Magnetic bead continuous separation device

Abstract

The invention relates to the technical field of nano magnetic bead preparation, and discloses a magnetic bead continuous separation device. The magnetic bead continuous separation device comprises a magnetic bead separator, a magnetic field generating device and a driving device, the driving device is used for driving the magnetic field generating device to be close to or away from the side wall of the magnetic bead separator, the magnetic bead separator is hollow, one end of the magnetic bead separator is provided with a first liquid inlet and a second liquid inlet, and the other end of the magnetic bead separator is provided with a first liquid outlet and a second liquid outlet. According to the invention, a plurality of separation processes can be integrated in the same structure, so that the system configuration is simplified, and the requirements of automation and large-scale continuous treatment in the magnetic bead purification process are effectively met.

Description

Technical Field

[0001] The present application relates to the technical field of nanomagnetic bead preparation, and in particular to a magnetic bead continuous separation device. Background Art

[0002] Magnetic beads are micron- or nanometer-scale particle structures with excellent magnetic response properties. Their core is usually composed of a magnetic inorganic material (such as ferroferric oxide), and the outer layer is coated with a polymer or silica material. Specific functional groups, such as carboxyl or amino groups, are introduced on the surface, giving them the ability to specifically bind to target molecules. Due to their magnetic control operability and high flexibility in functional modification, magnetic beads are widely used in multiple biological and industrial fields such as nucleic acid extraction, protein purification, cell sorting, immunoassays, and magnetically controlled drug delivery. After synthesis, magnetic beads often have problems such as uneven magnetism, residual impurities, and inconsistent particle size distribution. If they are not purified and screened, their magnetic responsiveness and binding specificity will be directly affected, thereby reducing their separation efficiency and reusability in subsequent applications. Therefore, after the magnetic beads are prepared, they usually need to be separated and purified to eliminate magnetic beads with weak magnetism and waste liquid from the preparation process.

[0003] At present, the separation and purification of magnetic beads mainly rely on manual operation or simple magnetic stand devices. Common methods include dividing the magnetic bead suspension into centrifuge tubes, manually achieving magnetic adsorption and discarding the liquid on a fixed magnetic stand, and then completing rough screening through multiple rounds of washing operations. Some scenarios also use magnetic rod devices, which are captured and transferred manually or by robotic arms. However, this method has problems such as fragmented operating procedures, reliance on manual intervention, high magnetic bead loss rate, and inability to standardize. Especially in large-scale sample processing scenarios, the processing efficiency is significantly limited due to the limited capacity of the magnetic stand or magnetic rod capture unit. Summary of the Invention

[0004] In order to integrate multiple separation processes into the same structure and simultaneously meet the requirements of automation and large-scale continuous processing of the magnetic bead purification process, the present application provides a magnetic bead continuous separation device.

[0005] The present application provides a magnetic bead continuous separation device, which adopts the following technical solution: A magnetic bead continuous separation device includes a magnetic bead separator, a magnetic field generating device and a driving device. The driving device is used to drive the magnetic field generating device to move closer to or away from the side wall of the magnetic bead separator. The magnetic bead separator is hollow and has a first liquid inlet and a second liquid inlet at one end and a first liquid discharge port and a second liquid discharge port at the other end.

[0006] Optionally, the magnetic bead separator is used for vertical placement, the first liquid inlet and the second liquid inlet are arranged at the top of the magnetic bead separator, and the first liquid discharge port and the second liquid discharge port are arranged at the bottom of the magnetic bead separator.

[0007] Optionally, the second liquid inlet of the magnetic bead separator is arranged on the side of the magnetic bead separator close to the magnetic field generating device relative to the first liquid inlet; the second liquid discharge port of the magnetic bead separator is arranged on the side of the end of the magnetic bead separator close to the magnetic field generating device relative to the first liquid discharge port.

[0008] Optionally, the second liquid inlet of the magnetic bead separator is arranged on the side of the end of the magnetic bead separator close to the magnetic field generating device relative to the first liquid inlet; the second liquid discharge port of the magnetic bead separator is arranged on the side of the magnetic bead separator close to the magnetic field generating device relative to the first liquid discharge port.

[0009] Optionally, the second liquid inlet is tangent to the tube wall of the magnetic bead separator.

[0010] Optionally, the second liquid discharge port is tangent to the tube wall of the magnetic bead separator.

[0011] Optionally, the magnetic field generating device generates a magnetic field in the magnetic bead separator that gradually weakens from the tube wall to the middle of the tube body.

[0012] Optionally, a magnetic bead separation zone and a magnetic bead capture zone are formed in the magnetic bead separator, and the magnetic bead separation zone and the magnetic bead capture zone are both distributed along the axial direction of the magnetic bead separator, the two ends of the magnetic bead separation zone are respectively connected to the first liquid inlet and the first liquid discharge port, and the two ends of the magnetic bead capture zone are respectively connected to the second liquid inlet and the second liquid discharge port, and a magnetic field gradient is formed from the magnetic bead separation zone to the magnetic bead capture zone.

[0013] Optionally, the driving device includes a motor module, a threaded transmission rod and a support rod, wherein the two ends of the support rod are respectively connected to the threaded transmission rod and the magnetic field generating device, and the motor module is used to drive the threaded transmission rod to push the support rod and the magnetic field generating device toward or away from the magnetic bead separator.

