A nuclear magnetic resonance guide wire for vascular intervention surgery and its preparation method

Abstract

The present invention discloses a nuclear magnetic resonance guide wire for vascular interventional surgery and a preparation method thereof. The nuclear magnetic resonance guide wire can be visualized under 19F-MRI. The nuclear magnetic resonance guide wire includes: a core wire, a coating layer disposed on the surface of the core wire, and a developing film layer disposed on the surface of the coating layer; the developing film layer includes: fluorinated MOFs and enzyme microcapsules adhered to the surface of the coating layer; the developing film layer can capture PFCs molecules in a complex biological system, generating 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals. Through computer data processing and image reconstruction, the visualization of the nuclear magnetic resonance guide wire under MRI is achieved. The two signals are intertwined to form a high-resolution image, significantly improving the image contrast and detail presentation under 19F-MRI. It solves the problems of image contrast and resolution of the nuclear magnetic resonance guide wire under 19F-MRI, provides more accurate image guidance for minimally invasive cardiovascular interventional surgery, and shows broad application prospects and potential.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and particularly to a nuclear magnetic resonance guide wire for vascular interventional surgery and a preparation method thereof. Background Art

[0002] Magnetic Resonance Imaging (MRI) is a non-invasive medical imaging technique that uses strong magnetic fields and radiofrequency waves to image the internal structures of the human body. 19F-MRI is a specific type of MRI that focuses on detecting the signals of fluorine (19F) atoms. Since the natural fluorine content in the human body is extremely low, 19F-MRI can provide highly specific image contrast, especially when using fluorine-containing contrast agents.

[0003] In vascular interventional surgery, doctors need to know the position of the guide wire in real time to ensure that they are accurately guided to the target area. Although traditional X-ray fluoroscopy can be used for this purpose, it has the risk of ionizing radiation and low resolution for soft tissues. In contrast, MRI has the advantages of being radiation-free and having high soft tissue contrast, but traditional guide wires cannot be visualized under MRI, which limits their application under MRI guidance.

[0004] Therefore, it is necessary to provide a nuclear magnetic resonance guide wire for vascular interventional surgery and a preparation method thereof to solve the above technical problems. Summary of the Invention

[0005] The present invention overcomes the deficiencies of the prior art and provides a nuclear magnetic resonance guide wire for vascular interventional surgery and a preparation method thereof.

[0006] To achieve the above object, the technical solution adopted by the present invention is: a nuclear magnetic resonance guide wire for vascular interventional surgery, which can be visualized under 19F-MRI;

[0007] The nuclear magnetic resonance guide wire includes: a core wire, a coating layer provided on the surface of the core wire, and a developing film layer provided on the surface of the coating layer;

[0008] The developing film layer includes: fluorinated MOFs and enzyme microcapsules adhered to the surface of the coating layer; the developing film layer is used to capture PFCs molecules, generating intertwined 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals, and realizing the visualization of the nuclear magnetic resonance guide wire under MRI through computer data processing and image reconstruction.

[0009] In a preferred embodiment of the present invention, the material of the core wire is carbon fiber, glass fiber, nickel-aluminum alloy, plastic or composite material.

[0010] In a preferred embodiment of the present invention, the coating layer is a polymer layer, and the polymer is one of polytetrafluoroethylene, polyurethane, nylon, polylactic acid, or polyetheretherketone.

[0011] Based on the preparation method of a magnetic resonance guide wire for vascular intervention surgery according to any one of the above, the method includes the following steps:

[0012] S1. Take a core wire, and obtain a magnetic resonance guide wire to be processed after wrapping a layer of coating on the surface of the core wire;

[0013] S2. Prepare fluorinated MOFs powder and enzyme microcapsules respectively;

[0014] S3. Disperse the prepared fluorinated MOFs powder and enzyme microcapsules into a DMF solvent, stir evenly to obtain a developing film layer suspension;

[0015] S4. Uniformly coat the developing film layer suspension on the surface of the magnetic resonance guide wire to be processed, and then dry and cure it at 30-50 °C to prepare a magnetic resonance guide wire.

[0016] In a preferred embodiment of the present invention, the preparation method of the fluorinated MOFs powder includes the following steps:

[0017] S211. Weigh a non-magnetic metal ion source and an organic ligand in a molar ratio of 3:1.5-2.5, and ultrasonically dissolve them in a DMF solvent respectively;

[0018] S212. Mix the ligand solution and the metal ion solution, and continue to perform ultrasonic treatment;

[0019] S213. Transfer the uniformly dispersed mixed solution to a reaction kettle, seal it, and place it in an oven for reaction for 12-24 hours;

[0020] S214. After cooling, centrifuge to separate the product, and wash it repeatedly with DMF, absolute ethanol, and deionized water until no precipitate is produced when adding NaOH;

[0021] S215. Place the washed product in a vacuum drying oven for activation, grind it and pass it through a sieve to obtain fluorinated MOFs powder.

