WO2020083373A1 - 一种大规模磁力纯化系统 - Google Patents

一种大规模磁力纯化系统 Download PDF

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Publication number
WO2020083373A1
WO2020083373A1 PCT/CN2019/113261 CN2019113261W WO2020083373A1 WO 2020083373 A1 WO2020083373 A1 WO 2020083373A1 CN 2019113261 W CN2019113261 W CN 2019113261W WO 2020083373 A1 WO2020083373 A1 WO 2020083373A1
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Prior art keywords
magnet
liquid storage
storage device
purification system
liquid
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PCT/CN2019/113261
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English (en)
French (fr)
Inventor
陈国栋
冯在东
贺瑞娜
钱红
白涛
Original Assignee
南京金斯瑞生物科技有限公司
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Priority to US17/288,491 priority Critical patent/US20210388307A1/en
Publication of WO2020083373A1 publication Critical patent/WO2020083373A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/10—Separation or concentration of fermentation products
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/11—Stirrers characterised by the configuration of the stirrers
    • B01F27/112—Stirrers characterised by the configuration of the stirrers with arms, paddles, vanes or blades
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/11—Stirrers characterised by the configuration of the stirrers
    • B01F27/114—Helically shaped stirrers, i.e. stirrers comprising a helically shaped band or helically shaped band sections
    • B01F27/1144—Helically shaped stirrers, i.e. stirrers comprising a helically shaped band or helically shaped band sections with a plurality of blades following a helical path on a shaft or a blade support
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/22—Control or regulation
    • B01F35/221—Control or regulation of operational parameters, e.g. level of material in the mixer, temperature or pressure
    • B01F35/2214—Speed during the operation
    • B01F35/22142—Speed of the mixing device during the operation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/005—Pretreatment specially adapted for magnetic separation
    • B03C1/01—Pretreatment specially adapted for magnetic separation by addition of magnetic adjuvants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/28—Magnetic plugs and dipsticks
    • B03C1/286—Magnetic plugs and dipsticks disposed at the inner circumference of a recipient, e.g. magnetic drain bolt
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/28—Magnetic plugs and dipsticks
    • B03C1/288—Magnetic plugs and dipsticks disposed at the outer circumference of a recipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/30—Combinations with other devices, not otherwise provided for
    • 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
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/12—Purification
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C2201/00—Details of magnetic or electrostatic separation
    • B03C2201/18—Magnetic separation whereby the particles are suspended in a liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C2201/00—Details of magnetic or electrostatic separation
    • B03C2201/26—Details of magnetic or electrostatic separation for use in medical applications

Definitions

  • the invention relates to a large-scale magnetic purification system, which is mainly used in the field of biological purification, for example, for large-scale extraction of proteins and nucleic acids.
  • the magnetic bead purification method generally uses a purification system to separate the magnetic beads by a magnetic field to achieve the purpose of separating and purifying substances such as cells, proteins, or nucleic acids. Compared with the commonly used precipitation method, centrifugal method, and column membrane method, the magnetic bead purification method has the characteristics of high extraction efficiency, fast separation speed, and simple equipment required.
  • the magnetic bead purification method based on magnetic adsorption relies on the combination of magnetic principle and incubation to quickly and efficiently enrich the target protein in the sample, effectively avoiding the pretreatment and loading of the sample by the resin.
  • the disadvantages such as the limitation of the system have got rid of the limitation of packing and flow rate.
  • the purification method using magnetic separation is easier to automate and can meet the needs of high-throughput purification for fast, automated, multi-channel simultaneous processing.
  • the magnetic bead purification devices currently on the market generally handle relatively small fluxes and require a lot of manual operations to assist the purification process.
  • the current operations are all open and open operations, it is difficult to prevent external environmental pollution, nor can it avoid damage to the environment caused by the volatilization of reagents during the purification process.
  • the magnetic rack of the prior art can meet the needs of some customers, there are still many deficiencies, such as: (1) the flux is small and cannot meet the needs of large-scale purification; (2) it needs to be transferred to a centrifuge tube or other container , The process is complicated, and there is a risk of damaging the sample; (3) additional equipment is required to achieve automation, increase additional cost, and occupy additional space; (4) the shape is fixed and cannot be flexibly adapted to the shape of the container.
  • the large-scale purification devices used in the market all adopt the method of resin purification, which requires deep filtration, consumes a large amount of disposable consumables, and requires a long time investment of many people.
  • An object of the present invention is to provide a large-scale magnetic purification system that does not require centrifugation and deep filtration, can directly purify the fermentation broth, and saves a lot of consumables and equipment for filtration.
