WO2022203290A1 - Development of method for intravascular injection of magnetic substance for induction of vasodilation and use thereof - Google Patents
Development of method for intravascular injection of magnetic substance for induction of vasodilation and use thereof Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vascular
- blood vessel
- animal model
- magnetic material
- present
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 57
- 230000005291 magnetic effect Effects 0.000 title claims description 40
- 239000000126 substance Substances 0.000 title claims description 5
- 238000002347 injection Methods 0.000 title description 9
- 239000007924 injection Substances 0.000 title description 9
- 238000011161 development Methods 0.000 title description 6
- 230000024883 vasodilation Effects 0.000 title description 5
- 230000006698 induction Effects 0.000 title 1
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 86
- 238000010171 animal model Methods 0.000 claims abstract description 55
- 230000006496 vascular abnormality Effects 0.000 claims abstract description 21
- 239000000696 magnetic material Substances 0.000 claims description 57
- 208000019553 vascular disease Diseases 0.000 claims description 37
- 238000004519 manufacturing process Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 23
- 206010020772 Hypertension Diseases 0.000 claims description 19
- 210000001367 artery Anatomy 0.000 claims description 19
- 238000012216 screening Methods 0.000 claims description 16
- 229910045601 alloy Inorganic materials 0.000 claims description 15
- 239000000956 alloy Substances 0.000 claims description 15
- 230000008602 contraction Effects 0.000 claims description 15
- 238000002591 computed tomography Methods 0.000 claims description 14
- 210000003462 vein Anatomy 0.000 claims description 14
- 238000002583 angiography Methods 0.000 claims description 13
- 238000002604 ultrasonography Methods 0.000 claims description 13
- 206010057469 Vascular stenosis Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 238000004088 simulation Methods 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 8
- 208000011191 Pulmonary vascular disease Diseases 0.000 claims description 8
- 230000002490 cerebral effect Effects 0.000 claims description 8
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 7
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 7
- 238000003384 imaging method Methods 0.000 claims description 7
- 230000001939 inductive effect Effects 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 229910001260 Pt alloy Inorganic materials 0.000 claims description 6
- 230000002159 abnormal effect Effects 0.000 claims description 6
- 229910017052 cobalt Inorganic materials 0.000 claims description 6
- 239000010941 cobalt Substances 0.000 claims description 6
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 6
- 238000004393 prognosis Methods 0.000 claims description 6
- 229910000859 α-Fe Inorganic materials 0.000 claims description 6
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 4
- 229910003321 CoFe Inorganic materials 0.000 claims description 3
- 229910002441 CoNi Inorganic materials 0.000 claims description 3
- 229910018979 CoPt Inorganic materials 0.000 claims description 3
- 229910002546 FeCo Inorganic materials 0.000 claims description 3
- 229910005335 FePt Inorganic materials 0.000 claims description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000990 Ni alloy Inorganic materials 0.000 claims description 3
- 229910001566 austenite Inorganic materials 0.000 claims description 3
- 238000009395 breeding Methods 0.000 claims description 3
- 230000001488 breeding effect Effects 0.000 claims description 3
- 230000005292 diamagnetic effect Effects 0.000 claims description 3
- 239000002889 diamagnetic material Substances 0.000 claims description 3
- 229940000406 drug candidate Drugs 0.000 claims description 3
- 239000003302 ferromagnetic material Substances 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052748 manganese Inorganic materials 0.000 claims description 3
- 239000011572 manganese Substances 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 230000005298 paramagnetic effect Effects 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- 229910001313 Cobalt-iron alloy Inorganic materials 0.000 claims 1
- ZGDWHDKHJKZZIQ-UHFFFAOYSA-N cobalt nickel Chemical compound [Co].[Ni].[Ni].[Ni] ZGDWHDKHJKZZIQ-UHFFFAOYSA-N 0.000 claims 1
- GUBSQCSIIDQXLB-UHFFFAOYSA-N cobalt platinum Chemical compound [Co].[Pt].[Pt].[Pt] GUBSQCSIIDQXLB-UHFFFAOYSA-N 0.000 claims 1
- OBACEDMBGYVZMP-UHFFFAOYSA-N iron platinum Chemical compound [Fe].[Fe].[Pt] OBACEDMBGYVZMP-UHFFFAOYSA-N 0.000 claims 1
- 238000010276 construction Methods 0.000 abstract 1
- 210000003090 iliac artery Anatomy 0.000 description 13
- 241000283973 Oryctolagus cuniculus Species 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- 206010003210 Arteriosclerosis Diseases 0.000 description 9
- 208000011775 arteriosclerosis disease Diseases 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 210000005166 vasculature Anatomy 0.000 description 6
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 238000012790 confirmation Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 206010028851 Necrosis Diseases 0.000 description 4
- 240000007711 Peperomia pellucida Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000001631 hypertensive effect Effects 0.000 description 4
- 230000017074 necrotic cell death Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229920002873 Polyethylenimine Polymers 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 101710120037 Toxin CcdB Proteins 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 210000003111 iliac vein Anatomy 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000001758 mesenteric vein Anatomy 0.000 description 3
- 239000002861 polymer material Substances 0.000 description 3
- 229920000193 polymethacrylate Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 210000003752 saphenous vein Anatomy 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000025033 vasoconstriction Effects 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 229910000531 Co alloy Inorganic materials 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 206010072563 Peripheral artery stenosis Diseases 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 241000270934 Rana catesbeiana Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- QVYYOKWPCQYKEY-UHFFFAOYSA-N [Fe].[Co] Chemical compound [Fe].[Co] QVYYOKWPCQYKEY-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000002302 brachial artery Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- NVIVJPRCKQTWLY-UHFFFAOYSA-N cobalt nickel Chemical compound [Co][Ni][Co] NVIVJPRCKQTWLY-UHFFFAOYSA-N 0.000 description 2
- AVMBSRQXOWNFTR-UHFFFAOYSA-N cobalt platinum Chemical compound [Pt][Co][Pt] AVMBSRQXOWNFTR-UHFFFAOYSA-N 0.000 description 2
- 238000010968 computed tomography angiography Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000005674 electromagnetic induction Effects 0.000 description 2
- 230000001815 facial effect Effects 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 210000003191 femoral vein Anatomy 0.000 description 2
- 229940084362 forane Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- PWBYYTXZCUZPRD-UHFFFAOYSA-N iron platinum Chemical compound [Fe][Pt][Pt] PWBYYTXZCUZPRD-UHFFFAOYSA-N 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000006249 magnetic particle Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000001872 metatarsal bone Anatomy 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 210000003492 pulmonary vein Anatomy 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 229940069575 rompun Drugs 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 2
- 229960001366 zolazepam Drugs 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000022211 Arteriovenous Malformations Diseases 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 206010068690 Pulmonary vein occlusion Diseases 0.000 description 1
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 1
- 206010038378 Renal artery stenosis Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001468181 Streptococcus sp. 'group C' Species 0.000 description 1
- 241000194005 Streptococcus sp. 'group G' Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000005744 arteriovenous malformation Effects 0.000 description 1
- 210000004191 axillary artery Anatomy 0.000 description 1
- 210000002048 axillary vein Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 208000006170 carotid stenosis Diseases 0.000 description 1
- 210000002434 celiac artery Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002585 cerebral angiography Methods 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000002767 hepatic artery Anatomy 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000002989 hepatic vein Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 1
- 208000015210 hypertensive heart disease Diseases 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 102000028557 immunoglobulin binding proteins Human genes 0.000 description 1
- 108091009323 immunoglobulin binding proteins Proteins 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229930190071 lycoside Natural products 0.000 description 1
- 210000001363 mesenteric artery superior Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002907 paramagnetic material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- -1 polyvinylamine Natural products 0.000 description 1
- 210000003137 popliteal artery Anatomy 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 208000009138 pulmonary valve stenosis Diseases 0.000 description 1
- 208000030390 pulmonic stenosis Diseases 0.000 description 1
- 210000002321 radial artery Anatomy 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 210000002563 splenic artery Anatomy 0.000 description 1
- 210000000955 splenic vein Anatomy 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 210000003270 subclavian artery Anatomy 0.000 description 1
- 210000001321 subclavian vein Anatomy 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
- 210000002465 tibial artery Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000002559 ulnar artery Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
Images
Classifications
-
- 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
The present invention relates to a method for construction of an animal model capable of realizing vascular abnormalities as desired without exposing blood vessels, an animal model constructed by the method, and a use thereof.
