WO2009047714A1 - Dispositif de manipulation magnétique pour des billes magnétiques - Google Patents
Dispositif de manipulation magnétique pour des billes magnétiques Download PDFInfo
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- WO2009047714A1 WO2009047714A1 PCT/IB2008/054119 IB2008054119W WO2009047714A1 WO 2009047714 A1 WO2009047714 A1 WO 2009047714A1 IB 2008054119 W IB2008054119 W IB 2008054119W WO 2009047714 A1 WO2009047714 A1 WO 2009047714A1
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Classifications
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- 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
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- 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
- B03C1/025—High gradient magnetic separators
- B03C1/031—Component parts; Auxiliary operations
- B03C1/033—Component parts; Auxiliary operations characterised by the magnetic circuit
- B03C1/0335—Component parts; Auxiliary operations characterised by the magnetic circuit using coils
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
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- B03C1/02—Magnetic separation acting directly on the substance being separated
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- B03C1/288—Magnetic plugs and dipsticks disposed at the outer circumference of a recipient
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- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
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- B03C2201/26—Details of magnetic or electrostatic separation for use in medical or biological applications
Definitions
- the invention relates to a magnetic manipulation device and an examination device comprising the former for generating magnetic fields in a manipulation region. Moreover, it relates to the use of such devices.
- the US 7 217 561 B2 discloses a device for generating magnetic fields with which magnetic beads can be moved in a sample.
- the device comprises two conductive structures running parallel to each other, wherein the current density and thus the induced magnetic field varies periodically along the structures.
- a two- dimensional matrix of individual coils for generating magnetic field gradients was disclosed in literature (R. Heer et al., "Acceleration of incubation processes in DNA bio chips by magnetic particles", Journal of Magnetism and Magnetic Materials 311, 244- 248 (2007)).
- the invention relates to a magnetic manipulation device for generating magnetic fields, particularly magnetic fields that comprise nonzero gradients, in a spatial region that will be called “manipulation region” the following.
- the generated magnetic fields may serve for different purposes, for example for the active movement of target particles like biological molecules labeled with magnetic beads.
- the manipulation device comprises the following components: a) At least one (geometrically connected) "core structure” or “core body” that comprises a magnetizable material and an array of pin- like structures that will be called “fingers” in the following and that extend towards the manipulation region.
- Typical numbers of fingers range from three to 50, preferably from 5 to 20.
- array shall denote here in the most general sense any one-, two- or three-dimensional arrangement of objects. In most cases, the array will be a one- or two-dimensional arrangement.
- a plurality of coils i.e. electrical conductor lines wound to a helix with at least one turn
- a controller for selectively supplying excitation currents to the aforementioned coils may comprise dedicated electronic hardware, e.g. driver circuits with current sources for generating the excitation currents, and/or digital data processing hardware with associated software for executing a higher-level control of the current supply to the coils.
- the selectivity of the current supply to the coils shall mean that at least two coils get different currents, e.g. some basic current with different phases.
- the controller is able to supply each coil with an individual excitation current.
- the magnetic manipulation device has the advantage to provide strong magnetic fields in a large region in space with a comparatively compact structure and with coils of moderate size. This is achieved by arranging a plurality of selectively controllable coils at the fingers of a connected core structure, wherein said core structure spreads the generated magnetic fields beyond the immediate vicinity of the individual coils.
- the invention further relates to an examination device for manipulating a sample in a sample chamber, wherein the term "manipulation” shall denote any interaction with said sample, for example measuring characteristic quantities of the sample, investigating its properties, processing it mechanically or chemically or the like.
- the examination device is characterized in that it comprises a magnetic manipulation device of the kind described above, i.e. a device for generating magnetic fields in a manipulation region with at least one core structure comprising a magnetizable material and an array of fingers with coils, and with a controller for selectively supplying the coils with excitation currents.
- the examination device may optionally comprise a seat (i.e. a void space or reservoir) for taking up an exchangeable microfluidic device.
- the microfluidic device that comes into contact with a sample to be manipulated can thus be handled separately from the examination device and can be designed as a disposable part.
