WO2020001493A1 - 一种浓缩富集的磁珠纯化仪 - Google Patents

一种浓缩富集的磁珠纯化仪 Download PDF

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WO2020001493A1
WO2020001493A1 PCT/CN2019/093092 CN2019093092W WO2020001493A1 WO 2020001493 A1 WO2020001493 A1 WO 2020001493A1 CN 2019093092 W CN2019093092 W CN 2019093092W WO 2020001493 A1 WO2020001493 A1 WO 2020001493A1
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container
magnetic
magnetic rod
washing
sleeve
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PCT/CN2019/093092
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English (en)
French (fr)
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李永梅
李莉
赵联浩
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嘉兴医脉赛科技有限公司
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Priority to US17/250,217 priority Critical patent/US20210254045A1/en
Priority to EP19827424.3A priority patent/EP3816275B1/en
Publication of WO2020001493A1 publication Critical patent/WO2020001493A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
    • 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
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50855—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates using modular assemblies of strips or of individual wells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/44—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement
    • B01F31/441—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement performing a rectilinear reciprocating movement
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80—Mixing plants; Combinations of mixers
    • B01F33/81—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles
    • B01F33/813—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles mixing simultaneously in two or more mixing receptacles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1003—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor
    • C12N15/1006—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor by means of a solid support carrier, e.g. particles, polymers
    • C12N15/1013—Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor by means of a solid support carrier, e.g. particles, polymers by using magnetic beads
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/34—Purifying; Cleaning
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation
    • 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
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • 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
    • B01L2300/0609—Holders integrated in container to position an object
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • 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
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00465—Separating and mixing arrangements
    • G01N2035/00564—Handling or washing solid phase elements, e.g. beads

Definitions

  • the invention belongs to the technical field of bio-instrument equipment, and particularly relates to a magnetic bead purifier for concentration.
  • Nucleic acid as a carrier of genetic information, is the material basis of gene expression. In addition to having a very important role in the normal growth, development, and reproduction of living organisms, it is related to abnormal conditions of life, such as tumorigenesis and radiation. Injuries and genetic diseases are also closely related. Therefore, nucleic acid isolation, purification and detection are very important links in molecular biology and medical research. In clinical diagnosis and treatment, or forensic identification, or genetic screening and recombination, people need to extract nucleic acids from samples (blood, saliva or other tissues). The process of extracting nucleic acids is also called nucleic acid purification. The effect of nucleic acid purification directly affects the progress and results of research and diagnosis. Therefore, nucleic acid purification technology is an important technology in biotechnology.
  • the magnetic rod method uses a magnetic rod to adsorb magnetic beads, and the magnetic beads adsorb nucleic acids to separate nucleic acids from a sample.
  • Biological samples are lysed, bound to magnetic beads, and purified by washing, and impurities are removed to achieve the purpose of nucleic acid extraction.
  • Nucleic acid extraction by magnetic rod method is generally divided into steps such as lysis, binding, washing and elution. The connection between the steps is to fully mix the magnetic beads with the solution in the absence of a magnetic field, so that the nucleic acids are bound to the magnetic beads and non-specifically adsorbed impurities are removed.
  • the magnetic beads are enriched and transferred under the action of a magnetic field.
  • the working principle of the magnetic rod method is shown in FIG. 1.
  • the magnetic rod 20, the stirring sleeve 21, and the deep hole plate 22 are arranged in order from top to bottom.
  • the deep well plate 22 has a set of deep holes, which include lysing solution holes 221, magnetic bead holes 222, washing solution holes 223 (multiple washing solution holes can be set), and eluent holes 224, which are For storing the corresponding reagents.
  • the specific steps of the nucleic acid purification process are: drop the sample into the lysate to lyse the nucleic acid --- collect the magnetic beads into the lysate well-the magnetic beads are combined with the nucleic acid-collect the magnetic beads into the wash well (can be washed multiple times) -Collect the magnetic beads into the elution wells-recover the magnetic beads after elution, and finally the nucleic acids remain in the eluate.
  • the nucleic acid purifier needs to realize the basic actions shown in FIG.
  • magnetic bead purifiers generally use a container of the same volume to purify nucleic acids, which is suitable for extracting nucleic acids from smaller volumes of liquid samples (50-400 microliters); or use larger containers (4-10ml) and large Diameter magnetic rod sleeves are used for extraction. Due to the limitation of large diameter magnetic rod sleeve equipment, the minimum elution volume is usually large (about 100-300 microliters). However, in some cases, it is necessary to extract trace nucleic acids from a larger volume of liquid sample, such as liquid biopsy, viral nucleic acid hypersensitivity detection.
  • magnetic beads need to adsorb nucleic acids in a larger volume of liquid sample, wash to remove impurities, and then use a small amount of eluent to elute the nucleic acids for subsequent detection.
  • eluent For projects such as liquid biopsy, it is usually necessary to extract nucleic acids from 2-5ml plasma samples, that is, bind nucleic acids to magnetic beads from about 10ml of lysed adsorption liquid, and finally wash the bound nucleic acids in 20-50ul eluent Take it off. Nucleic acid purifiers cannot currently perform this task efficiently.