Description
본 발명은 혈관 질환을 치료하기 위한 약물 또는 장치를 발굴하는 데에 사용할 수 있는 동물 모델의 제조 방법, 이에 의해 제조된 동물 모델과 이의 다양한 용도에 관한 것이다. 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.
고령화가 진행됨에 따라서 관상 동맥 질환은 한국 성인의 주요 사망원인으로 대두되고 있다. 동맥경화증(atherosclerosis)은 죽상경화증, 또는 죽상동맥경화증이라고도 하며, 주로 혈관의 가장 안쪽을 덮고 있는 내막(endothelium)에 콜레스테롤이 침착하고 내피세포의 증식이 일어난 결과, "죽종(atheroma)"이 형성되는 혈관질환을 말한다. 죽종에 의해서 혈관내부가 막히게 되면 혈액순환에 장애가 생기면서, 관상동맥질환(coronary artery disease) 또는 뇌경색(ischemic cerebrovascular disease)이 발생한다.As the aging population progresses, coronary artery disease is emerging as a major cause of death among Korean adults. Atherosclerosis (atherosclerosis), also called atherosclerosis or 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. When the inside of the blood vessel is blocked by an atheroma, blood circulation is impaired, and coronary artery disease or ischemic cerebrovascular disease occurs.
동맥경화증의 발생과 진행을 초래하는 주요 위험 인자로서 혈액 내에 총 콜레스테롤이 높아지거나, 고밀도 지단백 콜레스테롤(HDL-콜레스테롤)이 낮은 경우, 저밀도 지단백 콜레스테롤(LDL-콜레스테롤)이 높은 경우, 중성지방이 높은 경우, 혈압이 높은 경우 (140/90mmHg 이상), 흡연, 당뇨병, 심혈관 질환의 가족력, 연령 증가, 운동 부족, 과체중 및 복부비만 등이 그 원인으로 알려져 있다.High total cholesterol in the blood, low high-density lipoprotein cholesterol (HDL-cholesterol), high low-density lipoprotein cholesterol (LDL-cholesterol), and 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.
동맥경화증은 경동맥 초음파, CT(CTA, CT-angiography) 및 MR 혈관조영술(MRA, magenetic resonance angiography), 뇌혈관(cerebral angiography) 및 심혈관조영술(coronary angiography) 등과 같은 영상검사를 이용하여 진단하고 있다. Arteriosclerosis is diagnosed using imaging tests such as carotid ultrasound, CT (CTA, CT-angiography), MR angiography (MRA), cerebral angiography, and cardiovascular angiography.
또한, 동맥경화증을 치료하기 위하여 사용되는 관상동맥용 스텐트 (Stent)의 90% 이상을 수입에 의존하고 있으며, 의료기기 수입액 1위를 차지하고 있다. 관상동맥용 스텐트는 금속 스텐트로부터 약물 용출 스텐트까지 지속적인 연구개발이 진행되고 있으나, 혈관 평활근 세포의 증식 (Proliferation of vascular smooth muscle cells)으로 인한 신생 내막의 과증식증(Neointimal hyperplasia), 늦은 후기 혈전증 (Late Stent Thrombosis) 등의 문제를 여전히 과제로 남아있다. In addition, more than 90% of coronary stents used to treat arteriosclerosis depend on imports, and they occupy the first place in imports of medical devices. 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.
따라서 최근에는 동맥경화증 치료용 스텐트나 약물의 개발을 위하여, 동맥경화증의 발병 또는 진행 과정에 대한 정밀한 연구나 치료제 스크리닝을 가능케 하는 적절한 동맥경화증 발병 동물 모델의 개발에 대한 선행이 요구되고 있는 실정이다. Therefore, in recent years, for the development of stents or drugs for the treatment of arteriosclerosis, it is a situation that precedes the development of an appropriate arteriosclerosis-onset animal model that enables precise research on the onset or progression of arteriosclerosis or screening for therapeutic agents.
본 발명의 일 목적은 혈관을 드러내지 않고도 혈관 이상을 목적하고자 하는 대로 구현할 수 있는 동물 모델을 제조하는 방법을 제공하고자 한다.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.
본 발명의 다른 목적은 본 발명의 방법에 따라 제조된 동물 모델을 제공하고자 한다.Another object of the present invention is to provide an animal model prepared according to the method of the present invention.
본 발명의 또 다른 목적은 본 발명의 방법에 따라 제조된 동물 모델의 다양한 용도에 관한 것이다. Another object of the present invention relates to the various uses of animal models prepared according to the method of the present invention.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
본 발명의 일 구현 예에 따르면, 혈관 이상 동물 모델의 제조 방법에 관한 것이다. According to one embodiment of the present invention, it relates to a method of manufacturing an animal model of vascular abnormality.
본 발명의 제조 방법은 동물의 목적하는 혈관 내 목적하는 부위에 카테터(catheter)를 주입하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include injecting a catheter into a target site within a target blood vessel of an animal.
본 발명에서 이용되는 동물 개체의 종류는 특별히 제한되지 않으며, 인간을 제외한 동물일 수 있으나, 바람직하게는 인간을 제외한 포유 동물로, 예를 들면, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 마우스일 수 있다. 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.
본 발명에서 상기 혈관은 동맥, 정맥 또는 모세혈관일 수 있으나, 특별히 제한하지 않으며, 구현하고자 하는 질환의 종류에 따라 적절히 선택할 수 있다. In the present invention, 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.
