WO2022203290A1 - Développement de procédé d'injection intravasculaire de substance magnétique pour induction de vasodilatation et son utilisation - Google Patents

Développement de procédé d'injection intravasculaire de substance magnétique pour induction de vasodilatation et son utilisation Download PDF

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WO2022203290A1
WO2022203290A1 PCT/KR2022/003808 KR2022003808W WO2022203290A1 WO 2022203290 A1 WO2022203290 A1 WO 2022203290A1 KR 2022003808 W KR2022003808 W KR 2022003808W WO 2022203290 A1 WO2022203290 A1 WO 2022203290A1
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vascular
blood vessel
animal model
magnetic material
present
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PCT/KR2022/003808
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English (en)
Korean (ko)
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김중선
이슬기
이준상
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연세대학교 산학협력단
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
    • A61M25/0082—Catheter tip comprising a tool
    • A61M25/0084—Catheter tip comprising a tool being one or more injection needles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2503/00—Evaluating a particular growth phase or type of persons or animals
    • A61B2503/40—Animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2503/00—Evaluating a particular growth phase or type of persons or animals
    • A61B2503/42—Evaluating a particular growth phase or type of persons or animals for laboratory research
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M2025/0042—Microcatheters, cannula or the like having outside diameters around 1 mm or less
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2250/00—Specially adapted for animals

