Electromagnetic sampling device protected in a septum piercing needle

Abstract

An electromagnetic sampling device is disclosed, the device comprising a needle having a hollow housing extending from a proximal end to a distal end, and an electromagnet comprising an electromagnetic coil and a metal core, at least a portion of the metal core extending through the hollow housing of the needle and configured to transition between an extended position, wherein the distal end of the metal core extends beyond the distal end of the hollow housing of the needle, and a retracted position, wherein the distal end of the metal core is disposed within the housing of the needle, wherein activation of the electromagnetic coil magnetizes the metal core.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 984,192, filed on March 2, 2020, the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] The present teachings generally relate to electromagnetic devices that can be used in magnetic particle-based sampling techniques.

[0004] Vacutainer tubes and other similar tubes / vials with rubber caps are widely used in various fields, especially in clinical laboratories. Samples can be inserted into these containers by piercing the rubber cap with a needle without opening the container, thus reducing potential biohazards, sample contamination, and solvent evaporation.

[0005] Solid phase microextraction (SPME) devices have been developed that can perform sampling, sample preparation, and extraction in a single step, greatly simplifying sample analysis. Such SPME devices can include a fiber protected within a needle that can be used to pierce the septum of a sealed container. Once the needle is inserted into the container, the fiber can be pushed further down to immerse it in the sample for extraction of one or more analytes of interest. After the extraction process, the fiber is pulled back into the protective needle and removed from the sample vial.

[0006] While SPME devices have proven successful in extracting and transferring samples, they exhibit certain drawbacks. For example, the binding capacity of conventional SPME fibers is limited by their small surface area. While significant enhancements in extraction efficiency can be achieved when employing SPME membranes with larger surface areas, integrating SPME membranes with rubber piercing needles is difficult. Summary of the Invention

[0007] An electromagnetic sampling device is disclosed. The device includes a needle having a hollow housing extending from a proximal end to a distal end, and an electromagnet including an electromagnetic coil and a metal core. At least a portion of the metal core extends through the hollow housing of the needle and is configured to transition between an extended position and a retracted position. In the extended position, the distal end of the metal core extends beyond the distal end of the needle's hollow housing. In the retracted position, the distal end of the metal core is positioned within the needle housing. Activation of the electromagnetic coil can magnetize the metal core. This activation can occur in both the retracted and extended positions.

[0008] The electromagnetic sampling device further comprises a flange coupled to the metal core for moving the metal core between an extended position and a retracted position. In some embodiments, the housing of the needle is configured at its distal end to pierce a septum for sealing a container.

[0009] In some embodiments, the electromagnet is positioned outside the hollow housing of the needle.

[0010] When the metal core is magnetized via activation of the electromagnetic coil, the metal core can be configured to collect a plurality of magnetic particles placed in a container. In some embodiments, the hollow shell of the needle is substantially cylindrical. For example, in some embodiments, such a hollow cylindrical shell can have an inner diameter equal to or greater than about 0.5 mm. For example, the inner diameter of the hollow cylindrical shell can be in the range of about 0.5 mm to about 10 mm.

[0011] In some embodiments, the housing of the needle comprises a magnetic shielding material, such as ferromagnetic metal or MuMetal. In some embodiments, the metal core may be formed of any one of silicon steel or ferrite.

[0012] In some embodiments, in the extended position, the distal end of the metal core extends beyond the distal end of the needle housing by a length in a range from about 1 mm to about 100 mm.

[0013] In a related aspect, a method is disclosed for collecting magnetic particles from a particle container and transferring the collected magnetic particles to a container sealed by a diaphragm using an electromagnetic sampling device according to the present teachings. Such a method may include inserting at least the distal end of a needle into a container containing a plurality of magnetic particles. Typically, the distal end of the needle is inserted into the container with a metal core in a retracted position. Subsequently, the metal core can be transitioned from the retracted position to an extended position so that the distal end of the metal core is close to the magnetic particles. The electromagnetic coil can be activated to magnetize the metal core, and at least some of the magnetic particles can be captured via the magnetized metal core. The metal core and the associated collected magnetic particles can then be transitioned from the extended position to a retracted position, and the needle and the captured metal particles can be removed from the particle container.

[0014] The needle can then be used to pierce the septum of a sealed container in which one or more target analytes are placed, and at least the distal end of the needle can be inserted into the sealed container. The metal core can be transformed from a retracted position to an extended position, and the electromagnet can be deactivated to release the captured magnetic particles into a container in which (one or more) target analytes are placed. In certain embodiments, the magnetic particles are functionalized, for example, coated, to capture the target analyte. For example, in certain embodiments, the magnetic particles can be functionalized by antibodies that exhibit specific binding to the target analyte. In other embodiments, the magnetic particles can be functionalized by C18, antibodies, or any other suitable moiety.

