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WO2018137633A1 - Matériau embolique liquide et procédé de préparation associé - Google Patents

Matériau embolique liquide et procédé de préparation associé Download PDF

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WO2018137633A1
WO2018137633A1 PCT/CN2018/073903 CN2018073903W WO2018137633A1 WO 2018137633 A1 WO2018137633 A1 WO 2018137633A1 CN 2018073903 W CN2018073903 W CN 2018073903W WO 2018137633 A1 WO2018137633 A1 WO 2018137633A1
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agarose
nanoparticles
embolic material
coated
liquid embolic
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Chinese (zh)
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刘奕辰
邱海平
向建平
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珠海神平医疗科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the invention relates to a liquid embolic material and a preparation method thereof.
  • Arteriovenous malformation is a genetic variation in the congenital local cerebral blood vessels. There is a lack of capillaries between the cerebral artery and the cerebral vein in the lesion, causing the arteries and veins to communicate directly, forming a short circuit between the arteries and veins, resulting in a series of cerebral hemodynamic disorders. Clinically, acute brain and arteriovenous may cause intracranial hemorrhage, which is also the second leading cause of spontaneous subarachnoid hemorrhage in the brain. Hemangiomas are formed in arteriovenous vessels due to internal and external factors such as mechanical damage, vascular sclerosis, hypertension, proliferation of vascular smooth muscle cells, bacterial or viral infection, induction of venous valve disease, or blood flow impact.
  • Cerebral aneurysms are the leading cause of subarachnoid hemorrhage, leading to stroke in patients.
  • the incidence of cerebral arteriovenous malformation is about 1/7 to 1/4 of that of cerebral aneurysms, twice as many as males, and the peak age is 20 to 39 years old.
  • the average age is 25 years old.
  • the mortality caused by rupture of cerebral aneurysms is above 50%. Therefore, embolization or occlusion at the earliest stage of the occurrence of cerebral aneurysms is one of the best cures.
  • Treatment of cerebral aneurysms and AVM can be treated with surgery and intervention.
  • Surgical treatment of aneurysms mainly uses an aneurysm clip to clamp the aneurysm neck, thereby blocking the circulation of blood in the aneurysm.
  • the AVM can perform a total resection of the surgery.
  • this method of surgery takes a long time, the wound is large, the patient needs to recover for a long time, and the surgical treatment method may cause damage of the aneurysm and AVM.
  • embolization has gradually replaced the traditional surgery.
  • embolic materials have been disclosed, mainly divided into solid embolic materials and liquid embolic materials.
  • the solid material is mainly a platinum coil.
  • the method of using a platinum coil has a low embolic rate, is prone to recurrence, and may even form a wide range of thrombus and cause problems such as cerebral infarction.
  • the liquid embolic material can be directly injected into the aneurysm cavity or into the AVM to adapt to different shapes and sizes, so that no gap is left between the tumor wall and the embedding material, thereby achieving permanent occlusion.
  • the liquid embolic material has the advantage of being easy to operate, and can be directly injected into the aneurysm cavity or the AVM through the microcatheter, so the liquid embolic material is an ideal embolic material.
  • the prior art liquid embolic material comprises: (1) an adhesive liquid embolic material n-butyl cyanoacrylate viscous material, which has the disadvantage that "sticky tube” is prone to occur; (2) non-adhesive liquid embolic material, mainly Onyx gel, a suspension composed of EVOH, DMSO (dimethyl sulfoxide) and strontium powder particles in a certain proportion, is a novel intravascular non-adhesive liquid embolic agent, etc., and its disadvantages include the properties of the onyx gel itself. It does not bind closely to the diseased vessel wall. And both types of materials are not well embolized for microvascular aneurysms and vascular malformations that are difficult to fully fit in complex microcatheters.
  • the embolic material in CN103536972B is selected from ethylene vinyl polymer copolymer (EVOH), which has the disadvantage that the release process of the embolic material is uncontrollable.
