Nerve axon phantom model for multi-mode magnetic resonance imaging evaluation and preparation method thereof

Abstract

The invention discloses a nerve axon phantom model for multi-mode magnetic resonance imaging evaluation, which comprises a phantom model shell, a tube body is provided with an accommodating cavity, the accommodating cavity is filled with deionized water, the nerve axon phantom comprises a tube body with two open ends and a filling cavity, and the filling cavity is filled with deionized water. A plurality of layers of circular fiber membranes used for truly simulating nerve axons are sequentially stacked in the filling cavity in the axis direction of the tube body, a partition piece is arranged between every two adjacent circular fiber membranes, and through holes allowing deionized water to enter are formed in the partition pieces. Iron oxide nanoparticles for adjusting the relaxation time of the nerve axon phantom and realizing multi-modal imaging are added into the circular fiber diaphragm. According to the invention, the complex and fine microstructure and anisotropic diffusion characteristics of the nervous tissue can be truly and vividly simulated, the bionic structure and relaxation characteristics of the nervous tissue can be simulated at the same time, and the accuracy and reliability of the MRI technology in neuroscience research and clinical diagnosis are improved.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to a neural axon phantom model for multimodal magnetic resonance imaging evaluation and a preparation method thereof. Background Art

[0002] Magnetic resonance imaging (MRI) is a technique that applies a radio frequency pulse of a certain frequency to the human body in a static magnetic field, which excites the hydrogen protons in the human body and causes magnetic resonance. After the pulse stops, the protons generate MR signals during the relaxation process. MR signals are generated through the reception, spatial encoding and image reconstruction of MR signals. MRI has been applied to imaging diagnosis of various systems in the body. The best results are in the brain, spinal cord, heart and large blood vessels, joint bones, soft tissues and pelvic cavity. For cardiovascular diseases, not only can the anatomical changes of various chambers, large blood vessels and valves be observed, but also ventricular analysis can be performed for qualitative and semi-quantitative diagnosis. Multiple cross-sectional images can be made with high spatial resolution, showing the whole picture of the heart and lesions, and their relationship with surrounding structures, which is better than other X-ray imaging, two-dimensional ultrasound, radionuclide and CT examinations. When diagnosing brain and spinal cord lesions, coronary, sagittal and cross-sectional images can be made.

[0003] MRI phantoms are an essential tool for evaluating imaging performance. They are widely used for calibrating and checking imaging equipment, testing new systems and pulse sequence development, and training MRI operators. The most common test for sequence development is usually simulated before clinical studies. After the simulation is verified, the study of imaging sequences usually needs to be tested on healthy volunteers first, and then verified by several patient experiments before it can be widely promoted in clinical practice. However, since there are no pathological areas in healthy volunteers, the ability to verify the effectiveness of the method is insufficient, and clinical studies with a small number of patients are limited by the repeatability of the experiment. Phantom experiments can serve as a supplement to healthy human experiments. Therefore, the materials used to make MRI phantoms should have 1) relaxation times similar to human tissues; 2) provide uniform relaxation times within the phantom; 3) allow the generation of phantoms of various shapes and sizes; 4) be easy to handle; and 5) maintain chemical and physical stability for a long time.

[0004] Currently, magnetic resonance imaging (MRI) technology plays a vital role in neuroscience research and clinical diagnosis. In order to accurately evaluate MRI technology and quantify the microstructure of tissues, phantoms (also called body models) are needed for scanner performance evaluation, quality control, and the development of new imaging technologies. However, existing MRI phantom models have some shortcomings that hinder their application in the field of neuroscience.

[0005] Most existing MRI phantoms are based on simple geometric shapes, such as cylinders or spheres, and are made of homogeneous materials. They are unable to truly simulate the complex and delicate microstructure and anisotropic diffusion properties of neural tissue, especially in simulating the morphology and arrangement of nerve fibers. It is difficult to accurately reflect the diffusion behavior of water molecules in nerve fiber bundles (Zhou, F.-L., et al. "Coaxially Electrospun Axon-Mimicking Fibers for Diffusion Magnetic Resonance Imaging." ACS Applied Materials & Interfaces 4.11 (2012): 6311-6316).

[0006] Existing phantom models often focus only on a single MRI parameter, such as diffusion coefficient or T1 value, and lack the ability to comprehensively simulate multiple MRI parameters. This limits the comprehensive evaluation of MRI technology and the accurate quantification of tissue microstructure (Fieremans, E., and Lee, H.-H. "Physical and numerical phantoms for the validation of brain microstructural MRI: A cookbook." NeuroImage 182 (2018): 39-61).

[0007] Furthermore, there is currently no phantom model that can simultaneously simulate the bionic structure and relaxation properties (e.g., T2, T2*) of neural tissue, which limits the comprehensive evaluation of MRI technology and the accurate quantification of tissue microstructure. For example, when evaluating brain lesions (such as hemorrhage or ischemia), T2 and T2* relaxation times can help distinguish different types of lesions and assess their severity. However, due to the lack of phantoms with both biomimetic structures and relaxation properties, it is difficult for researchers to accurately evaluate and optimize the performance of MRI sequences in these lesions (Welsch, GH, et al. "T2 and T2 Mapping." Current Radiology Reports 2, (2014): 60; Ghassaban, K., et al. "Quantifying iron content inmagnetic resonance imaging." NeuroImage 187 (2019): 77-92; Ling, H.-W., et al. "Could Iron Accumulation Be an Etiology of the White Matter Change in Alzheimer's Disease: Using Phase Imaging to Detect White Matter Iron Deposition Based on Diffusion Tensor Imaging." Dementia and Geriatric Cognitive Disorders 31 (4) (2011): 300-308.).