[0022] In a preferred embodiment of the present invention, the non-magnetic metal ion source is Zn(NO3)2·6H2O;

[0023] The organic ligand is one of 2,3,5,6-tetrafluoroterephthalic acid or 2,3,5,6-tetrafluoroterephthalonitrile.

[0024] In a preferred embodiment of the present invention, the preparation method of the enzyme microcapsules includes the following steps:

[0025] S221. Dissolve the esterase in PBS buffer, add a protective agent to obtain an esterase solution;

[0026] S222. Mix the esterase solution with the wall material and stir evenly to obtain an aqueous phase;

[0027] S223. Add an emulsifier to the mineral oil and stir evenly to obtain an oil phase;

[0028] S224. Slowly add the prepared aqueous phase to the oil phase while stirring with a high-speed stirrer to form a uniform and stable W / O emulsion;

[0029] S225. Slowly add a cross-linking agent to the emulsion and continue to stir at room temperature for 20 - 30 min for reaction;

[0030] S226. Centrifuge the reacted emulsion, collect the enzyme microcapsules precipitated at the bottom, and wash them repeatedly with deionized water several times to obtain enzyme microcapsules with a diameter of 2 - 5 μm.

[0031] In a preferred embodiment of the present invention, in the step S222, the mixing ratio of the esterase solution to the wall material is 1:3.2 - 3.6.

[0032] In a preferred embodiment of the present invention, the thickness of the imaging film layer is 10 - 20 μm.

[0033] In a preferred embodiment of the present invention, in the suspension of the imaging film layer, the mixing ratio of the fluorinated MOFs powder to the enzyme microcapsules is 3 - 5:1.

[0034] The present invention solves the defects existing in the background art and has the following beneficial effects:

[0035] (1) The present invention provides a nuclear magnetic resonance guide wire for vascular interventional surgery and its preparation method. Its imaging film layer can capture PFCs molecules in a complex biological system, generating 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals. The two signals are intertwined to form a high-resolution image, significantly improving the image contrast and detail presentation under 19F-MRI. It solves the problems of image contrast and resolution of the nuclear magnetic resonance guide wire during imaging under 19F-MRI, provides more accurate image guidance for minimally invasive cardiovascular interventional surgery, and shows broad application prospects and potential.

[0036] (2) The imaging film layer in the present invention includes: fluorinated MOFs and enzyme microcapsules adhered to the surface of the coating layer. The prepared fluorinated MOFs are metal-organic frameworks modified by fluorination and have good adsorption performance for PFCs. The enzyme microcapsules release esterase at the required time to catalyze PFCs, causing PFCs to react with surrounding molecules to generate products with different chemical shifts, producing new nuclear magnetic resonance signals. In the present invention, the fluorinated MOFs and the enzyme microcapsules are doped with each other to form the imaging film layer. The 19F-MOFs nuclear magnetic resonance signal and the 19F-enzyme nuclear magnetic resonance signal under MRI are intertwined, and the image features are unique, further enhancing the specificity of the nuclear magnetic resonance signal.

[0037] (3) The present invention provides an enzyme microcapsule and its preparation method, which can prepare microcapsules that can remain stable at 30-50 °C and can degrade or rupture to release enzymes after entering the blood vessel or contacting PFCs molecules. This method not only improves the stability and functionality of the enzyme but also enhances its application potential in complex medical environments, ensuring that the enzyme can be activated under specific conditions and catalyze the chemical reaction of the PFCs contrast agent to generate products with different chemical shifts, thereby improving the effect of 19F-MRI imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings;

[0039] Figure 1 is the flow chart of the preparation method of the nuclear magnetic resonance guide wire of the preferred embodiment of the present invention;

[0040] Figure 2 is the scanning electron microscope image of the imaging film layer on the nuclear magnetic resonance guide wire prepared in Example 1 of the present invention;

[0041] Figure 3 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Example 1 of the present invention;

[0042] Figure 4 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Example 2 of the present invention;

[0043] Figure 5 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Example 3 of the present invention;

[0044] Figure 6 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Comparative Example 1 of the present invention;

[0045] Figure 7 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Comparative Example 2 of the present invention;

[0046] Figure 8 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Comparative Example 3 of the present invention;

[0047] Figure 9 is the 19F spectrum of the nuclear magnetic resonance guide wire prepared in Comparative Example 4 of the present invention. Detailed Embodiments

[0048] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0049] 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 different from those described herein. Therefore, the protection scope of the present invention is not limited by the specific embodiments disclosed below.

[0050] The present invention provides a nuclear magnetic resonance guide wire for vascular interventional surgery, which can be visualized under 19F-MRI. The nuclear magnetic resonance guide wire includes: a core wire, a coating layer provided on the surface of the core wire, and a visualization film layer provided on the surface of the coating layer; the visualization film layer includes: fluorinated MOFs and enzyme microcapsules adhered to the surface of the coating layer; the visualization film layer is used to capture PFCs molecules, generating intertwined 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals, and realizing the visualization of the nuclear magnetic resonance guide wire under 19F-MRI through computer data processing and image reconstruction.