[0014] Optionally, the magnetic field generating device includes an anti-stripping layer, an embedded magnetic layer and a shielding layer arranged in sequence from the inside to the outside, a magnet is embedded in the embedded magnetic layer, and the anti-stripping layer and the shielding layer cooperate with the embedded magnetic layer to form a cavity for accommodating and limiting the magnet.

[0015] Optionally, the inner side wall of the anti-stripping layer is in contact with the outer wall of the magnetic bead separator and its shape is adapted to the outer wall of the magnetic bead separator.

[0016] Optionally, the embedded magnetic layer includes a support plate and a plurality of magnetic tiles, the support plate is provided with a plurality of limiting grooves for limiting the movement of the magnetic tiles, and the magnetic tiles are installed in the limiting grooves.

[0017] Optionally, the magnetic tile is a block with a regular hexagonal, rhombus or parallelogram cross section.

[0018] Optionally, the embedding manner of the magnetic tiles on the support plate includes horizontal embedding, longitudinal embedding, and Halbach array embedding.

[0019] Optionally, the magnetic field generating device and the driving device are two or more groups and are arranged around the magnetic bead separator.

[0020] Optionally, different groups of magnetic field generating devices are provided with the same or different magnetic tile embedding methods; different groups of magnetic field generating devices are provided with magnetic tiles capable of generating the same or different magnetic field strengths.

[0021] Optionally, the diameter of the magnetic bead separator is 10 to 300 mm.

[0022] Optionally, the magnetic bead separator is a transparent tube.

[0023] Optionally, when the liquid to be separated passes through the magnetic bead separator, the magnetic beads are exposed to the magnetic field generated by the magnetic field generating device, and the magnetic field generating device can capture the target magnetic beads on the tube wall of the magnetic bead separator.

[0024] In summary, this application includes at least one of the following beneficial technical effects: 1. The continuous magnetic bead separation device has high-capacity processing capabilities and is adaptable to hollow separation tube structures with diameters ranging from 10 to 300 mm. One or more magnetic field generators are installed on the outer periphery of the tube. By using multiple sets of modular, circumferential magnetic field generators, combined with a drive device to control the magnetic field toward or away from the side walls of the separation tube, a stable magnetic field strength that decreases from the outside to the inside of the separation tube is formed inside the separation tube, effectively capturing the target magnetic beads on the tube wall.

[0025] 2. The magnetic field generator utilizes a variety of tile arrangements, including horizontal embedding, vertical embedding, and Halbach arrays. The tile cross-sections can be regular hexagonal, rhombus, or parallelogram. By adjusting the number of tiles, their arrangement, and the direction of the magnetic poles, the magnetic field intensity and distribution can be flexibly controlled, enabling the separation of magnetic beads of varying magnetic grades during batch processing.

[0026] 3. The magnetic bead continuous separation device allows the stock solution and washing solution to enter or be discharged from different paths respectively. In different processing stages, the capture, separation and washing steps of the target magnetic beads are completed respectively, thereby realizing functional reuse. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1a This is the first front view of the magnetic bead continuous separation device in a certain embodiment of the present application.

[0028] Figure 1bIt is an overall schematic diagram of a magnetic bead continuous separation device in a certain embodiment of the present application.

[0029] Figure 2 Used to illustrate the fully enclosed structure of the magnetic field generating device.

[0030] Figure 3 This is an overall schematic diagram of a magnetic field generating device in a certain embodiment of the present application.

[0031] Figure 4 This is an overall schematic diagram of a magnetic field generating device in a certain embodiment of the present application. Figure 2 .

[0032] Figure 5a-5b Schematic diagram of the structure of modular units of the embedded magnetic layer in an embodiment of the present application.

[0033] Figure 6 It is a structural schematic diagram of a fully enclosed embedded magnetic layer in a certain embodiment of the present application.

[0034] Figures 7a-7d Schematic diagram showing different embedded magnetic structures of magnetic tiles.

[0035] Figures 8a-8b Used to illustrate the effect of the magnetization accuracy of the diamond-shaped magnetic tile on the magnetic field capture area.

[0036] Figure 9 A schematic diagram showing that the magnetic tile adopts the Halbach array method as the embedded magnetic structure.

[0037] Figure 10 This is a front view of a magnetic bead continuous separation device in a certain embodiment Figure 2 .

[0038] Reference numerals: 1. Magnetic bead separator; 11. First liquid inlet; 12. Second liquid inlet; 13. First liquid discharge port; 14. Second liquid discharge port; 2. Magnetic field generating device; 21. Anti-stripping layer; 22. Embedded magnetic layer; 221. Support plate; 222. Magnetic tile; 223. Limiting groove; 23. Shielding layer; 3. Driving device; 31. Motor module; 32. Support rod; 33. Transmission rod; 4. Bracket; 5. Support column; 6. Sliding structure. DETAILED DESCRIPTION

[0039] Embodiments of the present application are described in detail below, examples of which are illustrated in the accompanying drawings.