[0008] To sum up, in view of the shortcomings of existing MRI phantom models, how to make the phantom model have both bionic structure and relaxation characteristics for multimodal magnetic resonance imaging, solve the problem that the existing phantom models cannot realistically and realistically simulate the complex and delicate microstructure and anisotropic diffusion characteristics of neural tissue, solve the shortcomings in simulating the morphology and arrangement of nerve fibers, accurately reflect the diffusion behavior of water molecules in nerve fiber bundles, and be able to simulate the bionic structure and relaxation characteristics of neural tissue at the same time, realistically simulate the complex microstructure of neural tissue and multiple MRI parameters, and improve the accuracy and reliability of MRI technology in neuroscience research and clinical diagnosis, has become a difficult problem that technicians in the biomedical field urgently need to solve. Summary of the invention

[0009] In view of the shortcomings of the prior art, the technical problem to be solved by the present invention is to provide a neural axon phantom model for multimodal magnetic resonance imaging evaluation and a preparation method thereof, which can realistically simulate the complex and fine microstructure and anisotropic diffusion characteristics of neural tissue, and can simultaneously simulate the bionic structure and relaxation characteristics of neural tissue, thereby improving the accuracy and reliability of MRI technology in neuroscience research and clinical diagnosis.

[0010] In order to solve the above technical problems, the technical solution adopted by the present invention is: a neural axon phantom model for multimodal magnetic resonance imaging evaluation, including a phantom model shell with a cover body and a tube body, the tube body having a accommodating cavity for placing the neural axon phantom, the accommodating cavity is filled with deionized water for simulating the water molecule exchange process inside and outside the neural axon and the diffusion characteristics of water molecules in the neural axon along the direction of the neural axon, the neural axon phantom includes a tube body with openings at both ends of the filling cavity, in the filling cavity, several layers of circular fiber diaphragms for truly simulating the neural axon are stacked in sequence along the axial direction of the tube body, a spacer for fixing the circular fiber diaphragms and narrowing the gap between adjacent circular fiber diaphragms is arranged between adjacent circular fiber diaphragms, a through hole for allowing deionized water to enter is opened on the spacer, and iron oxide nanoparticles are added to the circular fiber diaphragms for adjusting the relaxation time of the neural axon phantom and realizing multimodal imaging.

[0011] The above-mentioned nerve axon phantom model for multimodal magnetic resonance imaging evaluation, the circular fiber membrane is composed of a fiber bundle for simulating nerve fiber bundles formed by a number of hollow fibers for simulating nerve axons, and iron oxide nanoparticles are loaded on the surface of the hollow fibers.

[0012] In the above-mentioned nerve axon phantom model for multimodal magnetic resonance imaging evaluation, the iron oxide nanoparticles are any one of Fe3O4, γ-Fe2O3, and ultra-small superparamagnetic iron oxide, and the particle size is 15-20nm.

[0013] In the above-mentioned nerve axon phantom model for multimodal magnetic resonance imaging evaluation, the outer diameter of the hollow fiber is 8-9.2 μm, the inner diameter is 4-7.8 μm, and the thickness of the fiber bundle is 0.2-0.4 mm.

[0014] In the above-mentioned neural axon phantom model for multimodal magnetic resonance imaging evaluation, the plurality of circular fiber membranes and spacers in the tube body are pressed and formed by constant pressure, and the thickness compression rate after pressing and forming is 20%-50%.

[0015] A method for preparing a neural axon phantom model comprises the following steps:

[0016] 1. Preparation of hollow fiber membrane:

[0017] (1) dissolving a certain amount of polyethylene oxide in deionized water to prepare a core layer solution for later use;

[0018] (2) dissolving a certain amount of polycaprolactone in a mixed solvent of dichloromethane and dimethylformamide, and adding a certain amount of polysiloxane and iron oxide nanoparticles to prepare a shell solution, and ultrasonically treating the shell solution to fully disperse the iron oxide nanoparticles;

[0019] (3) Using a coaxial electrospinning device, the core layer solution and the shell layer solution are respectively injected into the inner needle and the outer needle, and coaxial electrospinning is performed under certain spinning conditions to collect the oriented hollow fibers, and after deposition, a hollow fiber membrane consisting of a fiber bundle formed by a plurality of hollow fibers is obtained;

[0020] 2. Assembling the axonal phantom:

[0021] (4) Cutting the hollow fiber membrane obtained in step (3) into a number of circular fiber membrane sheets of a certain diameter for later use;

[0022] (5) stacking a plurality of circular fiber membranes in parallel layer by layer, and placing annular thin sheets between adjacent circular fiber membranes, wherein the arrangement direction of the fiber bundles in each circular fiber membrane is the same;

[0023] (6) placing the stacked circular fiber membranes and annular sheets in a cylindrical inner tube, and applying a constant pressure to arrange the stacked circular fiber membranes tightly, thereby obtaining a nerve axon phantom;

[0024] 3. Packaging Simulation Model:

[0025] (7) placing the prepared neural axon biomimetic in a centrifuge tube, filling the centrifuge tube with deionized water, and sealing it with a lid;

[0026] (8) Vacuum the centrifuge tube to remove all bubbles;

[0027] (9) Obtain a neural axon phantom model.