  • the magnetic beads are in direct contact with the culture solution, no column packing is required, and there is no defect caused by directional flow purification: the probability of all antibodies and magnetic beads in large-scale magnetic bead purification is the same,
  • the resin purification is contacted in order from the front to the back.
  • the contact probability is high in the pre-stage and low in the post-stage.
  • the antibody collected in the pre-stage is saturated first and then saturated in the post-stage, so that the amount of antibody accumulation in the pre-stage will be higher than that in the post-stage. This caused inconsistency in antibodies.
  • the loss of all magnetic beads is equal, so the dosage is easier to control, and the resin is consumed before the first stage and after the second stage, so there is inconsistency.
  • the large-scale magnetic purification system of the present invention can easily realize large-throughput sample processing and can reduce the input of consumables and shorten the purification cycle.
  • a large-scale magnetic purification system which includes: a liquid storage device that can be connected to a liquid source and a waste liquid barrel through a liquid circuit system; and a stirring system installed above the liquid storage device , The stirring blade of the stirring system is inserted into the liquid storage device for stirring; a magnet installed around the liquid storage device; a magnet actuator for manipulating the magnet away from or close to the liquid storage device; and a control system, the control system and The fluid system, magnet actuator and stirring system are connected, and control the fluid system, magnet actuator and stirring system.
  • a vertical magnet capable of moving into the inside of the liquid storage device is also provided, which enters the liquid storage device by moving in a vertical direction.
  • the magnet is a horizontal magnet, which can move relative to the liquid storage device in the horizontal direction.
  • the magnet is a vertical magnet, which can move relative to the liquid storage device in a vertical direction.
  • the magnet includes a horizontal magnet and a vertical magnet, the horizontal magnet can move relative to the liquid storage device in a horizontal direction, and the vertical magnet can move relative to the liquid storage device in a vertical direction.
  • the liquid storage device is a liquid storage tank.
  • a disposable bag is provided in the liquid storage tank.
  • the stirring blade has a propeller blade, and includes two sets of blades with opposite directions installed on one blade shaft.
  • the magnet is composed of a strong magnet to quickly adsorb magnetic particles.
  • the magnet includes a horizontal magnet and a vertical magnet
  • the magnet actuator includes a horizontal magnet actuator and a vertical magnet actuator.
  • the vertical magnet can be manipulated by the vertical magnet actuator to enter or exit the liquid storage device.
  • the stirring system is automatically controlled by a speed-adjustable motor, and the rotation of the blades is controlled at different speeds.
  • the pipe of the liquid circuit system is made of a material that does not stick to magnetic beads to reduce the loss of magnetic beads.
  • a method of purifying a biological sample comprising injecting a biological sample containing a target component and magnetic beads capable of binding the target component into a liquid storage device according to the large-scale magnetic purification system described above
  • the large-scale magnetic purification system is used in the purification process.
  • the range of the biological sample in which the liquid storage device is injected in one time for purification is 100mL-10000L, preferably 1L-1000L, and more preferably 10L-500L.
  • FIG. 1 shows a horizontal moving magnet and a horizontal magnet actuator of a magnetic purification system according to an exemplary embodiment of the present invention.
  • Fig. 2 shows a tank in a magnetic purification system according to an exemplary embodiment of the present invention.
  • FIG. 3 shows a vertical moving magnet, a vertical magnet actuator, and a stirring system in a magnetic purification system according to an exemplary embodiment of the present invention.
  • FIG. 4 shows some solenoid valves, pumps, and piping in a magnetic purification system according to an exemplary embodiment of the present invention.
  • FIG. 5 shows the overall structure of a magnetic purification system according to an exemplary embodiment of the present invention.
  • a large-scale magnetic purification system which mainly includes a liquid storage device, a stirring system, a magnet, and a magnet actuator.
  • the liquid storage device, the stirring system, the magnet and the magnet actuator are all mounted on the frame structure.
  • the large-scale magnetic purification system may also include a pump and valve system to achieve the supply and discharge of liquid.
  • the liquid storage device is used to provide a place where the magnetic beads extract protein or other substances to be extracted from the solution, such as a liquid storage tank.
  • the volume of the liquid storage tank can be from several liters to tens of thousands of liters; preferably, its volume is greater than or equal to 10 liters.
  • Disposable bags can be placed in the storage tank.
  • the disposable bag for liquid storage can be made of non-stick magnetic beads, with a spray device that can spray the residual solution and magnetic beads stuck to the wall.
  • the disposable bag may have a shape that completely fits the inner wall of the liquid storage tank.
  • FIG. 2 shows an exemplary liquid storage device, which may be a liquid storage tank with a capacity of about 10 liters. In other embodiments, the capacity may be larger, for example, 10 liters to 1000 liters.
  • the shape of the liquid storage device may be round or square. For example, a square edge is used around it, but the inner wall of the container adopts an arc transition.
