Magnetic particle solution concentration measurement device

Abstract

The present invention provides a device for measuring the concentration of magnetic particles in a solution, comprising a quartz crystal oscillator, an oscillation circuit, a frequency detection circuit, and a controllable magnetic field generator; the quartz crystal oscillator operates in a thickness shear vibration mode; a coating position for a solution to be measured is provided on the quartz crystal oscillator; a resonant frequency value of the quartz crystal oscillator is defined as a first resonant frequency value when the magnetic field does not act on the quartz crystal oscillator; a resonant frequency value of the quartz crystal oscillator is defined as a second resonant frequency value when the magnetic field acts on the quartz crystal oscillator; the principle of the device for measuring the concentration of magnetic particles in a solution is to measure the concentration of magnetic particles by comparing the first resonant frequency value with the second resonant frequency value. The present invention utilizes an external magnetic field to change the distribution of magnetic particles in a solution and utilizes the sensitivity of the thickness shear quartz crystal oscillator to the density distribution of the solution to measure the concentration of magnetic beads in the solution to be measured, and has the characteristics of simplicity, speed, and wide applicability.

Description

Technical Field

[0001] The present invention relates to the technical field of detection instruments, and in particular to a device for measuring the concentration of a magnetic particle solution. Background Art

[0002] The use of magnetic particles (magnetic beads) to label biomolecules such as DNA, RNA, proteins, antibodies, antigens, receptors, and enzymes is a common method in modern molecular biotechnology. Magnetic labeling facilitates the capture, screening, separation, transport, and manipulation of target molecules. In detection, magnetic labeling can be used to concentrate and enrich target molecules, significantly increasing the concentration of the detected object and improving the sensitivity and robustness of the test. Because magnetically labeled biomolecules are magnetic, after removing the bare magnetic beads from uncoupled molecules, the magnetic properties of the labeled molecules can be directly measured to determine molecular concentration or count biomacromolecules.

[0003] However, due to the small size of magnetic particles and their limited magnetization strength, the stray field intensity generated by a single particle is very low, and the stray fields of multiple particles cancel each other out. Therefore, a highly sensitive and high-resolution magnetic detection sensor device is required to obtain effective magnetic field detection results.

[0004] The use of ultra-high sensitivity, ultra-low detection limit magnetic detection devices such as quantum interference magnetometers, atomic magnetometers and nuclear magnetic resonance devices to detect magnetically labeled biomolecules greatly limits the convenience and speed of the detection process, especially the inability to form an integrated, easy-to-operate and inexpensive micro-detection and analysis system.

[0005] Numerous studies have investigated the use of micro-scale magnetic sensors, such as Hall sensors, giant magneto-impedance sensors (GMI sensors), and magnetoresistive sensors (MR sensors), for the detection of magnetically labeled biomolecules. These sensors detect target molecules by sensing the stray field of magnetic particles. However, due to the inherent sensitivity limitations of these magnetic sensors and the characteristics of the stray field of magnetic particles, performance indicators such as reproducibility, sensitivity, and limit of detection (LOD) have been difficult to achieve in practical applications.

[0006] Patent document CN1317693A discloses a method for measuring the number of magnetic particles in a sample using a tuned circuit comprising a capacitor (C) and a coil (L). This method comprises: a) measuring the difference in resonant frequency of the tuned circuit when the sample is exposed to and not exposed to the magnetic field generated by the coil; and b) using this resonant frequency difference to measure the number of magnetic particles in the sample. However, this approach still suffers from drawbacks such as low reproducibility, low sensitivity, and a small limit of detection (LOD). Summary of the Invention

[0007] In view of the defects in the prior art, the present invention aims to provide a device for measuring the concentration of a magnetic particle solution.