[0028] In the method for preparing the above-mentioned neural axon phantom model, the concentration of polyethylene oxide in the core layer solution of step (1) is 4 w / v%.

[0029] In the above-mentioned method for preparing the neural axon phantom model, in the shell solution of step (2), the concentration of polycaprolactone is 15w / v%, the volume ratio of dichloromethane and dimethylformamide is 7:3, the concentration of polysiloxane is 0.5w / w% relative to the mass of polycaprolactone, and the amount of iron oxide nanoparticles added is 0.05-0.15wt% relative to the mass of polycaprolactone.

[0030] In the above-mentioned method for preparing the neural axon phantom model, in the step (2), the iron oxide nanoparticles are any one of Fe3O4, γ-Fe2O3, and ultra-small superparamagnetic iron oxide, and the particle size is 15-20nm.

[0031] In the preparation method of the above-mentioned nerve axon phantom model, in the step (3), the inner needle is 25G, the outer needle is 18G, the core solution extrusion rate is 0.5ml / h, the shell solution extrusion rate is 1ml / h, the spinning voltage is 12kV, the receiving distance is 16cm, and the receiving roller speed is 900rpm.

[0032] The advantages of the neural axon phantom model for multimodal magnetic resonance imaging assessment and the preparation method thereof of the present invention are: the provided iron oxide-containing neural axon phantom overcomes the limitations of existing MRI phantom models by combining bionic structure and adjustable relaxation characteristics. Specifically:

[0033] (1) More realistic simulation of the morphology and arrangement of nerve axons: Overcoming the limitations of the existing phantom models, which are simple in structure and homogeneous in material, more accurately simulates the complex structure and anisotropy of nerve fibers, and truly reflects the diffusion behavior of water molecules in nerve fiber bundles.

[0034] (2) Realize comprehensive simulation of multiple MRI parameters: not only simulate the diffusion characteristics, but also simulate the relaxation characteristics of tissues (such as T2, T2*), thereby achieving a more comprehensive simulation of MRI signals.

[0035] (3) Support for multi-modal MRI imaging: Support for multiple MRI imaging techniques such as diffusion imaging and T2 relaxation time imaging, providing a more comprehensive tool for the evaluation and application of MRI technology.

[0036] (4) Improving the application value of MRI technology: Improving the accuracy and reliability of MRI technology in the diagnosis and treatment evaluation of neurological diseases. For example, it can more accurately evaluate the integrity of white matter fiber bundles, as well as distinguish and evaluate brain lesions.

[0037] It can make the phantom model have both bionic structure and relaxation characteristics, and be used for multimodal magnetic resonance imaging. It can solve the problem that the existing phantom models cannot realistically and realistically simulate the complex and delicate microstructure and anisotropic diffusion characteristics of neural tissue, and solve the shortcomings in simulating the morphology and arrangement of nerve fibers. It can accurately reflect the diffusion behavior of water molecules in nerve fiber bundles, and can simultaneously simulate the bionic structure and relaxation characteristics of neural tissue, realistically simulate the complex microstructure of neural tissue and multiple MRI parameters, and improve the accuracy and reliability of MRI technology in neuroscience research and clinical diagnosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1The figure is a schematic diagram of the overall structure of the neural axon phantom model of the present invention;

[0039] Figure 2 This is an enlarged view of the structure of the neural axon phantom of the present invention;

[0040] Figure 3 It is a schematic diagram of a structure in which a number of circular fiber membranes and spacers are stacked in sequence;

[0041] Figure 4 Schematic diagram of the structure of the other two types of separators;

[0042] Figure 5 for Figure 2 A magnified view of the local structure of part A;

[0043] Figure 6 The single-tube and multi-tube products of the neural axon phantom model of the present invention are shown in the figure;

[0044] Figure 7 This is a diagram showing the use status of the neural axon phantom model of the present invention;

[0045] Figure 8 Schematic diagram of the preparation process of the neural axon phantom model of the present invention;

[0046] Fig. 9 The surface and cross-sectional SEM images of the hollow fiber membranes prepared in Examples 1-4 of the present invention;

[0047] Fig.10 The outer diameter, inner diameter and wall thickness distribution diagram of the hollow fibers prepared in Examples 1-3 of the present invention;

[0048] Fig.11 This is an EDS image of the three elements C, O, and Fe in the hollow fiber containing 0.15 wt% of iron oxide nanoparticles prepared in Example 3 of the present invention;

[0049] Fig.12 DTI parameter diagrams of the axon phantom model prepared in Examples 1-4 under different scanning directions on a 3T Philips Ingenia CX device;

[0050] Fig.13 These are T2 mapping and T2*mapping images of the nerve axon phantom model prepared in Examples 1-4 on different MRI devices. DETAILED DESCRIPTION

[0051] The present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0052] In the present invention, unless otherwise stated, directional words such as "upper" and "lower" generally refer to the upper and lower parts of the device in actual use or working state, specifically the drawing direction in the attached drawings; while "inside" and "outside" refer to the outline of the device. In addition, in the description of this application, the term "including" means "including but not limited to". The terms first, second, third, etc. are used only as labels and do not impose numerical requirements or establish an order. The term "plurality" means "two or more".

