Viscosity detection method and system based on harmonic amplitude phase drop intersection

Abstract

The invention belongs to the technical field of biomedical analysis and detection, relates to a viscosity detection method and system based on a harmonic amplitude phase drop cross point, and aims to solve the problem that the quantification precision and sensitivity of a traditional magnetic particle spectrometer technology in bioviscosity detection are limited. The method comprises the following steps: setting magnetic field parameters; preparing magnetic particle standard solutions with different viscosities and obtaining harmonic amplitude phase descending cross points corresponding to the viscosities so as to obtain a viscosity measurement calibration curve; and obtaining a harmonic amplitude phase descending cross point of the to-be-measured viscosity sample, and calculating the viscosity. According to the invention, a viscosity sample is marked by using magnetic nanoparticles, and viscosity measurement is realized by detecting a direct-current field scanning value corresponding to a harmonic amplitude phase drop cross point of the viscosity sample; the operation is simple and convenient, and rapid, high-sensitivity and high-precision viscosity detection of the magnetic particle spectrometer can be realized.

Description

Background Art

[0002] In the field of biomedical analysis and detection, accurate and sensitive detection of biological samples is crucial, which is directly related to disease diagnosis, evaluation of treatment effects, and advancement of life science research. The Magnetic Particle Spectroscopy (MPS) realizes highly sensitive biomedical detection and analysis by detecting and analyzing the non-linear response harmonic signals of magnetic nanoparticles.

[0003] In terms of biological viscosity detection, traditional MPS technology usually adopts the harmonic ratio, such as using the ratio of the third harmonic to the fifth harmonic as a measure to evaluate the viscosity of biological samples. Its principle is to eliminate the detection error caused by the change in the concentration of magnetic nanoparticles through this ratio. Because in actual detection, the fluctuation of the concentration of magnetic nanoparticles will interfere with the accurate judgment of the viscosity of biological samples. However, this traditional method has obvious limitations. Its quantization accuracy depends to a large extent on the signal-to-noise ratio of the harmonics. This means that in order to achieve relatively accurate detection, extremely strict requirements are imposed on the MPS hardware design, requiring the hardware to have extremely high signal processing capabilities and anti-interference performance; there are also relatively high requirements for the characteristics of the magnetic nanoparticles themselves, such as magnetization response characteristics, particle size distribution, etc. This limitation makes it difficult for traditional MPS to achieve high-sensitivity and high-precision biological viscosity detection in the face of complex biological sample environments, and it cannot meet the growing demand for detection technology in the current biomedical field. Summary of the Invention

[0004] In order to solve the above problems in the prior art, that is, the problem of limited quantization accuracy and sensitivity of traditional magnetic particle spectrometer technology in biological viscosity detection, the first aspect of the present invention proposes a viscosity detection method based on the cross point of harmonic amplitude-phase drop, which utilizes the characteristics of magnetic nanoparticles to efficiently detect the viscosity change of biological samples. The method includes: S1. Set magnetic field parameters, where the magnetic field parameters include the parameters of the excitation field and the DC scanning field; S2. Configure magnetic particle standard solutions with different viscosities, measure the harmonic response signals at different viscosities respectively, and determine the corresponding cross points of harmonic amplitude-phase drop, and then obtain a viscosity measurement calibration curve; S3. Obtain the cross point of harmonic amplitude-phase drop of the sample with the viscosity to be measured, and determine the viscosity of the sample with the viscosity to be measured through the viscosity measurement calibration curve.

[0005] In some preferred embodiments, set the magnetic field parameters so that the excitation field is orthogonal to the DC scanning field, and the receiving coil is coaxial with the DC scanning field.

