阅读说明：本技术 一种多模态光学和磁纳米粒子成像融合的脑检测系统 (Multi-modal optical and magnetic nanoparticle imaging fusion brain detection system ) 是由 钟江宏 岳杭琪 郑婵钰 陈重衡 田捷 于 2021-09-17 设计创作，主要内容包括：本发明公开了一种多模态光学和磁纳米粒子成像融合的脑检测系统,包括扫描仪、控制模块、信号接收模块,扫描仪包括驱动线圈、选择线圈及接收线圈,选择线圈设置于接收线圈的两端,用于构建静态梯度磁场即选择场,驱动除无场点附近的粒子之外的所有磁纳米粒子达到饱和；驱动线圈设置于接收线圈外侧用于构建正弦激励磁场即驱动场；接收线圈用于采集电压信号；控制模块用于控制电流使驱动线圈施加均匀的振荡磁场,无场点附近的粒子被驱动穿过感兴趣的物体,改变粒子磁化强度,从而在接收线圈中感应出电压信号,经过信号接收模块处理后采用X空间MPI进行图像重建。本发明有效提高了实验效率和分析效率,可用于单核细胞及T细胞的细胞外陷阱成像分析。(The invention discloses a brain detection system integrating multi-modal optical and magnetic nanoparticle imaging, which comprises a scanner, a control module and a signal receiving module, wherein the scanner comprises a driving coil, a selection coil and a receiving coil, the selection coil is arranged at two ends of the receiving coil and is used for constructing a static gradient magnetic field, namely a selection field, and all magnetic nanoparticles except particles near a field-free point are driven to be saturated; the driving coil is arranged on the outer side of the receiving coil and used for constructing a sinusoidal excitation magnetic field, namely a driving field; the receiving coil is used for collecting voltage signals; the control module is used for controlling current to enable the driving coil to apply a uniform oscillating magnetic field, particles near a field-free point are driven to penetrate through an interested object, the magnetization intensity of the particles is changed, voltage signals are induced in the receiving coil, and image reconstruction is carried out by adopting X space MPI after the voltage signals are processed by the signal receiving module. The invention effectively improves the experimental efficiency and the analysis efficiency, and can be used for extracellular trap imaging analysis of monocytes and T cells.)

1. A multi-modal optical and magnetic nanoparticle imaging fused brain examination system, comprising: a scanner, a control module, a signal receiving module, wherein,

the scanner comprises a driving coil, a selection coil and a receiving coil, wherein the selection coil is arranged at two ends of the receiving coil and used for constructing a static gradient magnetic field, namely a selection field, and driving all magnetic nano particles except particles near a field-free point to be saturated; the driving coil is arranged on the outer side of the receiving coil and used for constructing a sinusoidal excitation magnetic field, namely a driving field; the receiving coil is used for acquiring voltage signals; the signal receiving module comprises a band elimination filter, a low noise amplifier and an analog-to-digital converter which are connected in sequence;

the control module comprises a PC (personal computer) end, a digital-to-analog converter, a power amplifier and a band-pass filter which are sequentially connected and is used for controlling current to enable the driving coil to apply a uniform oscillating magnetic field, particles near a field-free point are driven to penetrate through an interested object, particle magnetization intensity is changed, voltage signals are induced in the receiving coil, and image reconstruction is carried out by adopting X space MPI after the voltage signals are processed by the signal receiving module.

2. The system of claim 1, wherein a permanent magnet is used as a selection coil, an excitation coil is used as a driving coil, and a gradiometer coil made of litz wire is used as a receiving coil.

3. The brain detection system with the multi-modal optical and magnetic nanoparticle imaging fusion function according to claim 1 or 2, wherein the receiving coil is attached to the brain of the object to be detected, and has a semi-elliptical cone shape, one end surface is a semi-ellipse, the other end surface is a semi-circle, the two end surfaces are parallel, and the connection line of the central points of the two end surfaces is perpendicular to the major axis of the ellipse.

4. The brain detection system with multimodal optical and magnetic nanoparticle imaging fusion according to claim 3, wherein the length a of the longer half axis of the hemielliptic end surface is at most 20mm, the length b of the shorter half axis is at most 25mm, and the angle θ between the horizontal line and the line between the vertex of the hemielliptic end surface and the vertex of the hemielliptic end surface is 18 ° -24 °.

5. A multi-modal optical and magnetic nanoparticle image fused brain examination system according to any one of claims 2 to 4, wherein the permanent magnet forms a static gradient magnetic field of 4-8T/m and the excitation coil forms a sinusoidal excitation magnetic field of 15-25 mT/m.