  • the container can be made of non-magnetized stainless steel, and the bottom of the container is inclined.
  • the disposable bag for liquid storage is made of non-stick magnetic beads, and the shape is customized according to the shape of the liquid storage device, which can ensure that the magnetic beads are closest to the magnet when they are adsorbed.
  • a spray device inside which can spray the residual solution and magnetic beads adhered to the wall, which can improve the recovery rate of the magnetic beads, at the same time improve the cleanliness of the system, and reduce the risk of infection of the purified sample.
  • a square edge can be used around the shape of the container carrying the bag to ensure that the magnet can completely fit the container when the magnetic beads are adsorbed. In this way the most effective distance of the magnet can be used.
  • a circular arc transition is used between the four walls of the container, and the shape of the bag matches the shape of the container, which makes it easy to put the disposable bag into the container, and does not form wrinkles, ensuring the recovery rate of the magnetic beads.
  • the container is made of non-magnetized stainless steel, which can ensure that the magnetic beads can be freely mixed in the solution when the magnetic field is evacuated.
  • the inclined angle at the bottom of the container can reduce the final residual volume of the solution, and at the same time can increase the height of the liquid level in a small volume, so that the magnetic force of the magnet can be used to the maximum when eluting in a small volume.
  • FIG. 3 shows a schematic diagram of the installation positions of the stirring paddle installation module and the stirring drive motor.
  • the figure also shows vertical magnets (such as magnetic bars), guide rails, vertical drive motors, and so on.
  • the stirring system uses a motor that can adjust the speed to automatically control the speed of rotation, and different speeds can be used to control the rotation of the blades, which are used in different situations. For example, when mixing with a higher speed, it can be mixed quickly, and when the magnetic beads are adsorbed, a lower speed can be used, which can not only achieve the effect of mixing, but also ensure that the magnetic beads are not disturbed by the rotation of the blades. At the same time, the blades can rotate forward and backward, which can improve the mixing effect to a greater extent.
  • the built-in mixing system of the disposable bag can use a stainless steel mixing paddle, which is located in the center of the top surface of the bag.
  • the stirring system adopts a motor with adjustable speed to automatically control the speed of rotation, and the blades can rotate in forward and reverse directions.
  • the bottom discharge tube is fixed to the bottom of the bag.
  • the inlet of the liquid enters the bag in a split manner.
  • Disposable bags can be made of transparent materials.
  • the size of the blade can be maximized.
  • the shape of the blade is a propeller blade.
  • two sets of blades in opposite directions are installed on one blade shaft, which can increase the disturbance of the solution.
  • the low rotation speed improves the liquid mixing effect as high as possible.
  • the reduced blade speed can reduce the shear force generated by the blade edge on the effective molecules in the solution, and maximize the preservation of the activity of the final collection.
  • the bottom liquid discharge tube is fixed to the bottom of the bag, and the fixing method can ensure that the magnetic beads are not discharged during the liquid discharge, and the waste liquid can be discharged to the maximum extent.
  • the inlet of the liquid enters the bag by way of split flow, there are many impurities, the solution with larger particle size enters from the wide caliber, and the clean solution such as reagents enters from the spray pipe, which can rinse the pipe without affecting Cause blockage.
  • the disposable bag is made of transparent material, which can facilitate the user to observe the reaction in the solution during the process.
  • the stirring system may be located above the liquid storage device.
  • the agitating paddle in the agitating system can go deep into the liquid storage device and be used to stir the mixed liquid evenly.
  • the liquid circuit system connects the liquid storage device and the liquid source, such as a reagent bottle or a reagent tube.
  • a pump and a valve for suctioning and discharging liquid may be provided in the pipeline of the liquid circuit system for supplying the solution to the liquid storage device or discharging it from the liquid storage device.
  • FIG. 1 shows an exemplary horizontal moving magnet and horizontal magnet actuator.
  • a magnet actuator such as a magnet moving device, is provided outside the liquid storage device to provide the magnets to approach and move away, so as to apply and withdraw magnetic fields.
  • the drive screw is driven to drive the magnet holder to move back and forth along the direction of the linear guide rail, thereby controlling the application and evacuation of the magnetic field.
  • Magnets include horizontal magnets and vertical magnets. Magnets can be composed of strong magnets to quickly attract magnetic particles or beads.
  • the magnet may be composed of N52 magnets with relatively strong magnetic force currently on the market, and the magnetic field strength may reach more than 5000Gs.
  • the layout of the magnet can be the same plane and the same polarity, which can ensure that the direction of the magnetic field is perpendicular to the fitting surface of the container.
  • the magnet can be fixed on the movable magnet actuator to control the position of the magnet relative to the liquid storage tank.
