecule conjugates, enzymes, metabolites, structural proteins, tissues, seeds, cells, organelles, membranes, blood, plasma, saliva, urine, semen, oocytes, skin, hair, feces, cheek swabs, pap smear lysate, organic molecules, pharmaceutical compounds, bacteria, viruses, or nanoparticles.

Concentration of magnetic material in liquid

[32] Using methods described herein, magnetic material may be concentrated in any liquid sample container that has accessible space for a magnet, e.g., a magnetic rod or pin, along at least one side or surface on the outside of the container. In certain embodiments, magnetic material may be concentrated in wells of a multiwell sample processing plate or in sample tubes in a tube rack.

[33] In some embodiments, a sample processing plate or sample tube rack is configured such that there is open space between the bottoms and at least a portion of the sides of adjacent wells of the plate, i.e., interwell spaces that are accessible from the bottom of the plate, or between adjacent sample tubes.

Magnets are configured to move up and down in the spaces between adjacent wells or tubes from beneath the plate or tube rack, thereby concentrating magnetic material in liquid in the wells or tubes by attraction to the external magnets.

[34] In an embodiment shown schematically in Fig. 2, a platform underneath a sample processing plate 240 is configured such that the magnets 230 may be moved up and down in the interwell spaces 244, thereby moving magnetic material 243, e.g., magnetic affinity beads, within the liquid 242 in the wells 241 and concentrating the magnetic material by attraction to the magnets. In other embodiments, the platform includes a plurality of magnets that are configured to fit into the open spaces between sample tubes in a tube rack, and the platform underneath the tube rack is configured such that the magnets may be moved up and down between the sample tubes, moving magnetic material, e.g., magnetic affinity beads, within the liquid in the sample tubes and concentrating the magnetic material by attraction to the magnets.

[35] In some embodiments, the magnets are used to concentrate magnetic material at a specific location within a container such as a well or sample tube, shown schematically in Figs. 3A-3C. For example, the magnets 230 may be moved slowly up and down alongside the container, for example, in the interwell space of a sample processing plate or between sample tubes, and then moved slowly down to concentrate the magnetic material 243, e.g., beads, in liquid 242, for example, at or near the bottom of the container, by attraction to magnet(s) on the outside of the container, e.g., well or sample tube. Movement of the magnets may be controlled by a control system.

Mixing of liquid

[36] Using methods described herein, liquid may be mixed in any liquid sample container that has accessible space for a magnet, e.g., a magnetic rod or pin, along at least one side or surface on the outside of the container. Liquid containing magnetic material therein may be mixed by using one or more magnet(s) to disperse the magnetic material, thereby mixing the liquid. In certain embodiments, magnetic material may be dispersed, mixing liquid in wells of a multiwell sample processing plate or in sample tubes in a tube rack.

[37] In some embodiments, a sample processing plate or sample tube rack is configured such that there is open space between the bottoms and at least a portion of the sides of adjacent wells of the plate, i.e., interwell spaces that are accessible from the bottom of the plate, or between adjacent sample tubes.

Magnets are configured to move up and down in the spaces between adjacent wells or tubes from beneath the plate or tube rack, thereby dispersing magnetic material in liquid in the wells or tubes that is attracted to the external magnets, thereby mixing liquid in the wells or tubes.

[38] In an embodiment shown schematically in Fig. 4, magnets are used to disperse magnetic material within a container such as a well or sample tube. For example, magnets 230 may be moved slowly to the top of the wells or sample tubes and then rapidly moved down to create a dispersion of the magnetic material 243 in the liquid 242. Quick movement may be used to break the magnetic field and disperse the magnetic material 243, e.g., magnetic affinity beads. The rate of movement of the magnet(s) may be adjusted depending on the amount of magnetic material and viscosity of liquid in the well or sample tube, thereby creating a uniform or substantially uniform dispersion of the magnetic material in the well or sample tube and facilitating contactless mixing of the liquid. Movement of the magnets may be controlled by a control system.

Magnet Arrays

[39] In some embodiments, a multiwell sample processing plate or a sample tube rack is supported on or suspended above a platform that includes a plurality of magnets, e.g., magnetic pins or rods, 230 that are configured to fit into the open spaces between the wells or the sample tubes. Two nonlimiting examples of magnet arrays are shown in Figs. 1A and 1 B. In some embodiments, the platform includes a plurality of magnets each configured underneath a well of a sample processing plate or a sample tube when the plate or sample tube rack is supported on the platform. In some embodiments, the platform includes a plurality of magnets configured to move between in the interwell space from below a sample processing plate or configured to move between sample tubes from below a sample tube rack when the sample processing plate or sample tube rack is supported on the platform.