[0040] Throughout this specification, reference to the terms "certain embodiments," "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0041] Magnetic beads are magnetic microspheres whose core is typically composed of a magnetic inorganic material (such as ferroferric oxide) and whose shell is coated with a polymer or silica material. By introducing functional groups such as carboxyl groups, amino groups, and streptavidin onto their surface, magnetic beads can be endowed with the ability to specifically bind to biomolecules, making them widely used in biomedical and industrial fields such as nucleic acid extraction, protein purification, cell sorting, immunoassays, and magnetically controlled drug delivery. Magnetic beads typically range in size from nanometers to micrometers and exhibit excellent magnetic responsiveness, allowing them to rapidly aggregate in the presence of an external magnetic field, enabling the efficient capture and transfer of target molecules.

[0042] However, after magnetic beads are synthesized, magnetic inhomogeneity often exists within the system, meaning that the magnetic response strength varies between different particles. Furthermore, some beads may harbor unremoved reaction byproducts, free monomers, or inorganic impurities, all of which can affect the separation efficiency and binding specificity of the beads in practical applications. Therefore, rigorous separation and screening procedures are required to eliminate particles with weak magnetism, high impurity content, or sizes that deviate from the specified range.

[0043] In this process, the magnetic beads with different magnetic strengths can be effectively screened with the help of an external magnetic field. Taking common laboratory operations as an example, researchers usually divide the magnetic bead suspension into centrifuge tubes, dilute them by manual pipetting, and place them on a fixed magnetic stand. The magnetic field is used to capture some particles with sufficient magnetic responsiveness on the tube wall, and the remaining non-magnetic or low-magnetic impurities are discarded with the supernatant. Subsequently, the retained magnetic beads are resuspended in liquid, and rough enrichment and purification are achieved through multiple "capture-discard liquid-add liquid-mix" operations. If a magnetic rod device is used, manual or robotic arm cooperation is required to immerse the magnetic rod in the magnetic bead suspension, and after capture, it is transferred to the cleaning solution or purification solution for further washing.

[0044] However, the above-mentioned traditional magnetic bead purification operation has obvious limitations. First, its operation process is highly fragmented, and each link often relies on manual step-by-step completion, which easily leads to increased magnetic bead loss and reduced processing efficiency. In addition, the operator is also burdened, and the single batch processing volume is also small. In addition, most existing magnetic bead purification systems adopt an open structure design, and the magnetic field capture area and the liquid handling module are separated from each other. In such devices, the magnetic bead separation operation cannot complete the injection, enrichment and discharge actions in the same closed space.

[0045] Therefore, the embodiment of the present application discloses a magnetic bead continuous separation device, which has a compact structure and high functional integration, can adapt to different processing requirements and support continuous process flow. Figure 1a and Figure 1b The magnetic bead continuous separation device includes a magnetic bead separator 1, a magnetic field generating device 2 and a driving device 3. The three together constitute a closed separation channel under a controllable magnetic field environment, which can realize the automatic capture, separation and washing of magnetic beads.

[0046] Specifically, the magnetic bead separator 1 is a hollow structure, which is used to pass the raw liquid to be processed carrying the target magnetic beads. The magnetic field generating device 2 is arranged on the periphery of the magnetic bead separator 1, which is used to form a stable strong magnetic field inside the magnetic bead separator 1 to capture the target magnetic beads to the tube wall. The driving device 3 is linked with the magnetic field generating device 2, and is used to adjust the distance between the magnetic field generating device 2 and the side wall of the magnetic bead separator 1 to change the magnetic field strength inside the magnetic bead separator 1. In different embodiments, the magnetic bead separator 1 can be fixed by a bracket 4 of different forms. The form of the bracket 4 can be determined according to the layout of the magnetic bead separator 1. When the magnetic bead separator 1 is horizontal or vertical, the bracket 4 should be adaptively adjusted, which is not specifically limited in this application.

[0047] 1 , a first liquid inlet 11 and a second liquid inlet 12 are provided at one end of the magnetic bead separator 1, and a first liquid discharge port 13 and a second liquid discharge port 14 are provided at the other end. The first liquid inlet 11 and the second liquid inlet 12 are used to introduce the raw liquid to be separated and the washing liquid containing the target magnetic beads, thereby realizing step-by-step alternating liquid input. The first liquid discharge port 13 is used to discharge impurities and suspended waste liquid contained in the raw liquid to be processed, while the second liquid discharge port 14 is used to output the magnetic bead liquid containing the target magnetic beads. With the help of the above-mentioned interface configuration, the entire process of raw liquid treatment, magnetic bead capture, and impurity flushing can be completed in a single cavity structure. The washing liquid can be selected in different ways according to the different raw materials of the magnetic beads, such as deionized water, ethanol, saline solution, high molecular polymer, etc.

[0048] In a plurality of embodiments of the present application, the magnetic bead separator 1 can select a variety of structures according to different application requirements and processing conditions, specifically including but not limited to circular tubes, square tubes, rectangular tubes, elliptical tubes, hexagonal tubes, U-shaped groove tubes, D-shaped groove tubes, trapezoidal groove tubes, horseshoe-shaped tubes, etc. As long as the selected structure can ensure that the fluid passes evenly, its tube wall has sufficient flatness, and there is no obvious dead angle in the opening area at both ends, it can be applied to the magnetic bead separation operation described in the present application. The diversity of the above-mentioned forms can be flexibly configured according to the specific equipment space and flux requirements.