  • the horizontal magnets may be arranged to distribute in a shape that completely fits the outer wall of the liquid storage tank. The magnet can cover the entire accessible area of the tank, and reserve appropriate gaps.
  • the magnet is a horizontal magnet that can move relative to the liquid storage device in the horizontal direction.
  • the magnet is a vertical magnet, which can move relative to the liquid storage device in the vertical direction.
  • the magnet includes a horizontal magnet and a vertical magnet, the horizontal magnet can move relative to the liquid storage device in the horizontal direction, and the vertical magnet can move relative to the liquid storage device in the vertical direction.
  • the approach and separation of the magnet relative to the liquid storage tank can be controlled by horizontal movement, or vertical movement, or the simultaneous action of vertical and horizontal.
  • a vertical magnet such as a magnetic rod
  • a horizontal magnet arranged as shown in FIG. 1 can be moved horizontally to attract near the magnet Magnetic beads nearby.
  • the vertical magnet entering the liquid storage device can attract magnetic beads through the aforementioned disposable bag.
  • the magnet actuator uses a ball screw, which works in a symmetrical manner by pulling to both sides.
  • the ball screw has the advantages of less noise, smaller vibration amplitude and longer life than other transmission methods. It can be used in the system to improve the stability of the magnetic ball after being attracted by the magnet, and can reduce the loss rate of the liquid discharge after the magnetic ball is absorbed.
  • Figure 4 shows some solenoid valves, pumps, and piping in the hydraulic system.
  • the pipeline of the liquid circuit system is made of non-stick magnetic beads to reduce the loss of magnetic beads.
  • an 8-hole valve can be used when the pipeline is switched, which can reduce the risk of mutual contamination between reagents.
  • the dosing pump is driven by a pulse-controlled motor, which can accurately inject or discharge the expected volume.
