JPH04152952A - Organism-compatible medical material - Google Patents
Organism-compatible medical materialInfo
- Publication number
- JPH04152952A JPH04152952A JP2280031A JP28003190A JPH04152952A JP H04152952 A JPH04152952 A JP H04152952A JP 2280031 A JP2280031 A JP 2280031A JP 28003190 A JP28003190 A JP 28003190A JP H04152952 A JPH04152952 A JP H04152952A
- Authority
- JP
- Japan
- Prior art keywords
- acrylate
- meth
- alkoxyalkyl
- contact
- blood
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000012567 medical material Substances 0.000 title claims abstract description 26
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims abstract description 16
- 210000001124 body fluid Anatomy 0.000 claims abstract description 13
- 239000010839 body fluid Substances 0.000 claims abstract description 13
- 229920001059 synthetic polymer Polymers 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- -1 methoxyethyl Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 abstract description 28
- 239000000178 monomer Substances 0.000 abstract description 26
- 230000004913 activation Effects 0.000 abstract description 17
- 210000004369 blood Anatomy 0.000 abstract description 16
- 239000008280 blood Substances 0.000 abstract description 16
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 12
- 229920000642 polymer Polymers 0.000 abstract description 9
- 229920001577 copolymer Polymers 0.000 abstract description 8
- 229920001519 homopolymer Polymers 0.000 abstract description 6
- 150000001252 acrylic acid derivatives Chemical class 0.000 abstract description 5
- 239000000470 constituent Substances 0.000 abstract description 4
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 230000000295 complement effect Effects 0.000 abstract 1
- 239000012528 membrane Substances 0.000 description 30
- 230000000052 comparative effect Effects 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 16
- HFCUBKYHMMPGBY-UHFFFAOYSA-N 2-methoxyethyl prop-2-enoate Chemical compound COCCOC(=O)C=C HFCUBKYHMMPGBY-UHFFFAOYSA-N 0.000 description 15
- 210000002381 plasma Anatomy 0.000 description 12
- 230000004154 complement system Effects 0.000 description 11
- 239000010408 film Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002473 artificial blood Substances 0.000 description 9
- 210000004204 blood vessel Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000004743 Polypropylene Substances 0.000 description 8
- 206010052428 Wound Diseases 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 229920001155 polypropylene Polymers 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229920000058 polyacrylate Polymers 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 244000028419 Styrax benzoin Species 0.000 description 3
- 235000000126 Styrax benzoin Nutrition 0.000 description 3
- 235000008411 Sumatra benzointree Nutrition 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229960002130 benzoin Drugs 0.000 description 3
- ISAOCJYIOMOJEB-UHFFFAOYSA-N desyl alcohol Natural products C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 235000019382 gum benzoic Nutrition 0.000 description 3
- 230000005661 hydrophobic surface Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 2
- 238000005266 casting Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 230000009881 electrostatic interaction Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000009477 glass transition Effects 0.000 description 2
- 229920000578 graft copolymer Polymers 0.000 description 2