Definitions

  • the present invention relates to a method for producing an animal model that can be used to discover a drug or device for treating a vascular disease, an animal model prepared thereby, and various uses thereof.
  • Atherosclerosis also called atherosclerosis or atherosclerosis
  • atherosclerosis is a result of cholesterol deposition in the endothelium, which mainly covers the innermost layer of blood vessels, and proliferation of endothelial cells, resulting in the formation of "atheroma” refers to vascular disease.
  • atherosclerosis also called atherosclerosis or atherosclerosis
  • atherosclerosis is a result of cholesterol deposition in the endothelium, which mainly covers the innermost layer of blood vessels, and proliferation of endothelial cells, resulting in the formation of "atheroma” refers to vascular disease.
  • HDL-cholesterol high-density lipoprotein cholesterol
  • LDL-cholesterol low-density lipoprotein cholesterol
  • high triglycerides as major risk factors for the development and progression of atherosclerosis , high blood pressure (140/90 mmHg or higher)
  • smoking diabetes
  • family history of cardiovascular disease age increase
  • lack of exercise overweight and abdominal obesity are known causes.
  • Arteriosclerosis is diagnosed using imaging tests such as carotid ultrasound, CT (CTA, CT-angiography), MR angiography (MRA), cerebral angiography, and cardiovascular angiography.
  • imaging tests such as carotid ultrasound, CT (CTA, CT-angiography), MR angiography (MRA), cerebral angiography, and cardiovascular angiography.
  • Coronary artery stents are being continuously researched and developed from metal stents to drug-eluting stents, but neointimal hyperplasia due to proliferation of vascular smooth muscle cells, late thrombosis Stent Thrombosis) remains a challenge.
  • One object of the present invention is to provide a method of manufacturing an animal model that can implement vascular abnormalities as desired without exposing blood vessels.
  • Another object of the present invention is to provide an animal model prepared according to the method of the present invention.
  • Another object of the present invention relates to the various uses of animal models prepared according to the method of the present invention.
  • the present invention relates to a method of manufacturing an animal model of vascular abnormality.
  • the manufacturing method of the present invention may include injecting a catheter into a target site within a target blood vessel of an animal.
  • the type of animal used in the present invention is not particularly limited, and may be an animal other than a human, but is preferably a mammal other than a human, for example, a rat, a mouse, a guinea pig, a hamster, a rabbit, a monkey, a dog. , cat, cow, horse, pig, sheep and goat may be selected from the group consisting of, more preferably may be a mouse.
  • the blood vessel may be an artery, a vein, or a capillary, but is not particularly limited and may be appropriately selected according to the type of disease to be implemented.
  • the artery may be a coronary artery or a peripheral artery, and as an example, it may be selected from the group consisting of a renal artery, a cerebral artery, a pulmonary artery, and a lower extremity artery, and more specifically, the abdominal aorta, the tibialis artery, and the aortic arch.
  • the veins are collateral cortical vein, axillary vein, ulnar cortical vein, brachial vein, coccygeal vein, common iliac vein, dorsal lateral vein, dorsal metatarsal vein, external bone vein, facial vein, femoral vein, vena cava Saphenous vein, hepatic vein, inferior mesenteric vein, inferior vena cava, middle forearm vein, iliac vein, intestinal vein, jugular vein, lateral convolution femoral vein, inferior left pulmonary vein, upper left pulmonary vein, iliac vein, portal vein, posterior tibial vein, renal vein , postmandibular vein, saphenous vein, small saphenous vein, splenic vein, subclavian vein, superior mesenteric vein, and superior mesenteric vein, but may be selected from the group consisting of, but is not limited thereto.
  • the blood vessel may be a part of the vasculature of the coronary vasculature (including arterial and venous vasculature), the brain vasculature, the hepatic vasculature, the peripheral vasculature, and other organ and tissue compartments, but is not limited thereto not.
  • the manufacturing method of the present invention may include injecting a magnetic material through the catheter.
  • the structure or material of the catheter is not particularly limited, but if it can inject a magnetic material into the media layer of a blood vessel, it may be used without limitation.
  • it may be a microinfusion catheter device, and as an example, it may be a Bullfrog® micro-infusion catheter (Mercator Medsystems), but is limited thereto not.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), if it can be a permanent magnet, the type of magnetic material is not particularly limited thereto.
  • the average diameter of the magnetic material in the present invention may be 1 nm to 100 ⁇ m, preferably 50 nm to 80 ⁇ m, and more preferably 1 ⁇ m to 50 ⁇ m, but is not limited thereto.
  • the magnetic material may be added at a concentration of 100 mg/ml to 10 mg/ml, preferably 50 mg/ml to 10 mg/ml, more preferably 40 mg/ml to 20 mg/ml, but limited thereto it is not
  • 0.1ml ⁇ 1ml of the magnetic material may be injected, but the amount may vary depending on the type of animal and blood vessel, preferably 0.1ml ⁇ 0.5ml, or more preferably 0.2ml ⁇ 0.4 It is preferable to inject about ml, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G Streptococcus bacteria (Streptococci.), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins.
  • Protein A is Staphylococcus aureus. As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic beads during antibody coating using the protein G or protein A.
  • the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the manufacturing method of the present invention may include inducing contraction or relaxation of the blood vessel by applying a magnetic force to the blood vessel site into which the magnetic material is injected.
  • the step of applying the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, and the like, wherein one or more magnets are included and may be applied in various arrangements such as series, parallel, circular, etc., any method capable of forming a magnetic field in general may be included without limitation.
  • the contraction or relaxation of the blood vessel can be induced by using the repulsive force or attraction between the magnetic material and the magnet, and as a specific example, it is located in the blood vessel, preferably in the middle membrane of the blood vessel. It is possible to induce vasoconstriction by the repulsive force between the magnetic material and an external magnet, or to induce vasodilation by attractive force.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted according to the desired degree of contraction or relaxation of the blood vessel, and is not particularly limited.
  • the strength of the magnetic field is 10 kA/m to 5000 kA/m, or more preferably 80 kA/m to 800 kA/m, but is not limited thereto.
  • the animal model is an animal model in which vascular abnormalities in which blood vessels are abnormally contracted or relaxed are implemented, and various vascular diseases may be induced due to such vascular abnormalities.
  • the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
  • the cardiovascular disease may be included without limitation as long as it is a disease in which an abnormality occurs in blood vessels supplying blood to the heart, but may include, for example, ischemic heart disease, coronary artery disease, angina, myocardial infarction, arrhythmia, or thrombosis.