[0051] It should be noted that in actual applications, it is necessary to first intravenously inject the PFCs contrast agent into the human body and then use the nuclear magnetic resonance guide wire of the present invention to be visualized under MRI.

[0052] Furthermore, the material of the core wire is carbon fiber, glass fiber, nickel-aluminum alloy, plastic or composite material. The core wire prepared from such materials can not generate artifacts and will not heat up in a strong magnetic field, and has sufficient mechanical strength and flexibility to be used as an interventional guide wire in an MRI environment.

[0053] Furthermore, the coating layer is a polymer layer, and the polymer is one of polytetrafluoroethylene, polyurethane, nylon, polylactic acid or polyether ether ketone, and polytetrafluoroethylene is preferably used.

[0054] It should be noted that the developing film layer is composed of fluorinated MOFs and enzyme microcapsules.

[0055] Among them, fluorinated MOFs are metal-organic frameworks modified by fluorination and have good adsorption performance for PFCs. Specifically, MOF is a crystalline porous material with a periodic network structure, having characteristics such as porosity and a large specific surface area, providing more adsorption sites. Moreover, when the MOF material is fluorinated, the fluorinated functional groups have good fluorine-fluorine interactions with PFCs, greatly improving the adsorption performance of the material for PFCs.

[0056] The enzyme microcapsules are composed of esterase and a microcapsule wall material wrapped outside the esterase. The microcapsule wall material ensures the activity of the enzyme and ensures its release of esterase at the required time, while the esterase catalyzes PFCs to promote its hydrolysis reaction, or causes PFCs to undergo addition or oxidation reactions with small molecules in the plasma (such as H2O, amino acids), generating products with different chemical shifts and producing new nuclear magnetic resonance signals (i.e., 19F-enzyme nuclear magnetic resonance signals).

[0057] Due to the similar molecular structures of PFCs, their chemical shifts are usually small, resulting in signal overlap, reducing the resolution and specificity of the image. In the present invention, near the nuclear magnetic guide wire, new PFCs products are generated through the catalytic reaction of esterase, and these products have different chemical shifts, thereby increasing the difference between the signals. This enables each PFCs molecule or its derivative product to be distinguished within a wider frequency spectrum range, improving the clarity and specificity of the image.

[0058] Furthermore, the fluorinated MOFs and the enzyme microcapsules are doped with each other to form the developing film layer, resulting in the intertwining of the 19F-MOFs nuclear magnetic resonance signal and the 19F-enzyme nuclear magnetic resonance signal under MRI, and the image features are unique, further enhancing the specificity of the nuclear magnetic resonance signal.

[0059] As Figure 1 shown, the present invention also provides a preparation method for a nuclear magnetic guide wire used in vascular intervention surgery, including the following steps:

[0060] S1. A nuclear magnetic guide wire to be processed is obtained by wrapping a coating layer on the surface of the core wire.

[0061] S2. Fluorinated MOFs powder and enzyme microcapsules are respectively prepared.

[0062] S3. The prepared fluorinated MOFs powder and enzyme microcapsules are dispersed into a DMF solvent and stirred evenly to obtain a developing film layer suspension.

[0063] S4. Uniformly coat the developing film layer suspension onto the surface of the magnetic resonance guide wire to be processed, and then dry and cure it at 30-50 °C to obtain the magnetic resonance guide wire.

[0064] Through the above steps, a magnetic resonance guide wire that can capture PFCs molecules and then develop under MRI can be prepared, which has broad application prospects in the field of image-guided minimally invasive interventional diagnosis and treatment.

[0065] In step S1, the specific steps for preparing the magnetic resonance guide wire to be processed are as follows:

[0066] Put the coating layer on the outer surface of the core wire, and use hot air to cause the coating layer to shrink thermally and tightly wrap around the surface of the core wire to obtain the magnetic resonance guide wire to be processed.

[0067] In one embodiment, the core wire uses a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube is used as the coating layer to be coated on the surface of the carbon fiber composite material to obtain the magnetic resonance guide wire to be processed.

[0068] It should be noted that the carbon fiber composite material is specifically a carbon fiber reinforced plastic wire, and the specific steps for coating the carbon fiber composite material with the polytetrafluoroethylene heat-shrinkable tube are as follows:

[0069] Put the polytetrafluoroethylene heat-shrinkable tube (inner diameter before heat shrinkage is 0.9-1.2 mm) on the outer surface of the carbon fiber composite material with an inner diameter of 0.8 mm, and then use hot air at 350-400 °C to cause the polytetrafluoroethylene heat-shrinkable tube to shrink and tightly wrap around the outer surface of the carbon fiber composite material to obtain the magnetic resonance guide wire to be processed with an inner diameter of 0.9-0.95 mm.