[0008] According to the present invention, a device for measuring the concentration of magnetic particles in a solution includes a quartz crystal oscillator, an oscillation circuit, a frequency detection circuit, and a controllable magnetic field generator;

[0009] The quartz crystal oscillator is connected to the output end of the oscillation circuit, and the oscillation circuit is connected to the frequency detection circuit;

[0010] The frequency detection circuit is used to detect the frequency of the oscillation signal of the oscillation circuit;

[0011] The controllable magnetic field generator is used to provide a magnetic field, and can make the magnetic field act on or not act on the quartz crystal oscillator; when the magnetic field acts on the quartz crystal oscillator, the quartz crystal oscillator operates in a thickness shear vibration mode;

[0012] The quartz crystal oscillator is provided with a coating position for the solution to be tested, and the solution to be tested is coated on the coating position for the solution to be tested;

[0013] The resonant frequency value of the quartz crystal oscillator is defined as a first resonant frequency value when the magnetic field does not act on the quartz crystal oscillator; and the resonant frequency value of the quartz crystal oscillator is defined as a second resonant frequency value when the magnetic field acts on the quartz crystal oscillator.

[0014] The principle of the device for measuring the concentration of magnetic particles in a solution is to measure the concentration of magnetic particles by comparing the first resonance frequency value with the second resonance frequency value.

[0015] Preferably, the quartz crystal oscillator comprises electrodes and a quartz crystal body;

[0016] The electrodes cover the central areas of the upper and lower surfaces of the quartz crystal, and the solution to be tested is coated on the electrodes.

[0017] Preferably, the controllable magnetic field generator includes an adjustable positioning mechanism and a permanent magnet;

[0018] The permanent magnet is mounted on the adjustable positioning mechanism;

[0019] The adjustable positioning mechanism can drive the permanent magnet so that the magnetic field generated by the permanent magnet acts on the quartz crystal oscillator;

[0020] The adjustable positioning mechanism can drive the permanent magnet so that the magnetic field generated by the permanent magnet does not act on the quartz crystal oscillator.

[0021] Preferably, the adjustable positioning mechanism includes a horizontal positioning component and a vertical positioning component;

[0022] The vertical positioning assembly is mounted on the horizontal positioning assembly, and the permanent magnet is mounted on the vertical positioning assembly;

[0023] The horizontal positioning assembly can drive the vertical positioning assembly to move in the horizontal direction, and the vertical positioning assembly can drive the permanent magnet to move in the vertical direction.

[0024] Preferably, the horizontal positioning assembly and the vertical positioning assembly are both screw-nut transmission structures.

[0025] Preferably, the controllable magnetic field generator includes a first coil, a second coil and a control drive circuit;

[0026] The first coil and the second coil are both electrically connected to the control drive circuit;

[0027] The first coil is located above the quartz crystal oscillator, and the second coil is located below the quartz crystal oscillator, and the first coil and the second coil apply a magnetic field to the quartz crystal oscillator;

[0028] The control drive circuit is used to control the opening or closing of the magnetic field.

[0029] Preferably, the intensity of the magnetic field is 0.3T.

[0030] Preferably, it further comprises a crank, which is connected to the screw in the screw-nut transmission structure.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] This method uses an external magnetic field to alter the distribution of magnetic particles in a solution and exploits the sensitivity of a thickness-shear quartz crystal oscillator to the solution's density distribution to measure the concentration of magnetic beads in the solution being measured. This method can be used to measure the concentration of a variety of magnetic particle solutions, offering simplicity, speed, and wide applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0034] Figure 1 It is a structural schematic diagram of the present invention.

[0035] Figure 2 This is an embodiment of the controllable magnetic field generator of the present invention;

[0036] Figure 3 This is another embodiment of the controllable magnetic field generator of the present invention;

[0037] Figure 4 A frequency shift diagram generated by a magnetic particle solution concentration measurement device provided by an embodiment of the present invention in the logarithmic concentration range of 10 ng / ml-10 μg / ml under the influence of a 0.3 T perpendicular magnetic field.

[0038] Figure 5 A diagram showing the relationship between the solution concentration in the range of 10 ng / ml-10 μg / ml and the resonant frequency shift of a quartz crystal under the influence of a 0.3 T vertical magnetic field for a magnetic particle solution concentration measurement device provided by an embodiment of the present invention.

