Magnetic field measuring device for detecting or imaging magnetic particles

Abstract

The present invention relates to a magnetic field measuring device (1) for detecting or imaging magnetic nanoparticles. The magnetic field measuring device (1) includes at least one transmitting coil (2) configured to generate a first magnetic field (MF1) that substantially uniformly magnetizes magnetic particles in a sensing region (SR) of a measurement target including a plurality of magnetic particles and a zero magnetic field line (MFL) outside the sensing region (SR), at least one coil driving and control circuit (3) configured to drive the at least one transmitting coil (2), at least one semiconductor material (4) having at least one defect center (DC) capable of changing electron spins and energy states when excited by electromagnetic energy, at least one optical assembly (5) having at least one optical sensor (not shown) configured to photoexcite the defect center (DC) in the structure of the semiconductor material (4) and detect radiation generated by the defect center (DC) due to the photoexcitation, at least one microwave antenna (6) configured to excite the electron spin state of the defect center (DC) located within the semiconductor material (4), and at least one microwave driving and control circuit (7) configured to drive the microwave antenna.

Description

Technical Field

[0001] The present invention relates to a magnetic field measuring device for detecting or imaging magnetic nanoparticles.

Background Art

[0002] Magnetic particles are particles in which a magnetic core such as iron oxide is coated for biocompatibility, medical functions, long residence time in the body, and prevention of aggregation. The use of magnetic particles in medical imaging and therapeutic applications for various purposes has been proposed in the known art. The location and amount of magnetic particles in the body are detected or imaged using magnetic particle detection methods and magnetic particle imaging methods.

[0003] In magnetic particle detection or imaging methods, magnetic nanoparticles or cells labeled with magnetic nanoparticles are introduced into the body, and the reaction of the particles in the body to a time-varying magnetic field applied from the outside is measured. Using this measured reaction, the position and density of the magnetic nanoparticles can be detected or visualized. This information can be used for both diagnosis and treatment.

[0004] In magnetic particle sensing, magnetic particles previously sent to a sensing site (for example, in the body) are detected by a manual scanning path using a magnetic field probe outside the body. In Patent Document 1 in the known art, an assembly for such a method has been proposed. In a magnetic particle detection system, a time-varying magnetic field is generated using a transmitting coil. The magnetization response of the magnetic particles to the magnetic field generated by the transmitting coil is detected using a receiving coil. By manually scanning a probe that houses the transmitting coil and the receiving coil outside the body, the location where the magnetic particles are located can be identified.

[0005] In magnetic particle imaging (MPI), as described in Patent Document 2 of the prior art, an image of the distribution of magnetic particles in the body can be obtained. The MPI method is based on the fast non-linear magnetization of magnetic nanoparticles. For imaging, a non-uniform magnetic field including a point where the magnetic field is zero (zero magnetic field point, MFP) or a line (zero magnetic field line, MFL) is first generated. A region including a point or line where the magnetic field is zero can also be referred to as a zero magnetic field region. The magnetic field including the zero magnetic field region is called a selection magnetic field because its distribution selects the imaging region. The magnetic nanoparticles within the zero magnetic field region can be magnetized by a magnetic field other than the selection magnetic field, while the magnetic nanoparticles outside the zero magnetic field region are magnetically saturated and thus cannot respond to an external magnetic field. In the MPI method, in addition to the selection magnetic field, another time-varying magnetic field, also known as an alternating magnetic field or driving magnetic field, is applied. This alternating magnetic field excites the magnetic nanoparticles in the zero magnetic field region and dynamically changes the magnetization of the magnetic nanoparticles. This time-changing magnetization is detected by a magnetic receiver. The detected magnetization originates from the magnetic nanoparticles existing only in the zero magnetic field region and increases in proportion to the magnetic nanoparticle density. The distribution of magnetic nanoparticles in the tissue is obtained by scanning the zero magnetic field region in the tissue and processing the signals received from the magnetic nanoparticles. As the amplitude of the alternating magnetic field increases, the imaging area expands. However, heating and nerve stimulation can occur, especially at high frequencies, so the frequency and amplitude of the alternating magnetic field should be limited for patient safety. In the case of an alternating magnetic field used within the safety limit, the size of the imaging area is several centimeters. To scan a large imaging area, a third magnetic field with a low frequency and a variable focus of the scanning point is used. When the third magnetic field is added to the selection magnetic field, this is regarded as a focus magnetic field because it displaces the zero magnetic field region. As a result, in the MPI method, in order to collect data from and perform imaging on an imaging area that can be used clinically, it is necessary to generate three separate magnetic fields including a selection magnetic field that does not change over time, a focus magnetic field that changes slowly over time, and an alternating magnetic field that changes rapidly over time.