  • the nucleic acid purification instrument includes a base 13, and a bracket lifting device 8 and a support provided on the base 13 and used to realize the up and down movement and the flat movement after the magnetic rod 20 and the stirring sleeve 21 are combined.
  • a rack translation device 7 and a stirring sleeve driving mechanism 6 provided on the base 13 and used to realize the single and vertical movement of the stirring sleeve 21 and perform stirring.
  • the nucleic acid purifier uses only one set of magnetic rods for the extraction of a certain nucleic acid. 20 and the stirring sleeve 21 move up and down to achieve mixing and magnetic bead transfer.
  • the translation device solves the conversion of the magnetic beads from a large volume to a small volume of liquid, but the mixing and stirring intensity is weak, and under certain conditions, the effects of the nucleic acid substance's full cleavage and release and the binding with the magnetic beads cannot be achieved.
  • the magnetic rod method can also be used for protein extraction and purification, using magnetic rods to adsorb magnetic beads, and magnetic beads to adsorb proteins to separate proteins from samples.
  • Biological samples used for protein purification may or may not be subjected to a lysis step.
  • Some protein purification samples also have large starting volumes, ranging from microliters to tens of liters. Instruments are also needed to adsorb proteins from large volumes of samples using magnetic beads, and then elute with small volumes of eluent to achieve purification enrichment. The purpose of the protein. Similar to the reasons for the above-mentioned nucleic acid extraction, current magnetic bead purifiers cannot efficiently perform the task of purifying large volumes of proteins.
  • the present invention provides a magnetic bead purification instrument that is advantageous for extracting high-purity nucleic acids / proteins from large-volume samples to meet user needs.
  • the concentrated and enriched magnetic bead purifying instrument comprises a machine base, at least one first stirring jacket frame movably disposed on the machine base, and at least one second stirring jacket frame movably disposed on the machine base, placing A plurality of reagent containers on the machine base, and a control device for controlling the first stirring sleeve and the second stirring sleeve.
  • the first stirring sleeve holder includes at least one first magnetic rod sleeve mounted on the machine base, and at least one first magnetic rod sleeve for sheathing the first magnetic rod.
  • the second stirring sleeve frame includes at least one second magnetic rod frame mounted on the machine base, and at least one second magnetic rod sleeve for covering the second magnetic rod.
  • a cross-sectional diameter of the second magnetic rod sleeve is smaller than a cross-sectional diameter of the first magnetic rod sleeve
  • the reagent container includes at least one adsorption container, at least one washing container, and at least one elution container.
  • the volume of the elution container is smaller than the volume of the adsorption container.
  • the control device is configured to control the first magnetic rod sleeve to stir or adsorb only in the adsorption container and the washing container, and control the second magnetic rod sleeve to stir or adsorb in the washing container and the elution container. .
  • first and second stirring jackets are used for mixing, enriching and transferring magnetic beads.
  • control device controls the second magnetic rod to be set in the washing container to stir, adsorb the magnetic beads contained in the washing container, and transfer the magnetic beads to the same or smaller volume container.
  • first magnetic rod and the second magnetic rod are magnetic rods of the same size, and the same magnetic rod is used to cooperate with the first magnetic rod sleeve and the second magnetic rod sleeve to complete the enrichment and transfer of magnetic beads.
  • the volume of the elution container is smaller than the volume of the adsorption container.
  • each of the elution containers includes an elution mixing section, and a maximum diameter of a cross section of the first magnetic rod sleeve is larger than a maximum diameter of the elution container and a cross section of a washing mixing section of a part of the washing container. Maximum diameter.
  • each of the washing containers includes a washing mixing section, and a maximum diameter of a cross section of the first magnetic rod sleeve is equal to or smaller than a maximum diameter of a cross section of the washing mixing section of the part or all of the washing containers.
  • the enrichment and enrichment magnetic bead purifier further includes at least one reagent container holder placed on the base, and the reagent container is disposed on the reagent holder to fix the relative position of the reagent container. .
  • the maximum volume of the liquid contained in the adsorption container is 1 to 200 times the maximum volume of the liquid contained in the washing container, and the maximum volume of the liquid contained in the adsorption container is The maximum volume of the liquid contained in the elution container is 2 to 1000 times.
  • the concentrated and enriched magnetic bead purifier uses the first magnetic rod holder or the second magnetic rod holder separately to complete the purification process from adsorption, washing and elution.
  • the concentrated and enriched magnetic bead purifier provided by the present invention has two first and second stirring jackets of different specifications and test tube containers with different volumes.
  • the test tube holds an enlarged volume of liquid sample and uses the first stirring sleeve holder for stirring, sufficient mixing and adsorption; and because the cross-sectional diameter of the second magnetic rod sleeve is smaller than the cross-sectional diameter of the first magnetic rod sleeve,
  • the magnetic beads that adsorb nucleic acids or proteins can be adsorbed and transferred to smaller volume washing and elution containers, and sufficient mixing and magnetic bead transfer in smaller volume containers can be achieved, so that magnetic beads can be removed from larger volume solutions Transfer to a smaller volume of washing and elution containers, especially using a small volume of elution containers, the largest amount of nucleic acid or protein can be adsorbed with magnetic beads from a large volume adsorption container and the eluent in a small volume It can be eluted from the solution to maximize the
  • FIG. 1 is a working principle diagram of the magnetic rod method in the prior art.