[0053] like Figure 1-3 As shown, a phantom model of axons for multimodal magnetic resonance imaging assessment includes a phantom model shell 3 having a cover 1 and a tube 2. The phantom model shell 3 of the present invention can be a centrifuge tube with a cover, a glass bottle with a cover, or a plastic bottle with a cover.

[0054] The tube body 2 has a receiving cavity 5 for placing the nerve axon phantom 4, and the receiving cavity 5 is filled with deionized water 6 for simulating the water molecule exchange process inside and outside the nerve axon and the diffusion characteristics of water molecules in the nerve axon along the direction of the nerve axon. The nerve axon phantom 4 includes a tube body 8 with two ends of a filling cavity 7, and several layers of circular fiber membranes 9 for simulating the nerve axon are stacked in sequence along the axial direction of the tube body 2 in the filling cavity 7, and a spacer 10 for fixing the circular fiber membranes 9 and reducing the gap between adjacent circular fiber membranes 9 is arranged between adjacent circular fiber membranes 9, and a through hole 11 for allowing the deionized water 6 to enter is opened on the spacer 10, and the spacer 10 of the present invention adopts a ring structure. Iron oxide nanoparticles are added to the circular fiber membrane 9 for adjusting the relaxation time of the nerve axon phantom and realizing multimodal imaging. The iron oxide nanoparticles are any one of Fe3O4, γ-Fe2O3, and ultra-small superparamagnetic iron oxide, with a particle size of 15-20 nm, or gadolinium-based contrast agents are used to replace the iron oxide nanoparticles.

[0055] The circular fiber membrane 9 of the present invention is prepared by coaxial electrospinning technology, and the circular fiber membrane 9 is composed of a fiber bundle for simulating nerve fiber bundles formed by a number of hollow fibers for simulating nerve axons. Among them, the hollow fibers obtained by coaxial electrospinning gradually form a fiber bundle arranged in a directional manner, and the fiber bundle is laid to form a fiber membrane, and the circular fiber membrane 9 is cut by a circular cutter. The outer diameter of the hollow fiber is 8-9.2μm, the inner diameter is 4-7.8μm, and the thickness of the fiber bundle is 0.2-0.4mm. Iron oxide nanoparticles are loaded on the surface of the hollow fiber. In order to simulate the nerve fiber bundle more realistically, during the stacking process of the circular fiber membrane 9, each circular fiber membrane 9 is rotated and adjusted to the same direction according to the arrangement direction of the fiber bundle, and then stacked layer by layer in the same manner as the arrangement direction of the fiber bundle in each circular fiber membrane 9.

[0056] like Figure 4 , 5 As shown, the present invention provides two other types of spacers. Since the spacers in the nerve axon phantom are used to fix the circular fiber diaphragms 9 and reduce the gaps between adjacent circular fiber diaphragms 9, and at the same time, to allow deionized water to enter each layer of the circular fiber diaphragms 9, the structure may also be porous or edge-opened.

[0057] like Figure 6 As shown in the figure, in order to construct a realistic axon bionic phantom, the hollow fiber membrane needs to be strictly controlled in structure to accurately simulate the microenvironment of nerve fibers and the diffusion behavior of water molecules. Specifically, the hollow fiber membrane should meet the following requirements:

[0058] 1. Minimize the membrane gap: The gap between adjacent circular fiber membranes 9 should be as small as possible to prevent free water from appearing between adjacent fiber membranes, thereby avoiding interference with the diffusion path of water molecules.

[0059] 2. Promote the free diffusion of water molecules inside and outside the fiber: ensure that water molecules can diffuse freely inside and outside the circular fiber membrane 9, including longitudinal and lateral diffusion, so as to simulate the water molecule exchange process inside and outside the axon and the diffusion characteristics of water molecules in the axon along the axon direction.

[0060] 3. Satisfy spatial resolution requirements: The thickness of the fiber layer in the axon phantom model should at least meet the spatial resolution of the MRI device used, so as to obtain measurement results in multiple voxels and ensure measurement accuracy and reliability. In the present invention, the circular fiber diaphragm 9 is stacked with 20-30 layers, and the total fiber layer thickness is 4-12 mm, which can meet the spatial resolution requirements of commonly used MRI equipment.

[0061] Therefore, a plurality of circular fiber membranes and spacers are pressed and formed in the tube body by constant pressure, and the thickness compression rate after pressing and forming is 20%-50%. At the same time, regarding the size ratio relationship between the circular fiber membrane 9, the spacer 10 and the inner diameter of the tube body 8, the diameter of the circular fiber membrane 9 in the present invention is the same as the inner diameter of the tube body 8, and the outer diameter of the spacer 10 is slightly smaller than the inner diameter of the tube body 8, so that free water can flow freely up and down between the spacer 10 and the inner wall of the tube body 8.