- 238000010559 graft polymerization reaction Methods 0.000 description 2
- 239000012510 hollow fiber Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229920005604 random copolymer Polymers 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- UYHNDEQBDLNIJY-UHFFFAOYSA-N 2,2-diaminoethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC(N)N UYHNDEQBDLNIJY-UHFFFAOYSA-N 0.000 description 1
- MHVYIBJBGFWZKA-UHFFFAOYSA-N 2,2-diaminoethyl prop-2-enoate Chemical compound NC(N)COC(=O)C=C MHVYIBJBGFWZKA-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- QLIBJPGWWSHWBF-UHFFFAOYSA-N 2-aminoethyl methacrylate Chemical compound CC(=C)C(=O)OCCN QLIBJPGWWSHWBF-UHFFFAOYSA-N 0.000 description 1
- UGIJCMNGQCUTPI-UHFFFAOYSA-N 2-aminoethyl prop-2-enoate Chemical compound NCCOC(=O)C=C UGIJCMNGQCUTPI-UHFFFAOYSA-N 0.000 description 1
- GSDBRJGLFJCCIT-UHFFFAOYSA-N 2-aminopropan-2-yl prop-2-enoate Chemical compound CC(C)(N)OC(=O)C=C GSDBRJGLFJCCIT-UHFFFAOYSA-N 0.000 description 1
- DJKKWVGWYCKUFC-UHFFFAOYSA-N 2-butoxyethyl 2-methylprop-2-enoate Chemical compound CCCCOCCOC(=O)C(C)=C DJKKWVGWYCKUFC-UHFFFAOYSA-N 0.000 description 1
- PTJDGKYFJYEAOK-UHFFFAOYSA-N 2-butoxyethyl prop-2-enoate Chemical compound CCCCOCCOC(=O)C=C PTJDGKYFJYEAOK-UHFFFAOYSA-N 0.000 description 1
- SFPNZPQIIAJXGL-UHFFFAOYSA-N 2-ethoxyethyl 2-methylprop-2-enoate Chemical compound CCOCCOC(=O)C(C)=C SFPNZPQIIAJXGL-UHFFFAOYSA-N 0.000 description 1
- FWWXYLGCHHIKNY-UHFFFAOYSA-N 2-ethoxyethyl prop-2-enoate Chemical compound CCOCCOC(=O)C=C FWWXYLGCHHIKNY-UHFFFAOYSA-N 0.000 description 1
- YXYJVFYWCLAXHO-UHFFFAOYSA-N 2-methoxyethyl 2-methylprop-2-enoate Chemical compound COCCOC(=O)C(C)=C YXYJVFYWCLAXHO-UHFFFAOYSA-N 0.000 description 1
- UACBZRBYLSMNGV-UHFFFAOYSA-N 3-ethoxypropyl prop-2-enoate Chemical compound CCOCCCOC(=O)C=C UACBZRBYLSMNGV-UHFFFAOYSA-N 0.000 description 1
- LHEKBWMWMVRJMO-UHFFFAOYSA-N 3-methoxypropyl prop-2-enoate Chemical compound COCCCOC(=O)C=C LHEKBWMWMVRJMO-UHFFFAOYSA-N 0.000 description 1
- MSXWFRKZPQMBKL-UHFFFAOYSA-N 4,4-diaminobutyl prop-2-enoate Chemical compound NC(N)CCCOC(=O)C=C MSXWFRKZPQMBKL-UHFFFAOYSA-N 0.000 description 1
- OYFJWLSZXKXLAT-UHFFFAOYSA-N 4-ethoxybutyl prop-2-enoate Chemical compound CCOCCCCOC(=O)C=C OYFJWLSZXKXLAT-UHFFFAOYSA-N 0.000 description 1
- GAKWESOCALHOKH-UHFFFAOYSA-N 4-methoxybutyl prop-2-enoate Chemical compound COCCCCOC(=O)C=C GAKWESOCALHOKH-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000003926 acrylamides Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- XRLSGYQIHTVOMC-UHFFFAOYSA-N aminomethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCN XRLSGYQIHTVOMC-UHFFFAOYSA-N 0.000 description 1
- QHOTVLWYQNKORC-UHFFFAOYSA-N aminomethyl prop-2-enoate Chemical compound NCOC(=O)C=C QHOTVLWYQNKORC-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- NIYJNIFGDHAKLZ-UHFFFAOYSA-N diaminomethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC(N)N NIYJNIFGDHAKLZ-UHFFFAOYSA-N 0.000 description 1
- WAHZRYJFFZMWOU-UHFFFAOYSA-N diaminomethyl prop-2-enoate Chemical compound NC(N)OC(=O)C=C WAHZRYJFFZMWOU-UHFFFAOYSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- WMAFNLQQGPUKCM-UHFFFAOYSA-N ethoxymethyl 2-methylprop-2-enoate Chemical compound CCOCOC(=O)C(C)=C WMAFNLQQGPUKCM-UHFFFAOYSA-N 0.000 description 1
- SZPUDSQPVUIVKC-UHFFFAOYSA-N ethoxymethyl prop-2-enoate Chemical compound CCOCOC(=O)C=C SZPUDSQPVUIVKC-UHFFFAOYSA-N 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- LNCPIMCVTKXXOY-UHFFFAOYSA-N hexyl 2-methylprop-2-enoate Chemical compound CCCCCCOC(=O)C(C)=C LNCPIMCVTKXXOY-UHFFFAOYSA-N 0.000 description 1