[0049] The inner wall of the magnetic bead separator 1 should be smooth to reduce the adhesion of magnetic beads after the magnetic bead generator 2 leaves the magnetic bead separator 1. In addition, its outer wall is preferably designed to fit tightly with the inner surface of the magnetic field generator 2, so that the magnetic field can effectively penetrate the tube wall and act on the interior of the tube lumen.

[0050] In terms of material selection, to ensure that the magnetic field can penetrate the tube wall and is not shielded, the magnetic bead separator 1 is preferably made of non-magnetic materials, including but not limited to transparent glass, borosilicate glass, quartz glass, organic glass (such as polymethyl methacrylate (PMMA), polycarbonate (PC), polyethylene terephthalate (PET), polystyrene (PS), polytetrafluoroethylene (PTFE), polyetheretherketone (PEEK), polyimide (PI), polypropylene (PP), or polyethylene (PE). These materials not only have excellent non-magnetic properties and magnetic permeability, but also easily produce a smooth inner wall surface after processing and molding.

[0051] Preferably, the magnetic bead separator 1 is made of a transparent tube, and the operator can observe the state of the target magnetic beads, the position of the liquid interface and the magnetic bead separation process in the tube in real time with the naked eye or a matching imaging device, thereby monitoring the separation process.

[0052] In various embodiments of the present application, the specific arrangement of the magnetic bead separator 1 can be adjusted based on the angle between its axis and the horizontal plane. The spatial configuration of the magnetic bead separator 1 may include, but is not limited to, vertical arrangement, horizontal arrangement, and diagonal arrangement. The vertical arrangement may also be referred to as a vertical arrangement, and the horizontal arrangement may also be referred to as a horizontal arrangement.

[0053] As an example, in a certain embodiment, the magnetic bead separator 1 is used to be placed vertically, the first liquid inlet 11 and the second liquid inlet 12 of the magnetic bead separator 1 are arranged at the top of the magnetic bead separator 1, and the first liquid discharge port 13 and the second liquid discharge port 14 of the magnetic bead separator 1 are arranged at the bottom of the magnetic bead separator 1.

[0054] Furthermore, the second liquid inlet 12 is arranged on the side of the magnetic bead separator 1 close to the magnetic field generating device 2 relative to the first liquid inlet 11, and the second liquid discharge port 14 is arranged on the side of the end of the magnetic bead separator 1 close to the magnetic field generating device 2 relative to the first liquid discharge port 13.

[0055] In another exemplary embodiment, the magnetic bead separator 1 is positioned horizontally, with the magnetic field generator 2 still attached to the outer fitting area of ​​the tube. In this arrangement, the first and second liquid inlets 11 and 12 are located at one end of the magnetic bead separator 1, while the first and second liquid outlets 13 and 14 are located at the other end. By controlling the horizontal flow of the liquid to be separated within the tube lumen, the target magnetic beads can be continuously captured.

[0056] Furthermore, the second liquid inlet 12 is arranged on the side of the magnetic bead separator 1 close to the magnetic field generating device 2 relative to the first liquid inlet 11, and the second liquid discharge port 14 is arranged on the side of the end of the magnetic bead separator 1 close to the magnetic field generating device 2 relative to the first liquid discharge port 13.

[0057] In a preferred embodiment, the edge of the second liquid inlet 12 is tangential to the tube wall of the magnetic bead separator 1, allowing the injected liquid to flow along the axial direction of the magnetic bead separator 1. The second liquid discharge port 14 is also configured in a similar manner to be tangential to the tube wall of the magnetic bead separator 1, so as to facilitate the axial guidance and discharge of the target magnetic beads. The advantage of this structural arrangement is that during the washing liquid injection stage, an axial impact is quickly generated through the second liquid inlet 12, so that the deposited target magnetic beads can be efficiently flushed to the second liquid discharge port 14.

[0058] In a preferred embodiment, the liquid inlet and outlet can also be designed in different shapes, such as an elliptical hole, a strip-shaped opening, a rectangular window, a chamfered short tube, or a bell-shaped cross-section, to produce different liquid jet diffusion effects. In addition, the number of second liquid inlet 12 and second liquid outlet 14 is not limited to one, and can be adjusted accordingly based on the configuration of the magnetic field generating device 2 and the specific layout of the magnetic bead separator 1.

[0059] Optionally, the diameter of the magnetic bead separator 1 is set within the range of 10 to 300 mm. This diameter range strikes a balance between the magnetic field strength and the flux requirements of the pipeline. Specifically, during the action of the magnetic field, the magnetic field gradient ΔB decays exponentially with the increase of the distance r from the surface of the magnetic source (ΔB∝1 / r²). When the diameter of the separation tube increases significantly, it will be difficult to maintain the effective magnetic field strength in the central area of ​​the tube, resulting in a sharp drop in the magnetic bead capture efficiency. For example, when the diameter of the magnetic bead separator 1 is expanded from 350 mm to 500 mm, the magnetic field gradient at its center may drop to less than 1% of the original value, and the capture effect of the target magnetic beads is significantly reduced. The capture efficiency drops sharply from more than 99% to less than 20%, seriously affecting the separation purity and recovery rate.