  • the present invention is not limited thereto.
  • the pulmonary vascular disease may be included without limitation as long as it is any disease affecting the blood circulation of the lungs, for example, pulmonary embolism, chronic thromboembolism, pulmonary arterial hypertension, pulmonary vein occlusion disease, arteriovenous malformation or pulmonary edema, etc. It may include, but is not limited to.
  • the cerebrovascular disease may include, without limitation, any disease in which an abnormality occurs in blood vessels supplying blood to the brain, but may include, for example, cerebral infarction, cerebral ischemia, stroke, cerebral hemorrhage, or vascular dementia, but is limited thereto. it's not going to be
  • the hypertension is hypertensive vascular disease, hypertensive pulmonary disease, hypertensive encephalopathy, hypertensive heart disease, hypertensive nephrosclerosis. ) or hypertensive retinitis, and the like, but is not limited thereto.
  • the vascular stenosis is cardiovascular stenosis, carotid artery stenosis, cerebral vascular stenosis, pulmonary stenosis, renal artery stenosis, femoral artery stenosis ( femoral artery stenosis), lower limb artery stenosis and vascular restenosis.
  • the vascular restenosis may be caused by vascular surgery or angioplasty.
  • the present invention relates to an animal model of vascular abnormalities manufactured according to the manufacturing method of the present invention.
  • the term “animal model” refers to an animal model of a disease.
  • the animal model may be an animal model that is afflicted with a disease similar to a human disease or is congenitally afflicted with the disease.
  • the animal model may be an animal model of vascular abnormalities, and furthermore, an animal model of vascular disease.
  • animals that can be used as animal models of the present invention are mammals other than humans, for example, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and more preferably a mouse, rabbit or pig, but is not limited thereto.
  • the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
  • the present invention relates to a method for screening a drug or device for preventing or treating vascular disease using the animal model provided by the present invention.
  • the "screening” refers to selecting a substance having a specific target property from a candidate group consisting of various substances or devices by a specific manipulation or evaluation method.
  • the screening method of the present invention may include first treating a drug candidate for preventing or treating vascular disease or applying a candidate device for preventing or treating vascular disease to the animal model provided by the present invention.
  • the candidate drug is preferably any one selected from the group consisting of natural compounds, synthetic compounds, RNA, DNA, polypeptides, enzymes, proteins, ligands, antibodies, antigens, bacterial or fungal metabolites and bioactive molecules.
  • the present invention is not limited thereto.
  • the screening method of the present invention may include the step of observing changes in blood vessels while treating the candidate drug or observing the blood vessels of an animal model to which the candidate device is applied, or confirming the prognosis while breeding the animal model.
  • the candidate drug or device may be determined as a drug or device for preventing or treating vascular diseases.
  • the observation of the blood vessels is performed using non-invasive imaging methods such as Computed Tomography (CT), Selective Computed Tomography, magnetic resonance imaging (MRI), and ultrasound (US).
  • CT Computed Tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • DSA digital subtraction angiography
  • the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
  • the present invention relates to a method for simulating the shape of blood vessels using the animal model provided by the present invention.
  • the simulation method of the present invention may include inducing contraction or relaxation of blood vessels by applying a magnetic force to the blood vessels of the animal model provided in the present invention.
  • the step of applying the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, and the like, wherein one or more magnets are included and may be applied in various arrangements such as series, parallel, circular, etc., any method capable of forming a magnetic field in general may be included without limitation.
  • the contraction or relaxation of the blood vessel can be induced by using the repulsive force or attraction between the magnetic material and the magnet, and as a specific example, it is located in the blood vessel, preferably in the middle membrane of the blood vessel. It is possible to induce vasoconstriction by the repulsive force between the magnetic material and an external magnet, or to induce vasodilation by attractive force.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted according to the desired degree of contraction or relaxation of the blood vessel, and is not particularly limited.
  • the simulation method of the present invention may include observing the blood vessels of the animal model to which the magnetic force is applied as described above.
  • the observation of the blood vessels is performed using a non-invasive imaging method such as Computed Tomography (CT), Selective Computed Tomography, Magnetic Resonance Imaging (MRI), Ultrasound (US), or digital It may be performed by an invasive imaging method such as subtractive angiography (DSA), but is not limited thereto.
  • CT Computed Tomography
  • MRI Magnetic Resonance Imaging
  • US Ultrasound
  • DSA subtractive angiography
  • the simulation method of the present invention can provide useful information necessary for the interpretation of vascular diseases by simulating the process in which vascular abnormalities are induced by inducing abnormal contraction or relaxation of blood vessels in an animal model, and accordingly, whether the patient has a disease can be identified or a disease treatment drug or device can be developed.
  • the method comprising: injecting a catheter into a target site within a target blood vessel of an animal other than a human; and injecting a magnetic material through the catheter.
  • the blood vessel is an artery, a vein or a capillary.
  • the magnetic material is injected into the media layer of the blood vessel through the catheter, there is provided a manufacturing method.
  • the catheter is a microinfusion catheter (microinfusion catheter device), it provides a manufacturing method.
  • the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  • the magnetic material is made of one or more materials selected from the group consisting of iron, cobalt, nickel, an oxide thereof, or an alloy thereof, provides a manufacturing method.
  • the magnetic material is maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) ,
  • a manufacturing method comprising an iron platinum alloy (FePt alloy), an iron cobalt alloy (FeCo alloy), a cobalt nickel alloy (CoNi alloy) or a cobalt platinum alloy (CoPt alloy).
  • the average diameter of the magnetic material is 1 nm to 50 ⁇ m, there is provided a manufacturing method.
  • the magnetic material provides a concentration of 10 mg/ml to 100 mg/ml, a manufacturing method.
  • the magnetic material is 0.1ml to 1ml input, it provides a manufacturing method.
  • the strength of the magnetic field strength is 10 kA / m ⁇ 5000 kA / m, it provides a manufacturing method.
  • a manufacturing method comprising the step of inducing contraction or relaxation of blood vessels by applying a magnetic force to the blood vessel site into which the magnetic material is injected.