[0070] Furthermore, the materials required for preparing the developing film layer are as follows:

[0071] Non-magnetic metal ion source: Zn(NO3)2·6H2O;

[0072] Organic ligand: 2,3,5,6-tetrafluoroterephthalic acid or 2,3,5,6-tetrafluoroterephthalonitrile;

[0073] Solvent: DMF (N,N-dimethylformamide);

[0074] Enzyme: esterase;

[0075] Wall material: polylactic acid (PLA), polycaprolactone (PCL), gelatin or chitosan;

[0076] Crosslinking agent: glutaraldehyde;

[0077] Protective agent: sucrose, glycerol.

[0078] The preparation method of the fluorinated MOFs powder in step S2 includes the following steps:

[0079] S211. Weigh the non-magnetic metal ion source and the organic ligand in a molar ratio of 3:1 to 2.5, and ultrasonically dissolve them separately in DMF solvent to ensure complete dissolution.

[0080] S212. Mix the ligand solution with the metal ion solution and continue ultrasonic treatment to uniformly disperse the non-magnetic metal ion source and the organic ligand in the solution.

[0081] S213. Transfer the uniformly dispersed mixed solution to a reaction kettle, seal it, place it in an oven, and react at 150 °C for 24 hours.

[0082] S214. After the reaction, take out the reaction kettle and cool it, then centrifuge to separate the solid product. Then wash it several times (at least three times) with DMF, absolute ethanol, and deionized water until no precipitate is formed when adding NaOH to ensure the removal of unreacted raw materials and by-products.

[0083] S215. Place the washed product in a vacuum drying oven and activate it at 80 °C for 24 hours to ensure complete drying. Grind the activated product through a 200-mesh sieve to obtain the fluorinated MOFs powder.

[0084] Next, conduct experiments to verify the adsorption capacity of the fluorinated MOFs prepared with different ratios of metal ions and ligands for PFCs.

[0085] Prepare fluorinated MOFs powder samples using Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in different molar ratios of 4:1, 3:1, 3:1.5, 3:2.5, and 3:3.5 respectively. Next, name them sample 1, 2, 3, 4, and 5 in sequence.

[0086] Weigh 8.0 mg of the fluorinated MOFs powder into a 50 mL centrifuge tube, add 8.0 mL of 10 mg / L PFCs aqueous solution, and add a certain amount of NaCl solution to make its concentration 0.01 mol / L. Make up the volume, oscillate and adsorb for a certain time at a speed of 250 rpm in a constant temperature oscillator, centrifuge the suspension at a speed of 10000 rpm for 5 min, filter with a filter head, analyze the residual PFCs concentration in the filtrate using an improved ultraviolet-visible spectrophotometer, and calculate the adsorption capacity of the fluorinated MOFs at the adsorption equilibrium for PFCs. The results are shown in Table 1.

[0087] Table 1 Adsorption performance of samples with different ratios for PFCs

[0088]

[0089] As can be seen from Table 1, when the dosage of ligand 2,3,5,6-tetrafluoroterephthalic acid increases, the adsorption capacity of fluorinated MOFs for PFCs also increases. When the ratio of metal ions to ligand is 3:2.5, the material has the maximum adsorption capacity, indicating that the fluorophilic effect varies due to the amount of fluorine introduced. However, when the sample 5 (the ratio reaches 3:3.5), the adsorption capacity does not increase but decreases because the adsorption sites provided by MOF reach the upper limit. If too much fluorine is introduced, there is no position to adsorb PFCs, which will only cause waste of ligands and increase in cost. Therefore, when preparing fluorinated MOFs, a molar ratio of 3:1.5 - 2.5 is preferred.

[0090] The preparation method of the enzyme microcapsules in step S2 includes the following steps:

[0091] S221. Dissolve esterase in PBS buffer (pH 7.4), add 10% (w / v) protective agent to obtain an esterase solution with a concentration of 5 mg / mL.

[0092] S222. Mix the esterase solution and the wall material in a ratio of 1:3.2 - 3.6, stir evenly to obtain an aqueous phase, and adjust the pH value of the aqueous phase to 6.5 - 7.5 to ensure the best encapsulation conditions.

[0093] S223. Add an emulsifier to mineral oil and stir evenly to obtain an oil phase; among them, the emulsifier is 2% (v / v) Span80.

[0094] S224. Slowly add the prepared aqueous phase to the oil phase, and at the same time use a high-speed stirrer to stir, with a stirring rate of 10000 rpm / min and a duration of 10 min, to form a uniform and stable W / O emulsion.

[0095] S225. Slowly add a crosslinking agent to the emulsion and continue to stir at room temperature for 20 - 30 min to generate enzyme microcapsules; among them, the crosslinking agent is 1% (v / v) glutaraldehyde, and the diameter of the enzyme microcapsules is controlled within the range of 2 - 5 μm.

[0096] S226. Centrifuge the reacted emulsion, collect the enzyme microcapsules precipitated at the bottom, and wash them repeatedly with deionized water (at least three times) to remove unreacted crosslinking agent and other impurities, to obtain enzyme microcapsules with a diameter of 2 - 5 μm.