[0006] In some preferred embodiments, to determine the corresponding cross point of harmonic amplitude-phase drop, the method is: The magnetic particle standard solution is excited by a sinusoidal alternating magnetic field, and at the same time, a DC scanning field is used for scanning to obtain the harmonic response signal of the magnetic particle standard solution at this viscosity; Perform Fourier transform on the harmonic response signal to obtain the corresponding frequency-domain signal, and extract the second harmonic based on the frequency-domain signal; Based on the second harmonic, determine its phase and amplitude, and then obtain the amplitude change curve and phase change curve that change with the DC scanning field to determine the harmonic amplitude-phase drop intersection point.

[0007] In some preferred embodiments, the harmonic amplitude-phase drop intersection point is the first intersection point of the amplitude change curve and the phase change curve when the amplitude change curve drops.

[0008] In some preferred embodiments, a viscosity measurement calibration curve is obtained, and the method is as follows: The DC scanning field value corresponding to the harmonic amplitude-phase drop intersection point is the DC scanning field value of the magnetic particle standard solution at this viscosity; One-to-one correspondence between different viscosities and their corresponding DC scanning values is obtained to obtain multiple discrete calibration points, and then the discrete point diagram of the viscosity and the DC scanning value is obtained; Perform curve fitting on the discrete point diagram to obtain the viscosity measurement calibration curve.

[0009] In some preferred embodiments, the viscosity of the sample with the viscosity to be measured is determined, and the method is as follows: Measure the harmonic response signal of the sample with the viscosity to be measured and determine the corresponding harmonic amplitude-phase drop intersection point, obtain the DC scanning field value of the sample with the viscosity to be measured, and determine the viscosity value of the sample with the viscosity to be measured based on the viscosity measurement calibration curve.

[0010] In the second aspect of the present invention, a viscosity detection system based on the harmonic amplitude-phase drop intersection point is proposed. The system includes a signal acquisition device and a central processing device; The signal acquisition device includes a magnetic particle spectrometer; the signal acquisition device is configured to set scanning parameters and obtain the harmonic response signal of the magnetic particle standard solution based on the scanning parameters; The central processing device includes a CPU and a GPU; the central processing device is configured to determine the corresponding harmonic amplitude-phase drop intersection point based on the harmonic response signals of magnetic particle standard solutions with different viscosities, and then obtain a viscosity measurement calibration curve; it is also configured to determine the harmonic amplitude-phase drop intersection point of the sample with the viscosity to be measured based on the harmonic response signal of the sample with the viscosity to be measured, and then determine the viscosity of the sample with the viscosity to be measured.

[0011] Advantages of the present invention: The present invention uses magnetic nanoparticles to label a sample to be measured, determines a calibration curve by means of the intersection point of the harmonic amplitude-phase drop of magnetic nanoparticles in standard viscosity solutions with different concentrations, detects the viscosity of the sample to determine the DC field scan value, thereby detecting biological viscosity, solves the over-reliance on the harmonic signal-to-noise ratio in the prior art, makes the detection accuracy free from the influence of fluctuations, greatly improves the accuracy and stability of the detection results, remains highly sensitive and accurate in a complex environment, significantly optimizes the biological viscosity detection process, effectively reduces the detection threshold, significantly improves the detection performance, and effectively meets the growing demand for detection technology in the biomedical field; Moreover, the operation is simple. Only magnetic nanoparticles are needed to label the sample, and then sinusoidal alternating magnetic field excitation and DC field scan detection are performed to complete the viscosity measurement. The configuration of the orthogonal receiving coil is beneficial to improving the detection robustness. The present invention greatly shortens the detection time, improves the detection efficiency, is convenient for large-scale popularization and application in actual clinical and scientific research work, and effectively reduces the experimental cost and operation difficulty. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Other features, objects, and advantages of the present application will become more apparent by reading the detailed description of the non-limiting embodiments with reference to the following drawings: Figure 1 is a flowchart of the viscosity detection method based on the intersection point of harmonic amplitude-phase drop of the present invention; Figure 2 is a schematic structural diagram of the viscosity detection system based on the intersection point of harmonic amplitude-phase drop of the present invention; Figure 3 is a schematic diagram of the magnetic field waveform of the excitation field in the embodiment of the present invention; Figure 4 is a schematic diagram of the magnetic field waveform of the scanned DC field in the embodiment of the present invention; Figure 5 is a schematic diagram of the change of the intersection point of the harmonic amplitude-phase drop of the response of magnetic nanoparticles affected by viscosity change in the embodiment of the present invention; Figure 6 is a schematic diagram of the viscosity measurement calibration curve in the embodiment of the present invention; The reference numerals are as follows: 1. Excitation coil, 2. DC scanning coil, 3. Receiving coil, 4. Sample to be measured. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0013] The following further describes the present application in detail with reference to the drawings and embodiments. It can be understood that the specific embodiments described herein are only used to explain the related invention and are not intended to limit the invention. In addition, it should be noted that for the sake of description, only parts related to the relevant invention are shown in the drawings.