6. The brain detection system with multi-modal optical and magnetic nanoparticle imaging fusion according to claim 5, wherein the permanent magnet forms a static gradient magnetic field of 6T/m and the excitation coil forms a sinusoidal excitation magnetic field of 20 mT/m.

7. The brain detection system with multimodal optical and magnetic nanoparticle imaging fusion according to any one of claims 1 to 6, wherein in order to realize the imaging analysis of extracellular traps of the brain of the object to be detected, the detection system is matched with the multimodal optical and magnetic nanoparticle probe, firstly, the magnetic nanoparticle is modified by fluorescent dye to obtain the optically labeled magnetic nanoparticle, then the magnetic nanoparticle is combined with the polypeptide to form the multimodal optical and magnetic nanoparticle probe, and then the brain of the object to be detected is imaged by the scanner.

8. The method for detecting a brain detection system with multi-modal optical and magnetic nanoparticle imaging fusion according to one of claims 1 to 7, comprising the following steps:

s1: establishing a tested object model;

s2: the encapsulated magnetic nanoparticles are combined with the polypeptide to form a multi-modal optical and magnetic nanoparticle probe, and an in-vivo labeling method is adopted for imaging analysis of a brain extracellular trap mechanism;

s3: moving the brain of the tested object into a receiving coil;

s4: controlling current through a control module to enable a driving coil to apply a uniform oscillating magnetic field;

s5: the signal collected by the receiving coil is collected after being processed by the signal receiving module;

s6: the acquired data are reconstructed by using the MPI in the X space.

Technical Field

The invention belongs to the technical field of biomedical imaging, and particularly relates to a multi-modal optical and magnetic nanoparticle imaging fusion brain detection system.

Background

Systemic Lupus Erythematosus (SLE), a complex autoimmune disease, affects multiple organs and tissues. The clinical manifestations and patterns of organ involvement are widely heterogeneous, with cognitive impairment present in up to 80% of lupus patients (Nat Rev Rheumatotol 2019; 15: 137-152). The cause of lupus encephalopathy is unknown, and the exploration of the pathological change evolution process and the molecular mechanism has very important significance. In a physiological environment, the redox balance system is maintained by Reactive Oxygen Species (ROS) and antioxidants. ROS are involved in various cellular pathways, are used as signal molecules for immune regulation, and are involved in physiological and pathological processes such as production of Neutrophil Extracellular Traps (NETs) and autophagy. The study at the beginning of this subject group found that mutation of the gene Ncf1 resulted in a decrease in ROS release and an increase in inflammation of the NOX2 complex. ROS are considered important signaling molecules that regulate autoimmune diseases and lupus, but the mechanism is unknown.

The optical imaging is widely applied to the field of biomedical engineering, and has the technical advantages of high specificity, high sensitivity and the like; magnetic Particle Imaging (MPI) is a new imaging technique, whose principle is to detect the spatial distribution of magnetic nanoparticle tracers by using the nonlinear magnetization characteristics of magnetic nanoparticles in a zero magnetic field. In recent years, MPI has begun to be applied to basic research fields such as cell tracking, angiography, and inflammation imaging.

In recent years, research shows that the existing magnetic particle imaging has the advantages of high sensitivity, high resolution, limitation of tissue penetration depth and the like, but few multimode optical-magnetic nanoparticle fusion devices are developed; most MPI receiving coils are cylindrical, and special-shaped coils attached to detection parts are rarely designed; in addition, the diameters of the magnetic nanoparticles are mainly distributed in the range of 2-20 nanometers, and although millimeter-level resolution can be realized in MPI of small animals, the magnetic particles can be endocytosed by immune cells and the like, so that the problem of imaging precision reduction caused by the off-target effect of molecular markers exists. Therefore, the method still has the specific defect of realizing single cell imaging, and is difficult to carry out imaging analysis and research on regulation mechanisms such as active oxygen induced extracellular traps and the like.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a multi-modal optical and magnetic nanoparticle imaging fusion brain detection system, and the specific technical scheme of the invention is as follows:

a multi-modal optical and magnetic nanoparticle imaging fused brain detection system, comprising: a scanner, a control module, a signal receiving module, wherein,

the scanner comprises a driving coil, a selection coil and a receiving coil, wherein the selection coil is arranged at two ends of the receiving coil and used for constructing a static gradient magnetic field, namely a selection field, and driving all magnetic nano particles except particles near a field-free point to be saturated; the driving coil is arranged on the outer side of the receiving coil and used for constructing a sinusoidal excitation magnetic field, namely a driving field; the receiving coil is used for acquiring voltage signals; the signal receiving module comprises a band elimination filter, a low noise amplifier and an analog-to-digital converter which are connected in sequence;

the control module comprises a PC (personal computer) end, a digital-to-analog converter, a power amplifier and a band-pass filter which are sequentially connected and is used for controlling current to enable the driving coil to apply a uniform oscillating magnetic field, particles near a field-free point are driven to penetrate through an interested object, particle magnetization intensity is changed, voltage signals are induced in the receiving coil, and image reconstruction is carried out by adopting X space MPI after the voltage signals are processed by the signal receiving module.