  • the control system is used to connect the electrical parts of the pump and solenoid valve in the hydraulic system, and is responsible for driving the action of the pump and valve.
  • the control system can also control the magnet actuator.
  • all actuators can be automatically controlled by the program, reducing manual intervention, and at the same time process data is collected into the system through AD to ensure real-time recording and storage of data.
  • the speed of the pump can be optimized during the control process, and closed-loop control can be used to increase the accuracy of the system's liquid addition and discharge.
  • the adjustment of the reagent's pH can also be more accurate and rapid.
  • the integrated man-machine interface can load the parameters frequently used by users, which improves the production efficiency.
  • An exemplary operation of the large-scale magnetic purification system according to the present invention is as follows.
  • Exemplary application examples of the large-scale magnetic purification system according to the present invention are as follows.
  • the magnetic bead-based purification method saves the operation and time of lower tank and deep filtration, and at the same time saves the loading time of protein A column. From 6 days to 4 days, single batch purification saves 5-7 manual labor (FTE).

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Abstract

本发明公开了一种大规模的磁力纯化系统，其包括：储液装置，能够通过液路系统与液体源及废液桶连接；安装在储液装置上方的搅拌系统，所述搅拌系统的搅拌桨插入所述储液装置进行搅拌；安装在储液装置周围的磁铁；用于操纵磁铁远离或接近储液装置的磁铁执行机构；和控制系统，所述控制系统与液路系统、磁铁执行机构和搅拌系统连接，并控制液路系统、磁铁执行机构和搅拌系统。

Description

一种大规模磁力纯化系统 技术领域
本发明涉及一种大规模磁力纯化系统，主要应用于生物纯化领域，例如用于蛋白和核酸的大规模提取。
背景技术
磁珠纯化法通常使用纯化系统通过磁场分离磁珠而达到分离和纯化细胞、蛋白或核酸等物质的目的。与常用的沉淀法、离心法、柱膜法相比，磁珠纯化法具有提取效率高、分离速度快、所需设备简单等特点。
与树脂纯化(Resin)相比，基于磁力吸附的磁珠纯化法依靠磁力原理和孵育的结合方式可以快速有效的富集样品中的目标蛋白，有效避免了树脂对样品预处理和对上样方式的限制等弊端，摆脱了装柱和流速等的限制。采用磁分离的纯化方法较易实现自动化，可满足快速、自动化、多通道同时处理的高通量纯化需求。
目前市面上存在的磁珠纯化装置普遍处理的通量都比较小，并且需要大量人工操作来辅助纯化流程。另外，目前操作都是敞口开放式操作，很难防止外部环境污染，也不能避免纯化过程中试剂的挥发对环境造成的伤害。现有技术的磁力架，虽可以满足部分客户需求，但仍存在诸多不足，如：(1)通量较小，不能满足大规模纯化的需求；(2)需要转移到离心管或者其它容器中，工序复杂，且有损坏样本的风险；(3)需要额外的装置才能实现自动化，增加额外的成本，且占用额外的场地；(4)形状固定，不能灵活适应容器的外形。
另外市面上采用的大规模纯化装置都是采用树脂纯化的方式，需要深层过滤，消耗大量的一次性耗材，需要多人次长时间投入。
因此，需要一种改进的磁力纯化系统，能够实现大规模磁珠纯化。
发明内容
