Measurement system and method for measuring concentration of magnetic nanoparticle samples and distance between samples and probes

Abstract

The present invention provides a system and method for measuring the concentration of a magnetic nanoparticle sample and the distance between the sample and the probe. The system and method for measuring the concentration of a magnetic nanoparticle sample and the distance between the sample and the probe comprises an excitation coil and a detection coil that cooperate with each other. The detection coil is connected to a filter, a phase-locked amplifier and a power supply, and the excitation coil is also connected to the power supply. Capacitors are also arranged between the filter and the detection coil, and between the power supply and the excitation coil.

Description

Technical Field

[0001] The invention belongs to the technical field of magnetic nanoparticle imaging, and in particular relates to a system and a method for measuring the concentration of a magnetic nanoparticle sample and the distance between the sample and a probe. Background Art

[0002] Sentinel lymph node biopsy for breast cancer is an intraoperative diagnostic technique for early and middle-stage breast cancer that has become almost necessary in recent years. Its purpose is to determine whether there is potential lymph node metastasis near the breast tumor to determine the scope of tumor resection and lymph node dissection. Sentinel lymph nodes generally refer to the first lymph node through which cancer cells spread. Accurate positioning of sentinel lymph nodes and intraoperative pathological biopsy are of great significance to tumor metastasis, intraoperative resection scope and even prognosis. However, there are often multiple lymphatic drainage circulations near the breast (including internal breast), including nearly 100 lymph nodes. Accurate positioning of sentinel lymph nodes is the most important step in sentinel lymph node biopsy. At present, foreign countries mainly use Tc-99m nuclear tracing and dye tracing combined methods to locate sentinel lymph nodes, and its accuracy can be as high as 98% or more. However, due to radioactive regulations and other reasons, domestic methods such as methylene blue single staining are mostly used, and the accuracy is nearly 10 percentage points lower than that of foreign countries. In addition, due to the characteristics of small molecules such as methylene blue, the false negative rate is extremely high.

[0003] The existing technology uses SPIONs as tracers for SLNB positioning, and adopts a handheld SLNB magnetic sensitive detection device with permanent magnetic excitation and Hall sensor, but its detection depth is only about 4 mm.

[0004] The Sentimag commercial magnetically sensitive SLNB instrument is equipped with Sienna+ superparamagnetic iron oxide particles, and its maximum detection depth is about 10mm. After SLN localization was performed on 108 patients using both magnetic technology and standard methods (isotope blue dye), the SLN identification accuracy rates were 98.1% and 97.2%, respectively.

[0005] However, as mentioned above, the detection method of permanent magnet combined with Hall or MR sensor adopted by the above-mentioned magnetic sensitive SLNB technology severely limits its detection depth and sensitivity, and inevitably makes it extremely susceptible to the complex external noise interference of the operating room, and cannot support the extremely important clinical tomographic positioning. It is more suitable as an intraoperative detection device with strict environmental requirements rather than a non-invasive preoperative SLN positioning technology based on imaging technology.

[0006] Application No.: 201110990219.5 records a method of sentinel lymph node tracing using open magnetic particle imaging technology. Its AC magnetization excitation and measurement method can effectively shield external electromagnetic and static magnetic field interference, and achieve highly sensitive sentinel lymph node signal detection. However, it only supports the detection and restoration of superparamagnetic tracer concentrations in sentinel lymph nodes at a fixed distance, and some lymph nodes may be hidden deep in the tissue during actual surgery. Under this condition, it is impossible to accurately restore the tracer concentration in the lymph nodes. This is mainly because the magnetic signal is an active field, and its magnetic field line distribution density decreases rapidly with the increase of spatial distance. Therefore, there is inaccuracy in the restoration of concentration information under unknown distance conditions.

[0007] In the existing sentinel lymph node biopsy for breast cancer, commonly used detection methods include radionuclide method, methylene blue method and fluorescent labeling method. However, these methods all have some disadvantages: Radionuclide method: The radionuclide method requires the use of radioactive isotope labeled substances to be injected into the body, and then the sentinel lymph nodes are located by radioactive detectors. This method has a high radiation dose, which may have a certain impact on the patient's health. It also requires equipment and facilities to handle radioactive waste, and the operation is complicated, which increases the operation time and risk.