[0014] It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments may be combined with each other. The present application will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

[0015] In the existing detection methods based on the harmonic ratio, it is difficult to balance the relationship among detection accuracy, sensitivity, and system complexity due to hardware performance and material property limitations in practical applications. The present invention conducts detection based on the intersection point of the harmonic amplitude and phase decline of magnetic nanoparticles, so that the detection accuracy is no longer limited by the fluctuation of the harmonic signal-to-noise ratio, significantly improving the accuracy and stability of the detection result.

[0016] To more clearly illustrate the viscosity detection method of the present invention based on the intersection point of the harmonic amplitude and phase decline, the following combines Figure 1 to elaborate on each step in the embodiments of the present invention. The method includes: S1. Set the magnetic field parameters, where the magnetic field parameters include the parameters of the excitation field and the DC scanning field; Set the magnetic field parameters, make the excitation field and the DC scanning field in an orthogonal relationship, and the receiving coil is coaxial with the DC scanning field.

[0017] Preferably, in this embodiment, the selected magnetic nanoparticles are magnetic particles dominated by Brownian relaxation. Among them, the excitation field is Figure 3 as shown, a sinusoidal alternating magnetic field with a field strength of 1 - 10 mT and an excitation frequency f0 ≤ 3 kHz. The excitation field H ac (t) is as shown in Equation 1: H ac (t) = H acpeak sin(2πf0t)e x (1) In the formula, H acpeak is the peak magnetic field strength of the excitation field, f0 is the excitation frequency, and e x represents the change of the excitation magnetic field on the x-axis; The DC scanning field is as Figure 3 shown, with a field strength of 1 - 10 mT and a scanning interval ≤ 1 mT. The DC scanning field H dc is as shown in Equation 2: In the formula, H dcpeak represents the peak magnetic field of the scanning DC field, k represents the interval of the peak scanning magnetic field, which is a positive integer, i = 0 - k, and e y represents the change of the DC scanning field along the y-axis; The total magnetic field is H i (t), as shown in Equation 3: H i (t) = H ac (t) + Hdc (3) Among them, the peak magnetic field H of the excitation field acpeak is not less than the peak H of the DC scanning field dcpeak ; The magnetization response signal of the magnetic nanoparticles is: The received voltage signal u(t) of the receiving coil 3 is: Among them, B r (r) is the sensitivity of the receiving coil 3.

[0018] S2. Prepare magnetic particle standard solutions with different viscosities, use a magnetic particle spectrometer to measure the harmonic response signals at different viscosities respectively, and determine the corresponding harmonic amplitude phase drop crossover points, so as to obtain a viscosity measurement calibration curve; Among them, the magnetic particles are one of paramagnetic particles dominated by Brownian relaxation such as magnetite and iron oxide. The magnetic particle standard solution is a magnetic particle solution with a known unit iron concentration. Use this standard solution to label different viscosity solutions, denoted as S1, S2, S3, Si.., Sw, w ∈ N+, and N ≥ 2.