本发明的一个目的在于提供一种大规模磁力纯化系统，不需要进行离心和深层过滤，可以直接将发酵液进行纯化，并节省大量用于过滤的耗材和设备。
大规模磁珠纯化时，磁珠直接与培养液自由接触，不需要进行装柱，没有定向流动纯化所带来的缺陷：大规模磁珠纯化所有的抗体和磁珠接触的概率是一样的，而树脂纯化是从前往后依次接触，从接触概率上前级高，后级低，前级收集抗体的先饱和，然后再后级饱和，这样前级的抗体聚集的量会比后级高，从而造成了抗体的不一致性。用过的磁珠再次利用时，所有磁珠的损耗是均等的，所以用量更容易控制，而树脂前级先损耗，后级后损耗，所以存在不一致性。
大规模磁珠纯化同样的培养液体积，所需要的时间是树脂纯化的1/4甚至更低。
以解决现有树脂纯化技术耗材成本高，操作时间长，工序繁杂的问题，利用本发明的大规模磁力纯化系统能够容易实现大通量的样品处理并能降低耗材的投入，缩短纯化的周期。
解决传统工艺耗时、成本较高、将传统工艺由多个步骤(离心、深层过滤、除菌过滤、层析、洗脱)简化为新工艺(孵育、洗脱)、人工成本显著降低、物料成本显著降低。
可以降低GMP车间空间和场地的使用。
根据本发明的一个方面，提供一种大规模的磁力纯化系统，其特征在于，包括：储液装置，能够通过液路系统与液体源及废液桶连接；安装在储液装置上方的搅拌系统，所述搅拌系统的搅拌桨插入所述储液装置进行搅拌；安装在储液装置周围的磁铁；用于操纵磁铁远离或接近储液装置的磁铁执行机构；和控制系统，所述控制系统与液路系统、磁铁执行机构和搅拌系统连接，并控制液路系统、磁铁执行机构和搅拌系统。
优选的，还设置有能够移动进入到所述储液装置内部的垂直磁铁，其通过在垂直方向上移动进入所述储液装置。
优选的，所述磁铁为水平磁铁，其能够在水平方向上相对于所述储液装置移动。
优选的，所述磁铁为垂直磁铁，其能够在垂直方向上相对于所述储液装置移动。
优选的，所述磁铁包括水平磁铁和垂直磁铁，所述水平磁铁能够在水平方向上相对于所述储液装置移动，并且所述垂直磁铁能够在垂直方向上相对于所述储液装置移动。
优选的，所述储液装置为储液罐。
优选的，所述储液罐中设置有一次性袋子。
优选的，所述搅拌桨具有螺旋推进式桨叶，并且包括在一个桨轴上安装的两套方向相反的桨叶。
优选的，所述磁铁由强磁铁组成，以快速吸附磁性颗粒。
优选的，所述磁铁包括水平磁铁和垂直磁铁，并且所述磁铁执行机构包括水平磁铁执行机构和垂直磁铁执行机构。
优选的，其中所述垂直磁铁能够被所述垂直磁铁执行机构操纵，以进入或者退出所述储液装置。
优选的，搅拌系统由可调速的电机自动控制旋转的速度，以不同的速度来控制桨叶的旋转。
优选的，所述液路系统的管路由不沾磁珠的材质制成，以减少磁珠的损失。
根据本发明另一个方面，提供一种纯化生物样品的方法，包括将含有目标成分的生物样品和能够结合所述目标成分的磁珠注入根据以上所述的大规模的磁力纯化系统的储液装置中利用所述大规模的磁力纯化系统进行纯化处理的步骤。
优选的，其中单次注入所述储液装置进行纯化的生物样品范围为100mL-10000L,优选为1L-1000L,更优选为10L-500L。
附图说明
附图中示例性地示出了根据本发明的优选实施例的大规模磁力纯化系统及部件。各附图只是示例性说明，其比例不必要一致。
图1示出了根据本发明的示例性实施例的磁力纯化系统的水平移动磁铁和水平磁铁执行机构。
图2示出了根据本发明的示例性实施例的磁力纯化系统中的罐体。
图3示出了根据本发明的示例性实施例的磁力纯化系统中的垂直移动磁铁、垂直磁铁执行机构和搅拌系统。
图4示出了根据本发明的示例性实施例的磁力纯化系统中的部分电磁阀、泵和管路。
图5示出了根据本发明的示例性实施例的磁力纯化系统的整体结构。
具体实施方式
为了更清楚地说明本发明实施例的技术方案，下面将对照附图说明本发明的具体实施方式。显而易见地，下面描述中的附图仅仅是本发明的一些示例性实施例。
根据本发明，如图5所示，提供了一种大规模磁力纯化系统，主要包括储液装置、搅拌系统、磁铁和磁铁执行机构。在此优选实施例中，储液装置、搅拌系统、磁铁和磁铁执行机构均安装在框架结构上。此外，大规模磁力纯化系统还可以包括泵阀系统，以实现液体的供给和排出。
储液装置用来提供磁珠从溶液中提取蛋白或其他待提取物质的场所，例如为储液罐。储液罐的容积可以从数升到上万升；优选的，其容积大于等于10升。储液罐中可放入一次性袋子。储液用的一次性袋子可以采用不沾磁珠的材质，内部带有可以喷淋粘在壁上的残余溶液和磁珠的喷淋装置。一次性袋子可以具有和储液罐的内壁完全贴合的形状。
图2示出了一个示例性的储液装置，其可以为储液罐，其容量约为10升。在其他实施例中，其容量可以更大，例如10升至1000升。储液装置的形状可以为圆形，或者方形，例如其四周采用了方形的边，但内部的容器四壁采用圆弧过渡。容器可以采用不被磁化的不锈钢材质，容器底部采用倾斜的角度。
优选的，储液用的一次性袋子采用不沾磁珠的材质，形状是根据储液装置的形状定制而成，可以最大限度保证磁珠被吸附时离磁铁最近。其内部带有可以喷淋粘在壁上的残余溶液和磁珠的喷淋装置，可以提升磁珠的回收率，同时提升系统的洁净度，降低了纯化样品被感染的风险。