[0006] The dynamic magnetic field used in magnetic particle imaging and the time-varying magnetic field used in magnetic particle detection are generated by a transmitting electromagnetic coil. The response of magnetic particles to the variable magnetic field is usually measured by magnetic induction using a receiving coil as described in Patent Documents 3, 4, and 5 of the known art level.

[0007] During the imaging or detection of magnetic particles, the excitation of magnetic particles using a transmitting coil and the reception of signals from a receiving coil are performed simultaneously. Therefore, not only the magnetization of magnetic particles but also the magnetic field generated by the transmitting coil induces a voltage in the receiving coil. Since the voltage induced by the transmitting coil is much larger than the voltage induced by magnetic particle magnetization, it is necessary to separate magnetic particle magnetization from the influence of the transmitting magnetic field. In the known art level, filtering methods, gradiometric receiving coil methods, and conjugate receiving system methods are used for this purpose.

[0008] The filtering method utilizes the fact that the magnetization signal of magnetic nanoparticles is non-linear and contains harmonic frequency components. The first harmonic of the magnetic particle-induced signal is at the same frequency as the transmitting coil signal. The signal induced in the receiving coil is passed through a band-stop filter to suppress the first harmonic of the received signal as much as possible. Thereby, the transmitting coil signal is removed (Non-Patent Document 1). However, this method removes not only the signal of the transmitting coil but also the magnetization signal of magnetic particles, so most of the magnetic particle signal is lost and the signal-to-noise ratio becomes small.

[0009] In the method using a gradiometric receiving coil, two conjugate receiving coils having opposite polarities to each other are used. These coils are arranged so as to make the voltage induced by the transmitting coil signal zero (Non-Patent Document 2). Since magnetic particles must induce a voltage only in one of the receiving coils to receive the magnetic particle signal, and thus the other receiving coil must be located in a region where the particles are not magnetized, the field of view of the imaging system is limited when using the above method.

[0010] The conjugate reception system method also functions in the same way as the method using a gradiometric reception coil. In the conjugate reception system method, a replica of the transmit-receive coil structure is added to the system to obtain a signal received in the absence of magnetic particles (Non-Patent Document 3). The signal due to magnetic particle magnetization is separated by subtracting this signal from the signal from the main system. In contrast, the conjugate reception system method requires two separate transmit-receive systems, which increases costs and power consumption, and at the same time, there is a risk of distortion of the received signal due to differences in ambient temperature, etc., between the main system and the conjugate system.

[0011] Therefore, in the prior art, there is a need for a device that significantly reduces the influence of the magnetic field generated by the transmit coil on the sensor that measures the magnetic particle response.

[0012] As described above, in magnetic particle imaging and sensing, the magnetization signal of magnetic particles is usually received by the voltage induced in the receive coil. The voltage induced in the coil is directly proportional to the time-dependent derivative of the magnetic flux passing through the coil. The magnetization of magnetic nanoparticles changes according to the magnetic field emitted from the transmit coil. Therefore, the amplitude of the signal measured by the receive coil changes according to the frequency of the magnetic field emitted from the transmit coil, and the received signal level decreases as the frequency decreases. The frequency used for magnetic particle imaging is usually about 25 kHz. It has been found that the signal level drops significantly at frequencies below this value (Non-Patent Document 4). On the other hand, as the diameter of the magnetic particles increases, the magnetization curve becomes steeper, and thus the imaging resolution improves. However, magnetized particles with a relatively large diameter cannot respond to high frequencies and therefore cannot be detected by an inductive receiver. This limits the resolution of magnetic particle imaging.

[0013] Therefore, in the prior art, in order to enable relatively large magnetic particles to react and improve the image resolution, an apparatus is required that can measure the magnetization response of magnetic particles at a low excitation frequency. Further, since the changes depending on the temperature and viscosity of the magnetic particles have significant characteristics at relatively low frequencies, in the prior art, an apparatus is also required that can measure the change in magnetic particle magnetization with respect to the temperature and viscosity of the medium.