[0097] Through the above steps, enzyme microcapsules are prepared, ensuring the stability of the microcapsules at high temperatures and enabling the effective release of enzymes under specific conditions. This not only improves the stability and functionality of the enzymes but also enhances their application potential in complex medical environments, ensuring that the enzymes can be activated and catalyze the chemical reactions of PFCs contrast agents under specific conditions to generate products with different chemical shifts, thereby improving the effect of 19F-MRI imaging.

[0098] Next, experiments were carried out to verify the stability and degradation performance of enzyme microcapsules prepared with esterase solutions in different ratios and different wall materials.

[0099] Aqueous phases were prepared by mixing esterase solutions with chitosan and gelatin in ratios of 1:2, 1:2.8, 1:3.2, 1:3.6, and 1:4.2 respectively, and then enzyme microcapsule specimens were prepared. They were named specimen 1 - 10 in sequence.

[0100] Stability test: The prepared enzyme microcapsule specimens were placed at 20°C, and the temperature was increased by 2°C every 3 minutes until it reached 60°C. The morphological changes of the enzyme microcapsule specimens were observed, and the temperature at which changes occurred was recorded.

[0101] Degradation performance test: 0.8 mg of the enzyme microcapsule specimen was weighed into a 50 mL centrifuge tube, 9 mL of plasma and 1 mL of 10 mg / L PFCs aqueous solution were added. The temperature of the plasma was maintained at 37°C. After standing for 30 s, it was centrifuged and filtered, and a scanning electron microscope was used to observe the changes on the surface of the microcapsules, especially cracks and holes.

[0102] The following are the test results of stability and degradation performance, as shown in Table 2.

[0103] Table 2 Stability and degradation performance

[0104]

[0105] In Table 2, stability (°C): represents the highest temperature at which the enzyme microcapsules maintain their morphology during the heating process. The higher this temperature, the better the thermal stability of the microcapsules. And the degree of degradation / rupture of the microcapsule wall material (%): represents the degree of cracks or holes on the surface of the microcapsules during the degradation performance test. The lower the percentage, the more complete the structure of the microcapsules and the slower the degradation.

[0106] As can be seen from Table 2, only the stability temperatures of specimens 3, 4, 5, 9, and 10 exceeded 50°C. That is to say, only these specimens can ensure that the microcapsule wall material does not rupture during the drying and curing process in step S4, and can ensure the stability of esterase. Among these 5 batches of specimens, only specimens 3, 4, and 9 had a degradation or rupture degree within 10% - 20% during the degradation performance test, which is the initial degradation process, and the esterase gradually emerged. To sum up, it is preferred to use a ratio of 1:3.2 - 3.6 to prepare chitosan microcapsules to ensure their stability at high temperatures and controlled release under specific conditions. The microcapsules within this ratio range can start to degrade or rupture 20 - 30 seconds after entering the blood environment or contacting with PFCs, leaving sufficient time to guide the nuclear magnetic wire to the designated position, avoiding premature release of esterase, resulting in insufficient imaging enhancement time and inability to accurately locate the nuclear magnetic wire.

[0107] Through the above detailed steps and parameter settings, microcapsules can be successfully prepared, which can remain stable at 30 - 50 °C and can degrade or rupture to release enzymes after entering blood vessels or contacting PFCs molecules. This method not only improves the stability and functionality of the enzymes, but also enhances their application potential in complex medical environments, ensuring that the enzymes can be activated under specific conditions to catalyze the chemical reactions of PFCs contrast agents, generating products with different chemical shifts, thereby improving the effect of 19F-MRI imaging.

[0108] In step S3, in the suspension of the imaging film layer, the mixing ratio of the fluorinated MOFs powder to the enzyme microcapsules is 3 - 5:1.

[0109] The coating method in step S4 adopts dip coating or spray coating, and the method of multiple drying and coating is used to ensure the formation of a dense imaging film layer on the coating layer, and the thickness of the imaging film layer is 10 - 20 μm.

[0110] In order to verify the influence of the mixing ratio of different fluorinated MOFs powders to enzyme microcapsules on the 19F-MRI imaging effect of the nuclear magnetic resonance wire, the following examples and comparative examples are made.

[0111] Example 1:

[0112] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube as the coating layer is coated on the surface of the carbon fiber composite material to prepare a nuclear magnetic resonance wire to be processed with an inner diameter of 0.95 mm.

[0113] 2) Prepare fluorinated MOFs powder by taking Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5.

[0114] 3) Take an esterase solution and chitosan in a ratio of 1:3.6 to prepare an aqueous phase, and adjust the pH value to 7, and then prepare enzyme microcapsules with a diameter of 2 - 5 μm.

[0115] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules in a DMF solvent in a ratio of 3:1, stir evenly to obtain a suspension of the imaging film layer.

[0116] 5) Uniformly coat the suspension of the imaging film layer on the surface of the nuclear magnetic resonance wire to be processed, and then dry and cure at 45 °C for 20 h to prepare a nuclear magnetic resonance wire. The average thickness of the imaging film layer of the nuclear magnetic resonance wire is 15 μm.