  • the step of applying the magnetic force is performed by using one or more magnets to form a magnetic field, and provides a manufacturing method.
  • the vascular abnormality is a vascular disease induced by abnormal contraction or relaxation of blood vessels, and there is provided a manufacturing method.
  • the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, and arteriosclerosis ( Arteriosclerosis), vascular stenosis or hypertension (hypertension), comprising a manufacturing method is provided.
  • an animal model with vascular abnormalities prepared according to the above manufacturing method.
  • a method of screening a drug for preventing or treating a vascular disease using the animal model of vascular abnormality is provided.
  • the screening method provides a screening method, further comprising treating the animal model with a drug candidate for the prevention or treatment of vascular disease.
  • a screening method further comprising the step of observing changes in blood vessels while observing the blood vessels of the animal model treated with the candidate drug or confirming the prognosis while breeding the animal model.
  • the constricted blood vessel is relaxed or the dilated blood vessel is constricted after the treatment of the candidate drug, or the vascular disease is prevented or treated by the candidate drug, or the prognosis is higher than that of the control substance
  • a screening method in which the candidate drug is determined as a drug or device for preventing or treating a vascular disease when enhanced.
  • the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, and arteriosclerosis ( Arteriosclerosis), vascular stenosis or hypertension (hypertension), comprising a screening method is provided.
  • the simulation method provides a simulation method, further comprising the step of inducing contraction or relaxation of the blood vessel by applying a magnetic force to the blood vessel of the animal model.
  • the simulation method provides a simulation method, further comprising the step of observing the blood vessels of the animal model.
  • the observation of the blood vessel is performed using computed tomography (CT), selective computed tomography, magnetic resonance imaging (MRI), or ultrasound (US). or by an invasive imaging method such as digital subtraction angiography (DSA).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • DSA digital subtraction angiography
  • an animal model in which a desired vascular abnormality is implemented non-invasively without exposing blood vessels can be manufactured.
  • the animal model produced by the method in the present invention it can be widely applied to the pathophysiology of vascular diseases and the development of therapeutic agents or devices.
  • FIG. 1 is a photograph showing the deformation of the blood vessel when the magnet is brought close to the rabbit by injecting a magnetic material into the blood vessel of the rabbit in an embodiment of the present invention.
  • FIG. 2 is a photograph confirming that necrosis and the like do not occur as a result of injecting 0.3ml of a magnetic material into a rabbit ear vein at a concentration of 100mg/3ml.
  • Figure 3 is a photograph showing the structure of an exemplary catheter that can be used to manufacture a blood vessel relaxation or constriction animal model in an embodiment of the present invention.
  • FIG. 4 is a photograph confirming the change in the inner diameter of the rabbit iliac artery blood vessel through angiography.
  • FIG. 5 shows the change in the inner diameter of the rabbit iliac artery blood vessel through ultrasound.
  • FIG. 6 shows the injection of a magnetic material by inserting a catheter into the pig iliac artery.
  • the present invention comprises the steps of injecting a catheter (catheter) into a target site in a target blood vessel of an animal other than a human; and injecting a magnetic material through the catheter.
  • the present invention provides an animal model with vascular abnormalities manufactured according to the above manufacturing method.
  • the present invention provides a method for screening a drug for preventing or treating a vascular disease using the animal model for vascular abnormalities.
  • the present invention provides a method for simulating blood vessel shape deformation by using the animal model for blood vessel abnormalities.
  • the rabbit blood vessels were separated and PLA-M (12-00-304) magnetic material was injected using an insulin syringe (Insulin Syringe (31G, 0.25 mm)) in an amount of 0.2 ml at a concentration of 100 mg/3 ml. Then, as a result of checking the deformation of the blood vessel using a magnet, it was confirmed that the blood vessel came with it compared to the control group that did not inject the magnetic material. Next, this time, after injecting the PLA-M (12-00-304) magnetic material with an insulin syringe (Insulin Syringe (31G, 0.25mm)) in an amount of 0.3ml at a concentration of 100mg/3ml, the deformation of the blood vessel is performed using a magnet. As a result of the confirmation, as shown in FIG. 1 , when the magnetic material was injected as much as 0.3 ml at a concentration of 100 mg/3 ml, it was confirmed that the deformation of the blood vessel was larger.
  • An animal model of cardiovascular disease in which abnormal dilation or constriction of blood vessels occurred using rabbits was prepared. Specifically, antibiotics and analgesics were administered before surgery, and tiletamine-zolazepam (10 mg/kg, Zoletil®, Virvac, Fort Worth, TX, USA) and xylazine (0.5 mg/kg, Rompun®, Bayer, Leverkusen, Germany) was injected intramuscularly and maintained under 1-2% isoflurane (Forane®, JW Pharm, Seoul, Korea) and oxygen conditions to induce anesthesia. After the iliac artery was cut open, heparin (150 units/kg) was injected to maintain the activated coagulation time of more than 250 seconds before the injection of the magnetic material. Then, magnetic bead material (PLA-M (12-00-304), 30 ⁇ m) of micromer®-M (Micromod® GmbH) was injected into the vessel wall using an insulin syringe.
  • tiletamine-zolazepam 10 mg
  • An animal model of cardiovascular disease in which blood vessels were abnormally dilated or contracted was prepared using pigs. Specifically, antibiotics and analgesics were administered before surgery, and tiletamine-zolazepam (10 mg/kg, Zoletil®, Virvac, Fort Worth, TX, USA) and xylazine (0.5 mg/kg, Rompun®, Bayer, Leverkusen, Germany) was injected intramuscularly and maintained under 1-2% isoflurane (Forane®, JW Pharm, Seoul, Korea) and oxygen conditions to induce anesthesia. The iliac artery was accessed via the carotid artery using sterile surgical technique.
  • heparin 150 units/kg was injected to maintain the activated coagulation time greater than 250 seconds. Then, endovascular intramural injection was performed using a Bullfrog® microinjection catheter (Mercator Medsystems, San Leandro, CA, USA). As shown in FIG. 3 , the catheter is a catheter capable of penetrating a blood vessel wall through a fine needle.
  • the microinjection catheter is placed on the target site of the blood vessel, and the balloon is inflated using quantitative angiography. Confirmed.
  • magnetic bead material PLA-M (08-02-503), 5 ⁇ m
  • an abnormal contraction or relaxation of the blood vessel was induced by applying a magnetic force to the vicinity of the injection site of the magnetic bead material using a permanent magnet.
  • an animal model in which a desired vascular abnormality is implemented non-invasively without exposing blood vessels can be manufactured.
  • the use of the animal model produced by the method in the present invention can be widely applied to the pathophysiology of vascular diseases and the development of therapeutic agents or devices, and thus industrial applicability is recognized.