본 발명에서 상기 동맥은 관상 동맥 또는 말초 동맥일 수 있고, 일 예시로는 신동맥, 뇌동맥, 폐동맥, 및 하지 동맥으로 이루어진 군으로부터 선택될 수 있으며, 보다 상세하게는 복부 대동맥, 전경골 동맥, 대동맥궁, 궁상 동맥, 액와 동맥, 상완 동맥, 경동맥, 복강 동맥, 회선 비골 동맥, 총간동맥, 총장골 동맥, 심부 대퇴 동맥, 심장동맥궁, 배측지동맥, 배측 중족 동맥, 외경동맥, 외장골 동맥, 안면 동맥, 대퇴 동맥, 하장간막 동맥, 내장골 동맥, 장 동맥, 외측슬하 동맥, 외측상슬 동맥, 장측지동맥, 비골 동맥, 슬와 동맥, 후경골 동맥, 심대퇴동맥, 폐동맥, 요골 동맥, 신동맥, 지라 동맥, 쇄골하 동맥, 천장동맥궁, 상장간막 동맥, 상척측측부동맥, 및 척골 동맥으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, 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. , arcuate artery, axillary artery, brachial artery, carotid artery, celiac artery, convolutional peroneal artery, common hepatic artery, common iliac artery, deep femoral artery, cardiac arch, dorsal branch artery, dorsal metatarsal artery, external carotid artery, external carotid artery, facial artery Arteries, femoral arteries, inferior mesenteric arteries, iliac arteries, intestinal arteries, lateral subpopliteal arteries, lateral brachial arteries, long collateral arteries, peroneal arteries, popliteal arteries, posterior tibial arteries, deep femoral arteries, pulmonary arteries, radial arteries, renal arteries, splenic arteries It may be selected from the group consisting of an artery, subclavian artery, sacroiliac arch, superior mesenteric artery, superior collateral artery, and ulnar artery, but is not limited thereto.
본 발명의 일 예시에서 상기 정맥은 부요측피정맥, 액와 정맥, 척측피정맥, 상완 정맥, 요측피정맥, 총장골정맥, 배측지정맥, 배측 중족 정맥, 외장골 정맥, 안면 정맥, 대퇴 정맥, 대복재 정맥, 간 정맥, 하장간막 정맥, 하대정맥, 중간 전완 정맥, 내장골 정맥, 장 정맥, 경정맥, 외측 회선 대퇴 정맥, 아래 좌폐 정맥, 위 좌폐 정맥, 장측지정맥, 문맥, 후경골 정맥, 신정맥, 후하악 정맥, 복재 정맥, 소복재 정맥, 지라 정맥, 쇄골하 정맥, 상장 간막 정맥, 및 상대정맥으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다. In an exemplary embodiment of the present invention, 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.
또한, 본 발명에서 상기 혈관은 관상 맥관구조 (동맥 및 정맥 맥관구조 포함), 뇌 맥관구조, 간 맥관구조, 말초 맥관구조, 및 다른 기관 및 조직 구획의 맥관구조의 일부일 수 있으나, 이에 제한되는 것은 아니다.Also, in the present invention, 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.
본 발명의 제조 방법은 상기 카테터를 통하여 자성 물질을 주입하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include injecting a magnetic material through the catheter.
본 발명에서 상기 카테터의 구조나 재료 등은 특별히 제한하지 않으나, 바람직하게는 혈관의 중간막(media) 층에 자성 물질을 주입할 수 있는 것이라면 제한없이 사용될 수 있다. 다만, 보다 바람직하게는 미세주입 카테터(microinfusion catheter device)일 수 있고, 일 예시로는 불프로그(Bullfrog)® 미세-주입 카테터 (메카토르 메드시스템즈(Mercator Medsystems))일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, 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. However, more preferably, 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.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, 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.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, 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 (γ-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.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm ~ 100μm, 바람직하게는 50 nm ~ 80 μm, 보다 바람직하게는 1um ~ 50 um일 수 있으나, 이에 제한되는 것은 아니다. The average diameter of the magnetic material in the present invention may be 1 nm to 100 μm, preferably 50 nm to 80 μm, and more preferably 1 μm to 50 μm, but is not limited thereto.
본 발명에서 상기 자성물질은 100mg/ml ~ 10mg/ml 농도로 투입하거나, 바람직하게는 50mg/ml ~ 10 mg/ml, 보다 바람직하게는 40mg/ml ~ 20mg/ml 투입할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, 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
본 발명에서 상기 자성물질은 0.1ml ~ 1ml 투입할 수 있으나, 동물과 혈관의 종류에 따라 그 양을 달라질 수 있으며, 바람직하게는 0.1ml ~ 0.5ml 투입하거나, 좀 더 바람직하게는 0.2ml ~ 0.4ml 정도 투입하는 것이 바람직하나 이에 제한되는 것은 아니다.In the present invention, 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.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, 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.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질을 도핑할 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질을 도핑하는 것이 좋으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, 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. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or 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.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 비드에 배향성을 부여할 수 있다.In addition, in the present invention, 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.
본 발명에서 상기 자성 물질은 그 자체로 사용하거나, 수용액에 분산되어 사용할 수 있으나, 수용액에 분산되어 사용하는 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1종이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, 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. At this time, 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.
본 발명의 제조 방법은 상기 자성 물질이 주입된 혈관 부위에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 포함할 수 있다. 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.
본 발명에서 상기 자기력을 인가하는 단계는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. 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.
본 발명에서는 상기 자기력을 인가하는 단계 시 상기 자성 물질과 상기 자석 간의 척력 또는 인력을 이용하여 혈관의 수축 또는 이완을 유도할 수 있고, 구체적인 일 예시로는 상기 혈관, 바람직하게는 혈관의 중간막 내에 위치하는 자성 물질과 외부 자석 사이의 척력에 의해 혈관 수축을 유도할 수 있고, 혹은 인력에 의해 혈관 이완을 유도할 수 있다. In the present invention, in the step of applying the magnetic force, 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.
본 발명에서 상기 자기력을 인가하는 단계 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 혈관의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. 바람직하게는 자기장(Magnetic field strength)의 세기는 10kA/m~5000kA/m이거나, 더욱 바람직하게는 80kA/m~800kA/m 인 것이 바람직하나 이에 제한되는 것은 아니다.In the present invention, in the step of applying the magnetic 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. Preferably, 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.
본 발명에서 상기 동물 모델은 혈관이 비정상적으로 수축 또는 이완되는 혈관 이상이 구현된 동물 모델로, 이러한 혈관 이상으로 인하여 다양한 혈관 질환이 유도된 것일 수 있다. In the present invention, 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.
본 발명에서 상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하며, 이에 제한되는 것은 아니다. In the present invention, the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
본 발명에서 상기 심혈관 질환은 심장에 혈액을 공급하는 혈관에 이상이 생긴 질환이라면 제한없이 포함될 수 있으나, 예를 들면, 허혈성 심장 질환, 관상동맥질환, 협심증, 심근경색증, 부정맥 또는 혈전 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, 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. However, the present invention is not limited thereto.
본 발명에서 상기 폐혈관 질환은 폐의 혈액 순환에 영향을 주는 모든 질환이라면 제한없이 포함될 수 있으나, 예를 들면, 폐색전, 만성혈전색전병, 폐동맥고혈압, 폐정맥폐쇄병, 동정맥기형 또는 폐부종 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, 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.
본 발명에서 상기 뇌혈관 질환은 뇌에 혈액을 공급하는 혈관에 이상이 생긴 질환이라면 제한없이 포함될 수 있으나, 예를 들면, 뇌경색, 뇌허혈, 뇌졸중, 뇌출혈 또는 혈관성 치매 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, 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
본 발명에서 상기 고혈압은 고혈압성 혈관질환(hypertensive vascular disease), 고혈압성 폐질환(hypertensive pulmonary disease), 고혈압성 뇌증(hypertensive encephalopathy), 고혈압성 심장질환(hypertensive heart disease), 고혈압성 신경화증(hypertensive nephrosclerosis) 또는 고혈압성 망막병증(hypertensive retinitis) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, 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.