  • FIG. 2 is a schematic structural diagram of a nucleic acid purifier provided in the prior art.
  • FIG. 3 is a schematic diagram of the three-dimensional structure of the magnetic bead purifier for concentration and enrichment provided by the present invention.
  • FIG. 4 is a schematic cross-sectional structure diagram of the magnetic bead purifier for concentration and enrichment shown in FIG. 3.
  • FIG. 5 is a schematic structural diagram of the magnetic bead purifier with concentration in FIG. 3.
  • the concentrated and enriched magnetic bead purifier includes a machine base 10, at least one first stirring sleeve 11 movably disposed on the machine base 10, and at least one second stirring movably disposed on the machine base 10.
  • the patent CN206956049U discloses a nucleic acid purifier.
  • the magnetic bead purifier also includes controlling the stirring according to the present invention.
  • the up and down movement of the frame, the magnetic bead transfer device and the electric control device, the electrical structure, and other assembly structures or installation structures should be techniques known to those skilled in the art, and will not be detailed here one by one. Instructions.
  • the machine base 10 is used for setting or placing various functional modules, such as the aforementioned mechanical device and electric control device, support device, and the reagent container described above.
  • the base 10 can have various structures and shapes to fit the installation and placement of various other devices.
  • the first stirring sleeve frame 11 is movably disposed on the frame 10 and includes at least one first magnetic rod 111 framed on the frame 10 and at least one for mounting the first magnetic rod. 111 ⁇ ⁇ ⁇ ⁇ 112 ⁇ The first magnetic rod sleeve 112.
  • the first stirring sleeve 11 should be stirred under the control of an independent horizontal and vertical moving device and an electronic control device, and the working principle of the stirring has already been demonstrated in the patent CN206956049U. It is disclosed in the technology and will not be repeated here. In use, when agitation is required, only the first magnetic rod sleeve 112 is driven into the reagent container 13 to be stirred and mixed.
  • the first magnetic rod 111 When magnetic beads need to be adsorbed, the first magnetic rod 111 is first driven to be inserted into the first magnetic rod sleeve 112, and then the first stirring sleeve frame 11 is driven to extend into the reagent container 13 for magnetic adsorption. Beads. It is conceivable that, in order to provide working efficiency, the first magnetic rod 111 may be single or multiple, such as 1, 2, 3, 4, 6, 8, 12, 24, and the like. Accordingly, the first magnetic rod sleeve 112 should also have a single or multiple ones to correspond to the first magnetic rod 111.
  • the second stirring sleeve frame 12 has the same structure and working principle as the first stirring sleeve frame 11. Both can be used for magnetic beads for adsorbing nucleic acids.
  • the second stirring sleeve frame 12 also includes at least one second frame mounted on the base 10.
  • the difference between the second stirring sleeve frame 12 and the first stirring sleeve frame 11 is only that the cross sections of the second magnetic rod 121 and the second magnetic rod sleeve 122 are different, and the second magnetic rod 121 and the second magnetic rod
  • the cross-sectional diameter of the sleeve 122 is smaller than the cross-sectional diameters of the first magnetic rod 111 and the first magnetic rod sleeve 112 to accommodate reagent containers 13 with different cross-sections.
  • the second magnetic rod 121 may have a single or multiple, such as 1, 2, 3, 4, 6, 8, 12, 24, and so on. Correspondingly, there should be a plurality of the second magnetic rod sleeves 122 to correspond to the second magnetic rod 121.
  • the first mixing jacket 11 and the second mixing jacket 12 can be selected according to the volume of the sample to be extracted and the size and shape of the container. Replacement.
  • the reagent container 13 is used to hold different types of liquid samples, so it includes at least one adsorption container 131, at least one washing container 132, and at least one elution container 133.
  • the adsorption container 131 is used for holding a lysate or a binding solution with an enlarged capacity, and the adsorption of the magnetic beads with nucleic acids or proteins is performed in the adsorption container 131.
  • the volume of the sample and the lysate or binding solution is sufficiently large in some cases.
  • Some nucleic acids and proteins can also be purified without lysis. In this case, only the binding solution is required, and no lysis solution is required.
  • the washing container 132 is used for washing, purifying, and further removing impurities from the nucleic acid or protein adsorbed from the adsorption container 131. Therefore, as much washing liquid as possible is contained in the washing container 132.
  • the volume of the washing container 132 may be as large as the volume of the adsorption container 131 or smaller than the volume of the adsorption container 131.
  • the elution container 133 is used to elute the purified nucleic acid or protein from the magnetic beads and leave it in the eluate to form a test sample that can be tested downstream or produced.
  • each of the adsorption container 131, the washing container 132, and the elution container 133 may include a plurality, for example, each type includes 1, 2, 3, Or 4, 5 etc.
  • the volume of the elution container 133 should be smaller than the volume of the adsorption container 131.