- the microfluidic device may for example be a cartridge or a well-plate to which a biological specimen (e.g. blood, saliva) is applied and which can be inserted into a reader for the execution of the desired biosensor operations.
- a biological specimen e.g. blood, saliva
- the examination device will comprise at least one sensor element for sensing a characteristic property of a sample and/or a temperature- regulator for controlling the temperature of a sample (i.e. for heating and/or cooling).
- the magnetic manipulation device can favorably be applied to affect the distribution of magnetic target particles in a sample, e.g. by attracting them towards a sensitive surface and/or by washing away unbound target particles from a binding surface.
- the mentioned sensor element may preferably be an optical, magnetic, mechanical, acoustic, thermal and/or electrical sensor element.
- a magnetic sensor element may particularly comprise a coil, Hall sensor, planar Hall sensor, flux gate sensor, SQUID (Superconducting Quantum Interference Device), magnetic resonance sensor, magneto -restrictive sensor, or magneto -resistive sensor of the kind described in the WO 2005/010543 Al or WO 2005/010542 A2, especially a GMR (Giant Magneto Resistance), a TMR (Tunnel Magneto Resistance), or an AMR (Anisotropic Magneto Resistance).
- An optical sensor element may particularly be adapted to detect variations in an output light beam that arise from a frustrated total internal reflection due to target particles at a sensing surface.
- the magnetizable material of the core structure may optionally comprise a soft magnetic material, particularly iron alloys (e.g. CoFe) and/or ferrites.
- a soft magnetic material particularly iron alloys (e.g. CoFe) and/or ferrites.
- preferred characteristics of the core material are: high permeability, high saturation magnetization, and a low remanence.
- the core structure may preferably have a comb-like form with fingers extending from a stem or backbone.
- two neighboring coils will be disposed on an U-shaped piece of the core structure, which allows an optimal concentration of magnetic field lines.
- the array of fingers of the core structure may particularly be two-dimensional.
- the array of fingers of the core structure comprises at least one linear section. Such a linear section can then be used to move magnetic particles in an adjacent sample along a line, e.g. along the extension of a microfluidic channel.
- the controller of the magnetic manipulation device is preferably adapted for generating activity patterns that move wave-like along the array of coils, wherein the "activity pattern" at a point in time is defined by the excitation currents momentarily applied to the individual coils.
- the moving activity pattern may for example comprise the sequential application of a given excitation current to one coil after the other along the line of coils/fingers.
- the moving activity pattern can particularly be used to move magnetically attracted material, e.g. magnetic beads, through the manipulation region.
- two core structures may be disposed on opposite sides of the manipulation region.
- the manipulation region can be reached by magnetic fields from two sides, allowing the control of larger volumes and reducing the risk that magnetic particles may escape from the reach of a single manipulation device.
- the fingers of the two core structures are interlaced.
- an optimal coverage of the manipulation region with magnetic fields can be achieved.
- magnetically attracted material can be moved in a desired direction by activating the two core structures in an alternating way.
- the manipulation region may lie anywhere in space where the generated magnetic fields are required.
- the manipulation region may extend freely into the ambience if for example environmental measurements in the ambient atmosphere or in water are intended.
- a microfluidic device is arranged in the manipulation region, wherein said device can provide a sample to be manipulated in a definite way.
- the aforementioned microfluidic device may optionally comprise different regions where different environmental conditions can be established. It may for example comprise several chambers containing different chemicals (e.g. for lysis, amplification, etc.) and/or with different temperatures.
- the invention further relates to the use of the magnetic manipulation device and/or the examination device described above for molecular diagnostics, biological sample analysis, or chemical sample analysis, food analysis, and/or forensic analysis.
- Molecular diagnostics may for example be accomplished with the help of magnetic beads or fluorescent particles or magnetizable fluorescent particles that are directly or indirectly attached to target molecules.
