CN113616181B - A Brain Detection System Fused with Multimodal Optical and Magnetic Nanoparticle Imaging - Google Patents

Abstract

The invention discloses a brain detection system integrating multi-mode 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 selecting coil and a receiving coil, the selecting coil is arranged at two ends of the receiving coil and is used for constructing a static gradient magnetic field, namely a selecting field, and driving all magnetic nanoparticles except particles near a field-free point to be saturated; the driving coil is arranged outside the receiving coil and used for constructing a sine excitation magnetic field, namely a driving field; the receiving coil is used for collecting voltage signals; the control module is used for controlling the current to enable the driving coil to apply a uniform oscillating magnetic field, particles near the field-free point are driven to pass through an object of interest, and the magnetization intensity of the particles is changed, so that a voltage signal is induced in the receiving coil, and the signal is processed by the signal receiving module and then image reconstruction is carried out by adopting an X space MPI. The invention effectively improves the experimental efficiency and the analysis efficiency, and can be used for the extracellular trap imaging analysis of monocytes and T cells.

Description

A Brain Detection System Fused with Multimodal Optical and Magnetic Nanoparticle Imaging

technical field

The invention belongs to the technical field of biomedical imaging, in particular to a brain detection system integrated with multimodal optical and magnetic nanoparticle imaging.

Background technique

Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs and tissues. There is wide heterogeneity in clinical presentation and patterns of organ involvement, with cognitive impairment present in up to 80% of patients with lupus (Nat Rev Rheumatol 2019; 15:137–152). The cause of lupus encephalopathy is unknown, and it is of great significance to explore its lesion evolution process and molecular mechanism. In the physiological environment, the redox balance system is maintained by reactive oxygen species (Reactive oxygen species, ROS) and antioxidants. ROS participates in a variety of cellular pathways, as signaling molecules of immune regulation, and participates in physiological and pathological processes such as the production of neutrophil extracellular traps (NET) and autophagy. Previous studies of our research group found that Ncf1 gene mutations lead to decreased release of NOX2 complex ROS and enhanced inflammation. ROS is considered to be an important signaling molecule in the regulation of autoimmune diseases and lupus, but the mechanism is unknown.

Optical imaging has been widely used in the field of biomedical engineering, and has technical advantages such as high specificity and high sensitivity. As a new imaging technology, magnetic particle imaging (MPI) uses the nonlinear magnetization characteristics of magnetic nanoparticles in zero magnetic field to detect the spatial distribution of magnetic nanoparticle tracers. In recent years, MPI has begun to be used in basic research fields such as cell tracking, angiography, and inflammation imaging.

In recent years, studies have found that the existing magnetic particle imaging has the advantages of high sensitivity, high resolution, and the limitation of tissue-free penetration depth, but there are few developments of multi-modal optical-magnetic nanoparticle fusion equipment; and most MPI receiving coils are cylindrical, and few special-shaped coils are designed to fit the detection site; in addition, the diameter of magnetic nanoparticles is mainly distributed in the range of 2-20 nanometers. Therefore, there are still specific defects in the realization of single-cell imaging, and it is difficult to perform imaging analysis and research on regulatory mechanisms such as reactive oxygen species-induced extracellular traps.

Contents of the invention

In order to solve the above-mentioned deficiencies in the prior art, the present invention proposes a brain detection system that combines multimodal optical and magnetic nanoparticle imaging. The specific technical solutions of the present invention are as follows:

A brain detection system integrated with multimodal optical and magnetic nanoparticle imaging, including: a scanner, a control module, and a signal receiving module, wherein,

The scanner includes a driving coil, a selection coil and a receiving coil, wherein the selection coil is arranged at both ends of the receiving coil for constructing a static gradient magnetic field, that is, a selection field, and drives all magnetic nanoparticles except particles near the no-field point to saturation; the driving coil is arranged outside the receiving coil for building a sinusoidal excitation magnetic field, that is, a driving field; the receiving coil is used for collecting voltage signals;

The control module includes a PC terminal, a digital-to-analog converter, a power amplifier, and a band-pass filter connected in sequence, and is used to control the current so that the driving coil applies a uniform oscillating magnetic field, and the particles near the field-free point are driven through the object of interest to change the magnetization of the particles, thereby inducing a voltage signal in the receiving coil. After being processed by the signal receiving module, the X-space MPI is used for image reconstruction.

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

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

Further, the major and semi-axis length a of the semi-elliptical end face is at most 20 mm, the minor axis length b is at most 25 mm, and the angle θ between the line between the apex of the semi-elliptical end face and the apex of the semi-circular end face and the horizontal line is 18°-24°.