[0014] In addition to all of these, in the prior art, the use of a non-inductive atomic magnetometer for magnetic particle imaging that detects a signal directly related to particle magnetization has also been proposed (Non-Patent Document 5). In this method proposal, an optical pumping magnetometer is arranged outside the transmission coil, and a magnetic particle-induced magnetization signal is obtained by the magnetometer. In order to reduce the magnetic field generated by the transmission coil, an inverse polarity compensation coil that generates a magnetic field in the opposite direction to the transmission coil is used in the region outside the transmission coil where the particles are located. Therefore, compared with the case where there is no compensation coil, more current is supplied to the transmission coil to apply a desired magnetic field to the magnetic particles. This requires the use of a large current generator, which reduces the system efficiency and increases the system cost and power consumption. Since the above compensation coil reduces the magnetic field outside the imaging field, the atomic magnetometer has to be arranged far away from the imaging field. Since the magnetic field decreases in proportion to the cube of the distance, arranging the atomic magnetometer away like this significantly reduces the received signal level and the signal-to-noise ratio.

[0015] In an embodiment of the prior art that enables magnetic particle detection, a technique based on an optical detection and magnetic resonance signal reception method is applied (Non-Patent Document 6). In this method, the above compensation coil is also used. Since the compensation coil must have the opposite polarity to the transmission coil, the above problems also apply to this embodiment.

[0016] Therefore, in the prior art, there is a need for an apparatus that completely eliminates the need for a compensation coil or, when using a compensation coil, ensures that the magnetic field generated by the compensation coil in the region of the magnetic particles is negligibly smaller than the magnetic field generated by the transmission coil in the region of the magnetic particles.

Prior Art Documents

Patent Documents

[0017]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0018]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0019] An object of the present invention is to provide a high-precision magnetic field measurement device capable of efficiently measuring the magnetization response of magnetic particles in a sensing region, particularly at excitation frequencies exceeding 5 kHz, but also at low excitation frequencies such as 0 kHz to 5 kHz.

Means for Solving the Problems

[0020] The magnetic field measurement device according to claim 1 and the dependent claims corresponding thereto, which enables highly sensitive detection of magnetic particle signals for detecting or imaging magnetic particles, includes at least one transmission coil configured to generate a first magnetic field that substantially uniformly magnetizes magnetic particles in a sensing region of a measurement target including a plurality of magnetic particles and a line on an extension axis where the magnetic field is zero, at least one coil drive and control circuit configured to drive the transmission coil under control, at least one semiconductor material including at least one defect center capable of changing electron spins and energy states when excited by electromagnetic energy, at least one optical assembly having at least one optical sensor configured to photoexcite the defect center and detect radiation emitted from the defect center by the photoexcitation, at least one microwave antenna configured to excite the electron spin state of the defect center, and at least one microwave drive and control circuit configured to operate the microwave antenna under control. The semiconductor material of the magnetic field measurement device of the present invention is positioned such that the defect center is located substantially above a line where at least one magnetic field is zero.

[0021] In a preferred embodiment of the present invention, the magnetization response of the magnetic nanoparticles is detected by a magnetic field sensor based on optically detected magnetic resonance (ODMR) measurement. This type of sensor can directly measure magnetization rather than the differentiation of magnetic flux like inductive sensing. Thereby, the limitations for low-frequency excitation and large magnetic particle diameters in the known state of the art are eliminated. Furthermore, by developing an ODMR sensor with higher sensitivity than an inductive coil, the sensitivity of magnetic particle detection and imaging can be improved. For ODMR, it is preferable to use nitrogen-vacancy defect centers that naturally exist in diamond or can be obtained synthetically. Depending on the embodiment, negatively charged boron-vacancy defect centers in a hexagonal boron nitride structure or single-carbon defect centers or double-vacancy defect centers in a silicon carbide structure can be used. Since the zero magnetic field region generated by the transmitting coil element can be linear, the optically detected magnetic resonance sensors can be positioned in a linear array. In this way, the sensor coverage area and the signal-to-noise ratio can be increased. It is also possible to increase the measurement sensitivity by applying the Ramsey method, the pulsed ODMR method, or the spin-echo ODMR method using a pulsed signal in the known state of the art.