[0060] To compensate for the magnetic field loss caused by the enlarged diameter, existing technologies require a high-intensity magnet system. Some related technologies even introduce superconducting magnets to maintain the required magnetic field gradient. However, this type of configuration is not only expensive (the cost of a superconducting system can exceed 3 million RMB), but also has extremely high requirements for energy consumption and thermal management during operation. The power of the equipment may surge from 1 kW to 100 kW, and the heat dissipation, space and safety design costs of the supporting system will also increase exponentially. In addition, large-diameter separators also face structural problems such as large size, low magnetic tile utilization, and packaging difficulties, which greatly weaken their practicality and scalability.

[0061] In a preferred embodiment of the present application, the magnetic field generating device 2 is arranged outside the magnetic bead separator 1, and its structure and magnet arrangement are designed to generate a magnetic field in the magnetic bead separator 1 that gradually weakens from the tube wall to the middle of the tube body.

[0062] Preferably, the magnetic bead separator 1 can be divided into a magnetic bead separation zone and a magnetic bead capture zone according to the magnetic field action characteristics and the fluid channel layout. Both zones are arranged along the axial direction of the magnetic bead separator 1. The two ends of the magnetic bead separation zone are connected to the first liquid inlet 11 and the first liquid discharge port 13, which mainly undertake the functions of injecting the original liquid and discharging the impurity waste liquid; the two ends of the magnetic bead capture zone are respectively connected to the second liquid inlet 12 and the second liquid discharge port 14, which are used for the injection of washing liquid and the output of magnetic bead liquid respectively. Specifically, the magnetic bead separation zone constitutes the main fluid channel, in which the target magnetic beads will be attracted by the magnetic force and move toward the magnetic bead capture zone; and the magnetic bead capture zone is close to the magnetic field action area, has a higher magnetic field strength, and can capture and fix the migrated magnetic beads.

[0063] It should be noted that the sizes of the first liquid inlet 11 and the first liquid discharge port 13 do not strictly correspond to the width of the magnetic bead separation zone, nor do the sizes of the second liquid inlet 12 and the second liquid discharge port 14 strictly correspond to the width of the magnetic bead capture zone. The magnetic bead separation zone and magnetic bead capture zone do not actually exist; rather, they are functional zoning within the magnetic bead separator 1 based on the behavior of the magnetic beads in the magnetic bead separation solution.

[0064] During operation, the target magnetic beads in the liquid to be separated maintain a certain spatial dispersion between the particles in the magnetic bead separation zone, and will not form agglomerations or sedimentation. However, under the action of the magnetic field, they gradually move toward the magnetic bead capture zone. As they enter the magnetic bead capture zone, the magnetic beads are quickly captured to the surface of the tube wall near the magnetic field generator and pressed against the tube wall, forming a densely arranged layer of magnetic beads. The magnetic bead particles are fixed to each other by the force of the magnetic field. During the operation of releasing the magnetic field, the magnetic field strength rapidly weakens, and the capture force between the particles suddenly decreases to a state of near-zero concentration. At this time, only a certain volume of washing liquid needs to be injected, and the impact force of the liquid can be used to quickly desorb the magnetic beads from the tube wall and bring them into the fluid.

[0065] In various embodiments, the magnetic field generating device 2 and the driving device 3 can be configured as a single group to partially enclose the magnetic bead separator 1; or they can be configured as multiple groups arranged around the magnetic bead separator 1 to increase the effective area of ​​the magnetic field. In specific implementations, the multiple groups of magnetic field generating devices 2 can be sequentially distributed around the circumference of the magnetic bead separator 1, or sequentially arranged along the axial direction of the magnetic bead separator 1, or distributed in an array on the surface of the magnetic bead separator 1, forming a composite magnetic field system with directional and gradient characteristics.

[0066] Specifically, in one typical form, reference Figure 2 The magnetic field generating device 2 adopts an all-inclusive configuration. That is, by combining two or more sets of magnetic field generating devices 2 with the driving device 3, the magnetic field generating device 2 forms a closed and surrounding structure along the outer wall of the magnetic bead separator 1, fully covering the entire circumference of the magnetic bead separator 1. This all-inclusive arrangement can generate a higher intensity and more uniform magnetic field within the magnetic bead separator 1, ensuring that target magnetic beads at any position in the lumen are effectively attracted.

[0067] Correspondingly, in another embodiment that is easy to assemble, the magnetic field generating device 2 can adopt a semi-enclosed configuration, that is, one or more groups of magnetic field generating devices 2 are only set on part of the outer wall area of ​​the magnetic bead separator 1, so that while forming an effective magnetic field capture area, part of the space is reserved for device observation or other functional module expansion.

[0068] Furthermore, by providing multiple sets of magnetic field generating devices 2, each set of magnetic field generating devices 2 can be equipped with magnetic tiles 222 or magnet assemblies of different types or strengths, or different magnetic tile 222 or magnet embedding methods can be employed, thereby forming spatially differentiated magnetic field intensity regions. Specifically, the magnetic field generating devices 2 can provide different magnetic field intensities (0.5T-80T), which can be selected based on different magnetic beads and separation requirements.

[0069] Reference Figure 3 and Figure 4 In an embodiment of the present application, the magnetic field generating device 2 includes an anti-stripping layer 21, an embedded magnetic layer 22 and a shielding layer 23 arranged in sequence from the inside to the outside. The three-layer structure is used to establish a suitable magnetic field environment inside the magnetic bead separator 1 to achieve the capture and release of the target magnetic beads.