[0039] Figure 6 A frequency shift diagram generated by a magnetic particle solution concentration measurement device provided by an embodiment of the present invention in a concentration range of 20-80 ng / ml under the influence of a 0.3 T perpendicular magnetic field.

[0040] Figure 7 This is a diagram showing the relationship between the solution concentration in the range of 20-80 ng / ml and the sensor frequency shift of a magnetic particle solution concentration measurement device provided by an embodiment of the present invention under the influence of a 0.3 T vertical magnetic field.

[0041] The figure shows:

[0042]

[0043] DETAILED DESCRIPTION

[0044] The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several changes and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0045] The present invention provides a device for measuring the concentration of magnetic particles in a solution, comprising a quartz crystal oscillator 301, an oscillation circuit 501, a frequency detection circuit 601 and a controllable magnetic field generator 101;

[0046] The quartz crystal oscillator 301 is connected to the output end of the oscillation circuit 501, and the oscillation circuit 501 is connected to the frequency detection circuit 601; the quartz crystal oscillator 301 is connected to the oscillation circuit 501 so that the oscillation circuit 501 outputs an oscillation signal with an oscillation frequency that is the resonant frequency of the quartz crystal oscillator 301.

[0047] The frequency detection circuit 601 is used to detect the oscillation signal frequency of the oscillation circuit 501, that is, the oscillation signal frequency of the quartz crystal oscillator 301; the controllable magnetic field generator 101 is used to provide a magnetic field, and can make the magnetic field act on or not act on the quartz crystal oscillator 301; when the magnetic field generated by the controllable magnetic field generator 101 acts on the quartz crystal oscillator 301, the magnetic field polarizes the magnetic particles in the solution being measured, changes the distribution of the magnetic particles in the solution, and causes the resonant frequency of the quartz crystal to change. The quartz crystal oscillator 301 is a thickness shear vibration mode quartz crystal oscillator, that is, when the magnetic field generated by the controllable magnetic field generator 101 acts on the quartz crystal oscillator 301, the quartz crystal oscillator 301 operates in the thickness shear vibration mode;

[0048] The quartz crystal oscillator 301 is provided with a coating position for the solution to be tested 201, and the solution to be tested 201 is coated on the coating position of the solution to be tested 201; when the magnetic field does not act on the quartz crystal oscillator 301, the resonant frequency value of the quartz crystal oscillator 301 is defined as a first resonant frequency value; when the magnetic field acts on the quartz crystal oscillator 301, the resonant frequency value of the quartz crystal oscillator 301 is defined as a second resonant frequency value; the principle of the device for measuring the concentration of magnetic particles in the solution is to achieve the measurement of the magnetic particle concentration by comparing the first resonant frequency value with the second resonant frequency value. Specifically, when the magnetic field generated by the controllable magnetic field generator 101 acts on the quartz crystal oscillator 301, the controllable magnetic field generator 101 outputs a dynamic magnetic field perpendicular to the surface of the quartz crystal oscillator 301, causing the magnetic particles in the measured solution to produce magnetic polarization motion and dynamically change their distribution in the solution. The frequency of the dynamic magnetic field is less than the resonant frequency of the quartz crystal oscillator 301. The principle of the device for measuring the concentration of magnetic particles in solution is to detect the change in the resonant frequency value of the quartz crystal oscillator 301 during the action of the dynamic magnetic field to achieve the measurement of the concentration of magnetic particles. More specifically, the device for measuring the concentration of magnetic particles in solution detects the oscillation signal frequency of the oscillation circuit 501 when the controllable magnetic field generator 101 has no output or the generated magnetic field does not act on the quartz crystal oscillator 301 through the frequency detection circuit 601; the device for measuring the concentration of magnetic particles in solution then detects the oscillation signal frequency of the quartz crystal oscillator 301 when the magnetic field generated by the controllable magnetic field generator 101 acts on the quartz crystal oscillator 301, and calculates the concentration of magnetic particles in solution based on the two frequency detection results.

