Nuclear magnetic guide wire for vascular interventional operation and preparation method of nuclear magnetic guide wire

Abstract

The invention discloses a nuclear magnetic guide wire for vascular interventional surgery and a preparation method thereof, the nuclear magnetic guide wire can develop under 19F-MRI, and 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 which are adhered to the surface of the coating layer; the development film layer can capture PFCs molecules in a complex biological system, a 19F-MOFs nuclear magnetic resonance signal and a 19F-enzyme nuclear magnetic resonance signal are generated, development of the nuclear magnetic guide wire under MRI is achieved through computer data processing and image reconstruction, the two signals are interwoven to form a high-resolution image, and the image contrast and detail presentation under the 19F-MRI are remarkably improved. The problems of image contrast and resolution of the nuclear magnetic guide wire developed under 19F-MRI are solved, more accurate image guidance is provided for cardiovascular minimally invasive interventional operations, and wide application prospects and potential are shown.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a nuclear magnetic guide wire for vascular intervention 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 signals from fluorine (19F) atoms. Because the amount of fluorine naturally present in the human body is extremely low, 19F-MRI is able to provide highly specific image contrast, especially when using fluorine-containing contrast agents.

[0003] During vascular interventional surgery, doctors need to know the position of guidewires 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 carries the risk of ionizing radiation and has low resolution for soft tissue. In contrast, MRI has the advantages of no radiation and high soft tissue contrast, but traditional guidewires cannot be visualized under MRI, limiting their application under MRI guidance.

[0004] Therefore, it is necessary to provide a nuclear magnetic 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 guide wire for vascular intervention surgery and a preparation method thereof.

[0006] To achieve the above object, the technical solution adopted by the present invention is: a nuclear magnetic guide wire for vascular intervention surgery, wherein the nuclear magnetic guide wire can be developed under 19F-MRI; 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 mutually 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.

[0007] In a preferred embodiment of the present invention, the core wire is made of carbon fiber, glass fiber, nickel-aluminum alloy, plastic or composite material.

[0008] 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.

[0009] A method for preparing a nuclear magnetic guidewire for vascular interventional surgery based on any of the above items 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 DMF solvent, stirring evenly, to obtain 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.

[0010] In a preferred embodiment of the present invention, 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.

[0011] In a preferred embodiment of the present invention, 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.

[0012] In a preferred embodiment of the present invention, the method for preparing the enzyme microcapsules 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.

[0013] In a preferred embodiment of the present invention, in S222, the mixing ratio of the esterase solution to the wall material is 1:3.2-3.6.

[0014] In a preferred embodiment of the present invention, the thickness of the developing film layer is 10-20 μm.

[0015] In a preferred embodiment of the present invention, in the developer film suspension, the mixing ratio of the fluorinated MOFs powder to the enzyme microcapsules is 3 to 5:1.

[0016] The present invention solves the defects existing in the background technology and has the following beneficial effects: (1) The present invention provides a nuclear magnetic guide wire for vascular interventional surgery and a preparation method thereof. The developing film layer can capture PFCs molecules in a complex biological system, generate 19F-MOFs nuclear magnetic resonance signals and 19F-enzyme nuclear magnetic resonance signals, and the two signals are interwoven to form a high-resolution image, which significantly improves the image contrast and detail presentation under 19F-MRI. The image contrast and resolution issues of nuclear magnetic guide wires developed under 19F-MRI are solved, providing more accurate image guidance for minimally invasive cardiovascular interventional surgery, showing broad application prospects and potential.

[0017] (2) The developing 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 fluorinated metal organic frameworks with good adsorption properties for PFCs, and the enzyme microcapsules release esterases at the required time to catalyze PFCs, so that PFCs react with surrounding molecules to generate products with different chemical shifts and generate new nuclear magnetic resonance signals. In the present invention, the fluorinated MOFs and the enzyme microcapsules are doped with each other to form a developing 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.