[0117] Figure 2 This is the scanning electron microscope image of the imaging film layer on the nuclear magnetic resonance wire prepared in this example. It can be seen from the figure that the fluorinated MOFs and enzyme microcapsules are stacked on the coating layer to form a dense and connected imaging film layer.

[0118] Next, the 19F-MRI imaging effect of the nuclear magnetic resonance guide wire prepared in this embodiment after intravenous injection of PFCs contrast agent was tested as follows:

[0119] Experimental equipment conditions:

[0120] MRI scanner: A 7 Tesla Bruker Avance III HD MRI system (Bruker, Germany) equipped with high-resolution gradient coils was used.

[0121] Radiofrequency coil: A dual resonance probe (19F and 1H) was used to detect both PFCs and water signals simultaneously.

[0122] Contrast agent: A commercially available perfluorooctanoic acid (PFOA) solution was prepared at a concentration of 10 mg / L.

[0123] Experimental animals: Healthy mice were used as models.

[0124] Experimental procedure:

[0125] The mice were anesthetized with isoflurane gas and fixed on the MRI scanning bed. 100 μL of PFCs contrast agent (10 mg / L) was slowly injected via the tail vein, and the injection time point was recorded.

[0126] The nuclear magnetic resonance guide wire prepared in Example 1 was slowly inserted into the vascular system of the mice.

[0127] Scanning parameter settings: A magnetic field strength of 7 Tesla, an RF pulse frequency of 282 MHz, and a gradient echo (GRE) sequence were used to obtain high-resolution images. Each time point was scanned for 5 minutes, and scans were performed before injection, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after injection.

[0128] As Figure 3 shown, in the 19F spectrum scanned in Example 1, three significant signals were shown:

[0129] Chemical shift δ = 168.64 ppm, corresponding to uncaptured PFCs molecules.

[0130] Chemical shift δ = 75.2 ppm, corresponding to PFCs molecules captured by fluorinated MOFs in the imaging film layer. This signal indicates that the imaging film layer successfully captured PFCs molecules and generated unique nuclear magnetic resonance signals.

[0131] Chemical shift δ = 88.3 ppm, corresponding to new PFCs molecules catalytically generated by esterase in the imaging film layer, generating unique nuclear magnetic resonance signals.

[0132] Two intertwined nuclear magnetic resonance signals are significantly different from the nuclear magnetic resonance signals of other free PFCs. Moreover, there are differences between the nuclear magnetic resonance signals of 19F-MOFs and 19F-enzymes, and the difference is lower than that between the two and the nuclear magnetic resonance signals of free PFCs, which improves the clarity and specificity of the image.

[0133] Example 2:

[0134] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a to-be-treated nuclear magnetic resonance guide wire with an inner diameter of 0.95 mm.

[0135] 2) Prepare fluorinated MOFs powder by taking Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5.

[0136] 3) Prepare an aqueous phase by mixing an esterase solution and chitosan in a ratio of 1:3.6, and adjust the pH value to 7 to obtain enzyme microcapsules with a diameter of 2-5 μm.

[0137] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules into a DMF solvent in a ratio of 4:1, and stir evenly to obtain a suspension of the imaging film layer.

[0138] 5) Uniformly coat the suspension of the imaging film layer on the surface of the to-be-treated nuclear magnetic resonance guide wire, and then dry and cure it at 45°C for 20 h to prepare a nuclear magnetic resonance guide wire with an average thickness of 15 μm for the imaging film layer.

[0139] Example 3:

[0140] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a to-be-treated nuclear magnetic resonance guide wire with an inner diameter of 0.95 mm.

[0141] 2) Prepare fluorinated MOFs powder by taking Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5.

[0142] 3) Prepare an aqueous phase by mixing an esterase solution and chitosan in a ratio of 1:3.6, and adjust the pH value to 7 to obtain enzyme microcapsules with a diameter of 2-5 μm.

[0143] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules into a DMF solvent in a ratio of 5:1, and stir evenly to obtain a suspension of the imaging film layer.

[0144] 5) Uniformly coat the developing film layer suspension onto the surface of the nuclear magnetic resonance guide wire to be treated, and then dry and cure it at 45 °C for 20 h to prepare the nuclear magnetic resonance guide wire. The average thickness of the developing film layer of the nuclear magnetic resonance guide wire is 15 μm.

[0145] Comparative Example 1:

[0146] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire and a polytetrafluoroethylene heat shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a nuclear magnetic resonance guide wire to be treated with an inner diameter of 0.95 mm.

[0147] 2) Prepare fluorinated MOFs powder by taking Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5.

[0148] 3) Prepare an aqueous phase by mixing an esterase solution and chitosan in a ratio of 1:3.6, and adjust the pH value to 7 to obtain enzyme microcapsules with a diameter of 2 - 5 μm.

[0149] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules into the DMF solvent in a ratio of 1:1, and stir evenly to obtain the developing film layer suspension.