[0019] In this embodiment, the solvent of the viscosity solution is any one of glycerol, gelatin, etc. Select deionized water and PBS solution for dilution, and prepare magnetic particle mixed solutions with different viscosities in the form of volume ratio, and then use a magnetic particle spectrometer to measure them one by one to obtain the corresponding harmonic amplitude phase drop crossover points.

[0020] Preferably, to determine the corresponding harmonic amplitude phase drop crossover point, the method is: Use a sinusoidal alternating magnetic field to excite the magnetic particle standard solution, and at the same time use a DC scanning field for scanning to obtain the harmonic response signal of the magnetic particle standard solution at each viscosity, that is, the magnetic particle response voltage signal is Perform Fourier transform on the harmonic response signal to obtain the corresponding frequency domain signal Among them, m represents the harmonic order of the magnetic particle response signal, w0 = 2πf0; Based on the frequency domain signal extract the second harmonic and then calculate its amplitude and phase θ(2w0): Combine Equation (8) and Equation (9), plot the curve with the change of the DC scanning field, as Figure 5 shown, obtain the amplitude change curve and phase change curve with the change of the DC scanning field to determine the harmonic amplitude-phase drop crossing point.

[0021] Further preferably, in this embodiment, the harmonic amplitude-phase drop crossing point is the first crossing point CP of the amplitude change curve when it drops and the phase change curve.

[0022] Preferably, obtain the viscosity measurement calibration curve, and the method is as follows: The DC scanning field value corresponding to the harmonic amplitude-phase drop crossing point is the DC scanning field value of the magnetic particle standard solution at this viscosity; Correspond different viscosities with their corresponding DC scanning values one by one to obtain multiple discrete calibration points, and then obtain the discrete point diagram of the viscosity and the DC scanning value; Perform curve fitting processing on the discrete point diagram to obtain the viscosity measurement calibration curve.

[0023] S3. Obtain the harmonic amplitude-phase drop crossing point of the viscosity sample to be measured, and determine the viscosity of the viscosity sample to be measured through the viscosity measurement calibration curve. The method is as follows: Measure the harmonic response signal of the viscosity sample to be measured and determine the corresponding harmonic amplitude-phase drop crossing point. Take the first crossing point between the drop of the harmonic amplitude change and the phase change as the DC scanning field value corresponding to the viscosity to be measured, and substitute it into the viscosity measurement calibration curve to determine the viscosity value of the viscosity sample to be measured.

[0024] Although each step is described in the above order in the above embodiments, those skilled in the art can understand that in order to achieve the effects of this embodiment, different steps do not have to be executed in such an order. They can be executed simultaneously (in parallel) or in a reversed order, and these simple changes are all within the protection scope of the present invention.

[0025] A viscosity detection system based on the harmonic amplitude-phase drop crossing point according to the second embodiment of the present invention, the system includes a signal acquisition device and a central processing device; The signal acquisition device includes a magnetic particle spectrometer; the signal acquisition device is configured to set scanning parameters and obtain the harmonic response signal of the magnetic particle standard solution based on the scanning parameters; The central processing device includes a CPU and a GPU; the central processing device is configured to determine the corresponding harmonic amplitude-phase drop crossover point based on the harmonic response signals of magnetic particle standard solutions with different viscosities, and further obtain a viscosity measurement calibration curve; it is also configured to determine the harmonic amplitude-phase drop crossover point of the viscosity sample to be measured based on the harmonic response signal of the viscosity sample to be measured, and further determine the viscosity of the viscosity sample to be measured.

[0026] In this embodiment, the magnetic particle spectrometer includes an excitation coil 1, a DC scanning coil 2, and a receiving coil 3. The harmonic response signal of the sample 4 to be measured is collected by the magnetic particle spectrometer, and its viscosity is calculated by the central processing device.