- Figure 1 shows schematically a cross section through a sensor device with a magnetic manipulation device having a comb-like core structure
- Figure 2 shows in a similar cross section a modified sensor device with a second comb-like core structure
- Figure 3 shows schematically a top view onto a microfluidic device with a magnetic manipulation device according to the present invention below it.
- the invention will in the following (without loss of generality) be described with respect to biological assays that rely on the detection of magnetic particles or beads serving as labels for biomolecules of interest.
- Suited detectors for such magnetic particles are magneto -resistive biochips or biosensors which have promising properties for bio-molecular diagnostics, in terms of sensitivity, specificity, integration, ease of use, and costs. Examples of such biochips are described in the WO 2003/054566, WO 2003/054523, WO 2005/010542 A2, WO 2005/010543 Al, and WO 2005/038911 Al, which are incorporated into the present application by reference.
- Magnetic labels in biological assays offer several advantages for use in point-of-care diagnostics tests, as they are:
- the magnetic beads can be homogeneously dispersed in a sample. This shortens the incubation time (not dependant on diffusion kinetics anymore). By actuating the beads and attracting them to the sensor surface an upconcentration of target molecules (bound to magnetic labels) takes place. This speeds up the binding to the detector surface.
- Lysis To break the cells and to access the DNA.
- - Amplification To increase the DNA concentration in the sample
- PCR Polymerase Chain Reaction
- NASBA Nucleic Acid Sequence Base Amplification
- Detection The final detection step to determine the DNA concentration of a certain type that matches with the complementary oligo that is immobilized on the sensor surface. All these steps may need a different buffer fluid (e.g. a lysis buffer with chemicals to break the cell- wall, an amplification buffer with specific enzymes for the PCR or NASBA protocol, and a detection buffer to optimize hybridization at the sensor surface).
- a buffer fluid e.g. a lysis buffer with chemicals to break the cell- wall, an amplification buffer with specific enzymes for the PCR or NASBA protocol, and a detection buffer to optimize hybridization at the sensor surface.
- One option is to apply pumps and valves and other microfluidic elements to provide a different buffer at different moments during the complete assay protocol.
- Another solution is to transport the biological molecules of interest by binding them to magnetic beads and move the beads by proper actuation fields from a first buffer solution in a first chamber or region to a second buffer solution in a second chamber or region.
- biological molecules can be moved from
- a large actuation structure is needed for moving the beads from one chamber of a microfluidic cartridge to another.
- magnetic fields and magnetic field gradients decrease rapidly at larger distances from the core material of an electromagnet. This makes single magnets not suitable for actuation over large distances.
- An alternative are magnetic actuation structures integrated in a fluidics cartridge; however, these structures add cost to the cartridge and typically require many electrical connections. Additionally, integrated structures tend to create large peaks in field gradient, due to their rather small dimensions. This could lead to unwanted non-specific binding events taking place.
- FIG. 1 shows a first embodiment of a sensor device 100 according to this approach.
- the sensor device 100 may for example be a biosensor with sensor elements (e.g. GMR sensors, not shown) for detecting magnetic particles in a sample that is provided in a disposable cartridge 10. It comprises a substrate 120 in which a magnetic manipulation device 110 according to the present invention is embedded. Above the substrate 120, the micro fluidic cartridge 10 is disposed in a seat of the sensor device 100.
- This cartridge 10 has a cover 11 with microfluidic channels and chambers 12 (in which a sample to be investigated can be provided) and a substrate 13 as a bottom.
- the substrate can be made of any material that does not cause flux guiding of the magnetic fields lines through its material, i.e. it can be an optical substrate made of injection molded polymer, or it can be some interconnect material that allows the integration of GMR chips in the integrated cartridge.
- the microfluidic cartridge 10 is typically a disposable made from plastics and thus a component separate from the sensor device 100.
- the magnetic manipulation device 100 that is embedded into the substrate 120 comprises the following components:
- Coils 114 that are wound around the fingers 113.
- a controller 115 that is connected to the coils 114 for selectively supplying them with excitation currents.