  • CN106535942A discloses a homogeneous nanocomposite cluster suspended in a liquid medium having a size of from about 1 nm to about 1000 nm, the nanocomposite comprising core nanoparticles and a coating, the core nanoparticles being superparamagnetically oxidized Iron (SPIO) nanoparticles, the coating is a silanized coating, which has the disadvantage that the suspension has a short settling time, resulting in a shorter operating time window.
  • SPIO superparamagnetically oxidized Iron
  • the prior art CN103483626B also discloses a magnetic agarose microsphere which uses superparamagnetic Fe 3 O 4 as the core of the magnetic core, and then fills the magnetic core into the agarose microsphere to obtain magnetic agarose microspheres, magnetic agar.
  • the sugar microspheres have good biocompatibility, and the disadvantage is that the agarose is easily decomposed in the human blood environment, resulting in the release of iron ions and causing ectopic embolization.
  • the liquid embolic material is easy to stick or is not well adhered to the diseased blood vessel wall, so that the microvascular aneurysm and the vascular malformation which are difficult to fully embed in the complicated microcatheter are not well embedd.
  • the invention provides a liquid embolic material and a preparation method thereof, which can embolize microvascular aneurysms and vascular malformations.
  • one of the technical solutions adopted by the present invention is a liquid embolic material comprising nano composite particles and a dispersing agent, wherein the nano composite particles are agarose-coated Fe 3 O 4 nanoparticles as a core.
  • the EVOH polymer is coated on the surface of the core to form a shell; the weight ratio of the agarose to the Fe 3 O 4 nanoparticles is 5:1 to 10:1; the agarose-coated Fe 3 O 4 nanoparticles and the The weight ratio of the EVOH polymer is from 25:2 to 25:5; the nanocomposite particles are dispersed in the dispersant.
  • the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 100 to 1000 nm; the nanocomposite particles have a viscosity of 30 to 1000 cps; and the polydispersity index of the Fe 3 O 4 nanoparticles (PDI) ⁇ 1.2; and/or the dispersing agent is dimethyl sulfoxide.
  • the weight ratio of the agarose to the Fe 3 O 4 nanoparticles is 10:1; and/or the weight of the agarose-coated Fe 3 O 4 nanoparticles and the EVOH polymer The ratio is 10:1.
  • the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 300 nm; the nanocomposite particles have a viscosity of 100 cps; and/or the PDI is 1.12.
  • the magnetic substance or a magnetic metallic element may be selected from compounds such as Fe 2 O 3, MnFe 2 O 4, CoFe 2 O 4, NiFe 2 O 4, FyFe 2 O 4 or one or more of oxides of ruthenium, osmium, iridium, osmium, iridium, osmium or iridium.
  • Arteriovenous malformation refers to a group of diseases in which at least one abnormal communication occurs in an artery or vein, resulting in a local tumor-like substance consisting mainly of blood vessels, which may be congenital or acquired. Sexual.
  • Formation of an embolic body refers to the partial or total occlusion of blood vessels that are filled with blood, such as by selective insertion of an embolic material into a blood vessel to selectively occlude a blood vessel.
  • an embolization is formed to occlude an artery or vein to correct a dysfunction such as an arteriovenous malformation or to block or slow the flow of blood to a solid tumor.
  • injection refers to the injection or infusion of a liquid embolic material into a particular location in the body by a syringe, catheter, needle or other means.
  • Treatment refers to reducing or ameliorating the development, severity, and/or duration of a disease or condition thereof.
  • the liquid embolic material used herein can be any shape, and in embodiments, the liquid embolic material is substantially spherical or spherical. However, it should be understood that in certain embodiments, the liquid embolic material described herein is not limited to a precise spherical or spheroidal shape.
  • the liquid embolic material can be sterilized by any method known in the art, such as X-ray, gamma ray irradiation or beta ray irradiation.