[0150] 5) Uniformly coat the developing film layer suspension onto the surface of the nuclear magnetic resonance guide wire to be treated, and then dry and cure it at 45 °C for 20 h to prepare the nuclear magnetic resonance guide wire. The average thickness of the developing film layer of the nuclear magnetic resonance guide wire is 15 μm.

[0151] Comparative Example 2:

[0152] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire and a polytetrafluoroethylene heat shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a nuclear magnetic resonance guide wire to be treated with an inner diameter of 0.95 mm.

[0153] 2) Prepare fluorinated MOFs powder by taking Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5.

[0154] 3) Prepare an aqueous phase by mixing an esterase solution and chitosan in a ratio of 1:3.6, and adjust the pH value to 7 to obtain enzyme microcapsules with a diameter of 2 - 5 μm.

[0155] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules into the DMF solvent in a ratio of 2:1, and stir evenly to obtain the developing film layer suspension.

[0156] 5) Uniformly coat the developing film layer suspension onto the surface of the nuclear magnetic resonance guide wire to be treated, and then dry and cure it at 45 °C for 20 h to prepare the nuclear magnetic resonance guide wire. The average thickness of the developing film layer of the nuclear magnetic resonance guide wire is 15 μm.

[0157] Comparative Example 3:

[0158] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a to-be-treated nuclear magnetic guiding wire with an inner diameter of 0.95 mm.

[0159] 2) Take Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5 to prepare fluorinated MOFs powder.

[0160] 3) Take an esterase solution and chitosan in a ratio of 1:3.6 and mix them to prepare an aqueous phase, and adjust the pH value to 7, and then prepare enzyme microcapsules with a diameter of 2 - 5 μm.

[0161] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules in a DMF solvent in a ratio of 6:1, and stir evenly to obtain a developing film layer suspension.

[0162] 5) Uniformly coat the developing film layer suspension on the surface of the to-be-treated nuclear magnetic guiding wire, and then dry and cure it at 45°C for 20 h to prepare a nuclear magnetic guiding wire, and the average thickness of the developing film layer of the nuclear magnetic guiding wire is 15 μm.

[0163] Comparative Example 4:

[0164] 1) Take a carbon fiber composite material with an inner diameter of 0.8 mm as the core wire, and a polytetrafluoroethylene heat-shrinkable tube as the coating layer, and coat it on the surface of the carbon fiber composite material to prepare a to-be-treated nuclear magnetic guiding wire with an inner diameter of 0.95 mm.

[0165] 2) Take Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid in a molar ratio of 3:2.5 to prepare fluorinated MOFs powder.

[0166] 3) Take an esterase solution and chitosan in a ratio of 1:3.6 and mix them to prepare an aqueous phase, and adjust the pH value to 7, and then prepare enzyme microcapsules with a diameter of 2 - 5 μm.

[0167] 4) Disperse the prepared fluorinated MOFs powder and enzyme microcapsules in a DMF solvent in a ratio of 7:1, and stir evenly to obtain a developing film layer suspension.

[0168] 5) Uniformly coat the developing film layer suspension on the surface of the to-be-treated nuclear magnetic guiding wire, and then dry and cure it at 45°C for 20 h to prepare a nuclear magnetic guiding wire, and the average thickness of the developing film layer of the nuclear magnetic guiding wire is 15 μm.

[0169] Next, verify the imaging effect of the nuclear magnetic guiding wire samples prepared in the above Examples 1 - 3 and Comparative Examples 1 - 4.

[0170] Experimental equipment conditions:

[0171] MRI scanner: A 7 Tesla Bruker Avance III HD MRI system (Bruker, Germany) equipped with high-resolution gradient coils was used.

[0172] Radiofrequency coil: A dual resonance probe (19F and 1H) was used to simultaneously detect PFCs and water signals.

[0173] Contrast agent: A commercially available perfluorooctanoic acid (PFOA) was formulated into a 10 mg / L solution.

[0174] Experimental animals: Healthy mice were used as models.

[0175] Experimental procedures:

[0176] The mice were anesthetized with isoflurane gas and fixed on the MRI scanning bed. 100 μL of PFCs contrast agent (10 mg / L) was slowly injected via the tail vein, and the injection time point was recorded.

[0177] The NMR guidewires prepared in Examples 1-3 and Comparative Examples 1-4 were slowly inserted into the vascular system of the mice.

[0178] Scanning parameter settings: A magnetic field strength of 7 Tesla, an RF pulse frequency of 282 MHz, and a gradient echo (GRE) sequence were used to obtain high-resolution images. Each time point was scanned for 5 minutes, and scans were performed before injection, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after injection. The resulting 19F spectra are as Figures 3 to 9 shown. After computer data processing and image reconstruction, the visualization of the NMR guidewire under MRI was obtained, and the difficulty of image resolution was judged. The results are shown in Table 3 below.