Further, the permanent magnet forms a static gradient magnetic field of 4-8T/m, and the excitation coil forms a sinusoidal excitation magnetic field of 15-25mT/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 20mT/m.

Further, in order to realize the imaging analysis of extracellular traps in the subject’s brain, the detection system cooperates with multimodal optical and magnetic nanoparticle probes, firstly, the magnetic nanoparticles are modified with fluorescent dyes to obtain optically labeled magnetic nanoparticles, and then the magnetic nanoparticles are combined with polypeptides to form multimodal optical and magnetic nanoparticle probes, and then the scanner is used to image the subject’s brain.

A detection method for a brain detection system fused with multimodal optical and magnetic nanoparticle imaging, comprising the following steps:

S1: Establish the model of the object under test;

S2: Combining encapsulated magnetic nanoparticles with peptides to form multimodal optical and magnetic nanoparticle probes, using in vivo labeling methods for imaging analysis of extracellular trap mechanisms in the brain;

S3: Move the brain of the subject under test into the receiving coil;

S4: Control the current through the control module to apply a uniform oscillating magnetic field to the drive coil;

S5: The signal collected by the receiving coil is collected after being processed by the signal receiving module;

S6: The collected data is reconstructed using X-space MPI.

The beneficial effects of the present invention are:

1. The present invention adopts the anti-winding gradiometer coil that fits the size and structure of the head of the measured object as the receiving coil, so as to be closer to the region of interest (ROI), improve signal quality and imaging sensitivity, and at the same time weaken strong signals from other parts of the measured object; thereby improving the analysis efficiency;

2. The present invention uses dual-mode molecular imaging to effectively improve the experimental efficiency;

3. The present invention combines the functional molecule neutral avidin on the surface of optically labeled low-diameter magnetic nanoparticles with biotin-conjugated labeled polypeptides to form a multimodal magnetic nanoparticle probe, which can achieve single-cell specific imaging.

Description of drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the accompanying drawings required in the embodiments. The features and advantages of the present invention will be more clearly understood by referring to the accompanying drawings. The accompanying drawings are schematic and should not be construed as limiting the present invention. For those of ordinary skill in the art, other drawings can be obtained according to these drawings without creative work. in:

Fig. 1 is the overall structural diagram of the present invention;

Fig. 2 is a scanner configuration diagram of the present invention;

Fig. 3 is a schematic structural diagram of the receiving coil of the present invention.

Detailed ways

In order to understand the above-mentioned purpose, features and advantages of the present invention more clearly, the present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be noted that, in the case of no conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other.

In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways than those described here. Therefore, the protection scope of the present invention is not limited by the specific embodiments disclosed below.

As shown in Figure 1, a brain detection system for the fusion of multimodal optical and magnetic nanoparticle imaging, including: a scanner, a control module, and a signal receiving module, wherein,

As shown in Figure 2, the scanner includes a driving coil, a selection coil and a receiving coil, wherein the selection coil is arranged at both ends of the receiving coil, and is used to construct a static gradient magnetic field, that is, a selection field, and drives all magnetic nanoparticles except particles near the no-field point to reach saturation; the driving coil is arranged outside the receiving coil for building a sinusoidal excitation magnetic field, that is, a driving field; the receiving coil is used for collecting voltage signals; the signal receiving module includes a band-stop filter, a low-noise amplifier, and an analog-to-digital converter connected in sequence;

The control module includes a PC terminal, a digital-to-analog converter, a power amplifier, and a band-pass filter connected in sequence. It is used to control the current so that the driving coil applies a uniform oscillating magnetic field. The particles near the field-free point are driven through the object of interest and the magnetization of the particles is changed. In this way, a voltage signal is induced in the receiving coil. After being processed by the signal receiving module, the X-space MPI is used for image reconstruction.

In some embodiments, a permanent magnet is used as a selection coil, an excitation coil is used as a driving coil, and a gradiometer coil composed of Litz wire is used as a receiving coil.

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

In some embodiments, the major and semi-axis length a of the semi-elliptical end face is at most 20 mm, the minor axis length b is at most 25 mm, and the angle θ between the line between the apex of the semi-elliptical end face and the apex of the semi-circular end face and the horizontal line is 18°-24°; for different measured objects, according to the shape and size of the head, the size of the receiving coil can be adjusted proportionally.