[40] In some embodiments, the magnets, e.g., magnetic pins or rods, may be movable relative to the plate or tube rack. In other embodiments, the plate or tube rack may be movable relative to the magnets. In some embodiments, the plate or tube rack is stationary and the magnets are individually movable (e.g., in a vertical ("z") direction relative to a horizontal configuration of the sample processing plate or tube rack) or magnets covering sections of a plate may be movable together as a group, for example, half plate, quadrants, rows, columns, or other subsections of a plate or tube rack. In one embodiment, the plate or tube rack is configured on a support base that fits beneath the plate rack or tube and contains an array of magnets (e.g., pins or rods) that are configured to move within the interwell spaces of the plate or between sample tubes in the tube. A cushioning material, for example, rubber, may be provided between the outer edges of the sample processing plate or tube rack and the corresponding edges of the support base that the plate or tube rack fits within, to absorb vibration from movement of the magnets. In another embodiment, the magnets are fixedly mounted to a base plate which is configured to be moved relative to the sample processing plate or sample tube rack, to move the magnets between wells of the plate or between sample tubes. In another embodiment, the magnets are fixedly mounted to a base plate and the sample processing plate or sample tube rack is configured to be moved relative to the base plate, to move the magnets between wells of the plate or between sample tubes.

[41 ] In embodiments in which the magnets are individually movable (i.e., not fixedly mounted to a base plate), magnets may be movable via mechanical devices (e.g., springs) or via actuators (e.g., hydraulic, pneumatic, electrical, thermal, mechanical). In one embodiment, the magnets are movable via an electronically controlled actuator mechanism. In one embodiment, an actuator is coupled to a spring for quick release in one direction.

[42] A magnet array may be configured such that one magnet is used per well or sample tube to move magnetic material within liquid in the well or sample tube, or the array may be configured such that the well or sample tube is surrounded to two or more magnets. For example, a well or sample tube may be surrounded by two magnets that are 180 ° apart. In one embodiment, a well or sample tube is surrounded by four magnets that are 90 ° apart.

[43] In some embodiments, the platform that contains the magnet array or a platform that supports a platform that contains the magnet array may be configured to perform one or more function(s) with regard to a sample processing plate or sample tube rack supported thereon, such as, but not limited to, shaking, heating, and/or cooling. In some embodiments, the platform includes tip-tilt mechanism.

Sample processing plates

[44] In some embodiments, the methods described herein are applied to concentration of magnetic material (e.g., pulling magnetic material to the bottom or near the bottom of wells) and/or mixing of liquid in wells of multiwell sample processing plates. A variety of sample processing plates, e.g., plates that include a plurality of wells, may be used, including, but not limited to, a 6-well plate, a 12-well plate, a 24-well plate, a 48-well plate, a 96-well plate, a 192-well plate, a 384-well plate, a 1536-well plate, or a multi-well plate capable of holding any number of separated samples. In some embodiments, maximum well volume of the sample processing plate may be about 18 microliters, about 250 microliters, about 1.1 milliliters, about 2.2 milliliters, about 5 milliliters, or about 10 milliliters. The sample processing plate is configured such that there is open space between the bottoms and at least a portion of the sides of adjacent wells of the plate, i.e., having interwell space that is accessible from the bottom of the plate.

[45] In some embodiments, magnetic material, e.g., magnetic affinity beads, is pre-loaded into the sample processing plate prior to transferring of a liquid sample into the sample processing plate. In some embodiments, magnetic material, e.g., magnetic affinity beads, is not pre-loaded into the sample processing plate, but are added simultaneously with or after transferring a liquid sample into the sample processing plate.

Sample tubes

[46] In some embodiments, the methods described herein are applied to concentration of magnetic material (e.g., pulling magnetic mate ial to the bottom or near the bottom of sample tubes) and/or mixing of liquid in sample tubes in a tube rack. A variety of sample tubes may be used that are capable of holding any number of separated samples. In some embodiments, the sample tubes are conical. In some embodiments, the sample tubes are Vacutainer ® or similar tubes (i.e., sterile glass or plastic tubes, e.g., round bottom tubes, with a closure, such as a rubber stopper, such that the tubes may be evacuated to create a vacuum inside the tube, thereby facilitating the draw of a predetermined amount of liquid, such as a biological sample). In various non-limiting embodiments, the sample tubes may be configured to contain 5 ml, 15 ml, or 50 ml liquid volumes. The tube rack is configured such that there is open space between the bottoms and sides of adjacent sample tubes, i.e., having space between tubes that is accessible from the bottom of the tube rack.