[0022] In one embodiment, the magnetization signal due to the relaxation response of the magnetic particles after the excitation of the transmitting coil is measured by the ODMR method. In this case, since the magnetic field sensor is not affected by the magnetic field released by the transmitting coil element before relaxation, the response can be accurately measured.

[0023] Particularly, since the defect center has a directionality, it is possible to measure the vector magnetic field. The negatively charged nitrogen-vacancy defect center in diamond can be oriented in four directions due to the atomic bond structure. A single negatively charged nitrogen defect center can be used for magnetic field measurement, or a diamond having many negatively charged nitrogen defect centers can also be used.

[0024] In magnetic particle sensing or imaging, the direction of the magnetic field generated by magnetic nanoparticles is determined by the direction of the magnetic field generated by the transmitting coil. In one embodiment, the angle of a diamond containing single or multiple negatively charged nitrogen vacancy defect centers is adjusted to maximize the detection of the signal of the magnetic particle magnetization direction.

[0025] m s The energy levels of negatively charged nitrogen vacancy defect centers in a diamond in an electron spin state of m = +1 to -1 are equal to the projection of the magnetic field in the direction of the negatively charged nitrogen vacancy defect centers. Therefore, it is possible to vectorially measure the magnetic particle magnetization. In one embodiment, the vectorial fluctuations of the magnetic particle magnetization are measured by tracking the resonance frequencies of the negatively charged nitrogen defect centers in the ODMR spectrum in four different directions. Magnetic particles respond to a magnetic field by two different mechanisms: Néel and Brown. In the Néel mechanism, the particles do not physically rotate and the magnetization changes rapidly, while in the Brown mechanism, the particles physically rotate. By measuring the vector magnetic field, it is possible to distinguish between these two mechanisms. By vectorially measuring the magnetic particle magnetization, the dynamics of the magnetization change of the particles can be obtained, and information about the surrounding viscosity and temperature can be obtained.

[0026] A magnetic field measuring device for achieving the object of the present invention is shown in the accompanying drawings.

Brief Description of the Drawings

[0027]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6a

Figure 6b

Figure 6c

Figure 7

Figure 8

Embodiments for Carrying Out the Invention

[0028] Each part in the figure is individually labeled with a reference numeral, and the equivalents of these reference numerals are listed below. 1. Magnetic field measurement device 2. Transmission coil 3. Coil drive and control circuit 4. Semiconductor material 5. Optical assembly 6. Microwave antenna 7. Microwave drive and control circuit 8. Compensation coil SR. Sensing region MF1. First magnetic field MFL. Zero magnetic field line DC. Defect center m s . Electron spin state of the defect center MF2. Second magnetic field 3 A. Ground state energy level 3 E. Excited state energy level