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

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

In some embodiments, in order to realize the imaging analysis of extracellular traps in the brain of the subject, the detection system cooperates with multimodal optical and magnetic nanoparticle probes. First, the magnetic nanoparticles are modified with fluorescent dyes to obtain optically labeled magnetic nanoparticles, and then the magnetic nanoparticles are combined with polypeptides to form multimodal optical and magnetic nanoparticle probes, and then the brain of the subject is imaged using a scanner.

A detection method for a brain detection system fused with multimodal optical and magnetic nanoparticle imaging, comprising the following steps:

S1: Establish the model of the object under test;

S2: Combining encapsulated magnetic nanoparticles with peptides to form multimodal optical and magnetic nanoparticle probes, using in vivo labeling methods for imaging analysis of the brain extracellular trap mechanism induced by reactive oxygen species;

S3: Move the brain of the subject under test into the receiving coil;

S4: Control the current through the control module to apply a uniform oscillating magnetic field to the drive coil;

S5: The signal collected by the receiving coil is collected after being processed by the signal receiving module;

S6: The collected data is reconstructed using X-space MPI.

In order to facilitate the understanding of the above-mentioned technical solution of the present invention, the above-mentioned technical solution of the present invention will be described in detail below through specific examples.

Example 1

Using the brain detection system fused with multimodal optical and magnetic nanoparticle imaging of the present invention to conduct experiments on mice, in order to perform specific imaging of extracellular traps of monocytes and T cells in the brain of mice, so as to analyze the mechanism of action of reactive oxygen species in autoimmune diseases. Specific steps are as follows:

S1: Establish a mouse model.

In the experiment, five healthy female C57BL/6J mice, weighing 25 g and aged 7 to 8 weeks, were used first;

By intraperitoneal injection, 0.5ml pristane was injected into each mouse to establish a lupus mouse model.

S2: Combining encapsulated magnetic nanoparticles with peptides to form multimodal optical and magnetic nanoparticle probes, using multimodal nanoparticle molecular probes for in vivo labeling for brain extracellular trap imaging;

S3: Use a special shape coil that fits the mouse brain to improve sensitivity, and use the mouse bed to move the mouse brain into the receiving coil;

S4: Control the current through the control module to apply a uniform oscillating magnetic field to the drive coil;

S5: The signal collected by the receiving coil is collected after being processed by the signal receiving module;

S6: The collected data is reconstructed using X-space MPI.

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

Conventional harmonic-space MPI image reconstruction relies on the system matrix to precharacterize the signal response of magnetic nanoparticles, implying that the system matrix is specific to the nanoparticle sample, and the accuracy of the reconstruction will be reduced if the nanoparticles behave differently in the tissue, the system drifts, or the model is inaccurate. Importantly, MPI must undergo well-conditioned image reconstruction to avoid any signal-to-noise ratio (SNR) loss. However, the signal of MPI image reconstruction in X space is time-scanned through X space, which only involves velocity compensation and gridding, thus improving the robustness and speed of MPI image reconstruction to a certain extent.

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

The basic principle of magnetic particle imaging is the Langevin equation:

in, is the saturation magnetic moment of a single magnetic particle, m is the concentration of the particle, /> Represents the saturation magnetization of Fe ₃ O ₄ , μ ₀ represents the vacuum permeability, d is the particle size of magnetic nanoparticles, and

Among them, α is the Langevin parameter, k _B is the Boltzmann constant, T is the absolute temperature, W is the strength of the external magnetic field, and the characteristics of the magnetic particles are characterized by the particle size d and the saturation magnetization M _S.

The magnetic field used by MPI is the superposition of the time-varying driving field W ^D (t) and the static gradient field ^WS (x). If the gradient field is uniform, ^WS (x) is described by ^WS (x) = Qx, and Q represents the applied gradient strength. Assuming it is diagonal, Q = diag(q ₁ , q ₂ , q ₃ ).

The drive field usually selects a periodic trajectory W ^D (t) with a period length of T _D. For the position of the field-free point (FFP), X ^FFP = -Q ^(-1) W ^D (t), and the voltage signal U _n (t) in the MPI is:

where s _n (X, t) (n ∈ {1, 2, 3}) represents the number of systems dependent on space and time, and the factor g _n is the inductance of the nth receiving coil, x _n ^FFP (t) represents the nth coordinate of FFP, x _n is the nth spatial coordinate, z represents the magnetic moment of a nanoparticle, m(x) is the spatial SPIO distribution, /> represents the Langevin function used to describe the magnetization behavior of SPIOs as a function of an external magnetic field, /> Denotes the Multivillion Langevin function with respect to the nth receiving coil.