  • the heights of the adsorption container 131, the washing container 132, and the elution container 133 are preferably the same.
  • the heights of the adsorption container 131, the washing container 132, and the elution container 133 may also be inconsistent.
  • the maximum diameter of the elution container 133 should be smaller than that of the adsorption container 131. The maximum diameter. In actual use, it is impossible for the adsorption container 131, the washing container 132, and the elution container 133 to be filled with the solution, otherwise, the liquid will overflow after the first and second magnetic rod sleeves 112 and 122 are inserted. .
  • the adsorption container 131, the washing container 132, and the elution container 133 respectively include an adsorption mixing section 1311, a washing mixing section 1321, and an elution mixing section 1331. Therefore, the maximum volume of the liquid contained in the adsorption container 131 is 1 to 200 times the maximum volume of the liquid contained in the washing container 132, and the maximum volume of the liquid contained in the adsorption container 131 is The volume is 2 to 1000 times the maximum volume of the liquid contained in the elution container 133, so as to maximize the concentration and enrichment of nucleic acids or proteins. In this embodiment, the number of the reagent containers 13 matches the number of the first and second stirring jackets 11 and 12.
  • the maximum diameter of the cross section of the first magnetic rod sleeve 112 is larger than the maximum diameter of the cross section of the elution mixing portion 1331 of the elution container 133.
  • the maximum diameter of the cross-section of the first magnetic rod sleeve 112 may be equal to or smaller than the maximum diameter of the washing and mixing section 1321 and the elution and mixing section 1331 of the washing container 132 and the elution container 133.
  • the control device 14 is used to control the operation of the mechanical devices and electrical control devices that translate up, down, left and right, and can implement the operating rules and parameters of these mechanical devices and electrical control devices through computer programs, as disclosed in the patent CN206956049U , which should be the prior art, and will not be repeated here.
  • the control device 14 is configured to control the first magnetic rod cover 112 to be stirred only in the adsorption container 131 and the washing container 132, and control the second magnetic rod cover 122 to be washed in the washing container 132 and the washing container 132.
  • the deaerator 133 is stirred or adsorbed.
  • the second magnetic rod sleeve 122 can also be controlled to adsorb the magnetic beads contained in the adsorption container 131 into the adsorption container 131.
  • the concentrated and enriched magnetic bead purifier further includes at least one reagent container holder 15 placed on the base 10.
  • the reagent container 13 is disposed on the reagent holder 15 to fix the relative position of the reagent container 13. It is conceivable that the reagent container fixing frame 15 should be a technique known to those skilled in the art, and will not be described again here.
  • the concentrated and enriched magnetic bead purifier provided by the present invention has two first and second stirring jackets 11 and 12 of different specifications and a test tube container 13 having different volumes.
  • the largest-volume adsorption test tube 131 holds a magnified volume of liquid sample and uses the first stirring sleeve holder 11 for stirring or adsorption, and because the cross-sectional diameter of the second magnetic rod sleeve 122 is smaller than the first magnetic rod sleeve 112
  • the cross-section diameter can be further stirred in a smaller container.
  • the maximum amount that can be adsorbed from the adsorption container 131 The nucleic acid or protein is eluted from the magnetic beads in a smaller volume of eluent, so that the concentration of the extracted nucleic acid or protein can be maximized, and the purpose of concentration and enrichment can be achieved to meet the needs of detection or production preparation.
  • the concentrated and enriched magnetic bead purifier can use the first magnetic rod holder or the second magnetic rod holder separately to complete the purification process from adsorption, washing and elution.
  • the concentrated and enriched magnetic bead purifier provided by the present invention can also be installed with multiple sets of extraction devices, including multiple adsorption containers, washing containers, elution containers, and agitation jackets.
  • the concentrated and enriched magnetic bead purifier provided by the present invention can also cooperate with a liquid workstation to complete the process of automatic aliquoting from a sample or solution and magnetic rod extraction and purification.