[0070] Among them, the first layer is an anti-stripping layer 21, that is, an inner layer bonding structure, which is used to prevent the magnetic tiles 222 in the embedded magnetic layer 22 from falling off, and to make the magnetic field generating device 2 in close contact with the outer wall of the magnetic bead separator 1. The anti-stripping layer 21 is usually made of stainless steel material, which has good mechanical strength and magnetic flux penetration. On the one hand, it can resist external stress impact and prevent the risk of displacement or falling off of the magnetic tiles 222. On the other hand, it will not significantly block or weaken the magnetic flux lines, ensuring that the magnetic field can effectively penetrate into the interior of the separation tube. In other embodiments, the anti-stripping layer 21 can also be made of non-magnetic titanium alloy, engineering plastic or aluminum alloy, but any material that has good mechanical strength, wear resistance and magnetic field penetration performance can be used. The geometric contour of the anti-stripping layer 21 is adapted to the shape of the outer wall surface of the magnetic bead separator 1 to achieve a close-fitting coating effect.

[0071] It should be noted that in some other embodiments, when the embedded magnetic layer 22 can stably fix the magnetic tile 222 alone, the anti-stripping layer 21 can be removed, that is, the magnetic field generating device 2 includes a two-layer structure of the embedded magnetic layer 22 and the shielding layer 23 arranged in sequence from the inside to the outside.

[0072] The second layer is the embedded magnetic layer 22, which is the core functional layer of the magnetic field generating device 2. It is embedded with multiple sets of magnetic tiles 222. Common materials of magnetic tiles 222 include neodymium iron boron, samarium cobalt or other high-performance rare earth magnetic materials. The embedded magnetic layer 22 is also made of stainless steel to take into account both structural support and traditional magnetic field characteristics. Accordingly, the structure of the embedded magnetic layer 22 can be divided into two types: semi-enclosed and fully enclosed according to the magnetic field distribution requirements. Figure 6 The all-inclusive structure covers the magnetic bead separator 1 through a continuously surrounding magnet module, which can significantly increase the capture area.

[0073] The third layer is the shielding layer 23, the outermost protective layer of the magnetic field generating device 2. It is used to shield against external magnetic field leakage. This shielding layer 23 restricts the spread of magnetic flux lines beyond the embedded magnetic layer 22, preventing the magnetic field from interfering with surrounding electronic components, signal lines, or operating equipment. Furthermore, the shielding layer 23 provides a certain degree of protection against external mechanical impact.

[0074] Reference Figure 5a and Figure 5b In a further embodiment of the present application, the embedded magnetic layer 22 includes a support plate 221 and a plurality of magnetic tiles 222. The support plate 221 is used to support and secure the magnetic tiles 222. The support plate 221 is integrally or separately connected to the shielding layer 23. A plurality of limiting grooves 223 are formed on the support plate 221 to limit the movement of the magnetic tiles 222. Each magnetic tile 222 is fixed by being embedded in a corresponding limiting groove 223, thereby ensuring that the magnetic tiles 222 do not deviate or become loose during operation of the device.

[0075] In the continuous magnetic bead separation device of the present application, a permanent magnet is preferably used to construct the magnetic field generating device 2, replacing traditional electromagnets. Although electromagnets have the ability to adjust the magnetic field, they suffer from drawbacks such as high energy consumption, heavy structure, and difficulty in heat dissipation. In contrast, permanent magnets (such as neodymium iron boron) can output magnetic fields of up to 8,000 gauss or more at room temperature. Permanent magnet structures do not require an external power supply to maintain the magnetic field, and their magnetic field output is stable and non-fluctuating, making them particularly suitable for solving magnetic screening problems. During the magnetic bead separation process, the purpose of the magnetic field generating device 2 is not to dynamically adjust the magnetic field, but to maintain a stable gradient magnetic field with a fixed magnetic field strength to achieve efficient capture of target magnetic beads. The magnetic field fluctuations generated by the electromagnet during the adjustment process can result in incomplete capture of target magnetic beads or the capture of impurity magnetic beads. Furthermore, the small magnetic tiles 222 have a higher edge-to-area ratio. By densely arranging a large number of small magnetic tiles 222 in the embedded magnetic layer 22, the magnetic flux lines are concentrated at the intersections between the magnetic poles, thereby expanding the effective capture area.

[0076] The magnetic tile 222 is preferably a block with a regular hexagonal, rhombus or parallelogram cross section. The specific cross-sectional shape can be selected according to the magnetic field arrangement requirements and processing technology limitations. Figures 7a-7d , Figure 7a The regular hexagonal magnetic tile 222 used for example top surface magnetization, Figure 7b The regular hexagonal magnetic tile 222 used for example top surface magnetization, Figure 7c The square magnetic tile 222 used for example longitudinal embedded magnetism, Figure 7d A square magnetic tile 222 is used to illustrate a transversely embedded magnet. The yellow area represents the magnetic attraction area, the blue area represents the north pole of the magnetic tile, and the red area represents the south pole of the magnetic tile.