[0049] The quartz crystal oscillator 301 includes electrodes 401 and a quartz crystal body. The electrodes 401 cover the central areas of the upper and lower surfaces of the quartz crystal, and the test solution 201 is applied to the electrodes 401. Specifically, the electrodes 401 are connected to the output end of the oscillation circuit 501 to generate an oscillation signal determined by the characteristics of the quartz crystal oscillator. The frequency of the oscillation signal is the resonant frequency of the quartz crystal body.

[0050] In a preferred embodiment, the controllable magnetic field generator 101 includes an adjustable positioning mechanism 701 and a permanent magnet 411; the permanent magnet 411 is mounted on the adjustable positioning mechanism 701; the adjustable positioning mechanism 701 can drive the permanent magnet 411 so that the magnetic field generated by the permanent magnet 411 acts on the quartz crystal oscillator 301; the adjustable positioning mechanism 701 can drive the permanent magnet 411 so that the magnetic field generated by the permanent magnet 411 does not act on the quartz crystal oscillator 301. In a preferred embodiment, the adjustable positioning mechanism 701 can cause the magnetic poles of the permanent magnet 411 to face and be close to the surface of the quartz crystal or cause the magnetic poles of the permanent magnet 411 to be misaligned and away from the surface of the quartz crystal. The adjustable positioning mechanism 701 includes a horizontal positioning assembly 311 and a vertical positioning assembly 211. The vertical positioning assembly 211 is mounted on the horizontal positioning assembly 311, and the permanent magnet 411 is mounted on the vertical positioning assembly 211. The horizontal positioning assembly 311 can drive the vertical positioning assembly 211 to move horizontally, and the vertical positioning assembly 211 can drive the permanent magnet 411 to move vertically. Both the horizontal positioning assembly 311 and the vertical positioning assembly 211 are screw-nut transmission structures. Specifically, in this preferred embodiment, a crank 111 is connected to the screw structure. An operator can use the crank 111 to rotate the screw to adjust the horizontal positioning assembly 311 and the vertical positioning assembly 211, thereby adjusting the relative position and distance between the permanent magnet 411 and the quartz crystal 511. This can either cause the magnetic poles of the permanent magnet 411 to face and be adjacent to the surface of the quartz crystal 511, or cause the magnetic poles of the permanent magnet 411 to be misaligned and away from the surface of the quartz crystal 511.

[0051] In another preferred example, the controllable magnetic field generator 101 includes a first coil 121, a second coil 321 and a control drive circuit 421; the first coil 121 and the second coil 321 are both electrically connected to the control drive circuit 421; the first coil 121 is located above the quartz crystal oscillator 301, and the second coil 321 is located below the quartz crystal oscillator 301, and the first coil 121 and the second coil 321 apply a magnetic field to the quartz crystal oscillator 301; the control drive circuit 421 is used to control the opening or closing of the magnetic field.

[0052] Specifically, in this embodiment, the resonant frequency of the quartz crystal oscillator 301 used is 5MHz, the thickness of the quartz crystal body is 334μm, and anchor-shaped metal gold electrodes are sputtered on the upper and lower surfaces of the quartz. A pipette is used to evenly load 10μL of the measured magnetic particle solution on the surface of the metal electrode. After the loading of the measured sample liquid is completed, it is allowed to stand for 10-15 minutes until the solution is stable before applying a magnetic field above the solution. The magnetic field is a magnetic field applied by a magnetic field generator 101, the amplitude of the magnetic field is 0.3T, and the direction of the magnetic field is perpendicular to the plane where the quartz wafer is located. When the magnetic field is applied, the magnetic particles in the solution agglomerate toward the top of the measured solution under the action of the external field, and the solution density is reduced, which in turn causes the resonant frequency of the quartz crystal oscillator 301 to decrease and be measured by the frequency detection circuit 601.