본 명세서에서 상기 혈관 협착은 심혈관 협착(cardiovascular stenosis), 경동맥 협착(carotid artery stenosis), 뇌혈관 협착(cerebral vascular stenosis), 폐동맥 협착(pulmonary stenosis), 신동맥 협착(renal artery stenosis), 대퇴동맥 협착(femoral artery stenosis), 하지동맥 협착(lower limb artery stenosis) 및 혈관 재협착(vascular restenosis)을 포함하며, 이에 한정되는 것은 아니다. 상기 혈관 재협착은 혈관 외과술(vascular surgery) 또는 혈관 성형술(angioplasty)에 의해 발생할 수 있다.In the present specification, 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.
본 발명의 다른 구현 예에 따르면, 본 발명의 제조 방법에 따라 제조된 혈관 이상 동물 모델에 관한 것이다. According to another embodiment of the present invention, it relates to an animal model of vascular abnormalities manufactured according to the manufacturing method of the present invention.
본 명세서에서 사용되는 용어, "동물 모델"은 질환 동물 모델을 의미한다. 구체적으로, 동물 모델은 인간의 질병과 유사한 상태의 질병에 걸리거나 선천적으로 그 질병에 걸리도록 만들어낸 동물 모델일 수 있다. 본 명세서에서 동물 모델은 혈관 이상 동물 모델, 더 나아가서는 혈관 질환의 동물 모델일 수 있다. 또한, 본 발명의 동물 모델로 이용될 수 있는 동물은 인간을 제외한 포유 동물로, 예를 들면, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 마우스, 토끼 또는 돼지 등일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term “animal model” refers to an animal model of a disease. Specifically, 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. In the present specification, the animal model may be an animal model of vascular abnormalities, and furthermore, an animal model of vascular disease. In addition, 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.
본 발명에서 상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하며, 이에 제한되는 것은 아니다. In the present invention, the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 혈관 질환의 예방 또는 치료용 약물 또는 장치를 스크리닝하는 방법에 관한 것이다. According to another embodiment of the present invention, it 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.
본 발명에서 상기 "스크리닝"이란, 여러 물질 또는 장치로 이루어진 후보군으로부터 목적으로 하는 어떤 특정한 성질을 갖는 물질을 특정한 조작 또는 평가 방법으로 선별하는 것이다. In 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.
본 발명의 스크리닝 방법은 우선, 본 발명에서 제공하는 동물 모델에 혈관 질환의 예방 또는 치료용 후보 약물을 처리하거나 혈관 질환의 예방 또는 치료용 후보 장치를 적용하는 단계를 포함할 수 있다. 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.
본 발명에서 상기 후보 약물은 천연 화합물, 합성 화합물, RNA, DNA, 폴리펩티드, 효소, 단백질, 리간드, 항체, 항원, 박테리아 또는 진균의 대사 산물 및 생활성 분자로 이루어진 군으로부터 선택되는 어느 하나인 것이 바람직하나, 이에 제한되는 것은 아니다. In 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. However, the present invention is not limited thereto.
본 발명의 스크리닝 방법은 상기 후보 약물을 처리하거나 후보 장치를 적용한 동물 모델의 혈관을 관찰하면서 혈관의 변화를 관찰하거나 상기 동물 모델을 사육하면서 예후를 확인하는 단계를 포함할 수 있다. 이때 상기 후보 약물의 처리 또는 후보 장치의 적용 후 수축된 혈관이 이완되거나 이완된 혈관이 수축된 경우, 또는 상기 후보 약물 또는 후보 장치에 의하여 혈관 질환이 예방되거나, 치료되거나, 대조군 물질에 비하여 예후가 증진된 경우에 상기 후보 약물 또는 장치를 혈관 질환의 예방 또는 치료용 약물 또는 장치로 결정할 수 있다.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. In this case, when the constricted blood vessel is relaxed or the relaxed blood vessel is constricted after the treatment of the candidate drug or application of the candidate device, or the candidate drug or the candidate device prevents or treats vascular disease, or the prognosis is lower than that of the control material When enhanced, the candidate drug or device may be determined as a drug or device for preventing or treating vascular diseases.
본 발명에서 상기 혈관의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, 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). Alternatively, it may be performed by an invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
본 발명에서 상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하며, 이에 제한되는 것은 아니다. In the present invention, the vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis ( vascular stenosis) or hypertension (hypertension).
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 혈관 형상 변형을 시뮬레이션하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method for simulating the shape of blood vessels using the animal model provided by the present invention.
본 발명의 시뮬레이션 방법은, 본 발명에서 제공하는 동물 모델의 혈관에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 포함할 수 있다. 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.
본 발명에서 상기 자기력을 인가하는 단계는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. 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.
본 발명에서는 상기 자기력을 인가하는 단계 시 상기 자성 물질과 상기 자석 간의 척력 또는 인력을 이용하여 혈관의 수축 또는 이완을 유도할 수 있고, 구체적인 일 예시로는 상기 혈관, 바람직하게는 혈관의 중간막 내에 위치하는 자성 물질과 외부 자석 사이의 척력에 의해 혈관 수축을 유도할 수 있고, 혹은 인력에 의해 혈관 이완을 유도할 수 있다. In the present invention, in the step of applying the magnetic force, 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.
본 발명에서 상기 자기력을 인가하는 단계 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 혈관의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, in the step of applying the magnetic 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.
본 발명의 시뮬레이션 방법은 상기와 같이 자기력이 인가된 동물 모델의 혈관을 관찰하는 단계를 포함할 수 있다. 여기서 상기 혈관의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. 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. Here, 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.
본 발명의 시뮬레이션 방법은 동물 모델의 혈관에 비정상적으로 수축 또는 이완을 유도함에 따라 혈관 이상이 유도되는 과정을 시뮬레이션함으로써 혈관 질환 등의 해석에 필요한 유용한 정보를 제공할 수 있고, 이에 따라 환자의 질병 여부를 판별할 수 있거나 질병 치료 약물 또는 장치를 개발할 수 있다. 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.
본 발명의 일 구체예에 따르면 인간을 제외한 동물의 목적하는 혈관 내 목적하는 부위에 카테터(catheter)를 주입하는 단계; 및 상기 카테터를 통하여 자성 물질을 주입하는 단계를 포함하는, 혈관 이상 동물 모델의 제조 방법을 제공한다.According to one embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면 상기 혈관은 동맥, 정맥 또는 모세혈관인, 제조 방법을 제공한다.According to another embodiment of the present invention, the blood vessel is an artery, a vein or a capillary.
본 발명의 다른 구체예에 따르면 상기 자성 물질은 상기 카테터를 통해 혈관의 중간막(media) 층에 주입되는, 제조 방법을 제공한다.According to another embodiment of the present invention, the magnetic material is injected into the media layer of the blood vessel through the catheter, there is provided a manufacturing method.