[0077] It should be noted that, referring to Figure 8aand Figure 8b Although the rhombus-shaped magnetic tile 222 can theoretically maximize the magnetic attraction area, it is difficult for the permanent magnet material factory to ensure that the magnetic poles fall accurately on the tip of the rhombus during the magnetization process of the magnetic tile 222, which easily causes the magnetic pole offset phenomenon at the edge of the rhombus. Figure 8b It can be seen that the magnetization processing error causes the loss of magnetic attraction area. However, the hexagonal magnetic tile 222 effectively avoids the above-mentioned offset problem by adding two symmetrical edges.

[0078] Regarding the embedding method of the magnetic tile 222, refer to Figure 7c 、 Figure 7d and Figure 9 , can be embedded horizontally, embedded vertically, or arranged in a Halbach array. The Halbach array uses a specific magnet arrangement to increase the magnetic field strength on one side of the magnetic field generator 2 while significantly weakening it on the other side. This creates a strong magnetic field on one side of the pipe wall while preventing magnetic field leakage.

[0079] In an optional embodiment of the present application, with reference to FIG1 , the drive device 3 includes a motor module 31, a transmission rod 33, and a support rod 32. The bracket 4 is located on both sides of the motor module 31 and is internally provided with a transmission rod 33. The motor module 31 is output through the transmission rod 33 and is transmitted to the transmission rod 33 in the bracket 4 through the helical gear. The rotation of the transmission rod 33 drives the sliding structure 6 screwed thereto to move upward, thereby pushing the magnetic field generating device 2 to translate up and down. In different embodiments, the motor module can be a cylinder, an electric push rod, or other different forms. In addition, the transmission form of the transmission rod 33 here can also be specifically embodied in different forms, such as equivalent replacement with a worm gear and worm gear transmission, or equivalent replacement with a gear and rack transmission, or equivalent replacement with a hydraulic transmission, a screw drive, etc. The motor module 31 is mounted on a pillar located in the middle of the bracket 4, and the support rod 32 is arranged at the top of the pillar and is slidably connected to the top of the pillar in the axial direction of the pillar, playing a directional role in the translation of the magnetic field generating device 2.

[0080] In another optional embodiment of the present application, referring to Figure 10The driving device 3 includes a motor module 31, a threaded transmission rod 33 and a support rod 32. The bracket 4 is located on both sides of the motor module 31 and the top is connected to the magnetic field generating device 2 through a sliding structure 6. The rotation of the threaded transmission rod 33 is controlled by the motor module 31. The motor module 31 can be a servo motor, a stepping motor or a DC motor, and its output shaft is connected to the threaded transmission rod 33. The support rod 32 is arranged between the brackets 4, and the top end is fixedly connected to the magnetic field generating device 2, and the bottom end is threadedly connected to the top end of the threaded transmission rod 33. The rotation of the threaded transmission rod 33 drives the support rod 32 screwed thereto to move axially, so that the magnetic field generating device 2 connected to one end of the support rod 32 can be translated up and down.

[0081] In practical applications, the above-mentioned drive mechanism can be adjusted according to different requirements of spatial layout, response speed or load intensity. For example, mechanical transmission methods such as turbines, worms, gears, and rack structures can be used to achieve high torque and small speed ratio transmission requirements; for example, linear drive elements such as electric push rods, ball screws, hydraulic cylinders or pneumatic cylinders can be used to achieve rapid linear movement.

[0082] Working principle: During the operation of the magnetic bead continuous separation device of the present application, when the liquid to be separated carrying the magnetic beads is injected into the magnetic bead separator 1 from the first liquid inlet 11, it will flow along the axial direction of the magnetic bead separator 1. The magnetic field generating device 2 is attached to the outer wall of the magnetic bead separator 1, and the magnetic tiles 222 embedded therein can form a stable magnetic field inside the magnetic bead separator 1. When the magnetic beads pass through the magnetic field action area, they will be affected by the magnetic field force, thereby causing an offset movement, and eventually being captured to the side of the inner wall of the magnetic bead separator 1 close to the magnetic field source. During this process, the waste liquid is discharged through the first liquid discharge port 13.

[0083] During the capture process, the target magnetic beads form a compacted mass, clinging to the tube wall under the influence of the magnetic field to form a deposited zone, preventing them from being swept away by the liquid flow. After the capture process is complete, the magnetic field generator 2 leaves the magnetic bead separator 1, significantly reducing the magnetic force on the beads. Washing liquid is introduced through the second liquid inlet 12, impacting the deposited zone of target magnetic beads and then being discharged from the second liquid outlet 14, carrying the target magnetic beads with it.

[0084] As an example, the magnetic bead continuous separation device can implement the processes of magnetic bead separation, washing, enrichment and purification through the following steps S1-S6.