[0179] Table 3 Visualization effect of NMR guidewire

[0180]

[0181] As can be seen from Table 3, as the proportion of enzyme microcapsules in the imaging film layer increases, the degree of interweaving of the two nuclear magnetic resonance signals at the nuclear magnetic wire becomes more complex, increasing the specificity of the nuclear magnetic resonance signal, that is, improving the spatial resolution. However, when the proportion of enzyme microcapsules exceeds one-fourth, there are not enough fluorinated MOFs to adsorb free PFCs, resulting in only a part of the enzymes on the surface of the fluorinated MOFs playing a role, and it is impossible to present an image with signal interweaving under MRI, with low contrast and difficult to distinguish. On the contrary, as the proportion of fluorinated MOFs increases, more PFCs can be adsorbed, and the nuclear magnetic resonance signal of 19F-MOFs is enhanced. However, the nuclear magnetic resonance signal of 19F-enzymes will be low and blocked, and it is also impossible to present an image with signal interweaving under MRI, with low contrast and difficult to distinguish. Therefore, in the present invention, the mixing ratio of fluorinated MOFs powder to enzyme microcapsules is selected to be 3-5:1 to prepare the imaging film layer. At this time, the molecular weight of PCFs adsorbed by the imaging film layer is sufficient, and the degree of interweaving of the two nuclear magnetic resonance signals is complex enough, solving the problem of the nuclear magnetic wire being visible under 19F-MRI and having broad application prospects.

[0182] Based on the ideal embodiments of the present invention as an inspiration, through the above description, relevant personnel can completely make various changes and modifications without departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the specification, and the technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing a nuclear magnetic guide wire for vascular intervention surgery, wherein the nuclear magnetic guide wire can be developed under 19F-MRI, characterized in that: The nuclear magnetic guide wire comprises: a core wire, a coating layer arranged on the surface of the core wire, and a developing film layer arranged on the surface of the coating layer; The developing film layer comprises: fluorinated MOFs and enzyme microcapsules adhered to the surface of the coating layer; the developing film layer is used to capture PFCs molecules, generate intertwined 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals, and realize the development of the nuclear magnetic guide wire under MRI through computer data processing and image reconstruction; The method for preparing the nuclear magnetic guide wire comprises the following steps: S1, taking a core wire, and wrapping a coating layer on the surface of the core wire to obtain a nuclear magnetic guide wire to be processed; S2, preparing fluorinated MOFs powder and enzyme microcapsules respectively; S3, dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in a DMF solvent at a ratio of 3 to 5:1, stirring evenly, and obtaining a developing film suspension; S4, uniformly coating the developing film layer suspension onto the surface of the nuclear magnetic guide wire to be treated, and then drying and curing at 30-50° C. to prepare the nuclear magnetic guide wire.

2. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 1, characterized in that: The material of the core wire is carbon fiber, glass fiber, nickel-aluminum alloy, plastic or composite material.

3. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 1, characterized in that: The coating layer is a high molecular polymer layer, and the high molecular polymer is one of polytetrafluoroethylene, polyurethane, nylon, polylactic acid or polyetheretherketone.

4. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 1, characterized in that: The method for preparing the fluorinated MOFs powder comprises the following steps: S211, weighing a non-magnetic metal ion source and an organic ligand in a molar ratio of 3:1.5-2.5, and dissolving them in a DMF solvent by ultrasonication; S212, mixing the ligand solution and the metal ion solution, and continuing to perform ultrasonic treatment; S213, transferring the uniformly dispersed mixed solution to a reaction kettle, sealing it, and placing it in an oven to react for 12 to 24 hours; S214, centrifugally separating the product after cooling, and repeatedly washing it with DMF, anhydrous ethanol and deionized water until no precipitation is produced by dropping NaOH; S215. The washed product is placed in a vacuum drying oven for activation, ground and sieved to obtain fluorinated MOFs powder.

5. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 4, characterized in that: The non-magnetic metal ion source is Zn(NO3)2·6H2O; The organic ligand is one of 2,3,5,6-tetrafluoroterephthalic acid or 2,3,5,6-tetrafluoroterephthalonitrile.

6. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 1, characterized in that: The preparation method of the enzyme microcapsule comprises the following steps: S221, dissolving the esterase in PBS buffer, adding a protective agent to obtain an esterase solution; S222, mixing the esterase solution with the wall material, and stirring evenly to obtain an aqueous phase; S223, adding an emulsifier to the mineral oil and stirring to obtain an oil phase; S224, slowly adding the prepared water phase to the oil phase, and stirring with a high-speed stirrer to form a uniform and stable W / O emulsion; S225, slowly adding a crosslinking agent to the emulsion and continuing stirring at room temperature for 20 to 30 minutes to react; S226. Centrifuge the emulsion after the reaction, collect the enzyme microcapsules precipitated at the bottom, and wash them repeatedly with deionized water for several times to obtain enzyme microcapsules with a diameter of 2 to 5 μm.

7. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 6, characterized in that: In the step S222, the mixing ratio of the esterase solution to the wall material is 1:3.2-3.

6.

8. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 1, characterized in that: The thickness of the developing film layer is 10-20 μm.

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