[47] In some embodiments, magnetic material, e.g., magnetic affinity beads, is pre-loaded into sample tubes prior to transferring of a liquid sample into the sample tubes. In some embodiments, magnetic mate ial, e.g., magnetic affinity beads, is not pre-loaded into the sample tubes, but is added simultaneously with or after transferring a liquid sample into the sample tubes. Separation of magnetic material from liquid

[48] In some embodiments, such as when magnetic affinity beads are used to bind target molecules, concentration of the magnetic material using magnets as described herein may be used for separation of the magnetic material from the liquid in the container, e.g. , well or sample tube. The magnetic base forces the magnetic affinity beads to a desired location within the container, e.g., well or sample tube, such as the bottom or near the bottom of the sample wells or tubes. In some embodiments in which liquid is aspirated, the magnetic force holding the magnetic material may avoid or reduce the suction force of aspiration, e.g., aspiration with liquid aspiration nozzles. This may substantially prevent sample loss during a liquid aspiration step, as it decreases the likelihood that the affinity beads will be unintentionally aspirated from the sample wells or tubes. In some embodiments, the magnets as described herein may be used to concentrate and immobilize magnetic affinity beads prior to aspiration of the liquid from the wells or sample tubes.

Assays

[49] The methods described herein may be used in assays and diagnostic methods. In some embodiments, each well of the sample processing plate or each tube in a tube rack includes magnetic affinity beads that can bind to a target molecule within a liquid sample. The magnetic affinity beads may be added to the wells or tubes prior to, simultaneously with, or after addition of liquid samples for analysis. For example, the magnetic affinity beads may be coated in antibodies or fragments thereof, streptavidin, or cationic or anionic moieties. In some

embodiments, the magnetic affinity beads are pre-loaded into wells of the sample processing plate prior into sample tubes prior to transferring of the liquid sample into wells of the sample processing plate or into the sample tubes. In some embodiments, the magnetic affinity beads are not pre-loaded into wells of the sample processing plate or into sample tubes, but are added after transferring of the liquid sample into wells of the sample processing plate or into the sample tubes, for example, via a liquid dispensing apparatus.

[50] In some embodiments, in an assay or diagnostic method, one or more affinity reagent(s) may be used that bind to target molecule(s) when present in a liquid sample. Affinity reagent(s) may include, but are not limited to, antibodies, peptides, nucleic acids, or other small molecules that specifically bind to a target molecule or substance. An affinity reagent may produce a detectable signal when bound to a target molecule or substance, or a secondary reagent may be added that produces a signal when bound to or when interacting with the affinity reagent that is bound to the target or that produces a signal when bound to or interacting with the target when separated from other components of a sample. For example, one or more affinity reagent(s) may be attached to the magnetic beads, which may be separated from other components of the sample using magnets to concentrate the magnetic beads, as described herein. In some embodiments, a further liquid reagent may be dispensed that contains a molecule or substance that produces a signal when in contact with a target molecule if bound to the affinity reagent(s).

[51 ] Nonlimiting examples of reagents that may be used for signal detection include ROX (carboxy-X-rhodamine) for volume measurement, and pico green or broad range dyes for DNA quantification.

Integration with liquid handling systems

[52] In some embodiments, a system (e.g., a system with magnets or a magnet array as described herein) for concentrating magnetic material in liquid and/or mixing liquid, for example, in wells of a multiwell sample processing plate or in sample tubes in a tube rack, may be integrated with a system for liquid handling in which any of a number of other operations on liquid are performed, for example, but not limited to, dispensing liquid, aspirating liquid, detecting a signal in liquid or in a container that previously contained liquid, and/or sensing a parameter such as liquid level and/or temperature, . Nonlimiting examples of such a system are provided in co-pending applications US15/230,394, filed August 6, 20 6, and PCT/US2016/045924, filed August 6, 2016, both of which are incorporated herein by reference in their entireties.

[53] In some embodiments, the system includes at least one device that dispenses liquid and at least one device that aspirates liquid. In some

embodiments, the system includes at least one device that dispenses liquid, at least one device that aspirates liquid, and at least one device that senses a parameter in wells of a sample processing plate or in sample tubes. In some embodiments, the system includes at least one device that dispenses liquid, at least one device that aspirates liquid, and at least one device that detects a signal in wells of a sample processing plate or in sample tubes. In some embodiments, the system includes at least one device that dispenses liquid, at least one device that aspirates liquid, at least one device that senses a parameter in wells of a sample processing plate or in sample tubes, and at least one device that detects a signal in wells of the sample processing plate or in sample tubes.

[54] In some embodiments, a liquid handling system includes at least one device that is configured to dispense magnetic affinity beads in liquid into wells of a sample processing plate or into sample tubes. The affinity beads may include, for example, one or more affinity moiety that is capable of binding to a target molecule when present in a sample. In some embodiments, the affinity beads are capable of separating one or more molecule(s) or component(s) of a sample from other components of the sample.

[55] Although the foregoing invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced without departing from the spirit and scope of the invention, which is delineated in the appended claims. Therefore, the description should not be construed as limiting the scope of the invention.

[56] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entireties for all purposes and to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be so incorporated by reference.