  • one of the technical solutions adopted by the present invention is a method for preparing the above liquid embolic material, which comprises the following steps in sequence:
  • nano composite particles wherein the nano composite particles are further composed of EVOH and further coated with agarose-coated Fe 3 O 4 nanoparticles;
  • the step (1) further comprises:
  • the reaction is carried out at a temperature of 2 to 3 atm and 200 ° C, and after the reaction, it is cooled to obtain a black product; preferably, the reaction is carried out in a polytetrafluoroethylene autoclave.
  • said step (1) further comprises: washing said black product and drying to obtain a black powder.
  • the washing is alternately washed with ethanol and water for 2 to 5 times; and/or, the drying is vacuum drying.
  • said step (2) comprises:
  • the agitation is mechanical agitation
  • the mechanical agitation time is at least 2 hours; and/or the agitation speed is 400 to 500 rpm.
  • the agitation speed is 450 rpm.
  • one of the technical solutions adopted by the present invention is the application of a liquid embolic material in preparing a drug or molecular imaging reagent for diagnosing and treating tumor or vascular malformation.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progressive effect of the present invention is that the liquid embolic material of the present invention is injected into the aneurysm cavity or the arteriovenous vascular malformation, and after being guided to a specific site by the magnetic device, the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent into the blood. Thereby forming a plug body.
  • the core-shell structure in the liquid embolic material greatly increases the density of the embolic body, thereby increasing the development efficiency and making the embolization more dense.
  • the liquid embolic material can be targeted by the external magnetic field, and the complex microvascular artery which is difficult to fully fit the microcatheter is well embedd. Tumors and complex vascular malformations.
  • 1 is a schematic view showing the structure of a nanocomposite particle according to an embodiment of the present invention, wherein 1 is a nanocomposite particle, 11 is agarose-coated Fe 3 O 4 nanoparticle, and shell 12 is an EVOH polymer.
  • Example 2 is a flow chart showing the preparation of agarose-coated Fe 3 O 4 nanoparticles according to Example 1 of the present invention.
  • Figure 3 is a flow chart showing the preparation of the liquid embolic material of Example 2 of the present invention.
  • FIG. 4 is a schematic view showing the operation of embedding a liquid embolic material in an AVM according to Embodiment 2 of the present invention, wherein 100 is a plug material, 110 is a microcatheter, and 120 is an external magnetic field.
  • Figure 5 is a flow chart showing the preparation of a liquid embolic material according to Embodiment 3 of the present invention.
  • FIG. 6 is a schematic view showing the operation of embolization of a liquid embolization material in a cerebral aneurysm according to Embodiment 3 of the present invention, wherein 200 is an embolic material, 210 is a microcatheter, 220 is an external magnetic field, 230 is a blood vessel, and 240 is a brain aneurysm.
  • the liquid embedding material provided by the invention comprises agarose-coated Fe 3 O 4 nanoparticles, an ethylene/vinyl alcohol copolymer (EVOH) polymer and a dispersing agent, and the EVOH polymer is wrapped in agarose-coated Fe.
  • the surface of the 3 O 4 nanoparticles forms nanocomposite particles.
  • the nanocomposite particles are agarose-coated Fe 3 O 4 nanoparticles as the core and the EVOH polymer as the shell, and the nanocomposite particles are dispersed in the dispersant.
  • Dimethyl sulfoxide can be used as a dispersing agent.
  • Fig. 1 is a schematic view showing the structure of a nanocomposite particle 1 comprising a core 11 and a shell 12, wherein the core 11 is composed of agarose-coated Fe 3 O 4 nanoparticles, and the shell 12 is composed of an EVOH polymer.
  • FIG. 2 is a flow chart for the preparation of agarose-coated Fe 3 O 4 nanoparticles.
  • step S1 is performed, 400 g of FeCl 3 ⁇ 6H 2 O is dissolved in a glass reaction bottle containing 2 L of ethylene glycol under ultrasonic conditions; then, step S2 is performed, and 40 g is added thereto at a temperature of 160 ° C.