Further, a permanent magnet is used as a selection coil, an excitation coil is used as a driving coil, and a gradiometer coil made of litz wire is used as a receiving coil.

Furthermore, the receiving coil is attached to the brain of the object to be measured and is in a semi-elliptical cone shape, one end face is in a semi-ellipse shape, the other end face is in a semi-circle shape, the two end faces are parallel, and the connecting line of the central points of the two end faces is perpendicular to the long axis of the ellipse.

Furthermore, the length a of the major axis and the minor axis of the semi-elliptical end surface is 20mm at most, the length b of the minor axis is 25mm at most, and the included angle theta between the connecting line between the vertex of the semi-elliptical end surface and the vertex of the semi-circular end surface and the horizontal line is 18-24 degrees.

Furthermore, the permanent magnet forms a static gradient magnetic field of 4-8T/m, and the excitation coil forms a sinusoidal excitation magnetic field of 15-25 mT/m.

Further, the permanent magnet constitutes a static gradient magnetic field of 6T/m and the excitation coil constitutes a sinusoidal excitation magnetic field of 20 mT/m.

Furthermore, in order to realize the imaging analysis of the brain extracellular trap of the tested object, the detection system is matched with the multimode optical and magnetic nanoparticle probe, firstly, the magnetic nanoparticle is modified by adopting fluorescent dye to obtain the optically marked magnetic nanoparticle, then, the magnetic nanoparticle is combined with the polypeptide to form the multimode optical and magnetic nanoparticle probe, and then, the scanner is utilized to image the brain of the tested object.

A detection method of a multi-modal optical and magnetic nanoparticle imaging fused brain detection system comprises the following steps:

s1: establishing a tested object model;

s2: the encapsulated magnetic nanoparticles are combined with the polypeptide to form a multi-modal optical and magnetic nanoparticle probe, and an in-vivo labeling method is adopted for imaging analysis of a brain extracellular trap mechanism;

s3: moving the brain of the tested object into a receiving coil;

s4: controlling current through a control module to enable a driving coil to apply a uniform oscillating magnetic field;

s5: the signal collected by the receiving coil is collected after being processed by the signal receiving module;

s6: the acquired data are reconstructed by using the MPI in the X space.

The invention has the beneficial effects that:

1. the invention adopts the anti-winding gradiometer coil which is attached to the size and the structure of the head of the measured object as the receiving coil, thereby being closer to a region of interest (ROI), improving the signal quality and the imaging sensitivity and weakening strong signals from other parts of the measured object; thereby improving the analysis efficiency;

2. the invention adopts the bimodal molecular image to effectively improve the experimental efficiency;

3. the invention combines functional molecule neutravidin on the surface of the low-diameter magnetic nanoparticle which is marked by optics with polypeptide which is marked by biotin conjugation to form a multi-modal magnetic nanoparticle probe, and can achieve the level imaging of single cell specificity.

Drawings

In order to illustrate embodiments of the present invention or technical solutions in the prior art more clearly, the drawings which are needed in the embodiments will be briefly described below, so that the features and advantages of the present invention can be understood more clearly by referring to the drawings, which are schematic and should not be construed as limiting the present invention in any way, and for a person skilled in the art, other drawings can be obtained on the basis of these drawings without any inventive effort. Wherein:

FIG. 1 is an overall block diagram of the present invention;

FIG. 2 is a scanner configuration of the present invention;

fig. 3 is a schematic diagram of a receiving coil structure according to the present invention.

Detailed Description

In order that the above objects, features and advantages of the present invention can be more clearly understood, a more particular description of the invention will be rendered by reference to the appended drawings. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced in other ways than those specifically described herein, and therefore the scope of the present invention is not limited by the specific embodiments disclosed below.