[0008] Methylene blue method: The methylene blue method locates sentinel lymph nodes by injecting a blue dye with staining properties. However, the methylene blue method has a certain instability in the staining effect, which may cause the dye to spread to other tissues or lymph nodes, affecting accurate positioning.

[0009] Fluorescence labeling method: Fluorescence labeling method locates sentinel lymph nodes by injecting fluorescent markers, and then uses fluorescent imaging equipment to observe and identify them. However, the fluorescence decay of fluorescent markers in the lymphatic system is fast, resulting in a short visualization time, and there are also problems of background interference and depth limitation. Summary of the invention

[0010] The present invention aims at the above problems and provides a system and method for measuring the concentration of magnetic nanoparticle samples and the distance between the samples and the probe.

[0011] To achieve the above-mentioned purpose of the present invention, the present invention adopts the following technical scheme: the measurement system of the concentration of magnetic nanoparticle samples and the distance between the samples and the probe of the present invention includes an excitation coil and a detection coil that cooperate with each other, the detection coil is connected to the filter, the phase-locked amplifier and the power supply, and the excitation coil is also connected to the power supply; capacitors are also arranged between the filter and the detection coil, and between the power supply and the excitation coil.

[0012] The measurement method using the above measurement system includes:

[0013] Step 1: The power supply of the measurement system outputs an AC source and a DC source to the excitation coil, wherein the AC source maintains a constant voltage value, and the DC source starts from 0V and superimposes a fixed voltage at intervals to a preset voltage;

[0014] The excitation coil generates an excitation field under the action of an AC source, and the magnetic nanoparticle sample generates a magnetic particle magnetization signal under the action of the excitation field;

[0015] The excitation coil forms a DC bias field acting on the sample under the action of a DC source. The magnetic particles in the magnetic nanoparticle sample are affected by the DC bias field to generate even harmonics, and the particle signal energy is mostly concentrated on the second harmonic.

[0016] Step 2: The detection coil receives the magnetic particle signal of the magnetic nanoparticle sample.

[0017] Step 3: Remove noise through a filter.

[0018] Step 4: The lock-in amplifier extracts and amplifies the second harmonic signal.

[0019] Step 5: Collect the signal data of the second harmonic and obtain the signal amplitude A x2 , signal peak x.

[0020] Step 6: Substitute the data into the following formulas:

[0021]

[0022] y=-6.203-1.83635ln(x-0.00305)

[0023] In the formula, H ac is the AC field strength, H dc is the DC field strength. M s is the saturation magnetization signal of the magnetic nanoparticles, k B is the Boltzmann constant, and T is the absolute temperature of the experimental environment.

[0024] M s , k B and T are known constants.

[0025] It is obtained that N is the sample concentration and y is the distance between the sample and the detection coil.

[0026] Preferably, in step one, the AC source maintains a voltage of 21.1 V peak-to-peak, and the DC source increases from 0 V to 3 V in intervals of 0.1 V.

[0027] Beneficial effects of the present invention:

[0028] The present invention uses a second harmonic magnetic particle signal detection method to detect signals of samples with the same concentration but different distances (the distance between the detection probe and the sample magnetic particles) and samples with the same distance but different concentrations, summarizes the experimental data, and obtains an experimental curve. Figure 6 and Figure 7 , analyze why the curve is distributed like this, prove it through a formula, and then find the experimental law, that is, when the distance between the sample and the detection coil is the same, particles of different concentrations reach the peak value of the harmonic signal under the same DC field; as the distance between the sample and the probe increases, the DC field required for the detection signal to reach its peak value becomes larger. It is found that when the sample concentration is the same, the distance between the probe and the sample can be deduced based on the particle detection signal. Similarly, when the distance is the same, the sample concentration can be deduced through known variables. The one-dimensional tomographic detection of the lymph node detection direction is innovatively realized, and the tracer (sample) depth and concentration information can be detected and restored simultaneously.