[0027] It should be noted that the viscosity detection system based on the harmonic amplitude-phase drop crossover point provided in the above embodiment is only illustrated by dividing the above functional modules. In practical applications, the above functions can be allocated to different functional modules according to needs, that is, the modules or steps in the embodiments of the present invention can be further decomposed or combined. For example, the modules in the above embodiment can be combined into one module, or further split into multiple sub-modules to complete all or part of the functions described above. For the names of the modules and steps involved in the embodiments of the present invention, they are only used to distinguish each module or step, and are not regarded as an improper limitation of the present invention.

[0028] Those skilled in the art can clearly understand that for the convenience and brevity of description, the specific working process and related descriptions of the system described above can refer to the corresponding process in the foregoing method embodiments, and will not be repeated here.

[0029] An electronic device according to a third embodiment of the present invention includes: At least one processor; and A memory communicatively connected to at least one of the processors; wherein, The memory stores instructions executable by the processor, and the instructions are used to be executed by the processor to implement the above-mentioned viscosity detection method based on the harmonic amplitude-phase drop crossover point.

[0030] A computer-readable storage medium according to a fourth embodiment of the present invention stores computer instructions, and the computer instructions are used to be executed by the computer to implement the above-mentioned viscosity detection method based on the harmonic amplitude-phase drop crossover point.

[0031] Those skilled in the art can clearly understand that for the convenience and brevity of description, the specific working process and related descriptions of the above-mentioned electronic device and computer-readable storage medium can refer to the corresponding process in the foregoing method embodiments, and will not be repeated here.

[0032] Those skilled in the art should be able to realize that the modules and method steps of each example described in combination with the embodiments disclosed herein can be implemented by electronic hardware, computer software, or a combination of the two. The programs corresponding to the software modules and method steps can be placed in a random access memory (RAM), internal memory, read-only memory (ROM), electrically programmable ROM, electrically erasable programmable ROM, registers, hard disk, removable disk, CD-ROM, or any other form of storage medium well-known in the technical field. To clearly illustrate the interchangeability of electronic hardware and software, the composition and steps of each example have been generally described according to functions in the above description. Whether these functions are executed in the form of electronic hardware or software depends on the specific application and design constraints of the technical solution. Those skilled in the art can use different methods to implement the described functions for each specific application, but such implementation should not be considered to exceed the scope of the present invention.

[0033] Computer program code for performing the operations of the present application can be written in one or more programming languages or combinations thereof. The above programming languages include object-oriented programming languages such as Java, Smalltalk, C++, and also include conventional procedural programming languages such as the "C" language or similar programming languages. The program code can be executed entirely on the user's computer, partially on the user's computer, executed as an independent software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In the case of a remote computer, the remote computer can be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or it can be connected to an external computer (for example, by using an Internet service provider to connect through the Internet).

[0034] The flowcharts and block diagrams in the accompanying drawings illustrate the possible architectures, functions, and operations of systems, methods, and computer program products according to various embodiments of the present application. In this regard, each block in the flowchart or block diagram may represent a module, a program segment, or a part of code that contains one or more executable instructions for implementing the specified logical function. It should also be noted that in some alternative implementations, the functions marked in the blocks may occur in a different order than that marked in the accompanying drawings. For example, two consecutive blocks shown may actually be executed substantially in parallel, and they may sometimes be executed in the reverse order, depending on the functions involved. It should also be noted that each block in the block diagram and / or flowchart, and the combination of blocks in the block diagram and / or flowchart, can be implemented by a dedicated hardware-based system for performing the specified functions or operations, or can be implemented by a combination of dedicated hardware and computer instructions.

[0035] The terms "first", "second", etc. are used to distinguish similar objects and are not used to describe or indicate a particular order or sequence.

[0036] The term "comprising" or any other similar term is intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus / device that comprises a series of elements includes not only those elements but also other elements not expressly listed, or elements inherent to those process, method, article, or apparatus / device.

[0037] So far, the technical solution of the present invention has been described in conjunction with the preferred embodiments shown in the accompanying drawings. However, it is easily understood by those skilled in the art that the protection scope of the present invention is obviously not limited to these specific embodiments. Without departing from the principle of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the protection scope of the present invention.