[0062] like Figure 6 , 7 As shown, regarding the method of using the axon phantom model of the present invention, the axon phantom model can provide multiple scanning modes, and the product can be used with a single tube or in combination with multiple tubes. Specifically, it includes scanning each sample individually to evaluate the effect of different Fe3O4 concentrations on MRI characteristics, and combining different samples to perform comparative analysis, simulate tissue heterogeneity, or evaluate imaging sequence performance. For example, Figure 6The individual tubes in the multi-tubes shown are numbered 0 to 7. Sample tubes 0, 1, and 3 can be combined to evaluate the effect of Fe3O4 concentration on T2 relaxation time, or sample tubes 2 and 4 can be combined to simulate tumor infiltration and evaluate its microstructural characteristics using DTI technology. The combination method can be flexibly selected according to actual needs during use.

[0063] like Figure 8 As shown, the method of the present invention for preparing a neural axon phantom model for multimodal magnetic resonance imaging evaluation comprises the following steps:

[0064] 1. Preparation of hollow fiber membrane:

[0065] (1) Dissolve 4 w / v% polyethylene oxide (PEO) in deionized water to prepare a core layer solution.

[0066] (2) 15 w / v% polycaprolactone (PCL) was dissolved in a mixed solvent of dichloromethane and dimethylformamide (volume ratio 7:3), and 0.5 w / w% (relative to the mass of PCL) of polysiloxane (PSi) and 0.05 wt% (relative to the mass of PCL) of iron oxide nanoparticles were added to prepare a shell solution. The shell solution was ultrasonically treated for 2 hours to fully disperse the iron oxide nanoparticles.

[0067] (3) Using a coaxial electrospinning device, the core layer solution and the shell layer solution were injected into the inner needle (25G) and the outer needle (18G), respectively. A voltage of 12 kV was applied, the shell layer propulsion speed was 1.0 ml / h, the core layer propulsion speed was 0.5 ml / h, the receiving distance was 16 cm, and the receiving device was a cylindrical roller with a rotation speed of 900 rpm. A hollow fiber bundle (i.e., hollow fiber membrane) with a thickness of 0.2 to 0.4 mm was collected. The outer diameter of the hollow fiber was 8-9.2 μm and the inner diameter was 4-7.8 μm.

[0068] 2. Assembling the axonal phantom:

[0069] (4) Use a circular cutter with an inner diameter of 13 mm to cut several circular fiber membrane pieces 9 with a diameter of 13 mm from the hollow fiber membrane.

[0070] (5) The circular fiber membranes 9 are stacked layer by layer in a parallel arrangement, and a 12.8×10.2×0.3 mm PVC annular thin gasket (ie, spacer 10) is placed between each layer of the circular fiber membrane 9.

[0071] (6) Place the stacked circular fiber membrane 9 and spacer 10 in a cylindrical inner tube with an inner diameter of 13 mm, and apply constant pressure on the press to make the fiber membranes more tightly arranged. Specifically, on a manual press, stack the fiber sheets and transparent gaskets in sequence and place them in a small tube, and the total height after stacking is about 28 mm. Subsequently, apply constant pressure for pressing, and the height of the phantom after pressing is about 14 mm, and the thickness compression rate is about 50%. Normally, the thickness compression rate of the phantom after pressing is between 20% and 50%.

[0072] 3. Packaging Simulation Model:

[0073] (7) Place the assembled fiber bundle in a 15 ml centrifuge tube and fill the centrifuge tube with deionized water.

[0074] (8) Use a vacuum drying dish to evacuate the centrifuge tube until no bubbles are generated, and finally form a neural axon phantom model.

[0075] The present invention is based on the coaxial electrospinning technology to prepare the neural axon phantom model, which can simulate neural tissue more realistically and can be used for a variety of MRI imaging techniques, such as DTI and T2 mapping, so as to improve the accuracy and reliability of MRI technology. Among them, the hollow fiber simulates the axon, simulates the intracellular and extracellular space of the neural tissue, forms a bionic structure, and the fiber bundle simulates the nerve fiber bundle, which can simulate the neural tissue more realistically. Iron oxide nanoparticles are added to adjust the T2 and T2* relaxation time. The concentration of the nanoparticles affects the T2 and T2* relaxation time of the phantom, and realizes the comprehensive simulation of multiple MRI parameters. The arrangement of the fiber bundles more realistically simulates the diffusion characteristics and MRI imaging effects of the neural axon phantom model, supports a variety of MRI imaging techniques such as DTI and T2mapping, and provides more comprehensive information. It is helpful to improve the accuracy of MRI technology in the diagnosis and treatment evaluation of neurological diseases, for example, more accurately evaluate the integrity of the white matter fiber bundles of the brain.

[0076] The present application is described in detail below through specific embodiments. The following embodiments are only partial embodiments of the present application and are not limitations of the present application.