[0029] The present invention is a magnetic nanoparticle signal detection method based on second harmonics, which can significantly reduce the interference of the excitation field compared with the use of basic signals. After the magnetic nanoparticles are injected through the lymph, they will flow into the lymphatic ducts with the lymph fluid and eventually enter the sentinel lymph node area. Under the action of the external AC magnetic field, the magnetic particles will generate magnetization signals to change the magnetic field around the particles. The receiving coil detects the particle signal, and after filtering through the filter, the second harmonic signal is extracted using a phase-locked amplifier. This patent superimposes a DC source in the excitation magnetic field, and uses an AC magnetic field and a DC bias field coupling field as the excitation field. The particles are affected by the DC bias field to generate even harmonics, and the particle signal energy is mostly concentrated on the second harmonic, and the detection signal becomes stronger. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a schematic diagram of the structure of the measurement system of the magnetic nanoparticle sample concentration and the distance between the sample and the probe of the present invention.

[0031] Figure 2 This is the signal detection diagram of a 30μg concentration magnetic nanoparticle sample at 0mm of the detection coil.

[0032] Figure 3 This is a graph showing the second harmonic amplitude intensity changing with the DC field.

[0033] Figure 4 This is a graph showing the changes in the magnetization signal and harmonic signal after adding a DC bias field.

[0034] Figure 5 The curve graph is obtained by substituting the independent variable into the calculation as the distance increases.

[0035] Figure 6 The excitation field is changed to obtain the dependence diagram of the second harmonic signal on the excitation field.

[0036] Figure 7 This is the result of signal detection of magnetic nanoparticle samples with different concentrations at a distance of 0 mm from the detection coil.

[0037] Figure 8 It is an experimental curve diagram obtained by detecting the signal of the magnetic particle sample at different distances from the detection coil.

[0038] Fig. 9 It is a trend graph of the change in the distance between the second harmonic signal peak and the samples. DETAILED DESCRIPTION

[0039] The measurement system of the magnetic nanoparticle sample concentration and the distance between the sample and the probe of the present invention has an experimental structure as follows: Figure 1 As shown, it includes an excitation coil and a detection coil that cooperate with each other, the detection coil is connected to a filter, a phase-locked amplifier and a power supply, and the excitation coil is also connected to the power supply; capacitors are also arranged between the filter and the detection coil, and between the power supply and the excitation coil.

[0040] The detection tracer used in this experiment is a nanoparticle material with a single magnetic domain structure, which has the characteristics of superparamagnetism and surface modifiability. Superparamagnetism means that magnetic nanoparticles can quickly produce a hysteresis-free response under the action of an external magnetic field, ensuring that the magnetic signal generated by the superparamagnetic magnetic nanoparticles is instantly captured by the detection coil; by modifying appropriate functional genes on the surface of superparamagnetic nanoparticles, highly selective recognition and binding of specific targets can be achieved, and through appropriate surface modification, the biocompatibility of superparamagnetic nanoparticles can be improved, reducing their toxicity and adverse reaction risks in the body (existing technology).

[0041] Verification experiment: The signal of the magnetic nanoparticle sample with a concentration of 30μg was detected at 0mm of the detection coil, and the experimental results were as follows Figure 2 As shown. The DC voltage starts from 0V and increases to 3V in intervals of 0.1V, and the AC voltage is always maintained at 21.1V p-p .