[0018] (3) The present invention provides enzyme microcapsules and preparation methods thereof, which can prepare microcapsules that 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 enzyme, but also enhances its application potential in complex medical environments, ensuring that the enzyme can activate and catalyze the chemical reaction of PFCs contrast agents under specific conditions to generate products with different chemical shifts, thereby improving the imaging effect of 19F-MRI. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative work. Figure 1 It is a flow chart of a method for preparing a nuclear magnetic guide wire according to a preferred embodiment of the present invention; Figure 2 This is a scanning electron microscope image of the developing film layer on the nuclear magnetic guide wire prepared in Example 1 of the present invention; Figure 3 is the 19F spectrum of the nuclear magnetic guide wire prepared in Example 1 of the present invention; Figure 4 is the 19F spectrum of the nuclear magnetic guide wire prepared in Example 2 of the present invention; Figure 5 is the 19F spectrum of the nuclear magnetic guide wire prepared in Example 3 of the present invention; Figure 6 is the 19F spectrum of the nuclear magnetic guide wire prepared in Comparative Example 1 of the present invention; Figure 7 This is the 19F spectrum of the nuclear magnetic guide wire prepared in Comparative Example 2 of the present invention; Figure 8 is the 19F spectrum of the nuclear magnetic guide wire prepared in Comparative Example 3 of the present invention; Fig. 9 It is the 19F spectrum of the nuclear magnetic guide wire prepared in Comparative Example 4 of the present invention. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0022] The present invention provides a nuclear magnetic guide wire for vascular interventional surgery, which can be developed under 19F-MRI. 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 19F-MRI through computer data processing and image reconstruction.

[0023] It is worth noting that, in actual applications, the PFCs contrast agent needs to be intravenously injected into the human body before it can be developed under MRI using the nuclear magnetic guide wire of the present invention.

[0024] Furthermore, the core wire is made of carbon fiber, glass fiber, nickel-aluminum alloy, plastic or composite material. The core wire made of such material can generate no artifacts or heat in a strong magnetic field, and has sufficient mechanical strength and flexibility, and can be used as an interventional guide wire in an MRI environment.

[0025] Furthermore, the coating layer is a polymer layer, and the polymer is one of polytetrafluoroethylene, polyurethane, nylon, polylactic acid or polyetheretherketone, and polytetrafluoroethylene is preferably used.

[0026] It is worth noting that the developing film layer is composed of fluorinated MOFs and enzyme microcapsules.

[0027] Among them, fluorinated MOFs are fluorinated metal organic frameworks that have good adsorption properties for PFCs. Specifically, MOF is a crystalline porous material with a periodic network structure, which has the characteristics of being porous and having a large specific surface area, providing more adsorption sites. Moreover, when the MOF material is fluorinated, the fluorinated functional groups have a good fluorine-fluorine interaction with PFCs, which greatly improves the material's adsorption performance for PFCs.

[0028] The enzyme microcapsule is composed of esterase and microcapsule wall material wrapped around the esterase. The microcapsule wall material guarantees the activity of the enzyme and ensures that the esterase is released at the required time, while the esterase catalyzes PFCs to promote their hydrolysis reaction, or causes PFCs to undergo addition or oxidation reaction with small molecules in plasma (such as H2O, amino acids), generating products with different chemical shifts and generating new nuclear magnetic resonance signals (i.e., 19F-enzyme nuclear magnetic resonance signals).

[0029] Since PFCs have similar molecular structures, their chemical shifts are usually small, resulting in signal overlap, which reduces the resolution and specificity of the image. The present invention generates new PFCs products by esterase catalysis near the nuclear magnetic guide wire, and these products have different chemical shifts, thereby increasing the difference between the signals. This allows each PFCs molecule or its derivative product to be distinguished in a wider spectrum range, improving the clarity and specificity of the image.

[0030] Furthermore, the fluorinated MOFs and enzyme microcapsules are doped with each other to form a developing film layer, which results in the 19F-MOFs nuclear magnetic resonance signal and the 19F-enzyme nuclear magnetic resonance signal under MRI being intertwined, and the image features are unique, further enhancing the specificity of the nuclear magnetic resonance signal.

[0031] like Figure 1 As shown, the present invention also provides a method for preparing a nuclear magnetic guide wire for vascular intervention surgery, comprising the following steps: S1. After wrapping a coating layer on the surface of the core wire, a nuclear magnetic guide wire to be processed is obtained.

[0032] S2. Prepare fluorinated MOFs powder and enzyme microcapsules respectively.

[0033] S3. Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent, stirring evenly, and obtaining a developing film layer suspension.

[0034] S4. The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and solidified at 30-50° C. to prepare the nuclear magnetic wire.

[0035] Through the above steps, a nuclear magnetic guide wire can be prepared which can capture PFCs molecules and then be visualized under MRI, and has broad application prospects in the field of image-guided minimally invasive interventional diagnosis and treatment.