[0077] Example 1

[0078] A method for preparing a neural axon phantom model for multimodal magnetic resonance imaging evaluation comprises the following steps:

[0079] 1. Preparation of hollow fiber membrane:

[0080] (1) Dissolve polyethylene oxide at a concentration of 4 w / v% in deionized water to prepare a core layer solution for later use;

[0081] (2) dissolving polycaprolactone with a concentration of 15 w / v% in a mixed solvent of dichloromethane and dimethylformamide, and adding a certain amount of polysiloxane and Fe3O4 nanoparticles, the volume ratio of dichloromethane to dimethylformamide is 7:3, the amount of Fe3O4 nanoparticles added is 0.05wt% relative to the mass of polycaprolactone, and the particle size of Fe3O4 nanoparticles is 15-20nm, to prepare a shell solution, and ultrasonically treating the shell solution to fully disperse the Fe3O4 nanoparticles;

[0082] (3) Using a coaxial electrospinning device, the core layer solution and the shell layer solution were respectively injected into the inner needle (25G) and the outer needle (18G) for coaxial electrospinning. The spinning conditions were as follows: the core layer solution extrusion rate was 0.5 ml / h, the shell layer solution extrusion rate was 1 ml / h, the spinning voltage was 12 kV, the receiving distance was 16 cm, the receiving roller speed was 900 rpm, and the directional hollow fibers were collected. The outer diameter of the hollow fibers was 9.2 μm and the inner diameter was 6 μm. After deposition, a hollow fiber membrane consisting of a fiber bundle formed by a plurality of hollow fibers was obtained.

[0083] 2. Assembling the axonal phantom:

[0084] (4) Cutting the hollow fiber membrane obtained in step (3) into a number of circular fiber membrane sheets of a certain diameter for later use;

[0085] (5) stacking a plurality of circular fiber membranes in parallel layer by layer, and placing annular thin sheets between adjacent circular fiber membranes, wherein the arrangement direction of the fiber bundles in each circular fiber membrane is the same;

[0086] (6) placing the stacked circular fiber membranes and annular sheets in a cylindrical inner tube, and applying a constant pressure to arrange the stacked circular fiber membranes tightly, thereby obtaining a nerve axon phantom;

[0087] 3. Packaging Simulation Model:

[0088] (7) placing the prepared neural axon biomimetic in a centrifuge tube, filling the centrifuge tube with deionized water, and sealing it with a lid;

[0089] (8) Vacuum the centrifuge tube to remove all bubbles;

[0090] (9) Obtain a neural axon phantom model.

[0091] Example 2

[0092] The similarities between this embodiment and embodiment 1 are not repeated here. The difference lies in that the amount of Fe3O4 nanoparticles added to the shell solution is 0.1 wt% (relative to the mass of polycaprolactone), and the outer diameter of the prepared hollow fiber is 8.7 μm and the inner diameter is 7.8 μm.

[0093] Example 3

[0094] The similarities between this embodiment and embodiments 1 and 2 are not repeated here. The difference lies in that the amount of Fe3O4 nanoparticles added in the shell solution is 0.15 wt% (relative to the mass of polycaprolactone), the outer diameter of the fiber is 8 μm, and the inner diameter is 4 μm.

[0095] Example 4

[0096] This example is used as a control group, and no iron oxide nanoparticles are added to prepare a nerve axon phantom model. The preparation method is the same as that of Examples 1-3, except that no iron oxide nanoparticles are added to the shell solution, and the prepared hollow fiber has an outer diameter of 8.3 microns and an inner diameter of 5.3 microns.

[0097] The performance test results of the axon phantom model used for multimodal magnetic resonance imaging evaluation of the present invention are as follows:

[0098] 1. Microstructure

[0099] like Fig. 9 As shown, Fig. 9 (a) and (e) are SEM images of the surface and cross section of the hollow fiber membrane prepared in the control group. Fig. 9 (b), (f), Fig. 9 (c), (g) and Fig. 9 (d) and (h) are SEM images of the surface and cross section of the hollow fiber membranes prepared in Examples 1 to 3. Comparative analysis of scanning electron microscope (SEM) images shows that all the axon phantom models, including the control group, have a hollow fiber structure similar to that of nerve tissue, with a smooth fiber surface and a fiber diameter between 8 and 9.2 μm, which is comparable to the size of the spinal cord white matter fiber bundles.

[0100] like Figure 10-11As shown, Fe3O4 particles are attached to the surface of the hollow fibers to which Fe3O4 is added in Examples 1-3, and as the concentration of Fe3O4 increases, the gap between the fibers shows a trend of decreasing and increasing adhesion. It can be seen that the addition of Fe3O4 nanoparticles leads to an increase in the adhesion between the fibers, simulating the close arrangement of cells in the nervous tissue. Energy spectrum analysis (EDS) confirmed that Fe3O4 was successfully spun into the hollow fibers. Size distribution analysis showed that the outer diameter, inner diameter and wall thickness of the fibers increased first and then decreased with the change of Fe3O4 concentration. The diameters of all fibers fell within the diameter range of the spinal white matter fiber bundle (0.3-15 μm). The addition of Fe3O4 particles can cause changes in solution properties, such as viscosity and conductivity, resulting in differences in the morphology and size of the resulting fibers. For example, when other spinning conditions remain unchanged, the addition of Fe3O4 particles may increase the viscosity of the solution, causing the fiber diameter to increase first; and as the concentration of Fe3O4 further increases, the conductivity of the solution increases, which may reduce the stability of the jet and cause the fiber diameter to decrease.