[0029] A magnetic field measurement device (1) for highly sensitive detection of magnetic particle signals in the detection or imaging of magnetic particles includes a first magnetic field (MF1) that magnetizes magnetic particles substantially coherently in a sensing region (SR) of a measurement object containing a plurality of magnetic particles, and at least one transmission coil (2) configured to generate a zero magnetic field line (MFL) outside the sensing region (SR); at least one coil drive and control circuit (3) configured to drive the at least one transmission coil (2); at least one semiconductor material (4) having at least one defect center (DC) capable of changing electron spins and energy states when excited by electromagnetic energy; at least one optical assembly (5) having at least one optical sensor (not shown) configured to photoexcite the defect center (DC) of the semiconductor material (4) and detect radiation emitted by the defect center (DC) in response to photoexcitation; at least one microwave antenna (6) configured to excite the electron spin state of the defect center (DC) located within the semiconductor material (4); and at least one microwave drive and control circuit (7) configured to drive the microwave antenna (6) (FIG. 1). In a preferred embodiment, the magnetic field measurement device (1) includes a plurality of, preferably two, transmission coils (2). In one embodiment, the transmission coils (2) are adapted as rectangular electromagnets arranged side by side on the same plane and extending substantially parallel to each other, preferably having substantially the same size, polarization, and number of turns. When the same current is supplied to the transmission coils (2), two lines (MFL) with zero magnetic field are formed, extending parallel to the parallel sides on an axis perpendicular to the plane in which the transmission coils (2) extend, centered on the midpoints of the parallel sides. Since the position of the zero magnetic field line (MFL) changes according to the distance between the center positions of the transmission coils (2), this position can be adjusted according to a specific embodiment. Depending on the requirements of different embodiments of the present invention, by adjusting this position, the zero magnetic field line (MFL) can be brought closer to or away from the transmission coils (2). In some embodiments, the transmission coils (2) can also be designed to be intertwined with each other.By applying electromagnetic energy at microwave frequencies to the defect center (DC) of the semiconductor material (4) via the microwave antenna (6), the electron spin state is m. s = 0 state to m s = +1 state and m s = -1 state, the magnetic field-sensitive resonance effect can be physically measured. The semiconductor material (4) is preferably at least one diamond that already contains negatively charged nitrogen vacancy defect centers (DC). In an alternative embodiment, the semiconductor material (4) can be, but is not limited to, hexagonal boron nitride having negatively charged boron vacancy defect centers (DC) or single carbon defect centers (DC), or silicon carbide having double vacancy defect centers (DC). In the following detailed description, reference is made to the negatively charged nitrogen vacancy defect centers (DC) in the diamond structure, but this is not meant to limit the present invention to negatively charged nitrogen vacancy defect centers (DC). In the measurement performed by the magnetic field measuring device (1), the ground energy state of the zero electron spin state (m s = 0) of the negatively charged nitrogen vacancy defect center (DC) ( 3 A) is photoexcited by the optical assembly (5). The energy state of the photoexcited negatively charged nitrogen vacancy defect center (DC) changes to the excited state ( 3 E), but when the photoexcitation is stopped, the already excited negatively charged nitrogen vacancy defect center (DC) returns to the non-excited state, i.e., its ground energy state ( 3 A). During this return, the negatively charged nitrogen vacancy defect center (DC) emits photons at optical frequencies (Figure 4). When the negatively charged nitrogen vacancy defect center (DC) in the ground energy state ( 3 A) is excited by the microwave antenna (6) at a specific microwave frequency of about 2.87 GHz, it is possible to raise the electron spin state (m s = 0 to m s = ±1) (Figure 5). The negatively charged nitrogen vacancy defect center (DC) with an increased electron spin state in the ground energy state ( 3 A) is also photoexcited by the optical assembly (5) to the excited state ( 3E) increases. When the excitation ends, the negatively charged nitrogen vacancy defect center (DC) can return to the ground energy state with zero electron spin state (m s = 0) in two different ways, either directly or through an intermediate singlet energy step (Fig. 5). In the direct transition, there is photon emission from the negatively charged nitrogen vacancy defect center (DC), while in the intermediate step transition, there is no photon emission. By measuring the amount of light emitted from the negatively charged nitrogen vacancy defect center (DC) at these stages, it is possible to understand whether the electron spin state (m s = ±1) of the negatively charged nitrogen vacancy defect center (DC) transitions to the excited state. When there is a magnetic field in the medium, the excited electron spin state (m s = ±1) splits into two (m s = +1 and m s = -1) due to the Zeeman effect. The energy between these two excited electron spin states (m s = +1 and m s = -1) is ΔE = 2γB, where γ ≈ 28 [GHz / T] is the magnetic gyromagnetic ratio and B [T] is the ambient magnetic field strength. This energy separation also changes the microwave resonance frequencies that enable transitions from the zero electron spin state (m s = 0) to different excited electron spin states (m s = +1 or m s = -1). To perform magnetic field measurement by magnetic imaging or detection with the magnetic field measuring device (1), the negatively charged nitrogen vacancy defect center (DC) in the ground energy state ( 3 A) is first excited to the excited energy level ( 3It is excited to (E). In one embodiment, light is transported from the optical assembly (5) to the semiconductor material (4) via an optical fiber cable. Following the optical excitation of the negatively charged nitrogen vacancy defect center (DC), a microwave signal is applied to the negatively charged nitrogen vacancy defect center (DC) by a microwave antenna (6) under the control of a microwave drive and control circuit (7), and the amount of light emitted from the negatively charged nitrogen vacancy defect center (DC) is measured by a photosensor of the optical assembly (5). In one embodiment, the light emitted from the negatively charged nitrogen vacancy defect center (DC) is transported to the photosensor via an optical fiber cable. After receiving light by the photosensor, the microwave frequency is scanned by the microwave drive and control circuit (7) to obtain information on the frequency at which the amount of light decreases, and using this information, the total magnetic field in the environment including the magnetization of the magnetic particles is calculated.