본 발명의 다른 구체예에 따르면 상기 카테터는 미세주입 카테터(microinfusion catheter device)인, 제조 방법을 제공한다.According to another embodiment of the present invention, the catheter is a microinfusion catheter (microinfusion catheter device), it provides a manufacturing method.
본 발명의 다른 구체예에 따르면 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 제조 방법을 제공한다.According to another embodiment of the present invention, there is provided a manufacturing method, wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
본 발명의 다른 구체예에 따르면 상기 자성 물질은 철, 코발트, 니켈, 그 산화물 또는 합금으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는, 제조 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면 상기 자성 물질은 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금(CoNi alloy) 또는 코발트백금 합금(CoPt alloy)을 포함하는, 제조 방법을 제공한다.According to another embodiment of the present invention, the magnetic material is maghemite (γ-Fe 2 O 3 ), magnetite (Fe 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , Provided is 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).
본 발명의 다른 구체예에 따르면 상기 자성 물질의 평균 직경은 1 nm ~ 50μm인, 제조 방법을 제공한다.According to another embodiment of the present invention, the average diameter of the magnetic material is 1 nm to 50 μm, there is provided a manufacturing method.
본 발명의 다른 구체예에 따르면 상기 자성 물질은 10mg/ml~100mg/ml 농도인, 제조 방법을 제공한다.According to another embodiment of the present invention, the magnetic material provides a concentration of 10 mg/ml to 100 mg/ml, a manufacturing method.
본 발명의 다른 구체예에 따르면, 상기 자성 물질은 0.1ml~1ml 투입하는 것인, 제조 방법을 제공한다.According to another embodiment of the present invention, the magnetic material is 0.1ml to 1ml input, it provides a manufacturing method.
본 발명의 다른 구체예에 따르면, 자기력(Magnetic field strength)의 세기는 10kA/m~5000kA/m인, 제조 방법을 제공한다.According to another embodiment of the present invention, the strength of the magnetic field strength is 10 kA / m ~ 5000 kA / m, it provides a manufacturing method.
본 발명의 다른 구체예에 따르면, 상기 자성 물질이 주입된 혈관 부위에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 포함하는, 제조 방법을 제공한다.According to another embodiment of the present invention, there is provided 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.
본 발명의 다른 구체예에 따르면, 상기 자기력을 인가하는 단계는 하나 이상의 자석을 이용하여 자기장을 형성하며 수행되는, 제조 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 상기 혈관 이상은 혈관의 비정상적으로 수축 또는 이완으로 인해 유도된 혈관 질환인, 제조 방법을 제공한다.According to another embodiment of the present invention, the vascular abnormality is a vascular disease induced by abnormal contraction or relaxation of blood vessels, and there is provided a manufacturing method.
본 발명의 다른 구체예에 따르면, 상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하는, 제조 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 상기 제조 방법에 따라 제조된 혈관 이상 동물 모델을 제공한다.According to another embodiment of the present invention, there is provided an animal model with vascular abnormalities prepared according to the above manufacturing method.
본 발명의 다른 구체예에 따르면, 상기 혈관 이상 동물 모델을 이용하여 혈관 질환의 예방 또는 치료용 약물의 스크리닝 방법을 제공한다.According to another embodiment of the present invention, there is provided a method of screening a drug for preventing or treating a vascular disease using the animal model of vascular abnormality.
본 발명의 다른 구체예에 따르면, 상기 스크리닝 방법은 상기 동물 모델에 혈관 질환의 예방 또는 치료용 후보 약물을 처리하는 단계를 더 포함하는, 스크리닝 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 상기 후보 약물을 처리한 동물 모델의 혈관을 관찰하면서 혈관의 변화를 관찰하거나 상기 동물 모델을 사육하면서 예후를 확인하는 단계를 더 포함하는, 스크리닝 방법을 제공한다.According to another embodiment of the present invention, there is provided 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.
본 발명의 다른 구체예에 따르면, 상기 후보 약물의 처리 후 수축된 혈관이 이완되거나 이완된 혈관이 수축된 경우, 또는 상기 후보 약물에 의하여 혈관 질환이 예방되거나, 치료되거나, 대조군 물질에 비하여 예후가 증진된 경우에 상기 후보 약물을 혈관 질환의 예방 또는 치료용 약물 또는 장치로 결정하는, 스크리닝 방법을 제공한다.According to another embodiment of the present invention, when 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 Provided is a screening method, in which the candidate drug is determined as a drug or device for preventing or treating a vascular disease when enhanced.
본 발명의 다른 구체예에 따르면, 상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하는, 스크리닝 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 혈관 이상 동물 모델을 이용하여 혈관 형상 변형의 시뮬레이션 방법을 제공한다.According to another embodiment of the present invention, there is provided a method for simulating blood vessel shape deformation using an animal model of blood vessel abnormality.
본 발명의 다른 구체예에 따르면, 상기 시뮬레이션 방법은 상기 동물 모델의 혈관에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 더 포함하는, 시뮬레이션 방법을 제공한다.According to another embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 상기 시뮬레이션 방법은 상기 동물 모델의 혈관을 관찰하는 단계를 더 포함하는, 시뮬레이션 방법을 제공한다.According to another embodiment of the present invention, the simulation method provides a simulation method, further comprising the step of observing the blood vessels of the animal model.
본 발명의 다른 구체예에 따르면, 상기 혈관의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US) 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행되는, 시뮬레이션 방법을 제공한다.According to another embodiment of the present invention, 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).
본 발명에서 제공하는 방법에 의하는 경우 혈관 노출 없이 비침습적으로 목적하는 혈관 이상이 구현된 동물 모델을 제작할 수 있다. 또한, 본 발명에서 상기 방법으로 제작된 동물 모델을 이용하여서는 혈관 질환의 병태 생리 규명과 치료 약제 또는 장치의 개발에도 널리 응용될 수 있다. In the case of the method provided in the present invention, an animal model in which a desired vascular abnormality is implemented non-invasively without exposing blood vessels can be manufactured. In addition, by using 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.
도 1은 본 발명의 일 실시예에서 자성물질을 토끼의 혈관에 주입하여 자석을 가까이하였을 때, 혈관이 변형되는 것을 나타낸 사진이다. 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.
도 2는 토끼 귀 정맥에 자성물질을 100mg/3ml농도로 0.3ml 주입한 결과 세포괴사(necrosis) 등이 일어나지 않음을 확인한 사진이다.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.
도 3은 본 발명의 일 실시예에서 혈관 이완 또는 수축 동물 모델 제작에 사용될 수 있는 예시적인 카테터의 구조를 나타낸 사진이다.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.
도 4는 혈관조영술을 통하여 토끼 장골동맥 혈관의 내경 변화를 확인한 사진이다.4 is a photograph confirming the change in the inner diameter of the rabbit iliac artery blood vessel through angiography.
도 5는 초음파를 통해 토끼 장골동맥 혈관의 내경 변화를 확인한 것이다.5 shows the change in the inner diameter of the rabbit iliac artery blood vessel through ultrasound.
도 6은 돼지 장골동맥에 카테터를 삽입하여 자성물질을 주입하는 것을 나타낸 것이다.6 shows the injection of a magnetic material by inserting a catheter into the pig iliac artery.