[0036] In step S1, the specific steps of preparing the nuclear magnetic guide wire to be treated are: The coating layer is put on the outer surface of the core wire, and hot air is used to make the coating layer heat-shrinked and tightly wrapped on the surface of the core wire to obtain the nuclear magnetic guide wire to be processed.

[0037] In one embodiment, a carbon fiber composite material with an inner diameter of 0.8 mm is used as the core wire, and a polytetrafluoroethylene heat shrinkable tube is used as a coating layer to coat the surface of the carbon fiber composite material to prepare the nuclear magnetic guide wire to be processed.

[0038] It is worth noting that the carbon fiber composite material is specifically carbon fiber reinforced plastic wire, and the specific steps of wrapping the carbon fiber composite material with polytetrafluoroethylene heat shrink tube are: A polytetrafluoroethylene heat shrink tube (with an inner diameter of 0.9-1.2 mm before heat shrinkage) is put on the outer surface of a carbon fiber composite material with an inner diameter of 0.8 mm, and then hot air at 350-400°C is used to shrink the polytetrafluoroethylene heat shrink tube and tightly wrap it around the outer surface of the carbon fiber composite material to prepare a nuclear magnetic guide wire with an inner diameter of 0.9-0.95 mm to be treated.

[0039] Furthermore, the materials required for preparing the developing film layer are as follows: Non-magnetic metal ion source: Zn(NO3)2·6H2O; Organic ligand: 2,3,5,6-tetrafluoroterephthalic acid or 2,3,5,6-tetrafluoroterephthalonitrile; Solvent: DMF (N,N-dimethylformamide); Enzyme: Esterase; Wall material: polylactic acid (PLA), polycaprolactone (PCL), gelatin or chitosan; Cross-linking agent: glutaraldehyde; Protective agents: sucrose, glycerol.

[0040] The method for preparing the fluorinated MOFs powder in step S2 comprises the following steps: S211. Weigh a non-magnetic metal ion source and an organic ligand in a molar ratio of 3:1 to 2.5, and dissolve them separately in a DMF solvent by ultrasonication to ensure that they are fully dissolved.

[0041] S212, mixing the ligand solution with the metal ion solution and continuing the ultrasonic treatment, the purpose of which is to evenly disperse the non-magnetic metal ion source and the organic ligand in the solution.

[0042] S213, transferring the uniformly dispersed mixed solution to a reaction kettle, sealing it, placing it in an oven, and reacting it at 150° C. for 24 hours.

[0043] S214. After the reaction is completed, the reactor is taken out and cooled, and then the solid product is separated by centrifugation. Then, DMF, anhydrous ethanol and deionized water are used to wash repeatedly several times (at least three times) until no precipitation is produced by adding NaOH dropwise, ensuring that unreacted raw materials and by-products are removed.

[0044] S215, the washed product is placed in a vacuum drying oven and activated at 80° C. for 24 hours to ensure complete drying. The activated product is ground through a 200-mesh sieve to obtain a fluorinated MOFs powder.

[0045] The following experiments were conducted to verify the adsorption capacity of PFCs by fluorinated MOFs prepared with different ratios of metal ions and ligands.

[0046] Fluorinated MOFs powder samples were prepared using Zn(NO3)2·6H2O and 2,3,5,6-tetrafluoroterephthalic acid at different molar ratios of 4:1, 3:1, 3:1.5, 3:2.5, and 3:3.5, respectively. Below, they are named as samples 1, 2, 3, 4, and 5 in order.

[0047] 8.0 mg of fluorinated MOFs powder was weighed into a 50 mL centrifuge tube, 8.0 mL of 10 mg / L PFCs aqueous solution was added, and a certain amount of NaCl solution was added to make its concentration 0.01 mol / L, the volume was fixed, and the suspension was oscillated at 250 rpm in a constant temperature oscillator for adsorption for a certain time. The suspension was centrifuged at 10000 rpm for 5 min, filtered with a filter head, and the residual PFCs concentration in the filtrate was analyzed by improved UV-visible spectrophotometry, and the adsorption amount of fluorinated MOFs on PFCs at adsorption equilibrium was calculated. The results are shown in Table 1.