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Abstract

一种浓缩富集的磁珠纯化仪，其包括一个机座（10），至少一个第一搅拌套架（11），至少一个第二搅拌套架（12），放置在所述机座上的多个试剂容器（13），以及一个控制装置（14）。所述第一搅拌套架（11）包括至少一个第一磁棒（111）及一个第一磁棒套（112）。所述第二搅拌套架（12）包括至少一个第二磁棒（121）及一个第二磁棒套（122）。所述第二磁棒套的横截面直径小于所述第一磁棒套的横截面直径。所述试剂容器（13）包括至少一个吸附容器（131），至少一个洗涤容器（132），以及至少一个洗脱容器（133）。所述洗脱容器的容积小于所述吸附容器的容积。所述控制装置（14）用于控制所述第一磁棒套（112）仅在所述吸附容器（131）及洗涤容器（132）中搅拌和吸附，并控制所述第二磁棒套（122）在所述洗涤容器（132）和洗脱容器（133）中搅拌或吸附。

Description

一种浓缩富集的磁珠纯化仪 技术领域
本发明属于生物仪器设备技术领域，特别是一种浓缩富集的磁珠纯化仪。
背景技术
核酸作为遗传信息的携带者，是基因表达的物质基础，除了在生物体正常的生长、发育、和繁殖等生命活动中具有十分重要的作用外，它与生命的异常情况，如肿瘤发生、放射损伤、遗传疾病等也有密切关系。因此核酸分离纯化及检测是分子生物学、医学研究中的非常重要的环节。在临床诊断与治疗，或法医学鉴定，或基因筛查与重组等工作中，人们需要将核酸从样本(血液、唾液或其他组织)中提取出来，提取核酸的过程也称为核酸纯化。核酸纯化的效果好坏直接影响研究和诊断的进程和结果，因此核酸纯化技术是生物科技中一项重要技术。
目前常见的一种核酸纯化方法是磁棒法。磁棒法是利用磁棒吸附磁珠，磁珠吸附核酸，将核酸从样本中分离出来。生物样本经裂解，结合到磁珠上，通过洗涤纯化，杂质被去除，从而达到提取核酸目的。磁棒法核酸提取一般分为裂解、结合、洗涤和洗脱等步骤，各步骤之间衔接则通过无磁场下磁珠与溶液充分混合，使核酸与磁珠结合并去除非特异性吸附的杂质，在磁场作用下磁珠富集及转移来实现。磁棒法的工作原理如图1所示，将磁棒20、搅拌套21、深孔板22从上到下依次布置。其中，深孔板22上有一组深孔，该组深孔包含裂解液孔221、磁珠孔222、洗涤液孔223(可设置多个洗涤液孔)、洗脱液孔224，其分别用于存放相应的试剂。核酸纯化流程的具体步骤是：将样本滴入裂解液中裂解出核酸---收集磁珠到裂解液孔--磁珠与核酸结合--收集磁珠至洗涤孔(可多次洗涤)--收集磁珠到洗脱孔--洗脱后回收磁珠，最后核酸留在洗脱液中。为了便于上述流程实现自动化操作，需要核酸纯化仪实现如图1所示的基本动作，即：(1)磁棒20的上下移动a，(2)搅拌套21的上下移动b及搅拌动作c，(3)磁棒20插入搅拌套21两者合体后的上下移动e，(4)磁棒20插入搅拌套21两者合体后的平移动作d。
目前市售磁珠纯化仪一般使用相同容积的容器对核酸进行纯化，适用于从较小体积的液体样本(50-400微升)中提取核酸；或使用较大容器(4-10ml) 及大直径磁棒套架进行提取，因大直径磁棒套设备限制，通常最小洗脱体积较大(大约100-300微升)。然而，在一些情况下，需要从较大体积的液体样本中提取微量核酸，如液体活检、病毒核酸超敏检测。在这类情况下，磁珠需要在较大体积的液体样本吸附核酸，经洗涤去除杂质，然后用少量洗脱液将核酸洗脱下来用于后续检测。例如对于液体活检等项目，通常需要将从2-5ml血浆样本中提取核酸，即从约10ml的裂解吸附液体中将核酸结合至磁珠，最后将结合的核酸在20～50ul洗脱液中洗脱下来。目前核酸纯化仪无法高效地完成该任务。
中国实用新型专利CN206956049U公开了一种核酸纯化仪。如图2所示，该核酸纯化仪包括有基座13，设置在所述基座13上并用于实现磁棒20与搅拌套21合体后的上下移动和平移动作的托架升降装置8和托架平移装置7，以及设置在所述基座13上并用于实现搅拌套21单独上下移动及进行搅拌的搅拌套驱动机构6但是该核酸纯化仪对某一种核酸的提取只使用一套磁棒20及搅拌套21的上下往复运动来实现混匀和磁珠转移。平移装置解决了磁珠从大体积到小体积液体的转换，但这种混合搅拌强度弱，某些条件下达不到核酸物质充分裂解释放和与磁珠结合的效果。
除了用于核酸提取，磁棒法也可用于蛋白的提取纯化，利用磁棒吸附磁珠，磁珠吸附蛋白，将蛋白从样本中分离出来。用于蛋白纯化的生物样本可经过裂解步骤也可不经过裂解步骤。有些蛋白纯化样本的起始体积也很大，从微升到几十升都有，也需要仪器从大体积样本中用磁珠吸附蛋白，再用小体积洗脱液洗脱，达到纯化富集蛋白的目的。与上述核酸提取原因相似，目前的磁珠纯化仪无法高效地完成大体积蛋白纯化的任务。
发明内容