[0053] Figure 4 This is a frequency shift diagram generated by a magnetic particle solution concentration measurement device in the present embodiment in the concentration range of 20-80 ng / ml under the influence of a 0.3 T magnetic field. Figure 2 The resonant frequency of the sensor loaded with the test solution changes under the influence of a 0.3 T external magnetic field, and the sensor's resonant frequency increases with increasing concentration of magnetic particles in the test solution. Furthermore, the sensor's resonant frequency increases rapidly when a magnetic field is applied, demonstrating the sensor's fast responsiveness.

[0054] Figure 5 The figure is a relationship diagram between the concentration of a magnetic particle solution in the range of 10ng / ml-10μg / ml and the sensor frequency shift under the influence of a 0.3T magnetic field. Figure 3 It can be seen that within the logarithmic concentration range of 10 ng / ml-10 μg / ml, the concentration of magnetic particles is proportional to the change in the resonant frequency of the sensor.

[0055] Figure 6 This is a frequency shift diagram generated by a magnetic particle solution concentration measurement device in this embodiment within the concentration range of 20-80 ng / ml under the action of a 0.3 T magnetic field. Figure 4 It can be seen that although the solution itself has certain instability due to the influence of Brownian thermal motion, after the magnetic field is applied around 300 seconds, the sensor responds quickly and produces a frequency shift of the response, and when the magnetic field is maintained, the frequency shift phenomenon is still maintained, further demonstrating that the sensor has a certain stability.

[0056] Figure 7 The relationship between the concentration of a magnetic particle solution and the sensor frequency shift in the range of 20-80 ng / ml under the action of a 0.3 T magnetic field is shown in the figure. Figure 5It can be seen that within the linear gradient concentration range of 20-80 ng / ml, the frequency offset generated by the sensor has an approximately linear relationship with the concentration of magnetic particles, further proving that the sensor has a certain linear detection capability.

[0057] The present invention discovered that a quartz crystal oscillator in thickness shear vibration mode (TSM) is extremely sensitive to the mechanical boundary conditions of vibration, that is, the mechanical state of the upper and lower surfaces of the oscillator. It is precisely this characteristic that has been used to produce a quartz microbalance (QCM). That is, the thickness shear quartz oscillator is extremely sensitive to the density distribution of the solution being measured. When the TSM quartz crystal oscillator is loaded with a magnetic particle solution, the magnetic particles produce magnetic polarization under the action of a magnetic field, causing the distribution of the magnetic particles to change. This will change the mechanical boundary conditions of the oscillator's TSM vibration, thereby causing the oscillator's resonant frequency to change relative to when there is no magnetic field. Utilizing a thickness shear quartz crystal oscillator, a magnetic particle solution concentration measurement device is provided that can circumvent the sensing sensitivity limitations of the magnetic sensor itself and the characteristics of the stray field of magnetic particles, and can achieve detection performance indicators such as reproducibility, sensitivity, and detection limit (LOD) that meet the requirements of practical applications.

[0058] The technical basis of the present invention is: in the absence of a magnetic field, magnetic particles are dispersed in the liquid due to the tension of the liquid and random thermal motion; under the action of a magnetic field, the magnetic particles in the solution are magnetically polarized, generating a magnetic force, which causes the distribution of the magnetic particles in the liquid to change, thereby causing the density distribution of the liquid containing the magnetic particles to change; a TSM quartz crystal resonator is used to sense this density distribution change to achieve the detection of magnetic particle concentration.

[0059] This method uses an external magnetic field to alter the distribution of magnetic particles in a solution and exploits the sensitivity of a thickness-shear quartz crystal oscillator to the solution's density distribution to measure the concentration of magnetic beads in the solution being measured. This method can be used to measure the concentration of a variety of magnetic particle solutions, offering simplicity, speed, and wide applicability.

[0060] In the description of this application, it should be understood that the terms "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", etc., indicating the orientation or position relationship, are based on the orientation or position relationship shown in the accompanying drawings, and are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on this application.