Abstract

La présente invention concerne un procédé de construction d'un modèle animal permettant de réaliser des anomalies vasculaires comme souhaité sans exposer les vaisseaux sanguins, un modèle animal construit par le procédé et son utilisation.
PCT/KR2022/003808 2021-03-23 2022-03-18 Développement de procédé d'injection intravasculaire de substance magnétique pour induction de vasodilatation et son utilisation WO2022203290A1 (fr)

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KR20180102872A (ko) * 2017-03-08 2018-09-18 대구가톨릭대학교산학협력단 전자기장 발생 및 제어를 이용한 혈전제거 장치

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US20050273130A1 (en) * 2002-11-18 2005-12-08 Sell Jonathan C Magnetically navigable balloon catheters
US20100168523A1 (en) * 2008-12-30 2010-07-01 Ducharme Richard W Magnetic retraction device
KR20180102872A (ko) * 2017-03-08 2018-09-18 대구가톨릭대학교산학협력단 전자기장 발생 및 제어를 이용한 혈전제거 장치

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CASSELMAN FILIP P, MECO MASSIMO, DOM HELGE, FOUBERT LUC, VAN PRAET FRANK, VANERMEN HUGO: "Multivessel distal sutureless off-pump coronary artery bypass grafting procedure using magnetic connectors", THE ANNALS OF THORACIC SURGERY, ELSEVIER, AMSTERDAM, NL, vol. 78, no. 2, 1 August 2004 (2004-08-01), AMSTERDAM, NL, pages e38 - e40, XP055970998, ISSN: 0003-4975, DOI: 10.1016/j.athoracsur.2003.07.050 *
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