As shown in fig. 1, a brain detection system with multi-modal optical and magnetic nanoparticle imaging fusion comprises: a scanner, a control module, a signal receiving module, wherein,

as shown in fig. 2, the scanner includes a driving coil, a selection coil and a receiving coil, wherein the selection coil is disposed at two ends of the receiving coil and is used for constructing a static gradient magnetic field, i.e., a selection field, and driving all magnetic nanoparticles except particles near a field-free point to be saturated; the driving coil is arranged on the outer side of the receiving coil and used for constructing a sinusoidal excitation magnetic field, namely a driving field; the receiving coil is used for collecting voltage signals; the signal receiving module comprises a band elimination filter, a low noise amplifier and an analog-to-digital converter which are connected in sequence;

the control module comprises a PC (personal computer) end, a digital-to-analog converter, a power amplifier and a band-pass filter which are sequentially connected and is used for controlling current to enable a driving coil to apply a uniform oscillating magnetic field, particles near a field-free point are driven to penetrate through an interested object, the magnetization intensity of the particles is changed, voltage signals are induced in a receiving coil, and the voltage signals are processed by the signal receiving module and then image reconstruction is carried out by adopting X space MPI.

In some embodiments, permanent magnets are used as the selection coils, excitation coils are used as the drive coils, and gradiometer coils of litz wire are used as the receive coils.

Preferably, the receiving coil is attached to the brain of the object to be measured, and is in the shape of a semi-elliptical cone, one end face is in the shape of a semi-ellipse, the other end face is in the shape of a semicircle, the two end faces are parallel, and the connecting line of the central points of the two end faces is perpendicular to the long axis of the ellipse.

In some embodiments, the semi-elliptical end surface has a major-minor axis length a of at most 20mm, a minor axis length b of at most 25mm, and an angle θ between a line connecting the vertex of the semi-elliptical end surface and the vertex of the semi-circular end surface and a horizontal line is 18 ° to 24 °; the size of the receiving coil can be adjusted in equal proportion to different measured objects according to the shape and the size of the head.

In some embodiments, the permanent magnets constitute a static gradient magnetic field of 4-8T/m and the field coils constitute a sinusoidal excitation field of 15-25 mT/m.

Preferably, the permanent magnet constitutes a static gradient magnetic field of 6T/m and the excitation coil constitutes a sinusoidal excitation magnetic field of 20 mT/m.

In some embodiments, in order to realize the imaging analysis of the extracellular trap of the brain of the measured object, the detection system is matched with the multi-modal optical and magnetic nanoparticle probe, the magnetic nanoparticle is modified by the fluorescent dye to obtain the optically labeled magnetic nanoparticle, then the magnetic nanoparticle is combined with the polypeptide to form the multi-modal optical and magnetic nanoparticle probe, and then the brain of the measured object is imaged by the scanner.

A detection method of a multi-modal optical and magnetic nanoparticle imaging fused brain detection system comprises the following steps:

s1: establishing a tested object model;

s2: the encapsulated magnetic nanoparticles are combined with the polypeptide to form a multi-modal optical and magnetic nanoparticle probe, and an in-vivo labeling method is adopted for imaging analysis of a brain extracellular trap mechanism induced by active oxygen;

s3: moving the brain of the tested object into a receiving coil;

s4: controlling current through a control module to enable a driving coil to apply a uniform oscillating magnetic field;

s5: the signal collected by the receiving coil is collected after being processed by the signal receiving module;

s6: the acquired data are reconstructed by using the MPI in the X space.

For the convenience of understanding the above technical aspects of the present invention, the following detailed description will be given of the above technical aspects of the present invention by way of specific examples.

Example 1

The brain detection system with the multi-modal optical and magnetic nanoparticle imaging fusion is adopted to carry out experiments on mice, and the brain of the mice is subjected to extracellular trap specific imaging of monocytes and T cells, so that the action mechanism of active oxygen in autoimmune diseases is analyzed. The method comprises the following specific steps:

s1: and establishing a mouse model.

In the experiment, 5 healthy female C57BL/6J mice with the weight of 25g and the age of 7-8 weeks are adopted;

injecting 0.5ml pristane into each mouse by intraperitoneal injection to establish a lupus mouse model.

S2: combining the encapsulated magnetic nanoparticles with the polypeptide to form a multi-modal optical and magnetic nanoparticle probe, and using the multi-modal nanoparticle molecular probe in-vivo labeling method for brain extracellular trap imaging;

s3: a special-shaped coil attached to the mouse brain is adopted to improve the sensitivity, and the mouse brain is moved into a receiving coil by using a mouse bed;

s4: controlling current through a control module to enable a driving coil to apply a uniform oscillating magnetic field;

s5: the signal collected by the receiving coil is collected after being processed by the signal receiving module;

s6: the acquired data are reconstructed by using the MPI in the X space.