[0030] In the magnetic field measuring device (1) of the present invention, the semiconductor material (4) is arranged such that the negatively charged nitrogen vacancy defect center (DC) therein coincides with at least one line (MFL) where the magnetic field is zero. By arranging the semiconductor material (4) configured to detect the magnetization of the magnetic particles in the sensing region (SR) on the zero magnetic field line (MFL), the first magnetic field (MF1) generated by the transmitting coil (2) is not detected by the negatively charged nitrogen vacancy defect center(s) (DC) in the semiconductor material (4), or is detected at a negligible level, and only the magnetization of the magnetic particles in the sensing region (SR) is detected. Thereby, the detection sensitivity of the magnetic field measuring device (1) of the present invention is significantly improved.

[0031] In one embodiment of the present invention, the magnetic field measuring device (1) is configured to generate at least a second magnetic field (MF2) for adjusting the position of the zero magnetic field line (MFL) by moving the zero magnetic field line (MFL) generated by the transmitting coil (2), and includes at least one compensation coil (8). In one embodiment, the magnetic field measuring device (1) has two different axes, one being the extension axis of the zero magnetic field line (MFL) of the transmitting coil (2), and the other being the extension axis of the zero magnetic field line (MFL) between the transmitting coils (2) parallel to each other, and includes at least two compensation coils (8) for generating two different second magnetic fields (MF2) for moving the zero magnetic field line (MFL) (FIG. 1). The compensation coil (8) is driven by the coil drive and control circuit (3), preferably at the same frequency as the transmitting coil (2), in phase or in antiphase. The second magnetic field (MF2) generated by the compensation coil (8) improves the detection sensitivity by ensuring that the position of the negatively charged nitrogen vacancy defect center(s) (DC) in the semiconductor material (4) is on the zero magnetic field line (MFL) before magnetic field measurement (FIG. 6b). Since the negatively charged nitrogen vacancy defect center (DC) is already substantially located in the region of the zero magnetic field line (MFL), a very small current is supplied to the compensation coil (8) compared to the transmitting coil (2) to ensure accurate positioning. Therefore, the second magnetic field (MF2) generated by the compensation coil (8) does not significantly affect the first magnetic field (MF1) generated by the transmitting coil (2) within the sensing region (SR) where the magnetic particles are present.

[0032] In one embodiment of the present invention, the compensation coil (8) is configured to generate a second magnetic field (MF2) having a magnetic field gradient that cancels out the change (gradient) in the position of the first magnetic field (MF1) generated by the transmission coil (2) around the zero magnetic field line (MFL) (FIG. 6c). By doing so, the size of the zero magnetic field region including the zero magnetic field line (MFL) increases. In one embodiment, at least two compensation coils (8) are arranged side by side to generate a magnetic field gradient such that the first magnetic field (MF1) becomes zero depending on the position (FIG. 7). In an alternative embodiment, at least two compensation coils (8) arranged parallel to each other and facing each other are used to generate a magnetic field gradient such that the first magnetic field (MF1) becomes zero depending on the position and the second magnetic field (MF2) is generated in the opposite direction (FIG. 8). In these embodiments, the compensation coil (8) is arranged to form a zero magnetic field region including the zero magnetic field line (MFL) generated by the transmission coil (2). The transmission coil (2) and the compensation coil (8) are fed in opposite phases to expand the zero magnetic field in the region where the negatively charged nitrogen vacancy defect center (DC) is located and the zero magnetic field line (MFL) is covered. For this purpose, the current of the compensation coil (8) is adjusted to generate a magnetic field gradient having the same amplitude but opposite phase to the magnetic field gradient generated by the transmission coil (2) in the vicinity of the zero magnetic field line (MFL). In one embodiment, the current of the compensation coil (8) is adjusted using the magnetic field measurement information measured by the magnetic field measurement device (1) of the present invention. The current of the compensation coil (8) that minimizes the measured magnetic field can be obtained using various optimization and control algorithms known in the art. In some embodiments, the current of the compensation coil (8) may need to be changed during operation due to changes in ambient parameters such as temperature. In such a case, using feedback and optimization algorithms known in the art, the current of the compensation coil (8) is optimized to minimize the magnetic field measured by the magnetic field measurement device (1).