도 7은 혈관조영술을 통하여 돼지 장골동맥 혈관의 내경 변화를 확인한 것이다.7 shows the change in the internal diameter of the pig iliac artery blood vessel through angiography.
도 8은 광학단층촬영을 통하여 돼지 장골동맥 혈관의 내경 변화를 확인한 것이다.8 is an optical tomography to confirm the change in the internal diameter of the pig iliac artery blood vessel.
본 발명은 인간을 제외한 동물의 목적하는 혈관 내 목적하는 부위에 카테터(catheter)를 주입하는 단계; 및 상기 카테터를 통하여 자성 물질을 주입하는 단계를 포함하는, 혈관 이상 동물 모델의 제조 방법을 제공한다.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.
본 발명은 상기 제조 방법에 따라 제조된 혈관 이상 동물 모델을 제공한다.The present invention provides an animal model with vascular abnormalities manufactured according to the above manufacturing method.
본 발명은 상기 혈관 이상 동물 모델을 이용하여 혈관 질환의 예방 또는 치료용 약물의 스크리닝 방법을 제공한다.The present invention provides a method for screening a drug for preventing or treating a vascular disease using the animal model for vascular abnormalities.
본 발명은 상기 혈관 이상 동물 모델을 이용하여 혈관 형상 변형의 시뮬레이션 방법을 제공한다.The present invention provides a method for simulating blood vessel shape deformation by using the animal model for blood vessel abnormalities.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
[실시예 1] 생체 외에서 토끼 혈관의 변형 확인[Example 1] Confirmation of deformation of rabbit blood vessels in vitro
토끼의 혈관을 분리하여 PLA-M(12-00-304) 자성물질을 100mg/3ml 농도로 0.2ml만큼 인슐린 주사기(Insulin Syringe (31G, 0.25mm))를 사용하여 주입하였다. 이어서 자석을 이용하여 혈관의 변형을 확인한 결과 자성물질을 주입하지 아니한 대조군에 비하여 혈관이 딸려 오는 것을 확인할 수 있었다. 이어서 이번에는 PLA-M(12-00-304) 자성물질을 100mg/3ml 농도로 0.3ml만큼 인슐린 주사기(Insulin Syringe (31G, 0.25mm))를 사용하여 주입한 후 자석을 이용하여 혈관의 변형을 확인한 결과 도 1에서 보는 것과 같이 자성물질을 100mg/3ml 농도로 0.3ml만큼 주입하는 경우에 좀 더 혈관의 변형이 큰 것을 확인할 수 있었다.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.
[실시예 2] 토끼 귀 정맥에서 세포 괴사(necrosis) 여부 확인[Example 2] Confirmation of cell necrosis in rabbit ear veins
이번에는 자성물질을 투입한 경우에 세포 괴사가 일어나는지 확인하기 위하여 이번에는 PLA-M(12-00-304) 자성물질을 100mg/3ml 농도로 0.3ml만큼 인슐린 주사기(Insulin Syringe (31G, 0.25mm))를 사용하여 토끼 귀 정맥에 주입하였다. 그 결과 도 2에서 보는 것과 같이 자성물질 주입 전, 후 토끼 귀 정맥에서 세포 괴사 등이 일어나지 아니함을 알 수 있었다.This time, in order to check whether cell necrosis occurs when a magnetic material is injected, this time, add 0.3 ml of PLA-M (12-00-304) magnetic material at a concentration of 100 mg/3 ml to Insulin Syringe (31G, 0.25 mm). ) was used to inject into the rabbit ear vein. As a result, as shown in FIG. 2 , it was found that cell necrosis did not occur in the rabbit ear veins before and after the injection of the magnetic material.
[실시예 3] 혈관조영술과 초음파를 통한 토끼 장골동맥에서 혈관 확장 확인[Example 3] Confirmation of vasodilation in rabbit iliac artery through angiography and ultrasound
토끼를 이용하여 혈관에 비정상적 이완 또는 수축이 발생된 심혈관계 질환의 동물 모델을 제작하였다. 구체적으로는 수술 전 항생제 및 진통제를 투여하고, 틸레타민-졸라제팜(10 mg/kg, Zoletil®, Virvac, Fort Worth, TX, USA) 및 자일라진(0.5 mg/kg, Rompun®, Bayer, Leverkusen, Germany)의 적절한 혼합물을 근육 내 주사하고 1-2% 이소플루란(Forane®, JW Pharm, Seoul, Korea) 및 산소 조건 하에서 유지시켜 마취를 유도하였다. 이후 장골동맥을 드러나게 자른 후 자성물질 주입 전 활성화된 응고 시간을 250 초 초과로 유지하기 위하여 헤파린(150 units/kg)을 주입하였다. 이후 인슐린 주사기를 사용하여 micromer®-M(Micromod® GmbH)의 자성 비드 물질(PLA-M(12-00-304), 30㎛)을 혈관 벽에 주입하였다.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 μm) of micromer®-M (Micromod® GmbH) was injected into the vessel wall using an insulin syringe.
이후 영구 자석을 이용하여 자성 비드 물질이 주입된 부위 부근에 자기력을 가함으로써 혈관의 비정상적 수축 또는 이완을 유도하였다. Thereafter, 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.
이어서 혈관조영술과 초음파를 통하여 토끼 장골동맥의 변형 여부를 확인하였다. 그 결과 도 4, 5에서 보는 것과 같이 자성물질 주입 후 자석을 가까이하는 경우 혈관이 확장하는 것을 확인할 수 있었다.Then, it was confirmed whether the rabbit iliac artery was deformed through angiography and ultrasound. As a result, as shown in FIGS. 4 and 5 , it was confirmed that the blood vessels expand when the magnet is brought close to the magnetic material after injection.
[실시예 4] 혈관조영술과 초음파를 통한 돼지 장골동맥에서 혈관 확장 확인[Example 4] Confirmation of vasodilation in pig iliac artery through angiography and ultrasound
돼지를 이용하여 혈관에 비정상적 이완 또는 수축이 발생된 심혈관계 질환의 동물 모델을 제작하였다. 구체적으로는 수술 전 항생제 및 진통제를 투여하고, 틸레타민-졸라제팜(10 mg/kg, Zoletil®, Virvac, Fort Worth, TX, USA) 및 자일라진(0.5 mg/kg, Rompun®, Bayer, Leverkusen, Germany)의 적절한 혼합물을 근육 내 주사하고 1-2% 이소플루란(Forane®, JW Pharm, Seoul, Korea) 및 산소 조건 하에서 유지시켜 마취를 유도하였다. 멸균된 수술 기술을 이용하여 경동맥을 통해 장골 동맥에 접근하였다. 카테터 주입 전 활성화된 응고 시간을 250 초 초과로 유지하기 위하여 헤파린(150 units/kg)을 주입하였다. 이어서 Bullfrog® 미세주입 카테터(Mercator Medsystems, San Leandro, CA, USA)를 이용하여 혈관 내 교내 주입(endovascular intramural injection)을 수행하였다. 도 3에서 보는 것과 같이 상기 카테터는 미세한 바늘을 통하여 혈관 벽을 관통할 수 있는 카테터이다.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. Before catheter injection, 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.