有鉴于此，本发明提供了一种有利于从大体积样本中提取高纯度核酸/蛋白的浓缩富集的磁珠纯化仪，以满足用户需求。
所述浓缩富集的磁珠纯化仪包括一个机座，至少一个活动设置在所述机座上的第一搅拌套架，至少一个活动设置在所述机座上的第二搅拌套架，放置在所述机座上的多个试剂容器，以及一个用于控制所述第一搅拌套架和第二搅拌套架的控制装置。所述第一搅拌套架包括至少一个架设在所述机座上的第一磁棒，以及至少一个用于套设所述第一磁棒的第一磁棒套。所述第二搅拌套架包 括至少一个架设在所述机座上的第二磁棒，以及至少一个用于套设所述第二磁棒的第二磁棒套。所述第二磁棒套的横截面直径小于所述第一磁棒套的横截面直径，所述试剂容器包括至少一个吸附容器，至少一个洗涤容器，以及至少一个洗脱容器。所述洗脱容器的容积小于所述吸附容器的容积。所述控制装置用于控制所述第一磁棒套仅在所述吸附容器及洗涤容器中搅拌或吸附，并控制所述第二磁棒套在所述洗涤容器和洗脱容器中搅拌或吸附。
进一步地，所述第一、第二搅拌套架用于混合、富集及转移磁珠。
进一步地，所述控制装置控制所述第二磁棒套到所述洗涤容器中搅拌、吸附容置在该洗涤容器中的磁珠，并将磁珠转移到相同或较小体积容器中。
进一步地，所述第一磁棒和第二磁棒为相同尺寸的磁棒并由同一磁棒配合第一磁棒套及第二磁棒套完成磁珠的富集和转移。
进一步地，所述洗脱容器的容积小于所述吸附容器的容积。
进一步地，每一个所述洗脱容器包括一个洗脱混合部，所述第一磁棒套的横截面的最大直径大于所述洗脱容器的最大直径和部分洗涤容器的洗涤混合部的横截面的最大直径。
进一步地，每一个所述洗涤容器包括一个洗涤混合部，所述第一磁棒套的横截面的最大直径等于或小于所述部分或全部洗涤容器的洗涤混合部的横截面的最大直径。
进一步地，所述浓缩富集的磁珠纯化仪还包括至少一个放置在所述机座上的试剂容器固定架，所述试剂容器设置在所述试剂固定架上以固定该试剂容器的相对位置。
进一步地，所述吸附容器中所盛的液体的最大容积是所述洗涤容器中所盛的液体的最大的容积的1倍至200倍，所述吸附容器中所盛的液体的最大的容积是所述洗脱容器中所盛的液体的最大的容积的2倍至1000倍。
进一步地，所述浓缩富集的磁珠纯化仪单独使用第一磁棒套架或第二磁棒套架完成从吸附、洗涤及洗脱的纯化过程。
与现有技术相比，本发明提供的浓缩富集的磁珠纯化仪具有两个不同规格大小的第一、第二搅拌套架，以及具有不同容积的试管容器，通过在具有最大容积的吸附试管里盛放大体积的液体样本并使用第一搅拌套架以进行搅拌、充 分混合与吸附；且由于所述第二磁棒套的横截面直径小于所述第一磁棒套的横截面直径，可以将吸附核酸或蛋白的磁珠吸附并转移至较小体积的洗涤容器和洗脱容器中，并实现较小体积容器中的充分混合及磁珠转移，从而可以将磁珠从较大体积溶液中转移到较小体积的洗涤容器及洗脱容器，特别是使用小体积的洗脱容器，可以从大体积吸附容器中用磁珠吸附到最大量的核酸或蛋白并在小体积的洗脱液中洗脱下来，从而可以最大程度地提高所提取的核酸或蛋白浓度，达到浓缩富集的目的，以满足检测和生产制备的需要。
附图说明
图1为现有技术中的磁棒法的工作原理图。
图2为现有技术中所提供的一种核酸纯化仪的结构示意图。
图3为本发明提供的浓缩富集的磁珠纯化仪的立体结构示意图。
图4为图3的浓缩富集的磁珠纯化仪的截面结构示意图。
图5为图3的浓缩富集的磁珠纯化仪的结构示意图
具体实施方式
以下对本发明的具体实施例进行进一步详细说明。应当理解的是，此处对本发明实施例的说明并不用于限定本发明的保护范围。
如图3至图5所示，其为本发明提供的浓缩富集的磁珠纯化仪的结构示意图。首先需要说明的是，所述浓缩富集的磁珠纯化仪用于通过磁珠来完成核酸或蛋白的提取与浓缩富集，其应当为现有技术，无需过多的说明。所述浓缩富集的磁珠纯化仪包括一个机座10，至少一个活动设置在所述机座10上的第一搅拌套架11，至少一个活动设置在所述机座10上的第二搅拌套架12，放置在所述机座10上的多个试剂容器13，以及一个用于控制所述第一搅拌套架11和第二搅拌套架12的控制装置14。可以想到的是，作为一个磁珠纯化仪，其一定还包括有其他的功用组件，如专利CN206956049U公开了一种核酸纯化仪所公开的，该磁珠纯化仪也包括控制本发明所述的搅拌套架上下移动、磁珠转移装置与电控装置，电气结构以及其他的一些组装结构或安装结构，其应当为本领域技术人员所习知的技术，在此不再对其进行一一的详细说明。
所述机座10用于设置或放置各种功能模块，如上述的机械装置与电控装置，支撑装置，以及所述的试剂容器等等。所述机座10可以为各种结构与形 状以适应其他各种装置的安装与放置。