  • step S3 Agarose and 200 g of NH 4 Ac were mechanically stirred at 250 rpm for 1 hour to obtain a mixed solution; then, step S3 was performed, and the mixed solution was transferred to an autoclave containing polytetrafluoroethylene; step S4 was further performed at 2 atm to 3atm (standard atmospheric pressure), reaction at 200 ° C for 12 hours; after the reaction, cooled to room temperature to obtain a black product; then step S5 is performed, the black product is repeatedly and alternately washed with ethanol and water several times, and then collected by a magnetic field.
  • step S6 is performed, and the collected black product is dried in a vacuum for 24 hours to obtain a black powder composed of agarose-coated Fe 3 O 4 nanoparticles, agarose-coated Fe 3 O 4 nanometer.
  • the particle diameter of the particles ranges from 100 nanometers to 1000 nanometers.
  • the PDI is made less than 1.2 by the above conventional control and preparation processes in the art such as temperature, time and stirring uniformity.
  • Example 2 EVOH-coated agarose Fe 3 O 4 nanoparticles (weight ratio 25:2)
  • FIG. 3 is a flow chart for the preparation of a liquid embolic material.
  • step S11 is performed, 100 g of the black powder of Example 1 and 8 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S12 is performed, and mechanical stirring is performed at 500 rpm for 2 hours.
  • a liquid embolic material is obtained, which contains a large amount of nanocomposite particles in which agarose-coated Fe 3 O 4 nanoparticles are cores and EVOH polymers are shells.
  • the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 100 nm, and the liquid embolic material has a low viscosity and a viscosity value of about 30 centipoise.
  • Embolization density 1.5-2.0g/ml, data fluctuations are due to changes in formulation and batch;
  • Embolization time 60 to 90 seconds
  • Diffuse Simulates the use of embolic material in the clinic, testing the ratio of forward and backward reflux in a small vessel model filled with a small sphere of 500 micrometers in diameter. This product is 5 times the safety limit distance of reflux, and the existing clinical embedding material, namely EVOH-coated Ta nanoparticles, is 2.3 times the safety limit distance of reflux.
  • Fig. 4 is a working principle diagram of embedding of the liquid embolic material in the AVM of the present embodiment.
  • the experimental means used in the evaluation of the effect is a conventional technique in the art.
  • the liquid embolic material 100 after the liquid embolic material 100 is injected into the arterial blood vessel of the AVM 100 through the microcatheter 110, the liquid embolic material 100 has a low viscosity and a strong penetrating ability, and is externally Under the guidance of the magnetic field 120, it is easily dispersed to the distal end by targeted positioning, and the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent in the blood to form an embolic body, which is well embolized.
  • Example 3 EVOH-coated agarose Fe 3 O 4 nanoparticles (weight ratio 25:5)
  • the agarose-coated Fe 3 O 4 nanoparticles were prepared in the same manner as in Example 1 except that 80 g of agarose was added to the reaction.
  • Fig. 5 is a flow chart for preparing a liquid embolic material of the present embodiment.
  • step S21 is performed, 100 g of the obtained black powder and 20 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at 400 rpm for 2 hours to obtain a liquid.
  • the embolic material contains a large amount of nano-composite particles in which agarose-coated Fe 3 O 4 nanoparticles are cores and EVOH polymers are shells.
  • the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 1000 nm.
  • the liquid embolic material has a high viscosity, a viscosity of 1000 centipoise and a PDI of 1.18.
  • Fig. 6 is a working principle diagram of embolization of the liquid embolic material in the cerebral aneurysm of the present embodiment.
  • the liquid embolic material (200) is injected into the position of the mouse brain aneurysm (240) from the blood vessel 230 through the microcatheter 210, and the liquid embolic material (200) can be cistern under the guidance of the external magnetic field (220).
  • the wall of the aneurysm is solidified.
  • the liquid embolic material (200) of the present embodiment has high viscosity and can achieve the purpose of reducing dead space as much as possible, and thus is particularly suitable for use in an embolization material for irregular brain aneurysms.
  • the embolization time and embolization rate were calculated based on the computer MITK (Medical Imaging Interaction Toolkit), that is, the CT embedding rate was calculated by CT three-dimensional reconstruction and then based on the three-dimensional reconstruction model.