Claims

1. A viscosity detection method based on harmonic amplitude phase drop intersection point, characterized in that: The following steps are involved: S1. Setting magnetic field parameters, wherein the magnetic field parameters include parameters of an excitation field and a DC scanning field; S2, preparing magnetic particle standard solutions of different viscosities, respectively measuring the harmonic response signals under different viscosities and determining the corresponding harmonic amplitude phase drop intersection points, thereby obtaining a viscosity measurement calibration curve; S3, obtaining the harmonic amplitude phase drop intersection point of the viscosity sample to be measured, and determining the viscosity of the viscosity sample to be measured through the viscosity measurement calibration curve.

2. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1 is characterized in that: The magnetic field parameters are set so that the excitation field is orthogonal to the DC scanning field and the receiving coil is coaxial with the DC scanning field.

3. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1, characterized in that: The corresponding harmonic amplitude phase drop intersection point is determined by: The magnetic particle standard solution is excited by a sinusoidal alternating magnetic field, and scanned by a DC scanning field to obtain a harmonic response signal of the magnetic particle standard solution at the viscosity; Performing Fourier transform on the harmonic response signal to obtain a corresponding frequency domain signal, and extracting the second harmonic based on the frequency domain signal; The phase and amplitude of the second harmonic are determined based on the second harmonic, and then the amplitude change curve and the phase change curve along with the change of the DC scanning field are obtained to determine the crossover point of the harmonic amplitude and phase decrease.

4. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 3 is characterized in that: The harmonic amplitude-phase decreasing intersection point is the first intersection point of the amplitude changing curve with the phase changing curve when the amplitude changing curve decreases.

5. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 4 is characterized in that: Determine the viscosity of the sample to be tested by: The harmonic response signal of the viscosity sample to be measured is measured and the corresponding harmonic amplitude phase drop intersection point is determined to obtain the DC scanning field value of the viscosity sample to be measured, and the viscosity value of the viscosity sample to be measured is determined based on the viscosity measurement calibration curve.

6. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1, characterized in that: The viscosity measurement calibration curve is obtained by: The DC scanning field value corresponding to the cross point of the harmonic amplitude phase decrease is the DC scanning field value of the magnetic particle standard solution at the viscosity; Matching different viscosities with their corresponding DC scanning values ​​one by one to obtain a plurality of discrete calibration points, and then obtaining a discrete point diagram of the viscosity and the DC scanning value; The discrete point graph is subjected to curve fitting processing to obtain the viscosity measurement calibration curve.

7. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1, characterized in that: The excitation field is a sinusoidal alternating magnetic field with a field strength of 1-10 mT and an excitation frequency of ≤3 kHz.

8. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1, characterized in that: The field intensity of the DC scanning field is 1-10 mT, and the scanning interval is ≤1 mT.

9. The viscosity detection method based on harmonic amplitude phase drop crossover point according to claim 1, characterized in that: The magnetic particles are paramagnetic particles dominated by Brownian relaxation.

10. A viscosity detection system based on harmonic amplitude phase drop intersection point, according to the viscosity detection method based on harmonic amplitude phase drop intersection point according to any one of claims 1-9, characterized in that: The system includes a signal acquisition device and a central processing device; The signal acquisition device comprises a magnetic particle spectrometer; the signal acquisition device is configured to set scanning parameters and acquire a harmonic response signal of the magnetic particle standard solution based on the scanning parameters; The central processing device includes a CPU and a GPU; the central processing device is configured to determine the corresponding harmonic amplitude phase drop intersection points based on the harmonic response signals of magnetic particle standard solutions with different viscosities, thereby obtaining a viscosity measurement calibration curve; and is also configured to determine the harmonic amplitude phase drop intersection points of the viscosity sample to be measured based on the harmonic response signals of the viscosity sample to be measured, thereby determining the viscosity of the viscosity sample to be measured.

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