Realize X-space MPI image reconstruction according to the following method:

In the x-space MPI theory, the image is represented as the convolution of the spatial distribution of nanoparticles with the system point spread function (PSF), and the key result of the analysis is to obtain the one-dimensional signal equation, which shows that the MPI signal samples the real spatial convolution of the magnetic nanoparticle density ρ at the instantaneous position FFP x _s (t) with the PSF z(x):

Among them, the PSF of the system is determined by the magnetization characteristics of the nanoparticles and the magnetic field gradient. The magnetization of superparamagnetic nanoparticles is nonlinear and obeys the so-called Langevin function. The receiving coil only detects changes in the magnetization level, therefore, the PSF is the derivative of the Langevin function.

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

The shape h(x) of the system PSF defines the native resolution of the imaging system. Using the derivative of the Langevin function, the spatial resolution of the MPI is:

Among them, Δx is the full width at half maximum of the PSF, M _sat is the saturation magnetization of the nanoparticle; d is the diameter of the nanoparticle; k _B is the Boltzmann constant, T is the temperature, and μ ₀ is the vacuum permeability.

In the present invention, unless otherwise clearly specified and limited, terms such as "installation", "connection", "connection" and "fixation" should be understood in a broad sense, for example, it may be a fixed connection, or a detachable connection, or integrated; it may be a mechanical connection or an electrical connection; it may be a direct connection or an indirect connection through an intermediary, and it may be the internal communication of two elements or the interaction relationship between two elements. Those of ordinary skill in the art can understand the specific meanings of the above terms in the present invention according to specific situations.

In the present invention, unless otherwise clearly specified and limited, a first feature being "on" or "under" a second feature may include that the first and second features are in direct contact, and may also include that the first and second features are not in direct contact but are in contact with another feature between them. Moreover, "above", "above" and "above" the first feature on the second feature include that the first feature is directly above and obliquely above the second feature, or simply means that the first feature is horizontally higher than the second feature. "Below", "beneath" and "under" the first feature to the second feature include that the first feature is directly below and obliquely below the second feature, or simply means that the first feature has a lower level than the second feature.

In the present invention, the terms "first", "second", "third", and "fourth" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance. The term "plurality" means two or more, unless otherwise clearly defined.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (8)

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

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

the control module comprises a PC 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 pass through an object of interest, the magnetization intensity of the particles is changed, so that a voltage signal is induced in the receiving coil, and the voltage signal is processed by the signal receiving module and then subjected to image reconstruction by adopting an X space MPI;

the multi-mode magnetic nanoparticle probe is formed by combining functional molecules of the surface of the optically marked low-diameter magnetic nanoparticle, namely, avidin and biotin conjugated marked polypeptide.

2. The brain detection 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 of claim 1 or 2, wherein the receiving coil is attached to the brain of the detected object, and is semi-elliptical cone-shaped, one end face is semi-elliptical, the other end face is semi-circular, 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.

4. A multi-modal optical and magnetic nanoparticle imaging fusion brain detection system as in claim 3 wherein the semi-elliptical end faces have a long semi-axis length a of at most 20mm and a short axis length b of at most 25mm, and the angle θ between the line of the vertices of the semi-elliptical end faces and the horizontal line is 18 ° -24 °.

5. The brain detection system of claim 4, wherein the permanent magnet forms a static gradient magnetic field of 4-8T/m and the exciting coil forms a sinusoidal excitation magnetic field of 15-25 mT/m.

6. The brain detection system of 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 multi-modal optical and magnetic nanoparticle imaging fusion according to claim 6, wherein to realize imaging analysis of extracellular traps of the brain of the detected object, the detection system is matched with a multi-modal optical and magnetic nanoparticle probe, firstly, the magnetic nanoparticle is modified by fluorescent dye to obtain optically marked magnetic nanoparticle, then the magnetic nanoparticle is combined with polypeptide to form the multi-modal optical and magnetic nanoparticle probe, and then the brain of the detected object is imaged by the scanner.

8. A method of detecting a multimodal optical and magnetic nanoparticle image fusion brain detection system according to any one of claims 1-7, comprising the steps of:

s1: establishing a tested object model;

s2: combining the wrapped magnetic nano particles with the polypeptide to form a multi-mode optical and magnetic nano particle probe, and using an in-vivo labeling method for imaging analysis of a brain extracellular trap mechanism;

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

s4: the control module controls the current to enable the 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 is reconstructed using X-space MPI.