이어서 상기 미세주입 카테터를 혈관의 목적하는 부위에 위치시킨 뒤 정량 조영술을 이용하여 풍선을 부풀리게 하고, 카테터의 바늘을 통해 혈관 벽을 관통시킨 뒤 풍선의 부풀림 후 완전한 응고 및 바늘의 모양을 조영술로 확인하였다. 도 6에서 보는 것과 같이 상기 미세주입 카테터를 이용하여 바늘 주입을 통해 혈관 벽의 외막 내 중간막까지 micromer®-M(Micromod® GmbH)의 자성 비드 물질(PLA-M(08-02-503), 5㎛)을 주입하였다. 이후 영구 자석을 이용하여 자성 비드 물질이 주입된 부위 부근에 자기력을 가함으로써 혈관의 비정상적 수축 또는 이완을 유도하였다. Then, the microinjection catheter is placed on the target site of the blood vessel, and the balloon is inflated using quantitative angiography. Confirmed. As shown in FIG. 6 , magnetic bead material (PLA-M (08-02-503), 5 μm) was injected. Thereafter, 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.
이어서 혈관조영술을 통하여 돼지 장골동맥의 변형 여부를 확인하였다. 그 결과 도 7에서 보는 것과 같이 2.31mm에서 자성물질 투입 후 자석을 가까이하는 경우에는 2.78mm로 혈관 내경이 약 120%가량 증가하는 것을 확인할 수 있었다. 또한, 광학단층촬영을 통해 돼지 장골동맥의 변형 여부를 확인하였다. 그 결과 도 8에서 보는 것과 같이 2.02mm에서 자성물질 투입 후 자석을 가까이하는 경우에는 2.39mm로 혈관 내경이 약 118%가량 증가하는 것을 확인할 수 있었다.Then, it was confirmed whether the pig iliac artery was deformed through angiography. As a result, as shown in FIG. 7 , it was confirmed that the inner diameter of the blood vessel increased by about 120% to 2.78 mm when the magnet was brought close to the magnet after the input of the magnetic material at 2.31 mm. In addition, it was confirmed whether the pig iliac artery was deformed through optical tomography. As a result, as shown in FIG. 8 , it was confirmed that the inner diameter of the blood vessel increased by about 118% to 2.39 mm when the magnet was brought close to the magnet after the input of the magnetic material at 2.02 mm.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명에서 제공하는 방법에 의하는 경우 혈관 노출 없이 비침습적으로 목적하는 혈관 이상이 구현된 동물 모델을 제작할 수 있다. 또한, 본 발명에서 상기 방법으로 제작된 동물 모델을 이용하여서는 혈관 질환의 병태 생리 규명과 치료 약제 또는 장치의 개발에도 널리 응용될 수 있으므로 산업상 이용가능성이 인정된다.In the case of the method provided in the present invention, an animal model in which a desired vascular abnormality is implemented non-invasively without exposing blood vessels can be manufactured. In addition, 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.
Claims (25)
- 인간을 제외한 동물의 목적하는 혈관 내 목적하는 부위에 카테터(catheter)를 주입하는 단계; 및 injecting a catheter into a target site within a target blood vessel of an animal other than a human; and상기 카테터를 통하여 자성 물질을 주입하는 단계를 포함하는, 혈관 이상 동물 모델의 제조 방법. Including the step of injecting a magnetic material through the catheter, manufacturing method of an animal model of vascular abnormality.
- 제1항에 있어서, According to claim 1,상기 혈관은 동맥, 정맥 또는 모세혈관인, 제조 방법. The method of claim 1, wherein the blood vessel is an artery, a vein or a capillary.
- 제1항에 있어서, According to claim 1,상기 자성 물질은 상기 카테터를 통해 혈관의 중간막(media) 층에 주입되는, 제조 방법. The method of claim 1, wherein the magnetic material is injected into the media layer of the blood vessel through the catheter.
- 제1항에 있어서, According to claim 1,상기 카테터는 미세주입 카테터(microinfusion catheter device)인, 제조 방법.The method of claim 1, wherein the catheter is a microinfusion catheter device.
- 제1항에 있어서, According to claim 1,상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 제조 방법.wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
- 제1항에 있어서, According to claim 1,상기 자성 물질은 철, 코발트, 니켈, 그 산화물 또는 합금으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는, 제조 방법. The magnetic material is made of one or more materials selected from the group consisting of iron, cobalt, nickel, oxides or alloys thereof.
- 제6항에 있어서, 7. The method of claim 6,상기 자성 물질은 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금(CoNi alloy) 또는 코발트백금 합금(CoPt alloy)을 포함하는, 제조 방법. The magnetic material is maghemite (γ-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), A manufacturing method comprising a cobalt iron alloy (FeCo alloy), a cobalt nickel alloy (CoNi alloy) or a cobalt platinum alloy (CoPt alloy).
- 제1항에 있어서, According to claim 1,상기 자성 물질의 평균 직경은 1 nm ~ 50μm인, 제조 방법. The average diameter of the magnetic material is 1 nm to 50 μm, the manufacturing method.
- 제8항에 있어서,9. The method of claim 8,상기 자성 물질은 10mg/ml~100mg/ml 농도인, 제조 방법.The magnetic material is 10mg / ml ~ 100mg / ml concentration, the manufacturing method.
- 제9항에 있어서,10. The method of claim 9,상기 자성 물질은 0.1ml~1ml 투입하는 것인, 제조 방법.The magnetic material is 0.1ml to 1ml input, the manufacturing method.
- 제1항에 있어서, According to claim 1,상기 자성 물질이 주입된 혈관 부위에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 포함하는, 제조 방법. and inducing contraction or relaxation of the blood vessel by applying a magnetic force to the blood vessel into which the magnetic material is injected.
- 제 11항에 있어서,12. The method of claim 11,상기 자기력(Magnetic field strength)의 세기는 10kA/m~5000kA/m인, 제조 방법.The strength of the magnetic force (Magnetic field strength) is 10 kA / m ~ 5000 kA / m, the manufacturing method.
- 제12항에 있어서, 13. The method of claim 12,상기 자기력을 인가하는 단계는 하나 이상의 자석을 이용하여 자기장을 형성하며 수행되는, 제조 방법. The step of applying the magnetic force is performed while forming a magnetic field using one or more magnets.
- 제1항에 있어서, According to claim 1,상기 혈관 이상은 혈관의 비정상적으로 수축 또는 이완으로 인해 유도된 혈관 질환인, 제조 방법. The vascular abnormality is a vascular disease induced by abnormal contraction or relaxation of blood vessels.
- 제14항에 있어서, 15. The method of claim 14,상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하는, 제조 방법. The vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis. or hypertension (hypertension).
- 제1항 내지 제15항 중 어느 한 항의 제조 방법에 따라 제조된 혈관 이상 동물 모델. An animal model with vascular abnormalities prepared according to the manufacturing method of any one of claims 1 to 15.
- 제16항의 혈관 이상 동물 모델을 이용하여 혈관 질환의 예방 또는 치료용 약물의 스크리닝 방법.A method of screening a drug for preventing or treating a vascular disease using the animal model of claim 16 .