[0033] In one embodiment, the magnetization of the magnetic particles is manipulated by applying a time-varying current, preferably a sinusoidal current, to the transmitting coil (2) for the detection of the magnetic particles. For the detection of the magnetic particles, an optical signal having a wavelength of preferably about 530 nm is sent to the negatively charged nitrogen vacancy defect center (DC). Under the control of the microwave drive and control circuit (7), a microwave signal is also applied to the negatively charged nitrogen vacancy defect center (DC) by the microwave antenna (6). The microwave signal can be applied as a continuous wave or frequency modulated for improving the detection sensitivity. The center frequency of the microwave signal applied to the negatively charged nitrogen vacancy defect center (DC) is scanned over a specific bandwidth. On the other hand, the radiation emitted from the negatively charged nitrogen vacancy defect center (DC) is measured by the optical sensor of the optical assembly (5). In one embodiment, the optical sensor signal is amplified using a "lock-in" amplifier. The lock-in amplifier amplifies the optical sensor signal in response to the microwave signal applied to the negatively charged nitrogen vacancy defect center (DC). By detecting the resonance frequency of the obtained microwave frequency-dependent optical radiation spectrum data, a magnetic field change due to the magnetization of the magnetic particles at the negatively charged nitrogen vacancy defect center (DC) is detected. In one embodiment of the present invention, the resonance frequency of the optical radiation spectrum shifts by 28 Hz / nT.

[0034] In one embodiment of the present invention, the coil drive and control circuit (3), the optical assembly (5), and the microwave drive and control circuit (7) are configured to communicate with each other to exchange data for applying the signal waveforms required for magnetic field measurement to the transmitting coil (2), the compensation coil (8), the negatively charged nitrogen vacancy defect center (DC), and the microwave antenna (6). In an alternative embodiment, an additional control computer or circuit (not shown) can be used to optimize the synchronization and measurement of these signals.

[0035] In one embodiment of the present invention, the microwave driving and control circuit (7) is configured to control the microwave antenna (6) so as to emit a microwave signal modulated at a frequency that excites "ultrafine" electron spin resonance to a negatively charged nitrogen vacancy defect center (DC). By this modulation, the measurement sensitivity is improved. The microwave driving and control circuit (7) preferably controls the microwave antenna so that a microwave signal modulated at a frequency of 2.16 MHz is emitted. In one embodiment of the present invention, the resonance frequency is detected in the absence of magnetic particles, and the frequency point of maximum sensitivity (the frequency point at which the change in optical emission with respect to frequency is maximum) is determined. In this embodiment, the microwave antenna (6) applies microwaves at this center frequency point. In the presence of magnetic particles, the magnetization of the magnetic particles is measured by measuring the deviation from this center frequency point.

[0036] In one embodiment of the present invention, a plurality of transmission coils (2) are positioned at different positions around the sensing region (SR) so as to increase the intensity of the first magnetic field (MF1) in the sensing region (SR) or to homogenize the first magnetic field (MF1) in the sensing region (SR). In this way, magnetic field measurement can be performed more accurately.

[0037] In one embodiment of the present invention, the magnetic field measuring device (1) further comprises at least one permanent magnet (not shown) arranged to separate the direction of the negatively charged nitrogen vacancy defect center (DC). Depending on the amplitude of the projection of the magnetic field direction generated by this magnet in the direction of the negatively charged nitrogen vacancy defect center (DC) in the semiconductor material (4), separation of the different directions of the negatively charged nitrogen vacancy defect center (DC) in the opto-detection magnetic resonance spectrum is brought about. In magnetic particle imaging, this separation occurs spontaneously due to the presence of a static selection magnetic field and a slowly time-varying magnetic field.

[0038] The present invention also relates to a magnetic particle detection system comprising a magnetic field measuring device (1) of the type described above.

[0039] The present invention also relates to a magnetic particle imaging system comprising a magnetic field measuring device (1) of the type described above.

[0040] The present invention also relates to a magnetic particle relaxation time measurement system including the magnetic field measurement device (1) of the above type.