[0085] S1. Pre-fill the magnetic bead separator 1 through the first liquid inlet 11 and input the washing solution into the interior thereof until it is full; S2. The driving device 3 controls the magnetic field generating device 2 to approach and adhere to the magnetic bead separator 1, and simultaneously introduces the untreated raw liquid containing the target magnetic beads into the first liquid inlet 11, so as to capture the magnetic particles in the magnetic bead capture zone through the magnetic field capture method, and discharge the non-magnetic waste liquid through the first liquid discharge port 13 until the target magnetic bead concentration at the first liquid discharge port 13 reaches a first set value; wherein the target magnetic beads are particles that can be effectively captured by the magnetic field generating device 2, and the non-magnetic components in the non-magnetic waste liquid are impurity components that are not captured by the magnetic field generating device 2; S3. The driving device 3 controls the magnetic field generating device 2 to move away from the magnetic bead separator 1 and injects a washing solution through the first liquid inlet 11 to flush the target magnetic beads enriched in the magnetic bead capture zone out to the external container via the second liquid discharge port 14; S4. Driving device 3 again controls magnetic field generating device 2 to approach and attach to magnetic bead separator 1, and reintroduces the enriched liquid stored in the external container into first liquid inlet 11, thereby capturing magnetic particles in the magnetic bead capture zone through magnetic field capture, and discharging non-magnetic waste liquid through first liquid discharge port 13; S5. The driving device 3 controls the magnetic field generating device 2 to move away from the magnetic bead separator 1 and injects a washing solution into the first liquid inlet 11 to flush the target magnetic beads enriched in the magnetic bead capture zone into the finished product tank through the second liquid discharge port 14 until the target magnetic bead concentration at the second liquid discharge port 14 is lower than a third set value. S6. Check whether all the raw liquid to be processed has been processed. If not, return to S1.

[0086] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A magnetic bead continuous separation device, characterized in that: The magnetic bead separator comprises a magnetic bead separator (1), a magnetic field generating device (2) and a driving device (3), wherein the driving device (3) is used to drive the magnetic field generating device (2) to move closer to or farther from the side wall of the magnetic bead separator (1); the magnetic bead separator (1) is hollow and has a first liquid inlet (11) and a second liquid inlet (12) at one end, and a first liquid discharge port (13) and a second liquid discharge port (14) at the other end.

2. The magnetic bead continuous separation device according to claim 1, characterized in that The magnetic bead separator (1) is used for vertical placement, the first liquid inlet (11) and the second liquid inlet (12) are arranged at the top end of the magnetic bead separator (1), and the first liquid discharge port (13) and the second liquid discharge port (14) are arranged at the bottom end of the magnetic bead separator (1); the second liquid inlet (12) of the magnetic bead separator (1) is arranged on a side of the magnetic bead separator (1) close to the magnetic field generating device (2) relative to the first liquid inlet (11); and the second liquid discharge port (14) of the magnetic bead separator (1) is arranged on a side of the end of the magnetic bead separator (1) close to the magnetic field generating device (2) relative to the first liquid discharge port (13).

3. The magnetic bead continuous separation device according to claim 1, characterized in that The magnetic bead separator (1) is used for horizontal placement, and the second liquid inlet (12) of the magnetic bead separator (1) is arranged on a side of the end of the magnetic bead separator (1) close to the magnetic field generating device (2) relative to the first liquid inlet (11); and the second liquid discharge port (14) of the magnetic bead separator (1) is arranged on a side of the magnetic bead separator (1) close to the magnetic field generating device (2) relative to the first liquid discharge port (13).

4. The magnetic bead continuous separation device according to claim 2 or 3, characterized in that: The second liquid inlet (12) is tangent to the tube wall of the magnetic bead separator (1); and / or the second liquid discharge port (14) is tangent to the tube wall of the magnetic bead separator (1).

5. The magnetic bead continuous separation device according to claim 1, characterized in that: The driving device (3) comprises a motor module (31), a transmission rod (33) and a support rod (32); the two ends of the support rod (32) are respectively connected to the transmission rod (33) and the magnetic field generating device (2); the motor module (31) is used to drive the transmission rod (33) to push the support rod (32) and the magnetic field generating device (2) toward the magnetic bead separator (1) or away from the magnetic bead separator (1).

6. The magnetic bead continuous separation device according to claim 7, characterized in that: The magnetic field generating device (2) comprises an anti-stripping layer (21), an embedded magnetic layer (22) and a shielding layer (23) which are sequentially arranged from the inside to the outside; a magnet is embedded in the embedded magnetic layer (22); and the anti-stripping layer (21) and the shielding layer (23) cooperate with the embedded magnetic layer (22) to form a cavity for accommodating and limiting the magnet.

7. The magnetic bead continuous separation device according to claim 6, characterized in that The inner side wall of the anti-stripping layer (21) is in contact with the outer wall of the magnetic bead separator (1) and its shape is adapted to the outer wall of the magnetic bead separator (1).

8. The magnetic bead continuous separation device according to claim 6, characterized in that: The embedded magnetic layer (22) comprises a support plate (221) and a plurality of magnetic tiles (222); the support plate (221) is provided with a plurality of limiting grooves (223) for limiting the movement of the magnetic tiles (222); the magnetic tiles (222) are installed in the limiting grooves (223).

9. The magnetic bead continuous separation device according to claim 8, characterized in that: The embedding manner of the magnetic tile (222) on the support plate (221) includes horizontal embedding, longitudinal embedding, and Halbach array embedding.

10. The magnetic bead continuous separation device according to claim 1, characterized in that: When the liquid to be separated passes through the magnetic bead separator (1), the magnetic beads are exposed to the magnetic field generated by the magnetic field generating device (2), and the magnetic field generating device (2) can capture the target magnetic beads on the tube wall of the magnetic bead separator (1).

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