- 제16항에 있어서,17. The method of claim 16,상기 스크리닝 방법은 상기 동물 모델에 혈관 질환의 예방 또는 치료용 후보 약물을 처리하는 단계를 더 포함하는, 스크리닝 방법. The screening method further comprises treating the animal model with a drug candidate for preventing or treating vascular disease.
- 제17항에 있어서,18. The method of claim 17,상기 후보 약물을 처리한 동물 모델의 혈관을 관찰하면서 혈관의 변화를 관찰하거나 상기 동물 모델을 사육하면서 예후를 확인하는 단계를 더 포함하는, 스크리닝 방법. The screening method further comprising the step of observing the blood vessels of the animal model treated with the candidate drug, observing changes in blood vessels, or confirming the prognosis while breeding the animal model.
- 제18항에 있어서,19. The method of claim 18,상기 후보 약물의 처리 후 수축된 혈관이 이완되거나 이완된 혈관이 수축된 경우, 또는 상기 후보 약물에 의하여 혈관 질환이 예방되거나, 치료되거나, 대조군 물질에 비하여 예후가 증진된 경우에 상기 후보 약물을 혈관 질환의 예방 또는 치료용 약물 또는 장치로 결정하는, 스크리닝 방법. When the constricted blood vessel is relaxed or the dilated blood vessel is constricted after treatment with the candidate drug, or when vascular disease is prevented or treated by the candidate drug, or the prognosis is improved compared to the control substance, the candidate drug is administered to the blood vessel A screening method for determining a drug or device for preventing or treating a disease.
- 제17항에 있어서,18. The method of claim 17,상기 혈관 질환은 심혈관 질환(cardiovascular diseases), 폐혈관질환(pulmonary vascular diseases), 뇌혈관질환(cerebral vascular diseases), 말초혈관질환(peripheral vascular diseases), 동맥경화증(arteriosclerosis), 혈관협착(vascular stenosis) 또는 고혈압(hypertension)을 포함하는, 스크리닝 방법. The vascular diseases include cardiovascular diseases, pulmonary vascular diseases, cerebral vascular diseases, peripheral vascular diseases, arteriosclerosis, and vascular stenosis. or hypertension.
- 제16항의 혈관 이상 동물 모델을 이용하여 혈관 형상 변형의 시뮬레이션 방법. A simulation method of vascular shape deformation using the vascular abnormality animal model of claim 16 .
- 제22항에 있어서, 23. The method of claim 22,상기 시뮬레이션 방법은 상기 동물 모델의 혈관에 자기력을 인가하여 혈관의 수축 또는 이완을 유도하는 단계를 더 포함하는, 시뮬레이션 방법. The simulation method further comprises the step of inducing contraction or relaxation of the blood vessel by applying a magnetic force to the blood vessel of the animal model.
- 제23항에 있어서, 24. The method of claim 23,상기 시뮬레이션 방법은 상기 동물 모델의 혈관을 관찰하는 단계를 더 포함하는, 시뮬레이션 방법. The simulation method further comprises the step of observing the blood vessels of the animal model.
- 제24항에 있어서, 25. The method of claim 24,상기 혈관의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US) 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행되는, 시뮬레이션 방법. Observation of the blood vessels is performed with computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) or digital subtraction angiography (DSA) and A simulation method, performed by the same invasive imaging method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20210037535 | 2021-03-23 | ||
| KR10-2021-0037535 | 2021-03-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022203290A1 true WO2022203290A1 (en) | 2022-09-29 |
Family
ID=83397629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2022/003808 WO2022203290A1 (en) | 2021-03-23 | 2022-03-18 | Development of method for intravascular injection of magnetic substance for induction of vasodilation and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20220132420A (en) |
| WO (1) | WO2022203290A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (en) * | 2017-03-08 | 2018-09-18 | 대구가톨릭대학교산학협력단 | thrombus remove device by electromagnetic field make and control |
-
2022
- 2022-02-17 KR KR1020220020742A patent/KR20220132420A/en not_active Application Discontinuation
- 2022-03-18 WO PCT/KR2022/003808 patent/WO2022203290A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (en) * | 2017-03-08 | 2018-09-18 | 대구가톨릭대학교산학협력단 | thrombus remove device by electromagnetic field make and control |
Non-Patent Citations (2)
| Title |
|---|
| 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 * |
| NACEV, A. ; BENI, C. ; BRUNO, O. ; SHAPIRO, B.: "The behaviors of ferromagnetic nano-particles in and around blood vessels under applied magnetic fields", JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 323, no. 6, 1 March 2011 (2011-03-01), AMSTERDAM, NL , pages 651 - 668, XP027568958, ISSN: 0304-8853 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220132420A (en) | 2022-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE60128451T2 (en) | COATING THAT STIMULATES A PLUG OF ENDOTHELIAL CELLS | |
| Li et al. | Neointimal hyperplasia associated with synthetic hemodialysis grafts | |
| Pislaru et al. | Magnetically targeted endothelial cell localization in stented vessels | |
| Rosengart et al. | Magnetizable implants and functionalized magnetic carriers: A novel approach for noninvasive yet targeted drug delivery | |
| Forauer et al. | Jugular vein catheter placement: histologic features and development of catheter-related (fibrin) sheaths in a swine model | |
| Forbes et al. | Validation of high gradient magnetic field based drug delivery to magnetizable implants under flow | |
| TWI558427B (en) | System for treating medical conditions of humans or animals | |
| JP5366542B2 (en) | Composition comprising magnetic iron oxide particles and use of the composition in imaging methods | |
| JP2005523050A (en) | Medical device having a coating that promotes endothelial cell adhesion and differentiation | |
| JP2007535389A (en) | Medical device with coating for capturing genetically modified cells and method of use thereof | |
| US20020133225A1 (en) | Methods and apparatuses for delivering a medical agent to a medical implant | |
| JP2008544968A (en) | Composition comprising magnetic iron oxide particles and use of the composition in imaging methods | |
| US20090216320A1 (en) | Magnetic Gradient Targeting And Sequestering Of Therapeutic Formulations And Therapeutic Systems Thereof | |
| Hu et al. | Silk embolic material for catheter‐directed endovascular drug delivery | |
| AU2005221396A1 (en) | Compositions comprising cells and magnetic materials for targeted delivery | |
| Fellows et al. | In vitro studies of heparin-coated magnetic nanoparticles for use in the treatment of neointimal hyperplasia | |
| WO2022203290A1 (en) | Development of method for intravascular injection of magnetic substance for induction of vasodilation and use thereof | |
| US20110196187A1 (en) | Magnetically sensitive drug carriers and delivery devices | |
| Cicha et al. | Cardiovascular applications of magnetic particles | |
| Uthamaraj et al. | Design and validation of a novel ferromagnetic bare metal stent capable of capturing and retaining endothelial cells | |
| JP2008520330A (en) | Therapeutic graft | |
| Jain et al. | The rabbit model of accelerated atherosclerosis: a methodological perspective of the iliac artery balloon injury | |
| San Valentin et al. | Nano‐embedded medical devices and delivery systems in interventional radiology | |
| EP2931367A1 (en) | Magnetic retention of regenerative cells for wound repair | |
| Kim et al. | Histological changes of the unligated vein wall adjacent to the central venous catheter after open cutdown in rats |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22775992 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 22775992 Country of ref document: EP Kind code of ref document: A1 |