[0061] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. The embodiments of this application and the features in the embodiments may be combined with each other in any manner unless there is a conflict.

Claims

1. A device for measuring the concentration of magnetic particles in a solution, characterized in that: It comprises a quartz crystal oscillator (301), an oscillation circuit (501), a frequency detection circuit (601) and a controllable magnetic field generator (101); The quartz crystal oscillator (301) is connected to the output end of the oscillation circuit (501), and the oscillation circuit (501) is connected to the frequency detection circuit (601); The frequency detection circuit (601) is used to detect the frequency of the oscillation signal of the oscillation circuit (501); The controllable magnetic field generator (101) is used to provide a magnetic field, and is capable of causing the magnetic field to act on or not act on the quartz crystal oscillator (301); when the magnetic field acts on the quartz crystal oscillator (301), the quartz crystal oscillator (301) operates in a thickness shear vibration mode; The quartz crystal oscillator (301) is provided with a coating position for the solution to be tested (201), and the solution to be tested (201) is coated on the coating position for the solution to be tested (201); The resonant frequency value of the quartz crystal oscillator (301) is defined as a first resonant frequency value when the magnetic field does not act on the quartz crystal oscillator (301); and the resonant frequency value of the quartz crystal oscillator (301) is defined as a second resonant frequency value when the magnetic field acts on the quartz crystal oscillator (301); The principle of the device for measuring the concentration of magnetic particles in a solution is to measure the concentration of magnetic particles by comparing the first resonance frequency value with the second resonance frequency value.

2. The device for measuring the concentration of magnetic particles in a solution according to claim 1, wherein: The quartz crystal oscillator (301) comprises an electrode (401) and a quartz crystal body; The electrodes (401) cover the central areas of the upper and lower surfaces of the quartz crystal, and the solution to be tested (201) is coated on the electrodes (401).

3. The device for measuring the concentration of magnetic particles in a solution according to claim 1, wherein: The controllable magnetic field generator (101) comprises an adjustable positioning mechanism (701) and a permanent magnet (411); The permanent magnet (411) is mounted on the adjustable positioning mechanism (701); The adjustable positioning mechanism (701) can drive the permanent magnet (411) so that the magnetic field emitted by the permanent magnet (411) acts on the quartz crystal oscillator (301); The adjustable positioning mechanism (701) can drive the permanent magnet (411) so that the magnetic field emitted by the permanent magnet (411) does not act on the quartz crystal oscillator (301).

4. The device for measuring the concentration of magnetic particles in a solution according to claim 3, wherein: The adjustable positioning mechanism (701) includes a horizontal positioning component (311) and a vertical positioning component (211); The vertical positioning component (211) is mounted on the horizontal positioning component (311), and the permanent magnet (411) is mounted on the vertical positioning component (211); The horizontal positioning component (311) can drive the vertical positioning component (211) to move in the horizontal direction, and the vertical positioning component (211) can drive the permanent magnet (411) to move in the vertical direction.

5. The device for measuring the concentration of magnetic particles in a solution according to claim 4, wherein: The horizontal positioning assembly (311) and the vertical positioning assembly (211) are both screw-nut transmission structures.

6. The device for measuring the concentration of magnetic particles in a solution according to claim 1, wherein: The controllable magnetic field generator (101) comprises a first coil (121), a second coil (321) and a control drive circuit (421); The first coil (121) and the second coil (321) are both electrically connected to the control drive circuit (421); The first coil (121) is located above the quartz crystal oscillator (301), and the second coil (321) is located below the quartz crystal oscillator (301); the first coil (121) and the second coil (321) apply a magnetic field to the quartz crystal oscillator (301); The control drive circuit (421) is used to control the opening or closing of the magnetic field.

7. The device for measuring the concentration of magnetic particles in a solution according to claim 1, wherein: The intensity of the magnetic field is 0.3T.

8. The device for measuring the concentration of magnetic particles in a solution according to claim 5, wherein: It also includes a crank (111), and the crank (111) is connected to the screw in the screw-nut transmission structure.

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