[0101] 2. Diffusion Characteristics

[0102] Since the diffusion of water molecules in biological tissues is a complex three-dimensional process, the diffusion rate may be different in different directions (anisotropy). This anisotropy mainly comes from the arrangement of fiber bundles in the tissue and the restriction of myelin sheath structure on the movement of water molecules. Fig.12 As shown, (a) 32 directions; (b) 48 directions; (c) 96 directions; (d) 128 directions. The present invention uses DTI technology to measure the anisotropy fraction FA, mean diffusivity MD, axial diffusivity AD and radial diffusion RD of phantoms with different Fe3O4 contents, and compares them with the reference values ​​of healthy spinal cord white matter (generally, the DTI parameter value range of healthy spinal cord white matter is as follows FA: 0.6-0.9, MD: 0.8-1.2×10 -9 m 2 / s, AD: 0.8-1.8×10 -9 m 2 / s, RD: 0.2-0.5×10 -9 m 2 / s) were compared.

[0103] Among them, the FA value reflects the degree of diffusion anisotropy of water molecules. The FA value of the control group phantom was between 0.6-0.7, which is consistent with the FA value range of healthy spinal cord white matter (0.6-0.9). However, after adding Fe3O4, the FA values ​​in all test sequences decreased significantly to around 0.25, which is similar to the DTI results of patients with inflammatory demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). This decrease in FA value may be related to the reduction in fiber uniformity and impaired uniformity of the surrounding magnetic field caused by Fe3O4. In addition, the number of scanning directions also has a certain effect on the FA value. The more scanning directions, the lower the FA value.

[0104] In addition, the MD, AD, and RD values ​​reflect the average diffusion rate of water molecules in the tissue, the diffusion rate along the fiber direction, and the diffusion rate perpendicular to the fiber direction, respectively. The MD, AD, and RD values ​​of the control group phantom were within the reference range of healthy spinal cord white matter or comparable to it, and the AD value was greater than the RD value, indicating that water molecules diffused more easily along the fiber direction. However, after the addition of Fe3O4, the MD, AD, and RD values ​​in all test sequences increased significantly, which is consistent with the DTI detection values ​​of patients with spinal cord injury. This increase may be due to the fact that Fe3O4 reduces the uniformity of the fibers and simulates the loss of integrity of spinal axons and myelin sheaths.

[0105] It can be seen that the DTI analysis results show that all phantoms exhibit obvious anisotropic diffusion characteristics, simulating the diffusion behavior of nerve fiber bundles. The FA value of the control group phantom is 0.65, and the MD value is 0.8×10 -9 m 2 / s, AD value is 1.2×10 - 9 m 2 / s, RD value is 0.5×10 -9 m 2 After adding 0.05wt% Fe3O4 nanoparticles, the FA value decreased to 0.35 and the MD value increased to 1.0×10 -9 m 2 / s, AD value increased to 1.5×10 -9 m 2 / s, the RD value increased to 0.6×10 -9 m 2 / s. With the increase of Fe3O4 concentration, the FA value gradually decreased, and the MD, AD and RD values ​​gradually increased, which was similar to the DTI detection values ​​of patients with spinal cord injury, indicating that the phantom can simulate the diffusion characteristics of diseased tissue.

[0106] 3. Relaxation characteristics

[0107] like Fig.13The following are T2 mapping and T2*mapping images of the axon phantom model on different MRI devices. Fig.13 (a) T2 mapping image on the 3T Philips Ingenia CX device; Fig.13 (b) is T2*mapping imaging on the 3TSiemens Skyra device. Caption: The phantom includes 7 centrifuge tubes. The numbers on the tubes in the figure are sample numbers 0-6. No. 0 is the control sample (i.e. the control group), and No. 1-2, 3-4 and 5-6 are samples of 0.05wt%, 0.1wt% and 0.15wt% Fe3O4 respectively. The numbers next to the tubes are the mean and standard deviation of T2 or T2* of the corresponding samples.

[0108] The T2 value reflects the time required for the transverse magnetization vector to decay to 37% of the initial value, which is mainly affected by the spin-spin interaction inside the tissue. The T2 value of the control group phantom without the addition of Fe3O4 was approximately 199.2ms. After the addition of Fe3O4, the T2 value dropped sharply to about 20ms (e.g., sample tubes 1-4), and showed an increasing trend with the increase of Fe3O4 concentration, but the difference was small. It is worth noting that excessive Fe3O4 content (e.g., sample tubes 5 and 6) will cause obvious artifacts.

[0109] The T2* value reflects the inherent attenuation of transverse magnetization, which is affected by both T2 and magnetic field inhomogeneity. Its normal value is usually above 40ms. This study found that the addition of Fe3O4 led to a decrease in the T2* value (for example, below 20ms), and the higher the Fe3O4 content, the faster the T2* relaxation and the more artifacts around the sample. This is because the addition of Fe3O4 increases the inhomogeneity of the magnetic field. In summary, the addition of Fe3O4 can significantly reduce the T2 and T2* relaxation times of the phantom. The T2 and T2* imaging results show that with the increase of Fe3O4 concentration, the T2 and T2* values ​​gradually decrease, indicating that the relaxation characteristics of the phantom can be controlled by adjusting the concentration of nanoparticles to achieve T2 and T2*mapping, thereby improving MRI imaging efficiency.