- LNMQRPPRQDGUDR-UHFFFAOYSA-N hexyl prop-2-enoate Chemical compound CCCCCCOC(=O)C=C LNMQRPPRQDGUDR-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000012690 ionic polymerization Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- LVQPBIMCRZQQBC-UHFFFAOYSA-N methoxymethyl 2-methylprop-2-enoate Chemical compound COCOC(=O)C(C)=C LVQPBIMCRZQQBC-UHFFFAOYSA-N 0.000 description 1
- SINFYWWJOCXYFD-UHFFFAOYSA-N methoxymethyl prop-2-enoate Chemical compound COCOC(=O)C=C SINFYWWJOCXYFD-UHFFFAOYSA-N 0.000 description 1
- BSDQITJYKQHXQR-UHFFFAOYSA-N methyl prop-2-eneperoxoate Chemical compound COOC(=O)C=C BSDQITJYKQHXQR-UHFFFAOYSA-N 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- QRWZCJXEAOZAAW-UHFFFAOYSA-N n,n,2-trimethylprop-2-enamide Chemical compound CN(C)C(=O)C(C)=C QRWZCJXEAOZAAW-UHFFFAOYSA-N 0.000 description 1
- JMCVCHBBHPFWBF-UHFFFAOYSA-N n,n-diethyl-2-methylprop-2-enamide Chemical compound CCN(CC)C(=O)C(C)=C JMCVCHBBHPFWBF-UHFFFAOYSA-N 0.000 description 1
- OVHHHVAVHBHXAK-UHFFFAOYSA-N n,n-diethylprop-2-enamide Chemical compound CCN(CC)C(=O)C=C OVHHHVAVHBHXAK-UHFFFAOYSA-N 0.000 description 1
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 description 1
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 description 1
- 230000017570 negative regulation of blood coagulation Effects 0.000 description 1
- 230000008692 neointimal formation Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000009832 plasma treatment Methods 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 229920001483 poly(ethyl methacrylate) polymer Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000120 polyethyl acrylate Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 0.000 description 1
- YOHLNKAKHLQGPN-UHFFFAOYSA-N propoxymethyl 2-methylprop-2-enoate Chemical compound CCCOCOC(=O)C(C)=C YOHLNKAKHLQGPN-UHFFFAOYSA-N 0.000 description 1
- RPGBCXPLDSDRMQ-UHFFFAOYSA-N propoxymethyl prop-2-enoate Chemical compound CCCOCOC(=O)C=C RPGBCXPLDSDRMQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 238000002166 wet spinning Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- External Artificial Organs (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、生体適合性医用材料に関するものである。詳
しく述べると、本発明は、血小板の粘着・活性化の抑制
効果、補体系の活性化の抑制効果、生体組織との親和性
を有する生体適合性医用材料に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to biocompatible medical materials. Specifically, the present invention relates to a biocompatible medical material that has an effect of suppressing adhesion and activation of platelets, an effect of suppressing activation of the complement system, and has an affinity with living tissues.
（従来の技術）
近年、各種の高分子材料を利用した医用材料の検討が進
められており、人工腎臓用膜、血漿分離用膜、カテーテ
ル５、人工肺用膜、人工血管、癒着防止膜、人工皮膚等
への利用が期待されている。(Prior art) In recent years, medical materials using various polymeric materials have been studied, including membranes for artificial kidneys, membranes for plasma separation, catheters 5, membranes for oxygenator lungs, artificial blood vessels, anti-adhesion membranes, It is expected to be used in artificial skin, etc.
生体にとって異物である合成材料を生体組織や体液と接
触させて使用することとなるため、医用材料が生体適合
性を有していることが要求される。Since synthetic materials that are foreign to living bodies are used in contact with living tissues and body fluids, medical materials are required to have biocompatibility.
この際に使用される生体適合性は、目的や使用法によっ
て意味が異なるが、以下に例を挙げて説明する。The term biocompatibility used in this case has different meanings depending on the purpose and usage, but will be explained below with examples.