所述第一搅拌套架11活动设置在所述机座10上，并包括至少一个架设在所述机座10上的第一磁棒111，以及至少一个用于套设所述第一磁棒111的第一磁棒套112。本领域技术人员应当习知的是，所述第一搅拌套架11应当在一个独立的水平和垂直移动装置与电控装置的控制下进行搅拌，其搅拌的工作原理已经在如专利CN206956049U的现有技术中公开，在此不再赘述。在使用时，当需要搅拌时，仅驱动所述第一磁棒套112伸入到所述试剂容器13中进行搅拌混合。而当需要吸附磁珠时，首先驱动所述第一磁棒111插入所述第一磁棒套112中，然后再驱动该第一搅拌套架11伸入到所述试剂容器13中进行吸附磁珠。可以想到的是，为了提供工作效率，所述第一磁棒111可以是单个也可具有多个，如1、2、3、4、6、8、12、24个等。相应地所述第一磁棒套112也应当具有单个或多个，以与所述第一磁棒111相对应。
所述第二搅拌套架12与所述第一搅拌套架11具有相同的结构与工作原理，都可用于吸附核酸的磁珠，其也包括至少一个架设在所述机座10上的第二磁棒121，以及至少一个用于套设所述第二磁棒121的第二磁棒套122。所述第二搅拌套架12与第一搅拌套架11的区别仅在于所述第二磁棒121与第二磁棒套122的横截面不同，所述第二磁棒121及第二磁棒套122的横截面直径小于所述第一磁棒111及第一磁棒套112的横截面直径，以适应不同横截面的试剂容器13。所述第二磁棒121可以具有单个或多个，如1、2、3、4、6、8、12、24个等。相应地所述第二磁棒套122也应当具有多个，以与所述第二磁棒121相对应。
更优的，所述第一搅拌套架11与第二搅拌套架12可根据提取样本的体积及容器大小及形状选择不同大小和形状的第一搅拌套架11与第二搅拌套架12进行置换。
所述试剂容器13用于盛放不同类型的液体样本，因此其包括至少一个吸附容器131，至少一个洗涤容器132，以及至少一个洗脱容器133。所述吸附容器131用于盛放大容量的裂解液或结合液，在该吸附容器131中进行磁珠与核酸或蛋白的结合。为了获得尽可能多的核酸或蛋白，因此某些情况下需要样本及裂解液或结合液的体积足够大。有些核酸和蛋白纯化也可以不经过裂解，在 这种情况下，只需要结合液，不需要裂解液。所述洗涤容器132用于将从吸附容器131中吸附过来的核酸或蛋白进行清洗，进行纯化，并进一步去除杂质，因此该洗涤容器132中盛放的洗涤液也尽可能多，因此，所述洗涤容器132的容积可以与该吸附容器131的容积一样大，也可以小于该吸附容器131的容积。所述洗脱容器133用于将纯化后的核酸或蛋白从磁珠上洗脱下来并留在洗脱液中形成可进行下游试验的或生产制备检测样本。当然可以想到的是，为了达到更高的纯度，所述吸附容器131、洗涤容器132、以及洗脱容器133的每一种都可以包括多个，如每一种都包括1、2、3、或4、5个等。为了提高所述洗脱容器133洗脱的核酸或蛋白的浓度，所述洗脱容器133的容积应当小于所述吸附容器131的容积，具体地，为了方便所述第一、第二搅拌套架11、12可以顺畅地平移，所述吸附容器131、洗涤容器132、以及洗脱容器133的高度优选是一致的。可以理解的是，通过调节磁棒套架的高度，吸附容器131、洗涤容器132、以及洗脱容器133的高度也可不一致，所述洗脱容器133的最大直径应当小于所述吸附容器131的最大直径。在实际使用中，所述吸附容器131、洗涤容器132、以及洗脱容器133不可能将溶液盛满的，否则在将所述第一、第二磁棒套112、122插入后会有液体溢出。因此，所述吸附容器131、洗涤容器132以及洗脱容器133分别包括吸附混合部1311，洗涤混合部1321，以及洗脱混合部1331。因此所述吸附容器131中所盛的液体的最大容积是所述洗涤容器132中所盛的液体的最大的容积的1倍至200倍，且所述吸附容器131中所盛的液体的最大的容积是所述洗脱容器133中所盛的液体的最大的容积的2倍至1000倍，以最大程度地完成核酸或蛋白的浓缩富集。在本实施例中，所述试剂容器13的个数与所述第一、第二搅拌套架11、12的个数相匹配，。为了提高混合效果及洗脱效果，所述第一磁棒套112的横截面的最大直径大于所述洗脱容器133的洗脱混合部1331的横截面的最大直径。当然可以想到的是，在需要的情况下，可以使用同样规格的吸附容器、洗涤容器、以及洗脱容器来盛放溶液。也因此，所述第一磁棒套112的横截面的最大直径可以等于或小于所述洗涤容器132及洗脱容器133的洗涤混合部1321及洗脱混合部1331的最大直径。
所述控制装置14用于控制所述上下、左右平移的机械装置与电控装置的 运行，其可以通过计算机程序来实现这些机械装置与电控装置的运行规则与参数，如专利CN206956049U所公开的，其应当为现有技术，在此不再赘述。所述控制装置14用于控制所述第一磁棒套112仅在所述吸附容器131和所述洗涤容器132中搅拌，并控制所述第二磁棒套122在所述洗涤容器132和洗脱容器133中搅拌或吸附。当然，如果需要的话，还可以控制所述第二磁棒套122到所述吸附容器131中吸附容置在该吸附容器131中的磁珠。