  • MITK Medical Imaging Interaction Toolkit
  • Embolization time 30 seconds to 90 seconds (existing product embolization time: 30 seconds - 2 minutes);
  • Embolization rate vascular closure rate of 70% (about 50% of existing products);
  • Magnetic guide 10-20G, visible magnetically guided material movement under development
  • Toxicity No significant toxic substances; the control group was based on DMSO and had some toxicity, but there was no significant difference.
  • Example 4 EVOH-coated agarose Fe 3 O 4 nanoparticles (weight ratio 25:2.5)
  • the agarose-coated Fe 3 O 4 nanoparticles were prepared in the same manner as in Example 1. First, step S21 is performed, 100 g of the black powder of Example 1 and 10 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at a speed of 450 rpm. Two hours, a liquid embolic material was obtained, which contained a large amount of nanocomposite particles in which agarose-coated Fe 3 O 4 nanoparticles were core and EVOH polymer was a shell. The agarose-coated Fe 3 O 4 nanoparticles have a diameter of 300 nm.
  • the liquid embolic material has a high viscosity, a viscosity of 100 centipoise and a PDI of 1.12.
  • the liquid embolic material is injected into the cerebral aneurysm from the blood vessel through the microcatheter, and the liquid embolic material can be solidified along the wall of the cerebral aneurysm under the guidance of the external magnetic field.
  • Embolization time and embolization rate are automatically calculated based on computer simulation.
  • Embolization time 60 seconds to 90 seconds
  • Embolization density 2.0g/ml
  • Embolization rate vascular closure rate of 75%
  • Magnetic guide 10-20G, visible magnetically guided material movement under development
  • Toxicity No significant toxic substances; the control group was based on DMSO and had some toxicity, but there was no significant difference.
  • the content of the vinyl group in the EVOH polymer was 60% by mol.
  • the agarose-coated Fe 3 O 4 nanoparticles interact with each other through hydrogen bonding, and further hydrogen bonds with the EVOH polymer to finally obtain agarose-coated Fe 3 O 4 nanoparticles as a core to EVOH polymer.
  • the nanocomposite particle of the shell the nanocomposite particle is discretely distributed in a dimethyl sulfoxide solvent, and a hydrogen bond combined with a micelle formed by a self-assembly method, which is a self-reinforced rubber-like composite embolic material.
  • Example 2 The procedure was the same as in Example 1 except that FeCl 3 ⁇ 6H 2 O in S1 was replaced by FeSO 4 to obtain a yellow-brown powder.
  • step S21 is performed, and 100 g of the yellow-brown color powder and 10 g of the EVOH polymer in step 1 are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at 450 rpm for 2 hours.
  • a control embedding material is obtained, which contains a large amount of nano-composite particles in which agarose-coated FeSO 4 nanoparticles are core and EVOH polymer is shell.
  • the agarose-coated FeSO 4 nanoparticles have a diameter of 200 nm and the liquid embolic material has a viscosity of 100 cps and a PDI of 1.15.
  • the liquid embolic material after the liquid embolic material is injected into the arterial blood vessel of the AVM through the microcatheter, the liquid embolic material has low viscosity and strong penetrating ability, but the polymer does not contain Fe 3 O 4 nanoparticles and cannot be outside. Targeted by a magnetic field. After the liquid embolic material is injected into the cerebral aneurysm from the blood vessel through the microcatheter, the liquid embolic material cannot be solidified by the wall of the cerebral aneurysm under the guidance of the external magnetic field.
  • the present invention also attempts to prepare agarose-free Fe 3 O 4 nanoparticles as a comparative example. It has been found experimentally that if agarose is not contained, Fe 3 O 4 particles cannot be stabilized in solution, and the suspension stability time is very short. .
  • the invention prepares Fe 3 O 4 nanoparticles without EVOH as a comparative example, and found that if EVOH is not contained, it will cause ectopic embolism caused by direct contact of iron particles with blood after agarose degradation as in the prior art. .