[0015] In certain embodiments, the mixing of magnetic particles is performed to promote the capture of target analytes by these particles. This mixing can be achieved, for example, via an AC mixing device. In certain embodiments, an RF source can be coupled to an electromagnetic sampling device to apply an AC signal to its metal core to promote three-dimensional (3D) mixing of magnetic particles. In some such embodiments, the frequency of the AC signal can be in the range of about 1 Hz to about 400 Hz. The field intensity generated by the AC signal can be, for example, in the range of 50 to 200 mT, for example, in the range of about 20 to 100 mT.

[0016] The metal core can then be retracted to bring the magnetic particles into the housing of the needle together with the target analyte attached thereto. The needle can then be removed from the target container to extract the magnetic particles and the associated attached target analyte. In some embodiments, the distal end of the needle can be inserted into an open port sampling interface of a mass spectrometer, and the magnetic particles can be released into the mass spectrometer via the metal core being transitioned from a retracted position to an extended position and deactivating the electromagnet. In some embodiments, the magnetic particles to which the analyte is attached are cleaned before being introduced into the open port sampling interface.

[0017] In certain embodiments, when the continuous liquid flow in the OPP washes out the analyte from the magnetic particles (beads), the electromagnet remains energized. In certain embodiments, the magnetic particles can be released into the OPP interface, and an electromagnetic mixer can be used to mix the release particles in the OPP sampling port. For example, the teachings of the application 2018 / 0369831 published by the U.S. can be used for this mixing of magnetic particles, and the application is hereby incorporated by reference in its entirety. Alternatively, the teachings of the application 2020 / 0043712 published by the U.S. can be used to provide this mixing of magnetic particles, and the application is hereby incorporated by reference in its entirety. Alternatively, in certain embodiments, the magnetic particles can enter the OPP interface, and they travel to the outlet, or can be captured / collected somewhere downstream.

[0018] A further understanding of various aspects of the present teachings can be obtained by referring to the following detailed description taken in conjunction with the associated drawings, which are briefly described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1A and Figure 1B schematically depicts an electromagnetic device according to an embodiment of the present teachings,

[0020] Figure 2 depicts an electromagnetic device according to the present teachings inserted into a container containing a plurality of magnetic particles,

[0021] Figure 3A Depicts Figure 2 an electromagnetic device wherein the magnetic core together with the magnetic particles attached thereto is in a retracted position, wherein the distal end of the needle is used to pierce a septum of a sealed container in which one or more target analytes are placed,

[0022] Figure 3B Shown Figure 3A An electromagnetic device in which a magnetic core and attached magnetic particles are retracted into the housing of a needle,

[0023] Figure 4 is a flow chart depicting various steps in a method according to an embodiment for extracting magnetic particles from a container and transferring the extracted magnetic particles to another container,

[0024] Figure 5 Schematic diagram of a fluid mixing system that can be used to stir and mix multiple magnetic particles. DETAILED DESCRIPTION

[0025] The present invention generally relates to an electromagnetic sampling device comprising a protective needle and an electromagnet comprising an electromagnetic coil and a magnetizable metal core extending at least partially through the hollow housing of the protective needle. The metal core is transitionable between an extended position and a retracted position to allow transfer of magnetic particles from one container to another. In some embodiments, the electromagnetic sampling device can be used to introduce an analyte attached to a plurality of magnetic particles into an input port of a mass spectrometer.

[0026] Figure 1A and Figure 1B An electromagnetic sampling device 100 according to an embodiment is schematically depicted and includes a needle 102 characterized by a hollow cylindrical housing extending from a proximal end (PE) to a distal end (DE). In some embodiments, the distal end of the needle is configured to pierce a septum of a sealed container, as will be discussed in more detail below.

[0027] The electromagnetic sampling device 100 further includes an electromagnet 104 having an electromagnetic coil 106 and a magnetizable metal core 108 that can be magnetized by the electromagnetic coil when the coil is activated. The metal core 108 extends through the hollow housing of the needle housing from the proximal end to the distal end thereof. A flange 110 attached to the metal core allows the magnetizable metal core to be transitioned from a retracted position to an extended position, in which the distal end of the metal core is located within the needle housing ( Figure 1A ), the distal end of the metal core extends beyond the distal end of the needle housing in the extended position ( Figure 1B). As discussed in more detail below, once magnetized, in the extended position, the metal core can collect magnetic particles placed in a particle container, which can then be transferred to another container containing one or more analytes of interest. In some embodiments, the metal core is transformed by a mechanical actuator. In some embodiments, the activation of the electromagnetic coil can be linked to the position of the metal core. For example, in one embodiment, when the metal core is in the extended position, the electromagnetic coil is energized, and when the metal core is in the retracted position, the electromagnetic coil is de-energized.