[0042] pass Figure 2 The influence of the DC field on the second harmonic signal can be clearly observed, and the dc = A peak value appears at 0.9v. MNP s The magnetic response of superparamagnetic nanoparticles is described by the Langevin function:

[0043]

[0044] In the formula, m is the magnetic moment of the magnetic nanoparticle, H is the strength of the external magnetic field, T is the absolute temperature, k isB is the Boltzmann constant. On the basis of the variable magnetic field, a DC bias source is added, and the external magnetic field strength H is equal to the excitation magnetic field strength H AC With the DC bias field magnetic field strength H DC Composite sum:

[0045]

[0046] Substitute it into the Langevin function, expand it into a Fourier series, and decompose it into k-th harmonic particle signals:

[0047]

[0048] The magnetization signal M is expanded by Taylor series and decomposed into the amplitude intensity A of each harmonic, where the amplitude intensity A of the first harmonic is x1 and the second harmonic amplitude intensity A x2 :

[0049]

[0050] Where N is MNP s Concentration, M s is the sample resovist magnetic moment, H ac is the AC field strength, H dc is the DC field strength. o , k B and T are known constants, keep the AC power unchanged, and only change the DC power. The DC voltage is superimposed from 0V to 3V at intervals of 0.1V. The second harmonic amplitude intensity changes with the DC field as shown in the following figure Figure 3 shown.

[0051] As you can see, Figure 3 The changing trends and Figure 2 The experimental curves show similar trends. The extracted harmonic signal begins to decline after reaching the first peak. This is due to the MNP s The nonlinear characteristics of the magnetization response, such as Figure 4 As shown. When a DC bias field is added, the AC excitation field is offset. As the DC voltage increases, the magnetization signal of the magnetic particles also increases in the linear region. When the DC voltage increases to a certain value, the applied field strength H = H k (H ac sin(ωt)+H dc ), the magnetization signal M=M k When saturation is reached and no more changes occur, the detected harmonic signal begins to decrease.

[0052] Keeping the AC excitation field, the dependence of the second harmonic signal on the DC field shows a Gaussian distribution:

[0053]

[0054] Where σ refers to the discreteness, assuming that d is the distance parameter between the probe and the sample, as the distance increases, the independent variable B is introduced dc The calculated curve is as follows Figure 5 As shown; changing the excitation field, the dependence of the second harmonic signal on the excitation field is obtained as follows Figure 6 As shown, it satisfies the logistic distribution:

[0055]

[0056] Where a is the horizontal coordinate parameter point corresponding to the equilibrium of the curve.

[0057] Combining the two curves, namely the effect of excitation and gradient field on the second harmonic signal intensity, we can get Figure 3 The detection signal strength increases rapidly under the action of AC and DC fields, and then Figure 6 It can be seen that after the AC excitation reaches a certain level, the detection signal does not change, but Figure 5 It shows that the harmonic signal strength drops rapidly with the increase of DC field, which causes the second harmonic signal strength to drop after reaching the peak value, such as Figure 3 shown.

[0058] like Figure 7 As shown in the figure, the signal detection results of magnetic nanoparticle samples with concentrations of 10μg, 20μg and 30μg at a distance of 0mm from the detection coil are respectively performed. Among them, the DC voltage starts from 0V and is superimposed at intervals of 0.1V to 3V.

[0059] according to Figure 7 It can be obtained that when the distance between the sample and the detection coil is the same, particles of different concentrations reach the peak value of the harmonic signal under the same DC field. Then through the above experiment, we can get the signal peak value and then know the amplitude strength. Substituting the signal amplitude strength into formula 5 can obtain the magnetic particle concentration N.

[0060] The signal of the 30 μg magnetic particle sample was detected at 0 mm, 2 mm, 4 mm, 7 mm and 12 mm from the detection coil to obtain the experimental curves as shown in the figure. Figure 8 shown.

[0061] Depend on Figure 8 It can be seen that as the distance between the sample and the probe increases, the DC field required for the detection signal to reach its peak value becomes larger; Figure 5It is also pointed out that as the parameter d (the distance between the magnetic nanoparticles and the detection coil) increases, the entire image shifts to the right. This is because as the distance between the magnetic nanoparticles and the detection coil increases, the detected magnetization signal becomes smaller, and the DC bias field required for the magnetic particles to reach saturation magnetization intensity becomes larger. By sorting out the experimental data, the trend of the change in the distance between the second harmonic signal peak and the sample is obtained, as shown in Fig. 9 As shown. Using the nonlinear fitting method, it is found that it develops in a logarithmic function and satisfies the expression:

[0062] y=-6.203-1.83635ln(x-0.00305) (6)

[0063] Without knowing how deep the sample is from the probe, the measurement curve of the signal and the DC source is obtained through experiments to know the peak value of the second harmonic signal, and then substitute it into formula 6 to calculate the distance between the detection coil and the sample.