- an array of magnetic poles can be present with an array of coils (either one-dimensional or two-dimensional). By driving the coils in a predetermined order bead transport in different directions is possible. This allows more freedom in designing different fluidic cartridges (i.e. different chamber and channel geometries) for a generic reader device. Depending on the fluidic cartridge that is used, particular sub-groups of the coils may be activated in this case (typically those below microfluidic channels). In contrast to the embodiment shown in Figure 1, the magnetic manipulation device might also be disposed above the microfluidic cartridge 10.
- Figure 2 shows a further embodiment of a microelectronic sensor device 200 in which a first core structure 211a with coils is disposed below the microfluidic cartridge 10 in a substrate 220a, and a second core structure 211b with coils is disposed above the microfluidic cartridge 10 in a substrate 220b, wherein the coils of both core structures are coupled to a controller 215.
- a magnetic manipulation device 210 with two core structures is realized.
- the coils/fingers of the top core structure 211b are shown to fall in between the coils/fingers of the bottom core structure 211a, i.e. the coils/fingers of the devices are interlaced. This helps to increase the efficiency of the transport.
- Figure 3 shows a top view onto a typical microfluidic cartridge 10 comprising an inlet 12a and two fluidic chambers 12c, 12e connected via fluidic channels 12b, 12d. Underneath the fluidic channel 12d a comb-like magnetic manipulation device 310 (like that shown in Figures 1 and 2) is present at the moment the fluidic cartridge 10 is inserted into the reader.
- a comb-like magnetic manipulation device 310 like that shown in Figures 1 and 2 is present at the moment the fluidic cartridge 10 is inserted into the reader.
- microfluidic device can be substantially non- magnetic, i.e. it can be made of plastic material made in an injection moulding process. Therefore, the cartridge can be simple and cheap.
- the comb-like actuation structure is present in the reader and will add cost to the reader only.
- the described mechanisms particularly allow to move magnetic samples along a flow-channel, which can be used to automate a series of pre-treatment steps. Further advantages of this solution are: a large lateral distance can be covered, so transport from one chamber to the other becomes feasible; the magnetic field of the external magnets extends over the full height of the channels; no moving parts; - no large peak-gradients are generated that could lead to nonspecific binding.
- the microelectronic sensor device can comprise any suitable sensor element to detect the presence of particles on or near to a sensor surface, based on any property of the particles, e.g. it can detect via magnetic methods, optical methods (e.g. imaging, fluorescence, chemiluminescence, absorption, scattering, surface plasmon resonance, Raman, etc.), sonic detection (e.g. surface acoustic wave, bulk acoustic wave, cantilever, quartz crystal etc), electrical detection (e.g. conduction, impedance, amperometric, redox cycling), etc.
- optical methods e.g. imaging, fluorescence, chemiluminescence, absorption, scattering, surface plasmon resonance, Raman, etc.
- sonic detection e.g. surface acoustic wave, bulk acoustic wave, cantilever, quartz crystal etc
- electrical detection e.g. conduction, impedance, amperometric, redox cycling
- a magnetic sensor can comprise any suitable sensor element based on the detection of the magnetic properties of the particle on or near to a sensor surface, e.g. a coil, magneto -resistive sensor, magneto -restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID, magnetic resonance sensor, etc.
- a sensor surface e.g. a coil, magneto -resistive sensor, magneto -restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID, magnetic resonance sensor, etc.
- moieties can be detected with sensor devices according to the invention, e.g. cells, viruses, or fractions of cells or viruses, tissue extract, etc.
- the detection can occur with or without scanning of the sensor element with respect to the sensor surface.
- Measurement data can be derived as an end-point measurement, as well as by recording signals kinetically or intermittently.
- the particles serving as labels can be detected directly by the sensing method.
- the particles can be further processed prior to detection.
- An example of further processing is that materials are added or that the
- the device and method can be used with several biochemical assay types, e.g. binding/unbinding assay, sandwich assay, competition assay, displacement assay, enzymatic assay, etc. It is especially suitable for DNA detection because large scale multiplexing is easily possible and different oligos can be spotted via ink-jet printing on the (e.g. optical) substrate.