[0041] In the magnetic field measurement device (1) of the present invention, the defect center(s) (DC) in the semiconductor material (4) is / are arranged such that at least one defect center (DC) in the semiconductor material (4) corresponds to a magnetic field zero line (MFL). As a result, the first magnetic field (MF1) generated by the transmission coil (2) is not detected or is detected to an ignorable extent through the defect center(s) (DC) in the semiconductor material (4), and only the magnetization of the magnetic particles in the sensing region (SR) is detected. Thereby, the detection sensitivity of the magnetic field measurement device (1) of the present invention is significantly improved.

Claims

1. A magnetic field measuring device (1) enabling highly sensitive detection of magnetic particle signals in the detection or imaging of magnetic particles, comprising: at least one transmitting coil (2) configured to magnetize the magnetic particles substantially coherently in a sensing region (SR) of a measurement object containing a plurality of magnetic particles and to generate a zero magnetic field line (MFL) outside the sensing region (SR); at least one coil driving and control circuit (3) configured to drive the at least one transmitting coil (2); at least one semiconductor material (4) having at least one defect center (DC) capable of changing electron spins and energy states when excited by electromagnetic energy; at least one optical assembly (5) having at least one optical sensor configured to optically excite the defect center (DC) located within the semiconductor material (4) and to detect radiation emitted by the defect center (DC) in response to the optical excitation; at least one microwave antenna (6) configured to excite the electron spin state of the defect center (DC) located within the semiconductor material (4); and at least one microwave driving and control circuit (7) configured to drive the microwave antenna, wherein the semiconductor material (4) is arranged such that the defect center (DC) coincides with at least one zero magnetic field line (MFL). Magnetic field measuring device (1).

2. The magnetic field measuring device (1) according to claim 1, wherein the semiconductor material (4) comprises at least one diamond having a negatively charged nitrogen vacancy defect center (DC) in its structure. Magnetic field measuring device (1).

3. The magnetic field measuring device (1) according to claim 1 or 2, further comprising at least one compensation coil (8) configured to generate at least a second magnetic field (MF2) for adjusting the position of the zero magnetic field line (MFL) by moving the zero magnetic field line (MFL) generated by the transmitting coil (2). Magnetic field measuring device (1).

4. The magnetic field measuring device (1) according to claim 3, wherein the compensation coil (8) is configured to generate a second magnetic field (MF2) having a magnetic field gradient that eliminates a change in the position of the first magnetic field (MF1) generated by the transmitting coil (2) around the zero magnetic field line (MFL). Magnetic field measuring device (1).

5. In the magnetic field measuring device (1) according to claim 3 or 4, a time-varying current having a sine wave shape is applied to the compensation coil (8) to manipulate the magnetization of the magnetic particles. The magnetic field measuring device (1) is characterized by this.

6. In the magnetic field measuring device (1) according to any one of claims 3 to 5, the coil drive and control circuit (3), the optical assembly (5), and the microwave drive and control circuit (7) are configured to communicate with each other to exchange data in order to apply signal waveforms necessary for magnetic field measurement to the transmission coil (2), the compensation coil (8), the defect center (DC), and the microwave antenna (6). The magnetic field measuring device (1) is characterized by this.

7. In the magnetic field measuring device (1) according to any one of claims 1 to 6, the microwave drive and control circuit (7) is configured to control the microwave antenna (6) so as to emit a microwave signal modulated at a frequency that excites ultra-fine electron spin resonance (DC) to the defect center. The magnetic field measuring device (1) is characterized by this.

8. In the magnetic field measuring device (1) according to any one of claims 1 to 7, a plurality of transmission coils (2) are positioned at different positions around the sensing region (SR) so as to increase the intensity of the first magnetic field (MF1) in the sensing region (SR) or to homogenize the first magnetic field (MF1) in the sensing region (SR). The magnetic field measuring device (1) is characterized by this.

9. In the magnetic field measuring device (1) according to any one of claims 1 to 8, the magnetic field measuring device (1) is characterized by including at least one permanent magnet arranged to separate the direction of the defect center (DC).

10. A magnetic particle detection system comprising the magnetic field measuring device (1) according to any one of claims 1 to 9.

11. A magnetic particle imaging system comprising the magnetic field measuring device (1) according to any one of claims 1 to 9.

12. A magnetic particle relaxation time measuring machine system comprising the magnetic field measuring device (1) according to any one of claims 1 to 9.

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