医用材料を血液と接する材料として使用する場合、（ａ
）血液凝固系の抑制、（ｂ）血小板の粘着・活性化の抑
制、（Ｃ）補体系の活性化の抑制の３要素が生体適合性
として重要な項目となる。When using medical materials as materials that come into contact with blood, (a
) Inhibition of blood coagulation system, (b) inhibition of adhesion and activation of platelets, and (C) inhibition of activation of complement system are three important factors for biocompatibility.
例えば、比較的短時間血液と接する体外循環用医用材料
（人工腎臓や血漿分離膜など）として使用する場合、一
般にヘパリンやクエン酸ナトリウム等の抗凝固剤を同時
に使用するため、特に（ｂ）及び、（ｃ）の血小板や補
体系の活性化の抑制が重要な課題となる。For example, when used as an extracorporeal circulation medical material that comes into contact with blood for a relatively short period of time (artificial kidney, plasma separation membrane, etc.), anticoagulants such as heparin and sodium citrate are generally used at the same time, so (b) and , (c) suppression of activation of platelets and the complement system is an important issue.
血小板の粘着・活性化の抑制については、ミクロ相分離
した表面や親水性表面、特に水溶性高分子を表面に結合
させたゲル化表面が優れており、ポリプロピレンなとの
疎水性表面は劣っていると言われている（例えば、トラ
ンスアクションズオブ アメリカン ソサエティ オブ
アーティフィカル インターナショナル オルガンズ
（Ｔｒａｎｓ、Ａｔｔｒ、ｓｏｃ、Ａｒｔｉｆ 、 Ｉ
ｎｔｅｒｎ、Ｏｒｇａｎｓ）、ｖｏｌ、ＸＸｘ■、第７
５〜８４頁（１９８７）や高分子と医療、三田出版会、
第７３頁（１９８９）などを参照）。しかし、ミクロ相
分離構造を有する表面は、適度な相分離状態に一コント
ロールすることにより良好な血液適合性を発現すること
が可能となるが、そのような相分離を作製できる条件が
限られており、用途に制限のあるものであった。また、
水溶性高分子を表面に結合させたゲル表面では、血小板
の粘着は抑制されるが、材料表面で活性化された血小板
や微小血栓が体内に返還され、しばしば異常な血球成分
（血小板）の変動が観察され、問題となることがあった
。In terms of suppressing platelet adhesion and activation, microphase-separated surfaces and hydrophilic surfaces, especially gel surfaces with water-soluble polymers bonded to the surface, are superior, while hydrophobic surfaces such as polypropylene are inferior. (For example, Transactions of American Society of Artificial International Organs (Trans, Attr, soc, Artif, I
ntern, Organs), vol, XXx■, 7th
5-84 (1987), Polymers and Medicine, Mita Publishing,
73 (1989), etc.). However, a surface with a microphase separation structure can exhibit good blood compatibility by controlling the state of phase separation to an appropriate level, but the conditions under which such phase separation can be created are limited. Therefore, its use was limited. Also,
Gel surfaces with water-soluble polymers bonded to the surface suppress the adhesion of platelets, but platelets and microthrombi activated on the material surface are returned to the body, often resulting in abnormal fluctuations in blood cell components (platelets). was observed and sometimes became a problem.
一方、補体系の活性化については、セルロースやエチレ
ン−ビニルアルコール共重合体などの水酸基を有する表
面が高い活性を示し、ポリプロピレンなどの疎水性表面
では軽微であることが知られている（例えば、人工臓器
１６ （２）、１０４５〜１０５０ （１９８７）など
を参照）。しかし、セルロース系やビニルアルコール系
の材料を、例えば人工臓器用膜に使用すると、補体系の
活性化の問題が生じ、また、ポリエチレンなどの疎水性
の表面を使用すると、血小板の粘着・活性化の問題が生
じてしまう。On the other hand, regarding the activation of the complement system, it is known that surfaces with hydroxyl groups such as cellulose and ethylene-vinyl alcohol copolymers exhibit high activity, while hydrophobic surfaces such as polypropylene have a slight activity (for example, Artificial Organs 16 (2), 1045-1050 (1987), etc.). However, when cellulose-based or vinyl alcohol-based materials are used, for example, in membranes for artificial organs, problems arise with activation of the complement system, and when hydrophobic surfaces such as polyethylene are used, platelet adhesion and activation occur. The problem arises.