[0048] Table 1 Adsorption performance of samples with different proportions on PFCs

[0049] As shown in Table 1, when the amount of ligand 2,3,5,6-tetrafluoroterephthalic acid increases, the adsorption of PFCs by fluorinated MOFs also increases. When the ratio of metal ions to ligands is 3:2.5, the material has the maximum adsorption capacity, indicating that the strength of the fluorine-philic effect caused by the amount of fluorine introduced is different. However, in sample 5 (the ratio reaches 3:3.5), the adsorption capacity decreases instead of increases, because the adsorption sites provided by MOF have reached the upper limit. If the fluorine content is introduced too much, 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 to 2.5 is preferred.

[0050] The method for preparing the enzyme microcapsules in step S2 comprises the following steps: S221. Dissolve the 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.

[0051] S222. The esterase solution and the wall material are mixed in a ratio of 1:3.2-3.6, stirred evenly to obtain an aqueous phase, and the pH value of the aqueous phase is adjusted to 6.5-7.5 to ensure optimal encapsulation conditions.

[0052] S223. Add an emulsifier to the mineral oil and stir evenly to obtain an oil phase; wherein the emulsifier is 2% (v / v) Span80.

[0053] S224. Slowly add the prepared water phase into the oil phase, and stir with a high-speed stirrer at a stirring rate of 10,000 rpm / min for 10 min to form a uniform and stable W / O emulsion.

[0054] S225. Slowly add a cross-linking agent to the emulsion and continue stirring at room temperature for 20-30 minutes to generate enzyme microcapsules; wherein the cross-linking agent is 1% (v / v) glutaraldehyde, and the diameter of the enzyme microcapsules is controlled within the range of 2-5 μm.

[0055] S226. Centrifuge the emulsion after the reaction, collect the enzyme microcapsules precipitated at the bottom, and wash them repeatedly with deionized water several times (at least three times) to remove unreacted cross-linking agent and other impurities, thereby obtaining enzyme microcapsules with a diameter of 2-5 μm.

[0056] Through the above steps, enzyme microcapsules are prepared to ensure the stability of the microcapsules at high temperatures and to effectively release the enzyme under specific conditions. This 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 activate and catalyze the chemical reaction of the PFCs contrast agent under specific conditions to generate products with different chemical shifts, thereby improving the imaging effect of 19F-MRI.

[0057] The following experiments were conducted to verify the stability and degradation performance of enzyme microcapsules prepared with different ratios of esterase solution and wall materials and different wall materials.

[0058] The esterase solution was mixed with chitosan and gelatin at a ratio of 1:2, 1:2.8, 1:3.2, 1:3.6, and 1:4.2 to prepare the aqueous phase, and then the enzyme microcapsule samples were prepared, which were named samples 1-10 in sequence.

[0059] Stability test: The prepared enzyme microcapsule sample was placed at 20°C, and the temperature was raised by 2°C every 3 minutes to a maximum of 60°C. The morphological changes of the enzyme microcapsule sample were observed, and the temperature at which the changes occurred was recorded.

[0060] Degradation performance test: Weigh 0.8 mg of enzyme microcapsule sample into a 50 mL centrifuge tube, add 9 mL of plasma and 1 mL of 10 mg / L PFCs aqueous solution, maintain the plasma temperature at 37°C, let it stand for 30 seconds, then centrifuge and filter, and use a scanning electron microscope to observe changes on the microcapsule surface, especially cracks and holes.

[0061] The following are the stability and degradation performance test results, see Table 2.

[0062] Table 2 Stability and degradation performance

[0063] In Table 2, stability (℃): indicates the highest temperature at which the enzyme microcapsules maintain their shape during the heating process. The higher the temperature, the better the thermal stability of the microcapsules. And the degree of degradation / rupture of the microcapsule wall material (%): indicates the degree of cracks or holes on the surface of the microcapsules in the degradation performance test. The lower the percentage, the more complete the structure of the microcapsules and the slower the degradation.

[0064] As can be seen from Table 2, only samples 3, 4, 5, 9 and 10 have a stability temperature exceeding 50°C, that is, only these samples can ensure that the microcapsule wall material does not break during the drying and curing process in step S4, and can ensure the stability of the esterase. Among these 5 batches of samples, only samples 3, 4 and 9 have a degradation or rupture degree within 10% to 20% in the degradation performance test, that is, in the initial degradation process, the esterase is gradually exposed. In summary, 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 controllable release under specific conditions. Microcapsules within this ratio range can begin to degrade or break after entering the blood environment or contacting PFCs for 20 to 30 seconds, leaving sufficient time to guide the nuclear magnetic guide wire to the specified position, avoiding premature release of esterase, resulting in insufficient development enhancement time, and unable to accurately locate the nuclear magnetic guide wire.