In vivo imaging system control and image processing is performed on a computer equipped with the Intel core TM2 dual core processor 2.33GHz and 3GB RAM.

Traditional harmonic space MPI image reconstruction relies on a system matrix to pre-characterize the signal response of magnetic nanoparticles, meaning that the system matrix is specific to the nanoparticle sample and the accuracy of the reconstruction is reduced if the behavior of the nanoparticles in the tissue is different, the system drifts or the model is inaccurate. Importantly, MPI must undergo well-conditioned image reconstruction to avoid any loss in signal-to-noise ratio (SNR). And the signal of the X-space MPI image reconstruction is obtained by time scanning of an X space, only speed compensation and gridding are involved, and therefore the robustness and the speed of the MPI image reconstruction are improved to a certain extent.

The in vivo imaging information is realized according to the following calculation method:

the basic principle of magnetic particle imaging is the langevin equation:

wherein the content of the first and second substances,is the saturation moment of a single magnetic particle, m is the concentration of the particle,represents Fe₃O₄Saturation magnetization of (u)₀Denotes the vacuum permeability, d is the magnetic nanoparticle diameter, and

wherein α is a Langmian parameter, k_BIs the Boltzmann constant, T is the absolute temperature, W is the intensity of the applied magnetic field, the magnetic particles are characterized by a particle diameter d and a saturation magnetization M_SAnd (5) characterizing.

The magnetic field used by MPI is a time-varying drive field W^D(t) and a static gradient field W^S(x) If the gradient field is homogeneous, W^S(x) By W^S(x) Described as Qx, Q denotes the strength of the applied gradient, assuming diagonal, Q-diag (Q)₁,q₂,q₃)。

The drive field is typically selected to have a period length T_DPeriodic track W of^D(t) obtaining X for the position of the Field Free Point (FFP)^FFP＝-Q^(-1)W^D(t), voltage signal U in MPI_n(t) is:

wherein s is_n(X, t) (n ∈ {1, 2, 3}) represents a space-and time-dependent system number, factorg_nIs the inductivity, x, of the nth receiving coil_n ^FFP(t) denotes the n-th coordinate, x, of the FFP_nIs the nth spatial coordinate, z represents the magnetic moment of a nanoparticle, m (x) is the spatial SPIO distribution,representing the Langevin function, describing the magnetization behavior of SPIOs as a function of the external magnetic field,representing a multi-dimensional langevin function with respect to the nth receive coil.

The reconstruction of the MPI image in the X space is realized according to the following method:

in the x-space MPI theory, an image is expressed as convolution of nanoparticle spatial distribution and a system Point Spread Function (PSF), and the key result of analysis is to obtain a one-dimensional signal equation, which shows that the MPI signal pair FFP x at the transient position_sThe true spatial convolution of magnetic nanoparticle density ρ and PSF z (x) of (t) is sampled:

the PSF of the system is determined, among other things, by the magnetization characteristics of the nanoparticles and the magnetic field gradient. The magnetization of superparamagnetic nanoparticles is non-linear and follows the so-called langevin function. The receiver coil only detects changes in the magnetization level and thus the PSF is the derivative of the langevin function.

The one-dimensional PSF is similar to the lorentz function, and divides the slew rate of the excitation field by various constants to generate an original image in x-space:

the shape h (x) of the system PSF defines the original resolution of the imaging system, using the derivative of the langevin function, the spatial resolution of MPI is:

where Δ x is the full width at half maximum of the PSF, M_satIs the saturation magnetization of the nanoparticle; d is the nanoparticle diameter; k is a radical of_BIs the Boltzmann constant, T is the temperature, μ₀Is the vacuum permeability.

In the present invention, unless otherwise expressly stated or limited, the terms "mounted," "connected," "secured," and the like are to be construed broadly and can, for example, be fixedly connected, detachably connected, or integrally formed; can be mechanically or electrically connected; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations.

In the present invention, unless otherwise expressly stated or limited, "above" or "below" a first feature means that the first and second features are in direct contact, or that the first and second features are not in direct contact but are in contact with each other via another feature therebetween. Also, the first feature being "on," "above" and "over" the second feature includes the first feature being directly on and obliquely above the second feature, or merely indicating that the first feature is at a higher level than the second feature. A first feature being "under," "below," and "beneath" a second feature includes the first feature being directly under and obliquely below the second feature, or simply meaning that the first feature is at a lesser elevation than the second feature.

In the present invention, the terms "first", "second", "third" and "fourth" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance. The term "plurality" means two or more unless expressly limited otherwise.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.