また、例えば長持間血液と接する人工血管として使用す
る場合には、上記３項目のほかに新生内膜形成や生体組
織の新生と再生が良好に行われるために生体組織（細胞
）との親和性のある材料である必要がある。この人工血
管の材料としては、例えば超極細ポリエステル繊維より
なる人工血管が挙げられる（人工臓器１９ （３） 、
１２８７〜１２９１）。この超極細ポリエステル繊維は
、生体の異物認識〜生体防御による創傷治癒〜自己組織
再生を利用した医用材料の１つであり、今日人工血管と
して主に使用されている。しかし、この人工血管を微小
血管に長期間適用すると、人工血管が閉塞してしまうと
いう問題が生じる。For example, when used as an artificial blood vessel that comes into contact with blood for a long period of time, in addition to the above three items, it is also necessary to have good compatibility with living tissue (cells) so that neointimal formation and new generation and regeneration of living tissue are performed well. It must be made of a certain material. Examples of materials for this artificial blood vessel include artificial blood vessels made of ultrafine polyester fibers (Artificial Organs 19 (3),
1287-1291). This ultra-fine polyester fiber is one of the medical materials that utilizes the biological body's recognition of foreign substances, wound healing through biological defense, and self-tissue regeneration, and is currently mainly used as artificial blood vessels. However, if this artificial blood vessel is applied to microvessels for a long period of time, a problem arises in that the artificial blood vessel becomes occluded.
さらに、血液以外にも生体組織や体液と接する医用材料
、例えば、生体内に長期間埋入して使用される！！ｉ＠
防止膜やインブラント材、あるいは創傷部に接して使用
される創傷被覆材では、生体からの異物認識が少なく、
生体から剥離しやすい表面（非癒着性表面）が必要とさ
れる。しかしながら、従来上記材料として使用されてい
るシリコーン、ポリウレタンお−よびポリテトラフルオ
ロエチレンでは、材料表面に組織が癒着してしまったり
、生体の異物認識が強すぎて、満足する性能が得られて
いなかった。Furthermore, in addition to blood, medical materials that come into contact with living tissue and body fluids, such as those that are implanted in living bodies for long periods of time, are used! ! i@
In the case of preventive membranes, implant materials, or wound dressings used in contact with the wound, there is little recognition of foreign objects by living organisms.
A surface that is easily peeled off from the living body (non-adhesive surface) is required. However, silicone, polyurethane, and polytetrafluoroethylene, which have been conventionally used as the above-mentioned materials, have not been able to provide satisfactory performance because tissues tend to adhere to the material surface and the body's ability to recognize foreign substances is too strong. Ta.
以上より、従来の医用材料においては、血小板の粘着・
活性化の抑制、補体系の活性化の抑制、生体組織との親
和性といった生体適合性を同時に満たす合成高分子表面
を容易に得ることができなかった。From the above, in conventional medical materials, platelet adhesion and
It has not been possible to easily obtain a synthetic polymer surface that simultaneously satisfies biocompatibility such as inhibition of activation, inhibition of complement system activation, and affinity with living tissues.
（発明が解決しようとする課題）
したがって、本発明は新規な生体適合性医用材料を提供
することを目的とするものである。本発明はまた、血小
板の粘着・活性化の抑制、補体系の活性化の抑制効果、
生体組織との親和性といった生体適合性を同時に満たす
合成高分子を表面に有する生体適合性医用材料を提供す
ることを目的・とするものである。(Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide a novel biocompatible medical material. The present invention also has the effect of suppressing adhesion and activation of platelets, suppressing activation of the complement system,
The object of the present invention is to provide a biocompatible medical material having a synthetic polymer on its surface that satisfies biocompatibility such as affinity with living tissues.