[0065] Through the above detailed steps and parameter settings, microcapsules that can remain stable at 30-50°C and can degrade or rupture to release enzymes after entering blood vessels or contacting PFCs molecules can be successfully prepared. 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 activate and catalyze the chemical reaction of PFCs contrast agents under specific conditions to generate products with different chemical shifts, thereby improving the effect of 19F-MRI imaging.

[0066] In step S3, in the developing film layer suspension, the mixing ratio of the fluorinated MOFs powder and the enzyme microcapsules is 3 to 5:1.

[0067] The coating method in step S4 adopts a dipping method or a spraying method, and adopts a multiple drying and coating method to ensure that a dense developing film layer is formed on the coating layer, and the thickness of the developing film layer is 10-20 μm.

[0068] In order to verify the influence of different mixing ratios of fluorinated MOFs powder and enzyme microcapsules on the 19F-MRI development effect of nuclear magnetic guide wire, the following examples and comparative examples were made.

[0069] Embodiment 1:

[0070] 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrinkable tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0071] 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.

[0072] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0073] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 3:1, stirring evenly, and obtaining a developing film suspension.

[0074] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0075] Figure 2 This is a scanning electron microscope image of the developing film layer on the nuclear magnetic guide wire prepared in this example. It can be seen from the image that the fluorinated MOFs and enzyme microcapsules are accumulated on the coating layer to form a densely connected developing film layer.

[0076] The 19F-MRI imaging effect of the nuclear magnetic guide wire prepared in this embodiment after intravenous injection of PFCs contrast agent was tested as follows: Experimental equipment conditions: MRI scanner: A 7 Tesla Bruker Avance III HD MRI system (Bruker, Germany) equipped with high-resolution gradient coils was used.

[0077] RF coil: Dual resonance probe (19F and 1H) for simultaneous detection of PFCs and water signals.

[0078] Contrast agent: Commercially available perfluorooctanoic acid (PFOA) was prepared into a 10 mg / L solution.

[0079] Experimental animals: Healthy mice were used as models.

[0080] Experimental steps: The mice were anesthetized with isoflurane gas and fixed on the MRI scanner bed. 100 μL of PFCs contrast agent (10 mg / L) was slowly injected through the tail vein, and the injection time point was recorded.

[0081] The nuclear magnetic guide wire prepared in Example 1 was slowly inserted into the vascular system of the mouse.

[0082] Scanning parameter settings: magnetic field strength of 7 Tesla, RF pulse frequency of 282 MHz, gradient echo (GRE) sequence to obtain high-resolution images, scanning for 5 minutes at each time point, and scanning before injection, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after injection.

[0083] like Figure 3 As shown, in the 19F spectrum scanned in Example 1, three significant signals are displayed: The chemical shift δ = 168.64 ppm corresponds to the untrapped PFCs molecules.

[0084] The chemical shift δ = 75.2 ppm corresponds to the PFCs molecules captured by the fluorinated MOFs in the developed film layer. This signal indicates that the developed film layer successfully captured the PFCs molecules and produced a unique NMR signal.

[0085] The chemical shift δ=88.3ppm corresponds to the esterase in the developed film layer catalyzing the generation of new PFCs molecules, which produces a unique NMR signal.

[0086] The two intertwined NMR signals are significantly different from other free PFCs NMR signals, and there are also differences between the 19F-MOFs NMR signal and the 19F-enzyme NMR signal, and the differences are lower than those between the two and the free PFCs NMR signal, which improves the clarity and specificity of the image.

[0087] Embodiment 2:

[0088] 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrinkable tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0089] 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.

[0090] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0091] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 4:1, stirring evenly, and obtaining a developing film suspension.

[0092] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0093] Embodiment 3:

[0094] 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrink tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0095] 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.

[0096] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0097] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 5:1, stirring evenly, and obtaining a developing film suspension.

[0098] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0099] Comparative Example 1: 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrink tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0100] 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.

[0101] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0102] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in a DMF solvent in a ratio of 1:1, stirring evenly, and obtaining a developing film suspension.

[0103] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0104] Comparative Example 2: 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrinkable tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0105] 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.

[0106] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0107] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 2:1, stirring evenly, and obtaining a developing film suspension.

[0108] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0109] Comparative Example 3: 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrinkable tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0110] 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.

[0111] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0112] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 6:1, stirring evenly, and obtaining a developing film suspension.