[0028] As discussed in more detail below, in many embodiments, the magnetic particles are functionalized, for example, coated with antibodies that can specifically bind to one or more analytes, to allow them to be extracted, for example, from a container. Additionally, in some embodiments, the target analytes extracted via the magnetic particles can be introduced into an open port interface of a mass spectrometer.

[0029] As discussed in more detail below, the shape and size of the distal end of the needle are designed to allow it to penetrate the septum of a sealed container. As described above, in the present embodiment, the needle 102 has a hollow housing that is substantially cylindrical and has an inner diameter equal to or greater than about 0.5 mm. For example, in some embodiments, the inner diameter of the housing of the needle can be in the range of about 0.5 mm to about 10 mm. Generally speaking, the inner diameter of the housing of the needle is selected to ensure that it can accommodate the metal core (and the magnetic particles collected by the metal core, as discussed in more detail below) and further allow the needle to be used to pierce the septum of a sealed container. The needle can have a variety of different lengths. For example, the length of the needle (i.e., the distance between its proximal and distal ends) can be in the range of about 0.5 cm to about 20 cm.

[0030] In general, the diameter of the portion of the metal core intended to be received within the needle housing is selected to allow it to be inserted into the needle housing with sufficient clearance relative to the inner wall of the needle so that magnetic particles collected by the distal end of the needle can be entrained into the needle housing when the metal core transitions from the extended position to the retracted position. For example, in some embodiments, the diameter of the metal core (or at least the portion thereof for insertion into the needle housing) can be in the range of about 0.1 mm to about 10 mm, for example, in the range of about 0.3 mm to about 5 mm. The length of the portion of the metal core that extends beyond the distal end of the needle housing in the extended position can be, for example, in the range of about 1 mm to about 10 mm.

[0031] The needle can be formed from a variety of different materials. In this embodiment, the needle is formed from a magnetic shielding material. Using a magnetic shielding material to form the needle can advantageously inhibit and preferably prevent magnetic particles from being trapped on the outer surface of the needle. Some suitable examples of such magnetic shielding materials include, but are not limited to, ferromagnetic metals or MuMetal (a nickel-iron soft ferromagnetic alloy with high magnetic permeability).

[0032] In this embodiment, the electromagnetic coil 106 is placed outside the needle.In some embodiments, the electromagnetic coil assembly can have an outer diameter, for example, in the range of about 0.1 to about 100 mm, such as about 20 mm.

[0033] Continue to refer Figure 1A 、 Figure 1B and Figure 2 、 Figure 3A and Figure 3B as well as Figure 4 Flowchart, the above electromagnetic sampling device 100 can be used to collect magnetic particles (also referred to herein as magnetic beads) contained in a particle container and transfer these particles to another container containing one or more analytes of interest. The magnetic particles can be formed, for example, of a magnetic metal, such as a magnetic alloy. For example, in some embodiments, the magnetic particles can have a silica core with a metal coating, or can have a metal core. In some embodiments, the outer surface of the magnetic particles can be functionalized, for example, with antibodies or C18, to allow the magnetic particles to bind to one or more analytes of interest.

[0034] For example, in a method of transferring magnetic particles from one container to another using an electromagnetic sampling device according to the present teachings, at least the distal end of a needle 102 is inserted into a particle container 200 having disposed therein a plurality of magnetic particles 202. As described above, the magnetic particles can be functionalized to collect one or more analytes of interest.

[0035] Typically, when the needle is inserted into the particle container, the magnetizable metal core 108 is in a retracted position within the needle housing, but in other cases, the needle can be inserted into the particle container with the magnetizable metal core in an extended position. The magnetizable metal core 108 can then be transitioned from its retracted position to its extended position using the flange 110 so that the distal end of the metal core is adjacent to the magnetic particles, such as Figure 2 As shown in FIG. , the electromagnetic coil 106 can be activated (before or after the metal core is transformed from the retracted position to the extended position) to magnetize the metal core. The distal end of the magnetized metal core can then attract the magnetic particles so as to collect at least a portion of these particles, as shown in FIG. Figure 2 Schematically shown in FIG.