[0064] Keep the AC power at 21.1v p-p , the DC voltage is superimposed from 0V to 3V at intervals of 0.1V, and five groups of detection signals with unknown distances and known concentrations are randomly measured to obtain the second harmonic intensity peaks of 0.0147mv, 0.0075mv, 0.0036mv, 0.0143mv and 0.0022mv respectively. Substituting these three values ​​into formula 6 respectively, the calculated distance is obtained, as shown in Table 1.

[0065]

[0066] Table 1

[0067] Similarly, the second harmonic peaks of three groups of detection signals with unknown concentrations and known distances were randomly measured to be 0.0336mv, 0.0290mv, and 0.0187mv, respectively. Figure 7 We can see that for samples with different concentrations of magnetic nanoparticles, the DC field required for the harmonic signal to reach its peak is the same, and it is known that M s , K B and T, then substitute the above three values ​​into Formula 5 in turn to calculate the sample concentration. The results are shown in Table 2.

[0068]

[0069] Table 2

[0070] It can be seen that, according to the above method, although there is a certain error, the definite sample concentration and the distance between the sample and the detection coil can be obtained.

[0071] The present invention innovatively realizes one-dimensional tomography detection of the lymph node detection direction through detailed analysis of the nonlinear magnetization characteristics of superparamagnetic signals, the magnetization response distance of superparamagnetic particles, etc., and can simultaneously detect and restore the tracer depth and concentration information.

[0072] The AC excitation field and the DC bias field coupling are used as the excitation field to extract the second harmonic signal in the magnetization response of the magnetic nanoparticles for detection, which effectively reduces the interference of the excitation field and enhances the energy of the magnetic nanoparticle detection signal.

[0073] It can be understood that the above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the protection scope of the present invention.

Claims

1. A method for measuring the concentration of a magnetic nanoparticle sample and the distance between the sample and a probe, characterized in that: It includes an excitation coil and a detection coil that cooperate with each other. The detection coil is connected to a filter, a phase-locked amplifier and a power supply, and the excitation coil is also connected to the power supply. Capacitors are also arranged between the filter and the detection coil, and between the power supply and the excitation coil. Also includes: Step 1: The power supply of the measurement system outputs an AC source and a DC source to the excitation coil, wherein the AC source maintains a constant voltage value, and the DC source starts from 0V and superimposes a fixed voltage at intervals to a preset voltage; The excitation coil generates an excitation field under the action of an AC source, and the magnetic nanoparticle sample generates a magnetic particle magnetization signal under the action of the excitation field; The excitation coil forms a DC bias field acting on the sample under the action of a DC source. The magnetic particles in the magnetic nanoparticle sample are affected by the DC bias field to generate even harmonics, and the particle signal energy is mostly concentrated on the second harmonic. Step 2, the detection coil receives the magnetic particle signal of the magnetic nanoparticle sample; Step 3: Remove noise through filters; Step 4: The lock-in amplifier extracts and amplifies the second harmonic signal; Step 5, collecting the signal data of the second harmonic to obtain the signal amplitude Ax2 and the signal peak value x; Step 6: Substitute the data into the following formulas: y=-6.203-1.83635ln(x-0.00305) In the formula, H ac is the AC field strength, H dc is the DC field strength; M s is the saturation magnetization signal of the magnetic nanoparticles, k B is the Boltzmann constant, T is the absolute temperature of the experimental environment; M s , k B and T are known constants; It is obtained that N is the sample concentration and y is the distance between the sample and the detection coil.

2. The method for measuring the concentration of a magnetic nanoparticle sample and the distance between the sample and the probe according to claim 1, characterized in that: In step 1, the AC source maintains a peak-to-peak voltage of 21.1 V, and the DC source starts from 0 V and increases in intervals of 0.1 V to 3 V.

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