[0113] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0114] Comparative Example 4: 1) A carbon fiber composite material with an inner diameter of 0.8 mm was used as the core wire and a polytetrafluoroethylene heat shrinkable tube was used as a coating layer to coat the surface of the carbon fiber composite material to obtain a nuclear magnetic guide wire with an inner diameter of 0.95 mm to be processed.

[0115] 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.

[0116] 3) The esterase solution and chitosan in a ratio of 1:3.6 are mixed to prepare an aqueous phase, and the pH value is adjusted to 7 to prepare enzyme microcapsules with a diameter of 2-5 μm.

[0117] 4) Dispersing the prepared fluorinated MOFs powder and enzyme microcapsules in DMF solvent at a ratio of 7:1, stirring evenly, and obtaining a developing film suspension.

[0118] 5) The developing film layer suspension is evenly coated on the surface of the nuclear magnetic wire to be treated, and then dried and cured at 45°C for 20 hours to prepare the nuclear magnetic wire. The average thickness of the developing film layer of the nuclear magnetic wire is 15 μm.

[0119] The development effect of the nuclear magnetic guide wire samples prepared in the above-mentioned Examples 1-3 and Comparative Examples 1-4 was verified below.

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

[0121] RF coil: Dual resonance probe (19F and 1H) for simultaneous detection of PFCs and water signals.

[0122] Contrast agent: Commercially available perfluorooctanoic acid (PFOA) was prepared into a 10 mg / L solution.

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

[0124] Experimental steps: The mice were anesthetized with isoflurane gas and fixed on the MRI scanner bed. 100 μL of PFCs contrast agent (10 mg / L) was slowly injected through the tail vein, and the injection time point was recorded.

[0125] The nuclear magnetic guidewires prepared in Examples 1-3 and Comparative Examples 1-4 were slowly inserted into the vascular system of mice.

[0126] Scanning parameter settings: 7 Tesla magnetic field strength, RF pulse frequency of 282 MHz, gradient echo (GRE) sequence to obtain high-resolution images, scanning for 5 minutes at each time point, scanning before injection, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after injection, respectively. The obtained 19F spectrum is as follows Figures 3 to 9As shown, after computer data processing and image reconstruction, the development of the nuclear magnetic guide wire under MRI is obtained to judge the difficulty of image resolution. The results are shown in Table 3 below.

[0127] Table 3 Nuclear magnetic wire development effect

[0128] As shown in Table 3, as the proportion of enzyme microcapsules in the developing film increases, the degree of interweaving of the two NMR signals at the NMR guide wire becomes more complex, which increases the specificity of the NMR signal, that is, improves the spatial resolution. However, when the proportion of enzyme microcapsules exceeds one-quarter, there are not enough fluorinated MOFs to adsorb free PFCs, which results in only a part of the enzyme on the surface of the fluorinated MOFs playing a role, and it is impossible to present an image of interwoven signals under MRI, with low contrast and difficult to distinguish. Conversely, as the proportion of fluorinated MOFs increases, more PFCs can be adsorbed, and the 19F-MOFs NMR signal is enhanced, but the 19F-enzyme NMR signal is low and blocked, and it is also impossible to present an image of interwoven signals under MRI, with low contrast and difficult to distinguish. Therefore, the present invention selects a mixing ratio of fluorinated MOFs powder and enzyme microcapsules of 3 to 5:1 to prepare a developing film layer. At this time, the molecular weight of PCFs adsorbed by the developing film layer is sufficient, and the degree of interweaving of the two nuclear magnetic resonance signals is complex enough, which solves the problem of developing nuclear magnetic guide wires under 19F-MRI and has broad application prospects.

[0129] The above is based on the ideal embodiment of the present invention. Through the above description, relevant personnel can make various changes and modifications without departing from the technical concept 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 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 mutually 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.

2. 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. 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. A method for preparing a nuclear magnetic guidewire for vascular intervention surgery based on any one of claims 1 to 3, characterized in that: The following steps are involved: 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 DMF solvent, stirring evenly, to obtain 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.

5. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 4, 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.

6. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 5, 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.

7. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 4, 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.

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

6.

9. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 7, characterized in that: The thickness of the developing film layer is 10-20 μm.

10. The method for preparing a nuclear magnetic guidewire for vascular interventional surgery according to claim 4, characterized in that: In the developing film layer suspension, the mixing ratio of the fluorinated MOFs powder and the enzyme microcapsules is 1 to 2:1.

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