  • Agarose different weight ratios of the present invention is prepared wrapped Fe 3 O 4 nanoparticles, agarose, and when the weight Fe 3 O 4 nanoparticles ratio is ⁇ 5: 1, not completely wrapped agarose Fe 3 O 4 nanoparticles This causes the Fe 3 O 4 nanoparticles to diffuse in the suspension to a location that should not be reached.
  • the weight ratio of the agarose to the Fe 3 O 4 nanoparticles is >10:1, the developability of the suspension is insufficient, which is not clinically applicable.
  • the present invention also prepared agarose-coated Fe 3 O 4 nanoparticles and EVOH polymers in different weight ratios.
  • the weight ratio of the agarose-coated Fe 3 O 4 nanoparticles to the EVOH polymer is >25:2, the EVOH concentration is too low, resulting in insufficient embolization effect.
  • the weight ratio of the agarose-coated Fe 3 O 4 nanoparticles to the EVOH polymer is ⁇ 25:5, the developability of the suspension is insufficient, which is not clinically applicable.
  • the invention prepares Fe 3 O 4 nanoparticles with different PDI.
  • the PDI is greater than 1.2, the size difference of the agarose-encapsulated Fe 3 O 4 nanoparticles is significant, resulting in a large difference in the sedimentation speed of the particles in the suspension, and the suspension is stable. Slightly lower than the nanoparticles with PDI ⁇ 1.2.
  • the viscosity of the nanocomposite particles is ⁇ 30 cP
  • the dispersion of the composite particles is too strong, and in a few cases, ectopic embolization in the clinic is caused.
  • the viscosity of the nanocomposite particles is >1000 cP
  • the dispersion of the composite particles is too poor, and in a few cases, the clogging of the injection route in the clinic is caused.
  • the dispersion of the composite particles is too strong, and in a few cases, it may cause ectopic embolization in the clinic.
  • the diameter of the nanocomposite particles is >1000 nm, the dispersion of the composite particles is too poor, and in a few cases, the clogging of the injection channel in the clinic is caused.
  • the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent in the blood to form an embolic body.
  • the core-shell structure in the liquid embolic material greatly increases the density of the embolic body, thereby increasing the development efficiency and making the embolization more dense.
  • the liquid embolic material can be targeted by the external magnetic field, and the complex microvascular artery which is difficult to fully fit the microcatheter is well embedd. Tumors and complex vascular malformations.

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Abstract

La présente invention concerne un matériau embolique liquide et un procédé de préparation associé et l'utilisation de celui-ci. Le matériau embolique liquide comprend des particules nanocomposites (1) et un dispersant, les particules nanocomposites étant constituées de nanoparticules de Fe3O4 (11) enveloppées dans de l'agarose en tant que noyau, et un polymère EVOH (12) enroulé autour de la surface du noyau; le rapport en poids de l'agarose et des nanoparticules de Fe3O4 est de 5 : 1 à 10 : 1; le rapport en poids des nanoparticules de Fe3O4 (11) enveloppées dans de l'agarose au polymère EVOH (12) est de 25 : 2 à 25 : 5; et les particules nanocomposites sont dispersées dans le dispersant. L'invention concerne également un procédé de préparation du matériau embolique liquide. A l'aide de l'effet superparamagnétique des nanoparticules de Fe3O4, sous le guidage d'un champ magnétique externe, par le biais d'une localisation de ciblage, le matériau embolique liquide peut complètement emboliser un anévrisme microvasculaire complexe et des malformations vasculaires complexes où il est difficile pour un microcathéter d'être complètement en place.
PCT/CN2018/073903 2017-01-24 2018-01-24 Matériau embolique liquide et procédé de préparation associé WO2018137633A1 (fr)

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CN114617971A (zh) * 2020-12-11 2022-06-14 上海交通大学医学院附属第九人民医院 磁性载药微球的用途及相关产品
CN117752846A (zh) * 2023-12-13 2024-03-26 中国科学院深圳先进技术研究院 一种可磁控液体栓塞机器人及磁控栓塞系统

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