优选地，承载袋子的容器形状四周可以采用方形的边，确保磁铁在吸附磁珠时可以完全贴合容器。这样磁铁的最有效距离可以被利用。容器四壁之间采用圆弧过渡，袋子的形状与容器的形状相匹配，使得在一次性袋子放入容器时很容易放入，并且不会形成褶皱，保障了磁珠的回收率。容器采用不被磁化的不锈钢材质，可以确保磁珠在磁场撤离时能够自由的混合在溶液中。容器底部采用倾斜的角度，可以降低溶液最后的残余体积，同时可以提升小体积时液面的高度，这样可以在小体积洗脱时能够最大限度地利用磁铁的磁力。
图3示出了搅拌桨安装模块和搅拌驱动电机的安装位置示意图。该图同时还示出了垂直磁铁(例如磁棒)、导轨和垂直驱动电机等。
搅拌系统采用可以调速的电机自动控制旋转的速度，可以用不同的速度来控制桨叶的旋转，分别用于不同的情况。例如在混匀时用较高的转速，可以快速混匀，而在磁珠吸附时可以用较低的速度，既能够达到混匀的效果，又可以保证磁珠不被桨叶的旋转扰动。同时桨叶可以正反向旋转，可以更大限度地提升混匀的效果。
一次性袋子内置的搅拌系统可以采用不锈钢的搅拌桨，搅拌桨位于袋子的顶面正中。搅拌系统采用可以调速的电机自动控制旋转的速度，同时桨叶可以 正反向旋转。底部出液管固定于袋子底部。进液口采用分流的方式进入袋子。一次性袋子可以采用透明材质。
可以最大限度地提升桨叶的尺寸，桨叶的形状采用螺旋推进式桨叶，同时在一个桨轴上安装两套方向相反的桨叶，可以增加溶液的扰动，在搅拌溶液时，用尽可能低的转速，尽可能高的提升了液体混合的效果。降低后的桨叶速度，可以减少桨叶边缘对溶液中的有效分子产生的剪切力，最大限度地保存了最终收集品的活性。底部出液管固定于袋子底部，固定的方式可以确保排液时磁珠不会被排出，同时废液可以最大限度地排除。进液口采用分流的方式进入袋子，杂质较多，粒径较大的溶液从宽口径中进入，试剂等洁净溶液从喷淋管路中进入，可以润洗管路，同时不会对管路造成堵塞。一次性袋子采用透明材质，可以方便用户在工艺流程中观察溶液中的反应情况。
搅拌系统可以位于储液装置的上方。搅拌系统中的搅拌桨可以深入到储液装置内部，用于将混合液搅拌均匀。
液路系统连接储液装置和液体源，例如试剂瓶或者试剂管路。液路系统的管路中可以设置有吸排液用的泵和阀门，用于将溶液供应到储液装置，或者从储液装置中排出。
图1示出了示例性的水平移动磁铁和水平磁铁执行机构。储液装置外部设置有磁铁执行机构，例如磁铁移动装置，用于提供磁铁的靠近和远离，从而施加磁场和撤离磁场。通过控制驱动电机的旋转，带动传动丝杠旋转来驱动磁铁架沿着直线导轨的方向来回运动，从而控制磁场的施加和撤离。
磁铁包括水平磁铁和垂直磁铁，磁铁可以由强磁铁构成，以快速吸附磁性颗粒或磁珠。例如，在一种实施方式中，磁铁可以由目前市面上磁力比较强的N52磁铁组成，磁场强度可以达到5000Gs以上。磁铁的布局可以采用同平面同极性的布局方式，这样可以确保磁场的方向都是与容器的贴合面垂直。磁铁可固定在能够移动的磁铁执行机构上，以实现磁铁相对于储液罐的位置控制。优选地，水平磁铁可设置成以与储液罐外壁完全贴合的形状分布。磁铁可以铺满整个罐体可接触的地方，并且预留适当间隙。
根据本发明的一种实施方式，磁铁为水平磁铁，其能够在水平方向上相对于储液装置移动。根据本发明的另一种实施方式，磁铁为垂直磁铁，其能够在垂直方向上相对于储液装置移动。根据本发明的再一种实施方式，磁铁包括水平磁铁和垂直磁铁，水平磁铁能够在水平方向上相对于储液装置移动，并且垂直磁铁能够在垂直方向上相对于储液装置移动。
为了实现有效的磁性吸附和释放，可以通过水平移动，或者垂直移动，或者垂直和水平同时协同作用来控制磁铁相对于储液罐的靠近和远离。例如，可垂直移动如图3所示的垂直磁铁(例如磁棒)进入储液装置，以吸附靠近磁棒附近的磁珠；可水平移动如图1所示布置的水平磁铁，以吸附靠近磁铁附近的磁珠。进入储液装置的垂直磁铁可以隔着前述一次性袋子吸附磁珠。
在一些实施例中，磁铁执行机构采用滚珠丝杠，向两边对拉的对称工作方式。滚珠丝杠比其他的传动方式具有噪音小，振动幅度小，寿命长的优势，运用在系统中可以提升磁珠被磁铁吸附后的稳定性，能够减少磁珠在吸附之后排液的损失率。
图4示出了液路系统中的部分电磁阀、泵和管路。
液路系统管路采用不沾磁珠的材质，减少磁珠的损失。管路切换时例如可以采用8孔阀，可以减少试剂之间相互污染的风险。加液泵采用脉冲控制的电机驱动，可以精确注入或排出预期的体积。控制系统用来连接液路系统中的泵和电磁阀的电气部分，负责驱动泵和阀的动作。控制系统还可以控制磁铁执行机构。
在控制系统中，所有的执行机构都可以采用程序自动控制，减少了人工的干预，同时过程数据经过AD采集进入系统，保证数据的实时记录和存储。控制过程中可以优化泵的转速，采用闭环控制，可以提升系统加液和排液的精度，对于试剂酸碱度的调定也可以更加准确和迅速。采用集成式的人机界面，可以将用户经常使用的参数进行载入，提升了生产的效率。
根据本发明的大规模的磁力纯化系统的示例性操作如下所述。
1.泵入磁珠
a)将25％磁珠混合液泵入反应容器中，用平衡缓冲液冲洗磁珠，搅拌之后，通过控制磁铁执行机构移动磁铁，使得磁铁靠近容器，将磁珠完全吸附，用管路排除上清，重复用平衡缓冲液冲洗2～3次，排除上清。
2.磁珠消毒