[0036] The distal end of the metal core and the magnetic particles attached thereto can then be retracted into the protective housing of the needle, and the needle can be removed from the particle container. The electromagnetic coil remains energized to ensure that the magnetic particles continue to remain attached to the magnetized distal end of the metal core. In many embodiments, the maximum value of the magnetic field strength is at the tip of the metal core, where most of the magnetic particles are typically captured. In order to quantitatively dispense the magnetic particles, in some embodiments, the magnetic particles are suspended in a solution and can be pre-stirred (e.g., via mechanical shaking) or with an electromagnetic mixer.

[0037] The distal end of the needle can then be used to pierce a septum 302 of a sealed container 300 in which a sample 304 containing at least one analyte of interest 305 is placed, such as Figure 3A For example, the analyte may be dispersed in a medium 306, such as a liquid. Once inserted into the sealed container 300, the metal core 108 may be moved from a retracted position to an extended position so as to bring the distal end of the metal core into proximity with the analyte 304, such as Figure 3B The electromagnetic coil may then be deactivated in order to demagnetize the metal core, thereby releasing the captured magnetic particles into the container 300.

[0038] In some embodiments, the released functionalized magnetic particles can be manipulated to facilitate the capture of (one or more) target analytes in the sample. For example, AC mixing of functionalized released particles can be used to facilitate the capture of (one or more) target analytes by the released particles. For example, published PCT application No. PCT / IB2018 / 050399, entitled “Electromagnetic Assemblies for Processing Fluid,” discloses methods and systems for mixing fluids that can be employed in some embodiments of the present teachings, and the application is incorporated herein by reference in its entirety. The publication generally discloses a fluid processing system comprising a magnetic assembly having a plurality of magnetic structures that are configured to generate a magnetic field gradient within a fluid container. The magnetic structure can be formed as a plurality of electromagnets that can be individually actuated by a controller, wherein each electromagnet can generate a magnetic field within a container. More specifically, the present invention is reproduced herein as Figure 5 The published Figure 2A fluid handling magnetic assembly 204 is depicted, comprising an upper magnetic structure 245a and a lower magnetic structure 245b, wherein each magnetic structure includes four electromagnets 210, each comprising a conductive wire 212 in the form of a coil. The inner ends of the electromagnets 210a-d are spaced from a central axis to accommodate a container of liquid therebetween. An AC signal can be applied to each of the electromagnets 210a-d to cause a magnetic field gradient to vary over time, thereby causing the fluid to mix due to the corresponding movement of magnetic particles within the container of fluid.

[0039] Furthermore, in some embodiments, Figure 3B As schematically shown in FIG, an RF source 400 can be coupled to the metal core 108 to apply an RF signal thereto to enhance three-dimensional mixing of the magnetic particles, for example, by mixing a medium in which an analyte is dispersed. The mixing of the particles can advantageously enhance their ability to capture the analyte(s) of interest.

[0040] After capturing the analyte(s) of interest, the magnetic particles can be removed from the sealed container using the electromagnetic sampling device 100. Specifically, the electromagnetic coil 106 can be re-energized to magnetize the metal core, and the magnetized metal core can be used to capture the magnetic particles, for example, by capturing the particles at the distal end of the metal core. The metal core, along with the captured magnetic particles, can be retracted into a housing protecting the needle, and the needle can be removed from the sealed container.

[0041] In some embodiments, the magnetic particles can include at least two groups of particles that are functionalized differently to capture different types of analytes. For example, in some such embodiments, one group of magnetic particles can be functionalized to capture proteins, while another group of magnetic particles can be functionalized to capture lipids. In this case, the methods discussed above can be used to independently perform sequential extraction of different analytes within a sample using different magnetic particles. In such embodiments, the extraction of one analyte does not adversely affect the extraction of another analyte.

[0042] In some embodiments, functionalized magnetic particles can be used to pre-treat the analyte of interest. For example, trypsin-coated magnetic particles can be introduced into a sample to decompose one or more analytes of interest. The trypsin-coated magnetic particles can then be removed and C18-functionalized magnetic particles can be introduced into the sample, for example, to extract peptides.

[0043] In some embodiments, the sampling device can be mechanically connected to the manipulator. The manipulator can be configured to operatively position the sampling device above the sample so that the distal end extends to contact the sample in the first container when in the extended position, and the distal end is retracted to move away from the sample when in the retracted position. In some embodiments, the manipulator may include a robotic arm. In some embodiments, the manipulator may be further configured to and operable to position the sampling device above the second container after capturing magnetic particles from the first container. The second container may include a liquid (e.g., a solvent) that can be used to clean the distal end and any magnetic particles contained therein. In some embodiments, the manipulator is further configured to and operable to position the sampling device opposite the open end of the open port sampling interface so that when in the extended position, the distal end extends and is immersed in the solvent flowing at the open end of the open port sampling interface, and retracts from the solvent when retracted into the retracted position.