- biochemical assay types e.g. binding/unbinding assay, sandwich assay, competition assay, displacement assay, enzymatic assay, etc. It is especially suitable for DNA detection because large scale multiplexing is easily possible and different oligos can be spotted via ink-jet printing on the (e.g. optical) substrate.
- the device and method are suited for sensor multiplexing (i.e. the parallel use of different sensors and sensor surfaces), label multiplexing (i.e. the parallel use of different types of labels) and chamber multiplexing (i.e. the parallel use of different reaction chambers).
- the device and method can be used as rapid, robust, and easy to use point-of-care biosensors for small sample volumes.
- the reaction chamber can be a disposable item to be used with a compact reader, containing the one or more field generating means and one or more detection means.
- the device, methods and systems of the present invention can be used in automated high- throughput testing.
- the reaction chamber is e.g. a well-plate or cuvette, fitting into an automated instrument.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Fluid Mechanics (AREA)
- Dispersion Chemistry (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
Abstract
L'invention porte sur un dispositif de manipulation magnétique (110) qui peut, par exemple, être intégré dans un biodétecteur magnétique (100). Le dispositif de manipulation magnétique (110) comprend au moins une structure de noyau (111) avec un réseau de doigts (113) portant des bobines (114) qui peuvent être sélectivement alimentées avec des courants d'excitation par un dispositif de commande (115). La structure de noyau (111) a, de préférence, une forme de type peigne et peut, par exemple, s'étendre le long de canaux (12) d'un dispositif microfluidique échangeable (10) dans lequel un échantillon avec des particules cibles magnétiques peut être introduit. Le dispositif de commande (115) est, de préférence, conçu pour générer des motifs d'activité mobiles.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP07118260.4 | 2007-10-11 | ||
EP07118260 | 2007-10-11 |
Publications (1)
Publication Number | Publication Date |
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WO2009047714A1 true WO2009047714A1 (fr) | 2009-04-16 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IB2008/054119 WO2009047714A1 (fr) | 2007-10-11 | 2008-10-08 | Dispositif de manipulation magnétique pour des billes magnétiques |
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WO (1) | WO2009047714A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102012210077A1 (de) * | 2012-06-15 | 2013-12-19 | Siemens Aktiengesellschaft | Verfahren und Anordnung zur Markierung von Zellen in einer Zellsuspension |
CN109746064A (zh) * | 2019-01-28 | 2019-05-14 | 武汉纺织大学 | 一种梯度磁场微流控芯片 |
US10725126B2 (en) | 2016-09-05 | 2020-07-28 | Industrial Technology Research Institute | Biomolecule magnetic sensor |
FR3125442A1 (fr) * | 2021-07-26 | 2023-01-27 | Airbus Helicopters | Procédé et dispositif de captation de particules ferromagnétiques pour un système mécanique, et système mécanique associé |
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US20020022276A1 (en) * | 1999-03-15 | 2002-02-21 | Yuxiang Zhou | Individually addressable micro-electromagnetic unit array chips |
US6716642B1 (en) * | 1999-03-15 | 2004-04-06 | Aviva Biosciences Corporation | Individually addressable micro-electromagnetic unit array chips in horizontal configurations |
US20030012693A1 (en) * | 2000-08-24 | 2003-01-16 | Imego Ab | Systems and methods for localizing and analyzing samples on a bio-sensor chip |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102012210077A1 (de) * | 2012-06-15 | 2013-12-19 | Siemens Aktiengesellschaft | Verfahren und Anordnung zur Markierung von Zellen in einer Zellsuspension |
US10725126B2 (en) | 2016-09-05 | 2020-07-28 | Industrial Technology Research Institute | Biomolecule magnetic sensor |
CN109746064A (zh) * | 2019-01-28 | 2019-05-14 | 武汉纺织大学 | 一种梯度磁场微流控芯片 |
FR3125442A1 (fr) * | 2021-07-26 | 2023-01-27 | Airbus Helicopters | Procédé et dispositif de captation de particules ferromagnétiques pour un système mécanique, et système mécanique associé |
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