[0110] Of course, the above description is not a limitation of the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by ordinary technicians in this technical field within the essential scope of the present invention should fall within the protection scope of the present invention.

Claims

1. A phantom model of axons for multimodal magnetic resonance imaging assessment, comprising a phantom model housing having a cover and a tube, the tube having a receiving cavity for placing the phantom of the axons, the receiving cavity being filled with deionized water for simulating the water molecule exchange process inside and outside the axons and the diffusion characteristics of water molecules in the axons along the direction of the axons, characterized in that: The nerve axon phantom includes a tube body with openings at both ends having a filling cavity, in which several layers of circular fiber membranes for realistically simulating nerve axons are stacked in sequence along the axial direction of the tube body, and between adjacent circular fiber membranes, a spacer is provided for fixing the circular fiber membranes and narrowing the gap between adjacent circular fiber membranes, and a through hole for allowing deionized water to enter is opened on the spacer, and iron oxide nanoparticles are added to the circular fiber membranes for adjusting the relaxation time of the nerve axon phantom and realizing multimodal imaging.

2. The neural axon phantom model for multimodal magnetic resonance imaging evaluation according to claim 1, characterized in that: The circular fiber membrane is composed of a fiber bundle for simulating a nerve fiber bundle formed by a plurality of hollow fibers for simulating nerve axons, and iron oxide nanoparticles are loaded on the surface of the hollow fibers.

3. The neural axon phantom model for multimodal magnetic resonance imaging evaluation according to claim 1 or 2, characterized in that: The iron oxide nanoparticles are any one of Fe3O4, γ-Fe2O3, and ultra-small superparamagnetic iron oxide, and the particle size is 15-20nm.

4. The neural axon phantom model for multimodal magnetic resonance imaging evaluation according to claim 1 or 2, characterized in that: The outer diameter of the hollow fiber is 8-9.2 μm, the inner diameter is 4-7.8 μm, and the thickness of the fiber bundle is 0.2-0.4 mm.

5. The neural axon phantom model for multimodal magnetic resonance imaging evaluation according to claim 1, characterized in that: The plurality of circular fiber membranes and spacers in the tube body are pressed and formed by constant pressure, and the thickness compression rate after pressing and forming is 20%-50%.

6. A method for preparing the neural axon phantom model according to any one of claims 1 to 5, characterized in that: The steps include:

1. Preparation of hollow fiber membrane: (1) dissolving a certain amount of polyethylene oxide in deionized water to prepare a core layer solution for later use; (2) dissolving a certain amount of polycaprolactone in a mixed solvent of dichloromethane and dimethylformamide, and adding a certain amount of polysiloxane and iron oxide nanoparticles to prepare a shell solution, and ultrasonically treating the shell solution to fully disperse the iron oxide nanoparticles; (3) Using a coaxial electrospinning device, the core layer solution and the shell layer solution are respectively injected into the inner needle and the outer needle, and coaxial electrospinning is performed under certain spinning conditions to collect the oriented hollow fibers, and after deposition, a hollow fiber membrane consisting of a fiber bundle formed by a plurality of hollow fibers is obtained; 2. Assembling the axonal phantom: (4) Cutting the hollow fiber membrane obtained in step (3) into a number of circular fiber membrane sheets of a certain diameter for later use; (5) stacking a plurality of circular fiber membranes in parallel layer by layer, and placing annular thin sheets between adjacent circular fiber membranes, wherein the arrangement direction of the fiber bundles in each circular fiber membrane is the same; (6) placing the stacked circular fiber membranes and annular sheets in a cylindrical inner tube, and applying a constant pressure to arrange the stacked circular fiber membranes tightly, thereby obtaining a nerve axon phantom; 3. Packaging Simulation Model: (7) placing the prepared neural axon biomimetic in a centrifuge tube, filling the centrifuge tube with deionized water, and sealing it with a lid; (8) Vacuum the centrifuge tube to remove all bubbles; (9) Obtain a neural axon phantom model.

7. The method for preparing a neural axon phantom model according to claim 1, characterized in that: In the core layer solution of step (1), the concentration of polyethylene oxide is 4 w / v%.

8. The method for preparing a neural axon phantom model according to claim 1, characterized in that: In the shell solution of step (2), the concentration of polycaprolactone is 15 w / v%, the volume ratio of dichloromethane to dimethylformamide is 7:3, the concentration of polysiloxane is 0.5 w / w% relative to the mass of polycaprolactone, and the added amount of iron oxide nanoparticles is 0.05-0.15 wt% relative to the mass of polycaprolactone.

9. The method for preparing a neural axon phantom model according to claim 1, characterized in that: In the step (2), the iron oxide nanoparticles are any one of Fe3O4, γ-Fe2O3, and ultra-small superparamagnetic iron oxide, and the particle size is 15-20 nm.

10. The method for preparing a nerve axon phantom model according to claim 1, characterized in that: In the step (3), the inner needle is 25G, the outer needle is 18G, the core solution extrusion rate is 0.5ml / h, the shell solution extrusion rate is 1ml / h, the spinning voltage is 12kV, the receiving distance is 16cm, and the receiving roller speed is 900rpm.

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