[0044] Electromagnetic sampling devices according to the present teachings offer numerous advantages. For example, such devices can provide a higher surface area for capturing magnetic particles, thereby improving extraction efficiency. Furthermore, such electromagnetic sampling devices can be integrated with the RF frequency mixing discussed above.

[0045] It will be apparent to those skilled in the art that various changes can be made to the above embodiments without departing from the scope of the present invention.

Claims

1. An electromagnetic sampling device, comprising: a needle comprising a hollow housing extending from a proximal end to a distal end, and an electromagnet comprising an electromagnetic coil and a metal core, wherein activation of the electromagnetic coil magnetizes the metal core and causes the metal core to attract magnetic particles; wherein at least a portion of the metal core is capable of extending through the hollow shell of the needle; wherein the metal core is configured to transition between the following positions: an extended position in which the distal end of the metal core extends beyond the distal end of the hollow housing of the needle, and The distal end of the metal core and any magnetic particles attached thereto are disposed within the housing of the needle in the retracted position. 2 . The electromagnetic sampling device of claim 1 , further comprising a handle coupled to the metal core for moving the metal core between the extended position and the retracted position.

3. The electromagnetic sampling device according to claim 1, wherein: The needle housing is configured at its distal end to pierce a septum sealing a container.

4. The electromagnetic sampling device according to claim 3, wherein: The electromagnetic coil is placed outside the hollow housing of the needle.

5. The electromagnetic sampling device according to claim 3, wherein: The magnetic metal core is configured to collect a plurality of magnetic particles contained within the container.

6. The electromagnetic sampling device according to claim 5, wherein: The hollow housing of the needle is cylindrical.

7. The electromagnetic sampling device according to claim 6, wherein: The inner diameter of the cylindrical shell is equal to or greater than 2 mm.

8. The electromagnetic sampling device according to claim 7, wherein: The inner diameter of the needle housing is in the range of 0.5 mm to 10 mm.

9. The electromagnetic sampling device according to claim 1, wherein: The housing of the needle includes a magnetic shielding material.

10. The electromagnetic sampling device according to claim 9, wherein: The magnetic shielding material includes any ferromagnetic metal from MuMetal.

11. The electromagnetic sampling device according to claim 1, wherein: The metal core includes any one of silicon steel and ferrite.

12. The electromagnetic sampling device according to claim 1, wherein: The distal end of the metal core extends beyond the distal end of the needle housing by a length in the range of 1 mm to 100 mm.

13. A method of collecting magnetic particles from a particle container using an electromagnetic sampling device and transferring the collected magnetic particles to a container sealed by a septum, the electromagnetic sampling device comprising: a needle having a hollow housing for receiving a metal core of an electromagnet having an electromagnetic coil for magnetically energizing the metal core, wherein activation of the electromagnetic coil magnetizes the metal core and causes the metal core to attract magnetic particles; wherein the metal core is capable of transitioning from an extended position, the distal end of the metal core extending beyond the distal end of the needle housing in the extended position, to a retracted position, the distal end of the metal core and any magnetic particles attached thereto being disposed within the needle housing in the retracted position, the method comprising: With the metal core in the retracted position, inserting at least the distal end of the needle into a container containing a plurality of magnetic particles, transitioning the metal core from a retracted position to an extended position such that the distal end of the metal core is proximate to the magnetic particle, activating the electromagnet to magnetize the metal core, and At least a portion of the magnetic particles are collected via the distal end of the metal core.

14. The method of claim 13, further comprising transitioning the metal core and associated collected magnetic particles from the extended position to the retracted position.

15. The method of claim 14, further comprising removing the needle from the container.

16. The method of claim 15, further comprising piercing the septum of the sealed container with a distal end of a needle and introducing at least the distal end of the needle into the sealed container.

17. The method of claim 16, further comprising transitioning the metal core from a retracted position to an extended position to move the collected magnetic particles from inside the needle housing to outside the needle housing.

18. The method of claim 17, further comprising deactivating the electromagnet to release the collected magnetic particles into the sealed container.

19. The method according to claim 18, wherein The magnetic particles are functionalized to capture one or more target analytes within the sealed container.

20. The method of claim 19, further comprising removing the needle from the sealed container to remove the magnetic particles and associated captured target analyte from the container.

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