a)将0.1M的NaOH 3CV泵入反应容器，搅拌之后，移动磁铁，将磁珠完全吸附，用管路排除上清，再次加入0.1M的NaOH 3CV，浸泡30Min以上，搅拌之后，移动磁铁，将磁珠完全吸附后，用管路排除上清。
3.磁珠平衡
a)将平衡缓冲液3～5CV泵入反应容器中，搅拌之后，移动磁铁，将磁珠完全吸附后，用管路排除上清，重复用平衡缓冲液冲洗5～3次，排除上清。每次2～5Min。
4.发酵液孵育
a)将细胞培养液泵入反应容器中，一直搅拌，持续2h
5.洗杂
a)将平衡缓冲液3～5CV泵入反应容器中，搅拌之后，移动磁铁，将磁珠完全吸附后，用管路排除上清，重复用平衡缓冲液冲洗5～3次，排除上清。每次2～5Min。
6.洗脱
a)将洗脱缓冲液5CV泵入反应容器中，搅拌之后，移动磁铁，将磁珠完全吸附后，收集洗脱液，重复3次。
7.磁珠消毒
a)将0.1M的NaOH 3CV泵入反应容器，搅拌之后，移动磁铁，将磁珠完全吸附，用管路排除上清，再次加入0.1M的NaOH 3CV，浸泡30Min以上，搅拌之后，移动磁铁装置，将磁珠完全吸附后，用管路排除上清。8.磁珠收集
a)将2CV 0.01M NaOH或20％乙醇泵入反应容器，搅拌之后，用管路收集磁珠溶液，再次泵入2CV 0.01M NaOH或20％乙醇泵入反应容器，搅拌之后，用管路收集磁珠溶液，收集泵出磁珠混合液保存于2-8℃。
根据本发明的大规模的磁力纯化系统的示例性应用实例如下所述。
与传统的树脂相比，基于磁珠的大规模纯化显著提高纯化效率，节约时间和人力。
以200L的发酵液纯化为例，基于磁珠的纯化方式节省了下罐和深层过滤的操作和时间，同时节省蛋白A柱的上样时间。从6天节省至4天，单批次纯化节省5-7个人工(FTE)。
Figure PCTCN2019113261-appb-000001
Figure PCTCN2019113261-appb-000002
应当说明的是，上述实施例均可根据需要自由组合。以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干变化和改进，这些变化和改进也应视为落入本发明的保护范围。

Claims (15)

  1. 一种大规模的磁力纯化系统，其特征在于，包括：
    储液装置，能够通过液路系统与液体源及废液桶连接；
    安装在储液装置上方的搅拌系统，所述搅拌系统的搅拌桨插入所述储液装置进行搅拌；
    安装在储液装置周围的磁铁；
    用于操纵磁铁远离或接近储液装置的磁铁执行机构；和
    控制系统，所述控制系统与液路系统、磁铁执行机构和搅拌系统连接，并控制液路系统、磁铁执行机构和搅拌系统。
  2. 根据权利要求1所述的大规模的磁力纯化系统，其特征在于，还设置有能够移动进入到所述储液装置内部的垂直磁铁，其通过在垂直方向上移动进入所述储液装置。
  3. 根据权利要求1所述的大规模的磁力纯化系统，其特征在于，所述磁铁为水平磁铁，其能够在水平方向上相对于所述储液装置移动。
  4. 根据权利要求1所述的大规模的磁力纯化系统，其特征在于，所述磁铁为垂直磁铁，其能够在垂直方向上相对于所述储液装置移动。
  5. 根据权利要求1所述的大规模的磁力纯化系统，其特征在于，所述磁铁包括水平磁铁和垂直磁铁，所述水平磁铁能够在水平方向上相对于所述储液装置移动，并且所述垂直磁铁能够在垂直方向上相对于所述储液装置移动。
  6. 根据权利要求2-5中任一项所述的大规模的磁力纯化系统，其特征在于，所述储液装置为储液罐。
  7. 根据权利要求6所述的大规模的磁力纯化系统，其特征在于，所述储液罐中设置有一次性袋子。
  8. 根据权利要求1-5中任一项所述的大规模的磁力纯化系统，其特征在于，所述搅拌桨具有螺旋推进式桨叶，并且包括在一个桨轴上安装的两套方向相反的桨叶。
  9. 根据权利要求1-5中任一项所述的大规模的磁力纯化系统，其特征在于，所述磁铁由强磁铁组成，以快速吸附磁性颗粒。
  10. 根据权利要求1-5中任一项所述的大规模的磁力纯化系统，其特征在于，所述磁铁包括水平磁铁和垂直磁铁，并且所述磁铁执行机构包括水平磁铁执行机构和垂直磁铁执行机构。
  11. 根据权利要求10所述的大规模的磁力纯化系统，其中所述垂直磁铁能够被所述垂直磁铁执行机构操纵，以进入或者退出所述储液装置。
  12. 根据权利要求1-5中任一项所述的大规模的磁力纯化系统，其特征在于，搅拌系统由可调速的电机自动控制旋转的速度，以不同的速度来控制桨叶的旋转。
  13. 根据权利要求1-5中任一项所述的大规模的磁力纯化系统，其特征在于，所述液路系统的管路由不沾磁珠的材质制成，以减少磁珠的损失。
  14. 一种纯化生物样品的方法，包括将含有目标成分的生物样品和能够结合所述目标成分的磁珠注入根据权利要求1至13中任一项所述的大规模的磁力纯化系统的储液装置中利用所述大规模的磁力纯化系统进行纯化处理的步骤。
  15. 根据权利要求14所述的方法，其中单次注入所述储液装置进行纯化的生物样品范围为100mL-10000L,优选为1L-1000L,更优选为10L-500L。
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