所述浓缩富集的磁珠纯化仪还包括至少一个放置在所述机座10上的试剂容器固定架15。所述试剂容器13设置在所述试剂固定架15上以固定该试剂容器13的相对位置。可以想到的是，该试剂容器固定架15应当为本领域技术人员所习知的技术，在此不再赘述。
与现有技术相比，本发明提供的浓缩富集的磁珠纯化仪具有两个不同规格大小的第一、第二搅拌套架11、12，以及具有不同容积的试管容器13，通过在具有最大容积的吸附试管131里盛放大体积的液体样本并使用第一搅拌套架11以进行搅拌或吸附，且由于所述第二磁棒套122的横截面直径小于所述第一磁棒套112的横截面直径，可以进一步在较小容器中将磁珠搅拌均匀使用小体积的洗涤容器132，特别是使用相同体积或小体积的洗脱容器133，可以从吸附容器131中吸附到的最大量的核酸或蛋白从磁珠上在较小体积洗脱液中洗脱下来，从而可以最大程度地提高所提取的核酸或蛋白浓度，达到浓缩富集的目的，以满足检测或生产制备的需要。
此外，所述浓缩富集的磁珠纯化仪可单独使用第一磁棒套架或第二磁棒套架完成从吸附、洗涤及洗脱的纯化过程。
为增加提取的样本数，本发明提供的浓缩富集的磁珠纯化仪还可安装多套提取装置，包括多个吸附容器，洗涤容器，洗脱容器，以及搅拌套架。
本发明提供的浓缩富集的磁珠纯化仪也可与液体工作站配合，完成从样本或溶液自动分装及磁棒式提取纯化的过程。
以上仅为本发明的较佳实施例，并不用于局限本发明的保护范围，任何在本发明精神内的修改、等同替换或改进等，都涵盖在本发明的权利要求范围内。

Claims (10)

  1. 一种浓缩富集的磁珠纯化仪，其特征在于：所述浓缩富集的磁珠纯化仪包括一个机座，至少一个活动设置在所述机座上的第一搅拌套架，至少一个活动设置在所述机座上的第二搅拌套架，放置在所述机座上的多个试剂容器，以及一个用于控制所述第一搅拌套架和第二搅拌套架的控制装置，所述第一搅拌套架包括至少一个架设在所述机座上的第一磁棒，以及至少一个用于套设所述第一磁棒的第一磁棒套，所述第二搅拌套架包括至少一个架设在所述机座上的第二磁棒，以及至少一个用于套设所述第二磁棒的第二磁棒套，所述第二磁棒套的横截面直径小于所述第一磁棒套的横截面直径，所述试剂容器包括至少一个吸附容器，至少一个洗涤容器，以及至少一个洗脱容器，所述洗脱容器的容积小于所述吸附容器的容积，所述控制装置用于控制所述第一磁棒套仅在所述吸附容器及洗涤容器中搅拌或吸附，并控制所述第二磁棒套在所述洗涤容器和洗脱容器中搅拌或吸附。
  2. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：所述第一、第二搅拌套架用于混合、富集及转移磁珠。
  3. 如权利要求2所述的浓缩富集的磁珠纯化仪，其特征在于：所述控制装置控制所述第二磁棒套到所述洗涤容器中搅拌、吸附容置在该洗涤容器中的磁珠，并将磁珠转移到相同或较小体积容器中。
  4. 如权利要求2所述的浓缩富集的磁珠纯化仪，其特征在于：所述第一磁棒和第二磁棒为相同尺寸的磁棒并由同一磁棒配合第一磁棒套及第二磁棒套完成磁珠的富集和转移。
  5. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：所述洗脱容器的容积小于所述吸附容器的容积。
  6. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：每一个所述洗脱容器包括一个洗脱混合部，所述第一磁棒套的横截面的最大直径大于所述洗脱容器的最大直径和部分洗涤容器的洗涤混合部的横截面的最大直径。
  7. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：每一个所述洗涤容器包括一个洗涤混合部，所述第一磁棒套的横截面的最大直径等于 或小于所述部分或全部洗涤容器的洗涤混合部的横截面的最大直径。
  8. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：所述浓缩富集的磁珠纯化仪还包括至少一个放置在所述机座上的试剂容器固定架，所述试剂容器设置在所述试剂固定架上以固定该试剂容器的相对位置。
  9. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：所述吸附容器中所盛的液体的最大容积是所述洗涤容器中所盛的液体的最大的容积的1倍至200倍，所述吸附容器中所盛的液体的最大的容积是所述洗脱容器中所盛的液体的最大的容积的2倍至1000倍。
  10. 如权利要求1所述的浓缩富集的磁珠纯化仪，其特征在于：所述浓缩富集的磁珠纯化仪单独使用第一磁棒套架或第二磁棒套架完成从吸附、洗涤及洗脱的纯化过程。
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