（課題を解決するための手段）
これらの諸口的は、一般式■で表わされる繰返し単位を
構成成分をする合成高分子を表面に有することを特徴と
する生体組織や体液と接して使用される生体適合性医用
材料によって達成される。(Means for Solving the Problems) These polymers are used in contact with biological tissues and body fluids, and are characterized by having on their surface a synthetic polymer composed of repeating units represented by the general formula (■). Achieved by biocompatible medical materials.
ＣＨ２−ＣＲ３Ｈ−（Ｉ）
Ｃｏｏ−Ｒ’ −０−Ｒ２
（ただし、式中、Ｒ１は炭素数１〜４のアルキレン、Ｒ
２は炭素数１〜４のアルキルであり、またＲ３はＨまた
はＣＨ３をそれぞれ表す）本発明はまた、メトキシエチ
ルアクリレートを主成分とする合成高分子を表面に有す
ることを特徴とする生体組織や体液と接して使用される
生体適合性医用材料である。CH2-CR3H-(I) Coo-R' -0-R2 (wherein, R1 is alkylene having 1 to 4 carbon atoms, R
2 is alkyl having 1 to 4 carbon atoms, and R3 represents H or CH3, respectively. It is a biocompatible medical material used in contact with body fluids.
（作用）
本発明に係わる生体適合性医用材料は、一般式１で表わ
される繰返し単位、いわゆるアルコキシアルキル（メタ
）アクリレートを構成成分とする合成高分子を表面に有
することを特徴とするものである。(Function) The biocompatible medical material according to the present invention is characterized by having on its surface a synthetic polymer containing a repeating unit represented by general formula 1, a so-called alkoxyalkyl (meth)acrylate. .
ＣＨ２ＣＲ３Ｈ（Ｉ）
ＣＯＯ−Ｒ’ −０−Ｒ２
（ただし、式中、Ｒ１は炭素数１〜４、好ましくは炭素
数１〜３、最も好ましくは炭素数１〜２のアルキレン、
Ｒ２は炭素数１〜４、好ましくは炭素数１〜３、最も好
ましくは炭素数１〜２のアルキルであり、またＲ３はＨ
またはＣＨ３をそれぞれ表す。）
前記アルコキシアルキル（メタ）アクリレートの重合体
は、下記のごときアルコキシアルキル（メタ）アクリレ
ートの１種または２種以上の単量体の単独重合体または
共重合体あるいは該アルコキシアルキル（メタ）アクリ
レートとこれと共重合し得る単量体との共重合体である
。CH2CR3H(I) COO-R' -0-R2 (wherein, R1 is alkylene having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, most preferably 1 to 2 carbon atoms,
R2 is alkyl having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, most preferably 1 to 2 carbon atoms, and R3 is H
or CH3, respectively. ) The alkoxyalkyl (meth)acrylate polymer is a homopolymer or copolymer of one or more monomers of the following alkoxyalkyl (meth)acrylates, or a copolymer with the alkoxyalkyl (meth)acrylates. It is a copolymer with a monomer that can be copolymerized with this.
アルコキシアルキル（メタ）アクリレートとしては、メ
トキシメチルアクリレート、メトキシエチルアクリレー
ト、メトキシプロピルアクリレート、エトキシメチルア
クリレート、エトキシエチルアクリレート、エトキシプ
ロピルアクリレート、エトキシブチルアクリレート、プ
ロポキシメチルアクリレート、ブトキシエチルアクリレ
ート、メトキシブチルアクリレート、メトキシメチルメ
タクリレート、メトキシエチルメタクリレート、エトキ
シメチルメタクリレート１．エトキシエチルメタクリレ
ート、プロポキシメチルメタクリレート、ブトキシエチ
ルメタクリレート等があり、このうち、経済性や操作性
の点より特にメトキシエチルアクリレートが好ましい。Alkoxyalkyl (meth)acrylates include methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, methoxy Methyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate 1. Examples include ethoxyethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, and among these, methoxyethyl acrylate is particularly preferred in terms of economy and operability.
アルコキシアルキル（メタ）アクリレートと共重合し得
る単量体としては、例えば、アクリルアミド、Ｎ、Ｎ−
ジメチルアクリルアミド、Ｎ、 Ｎ−ジエチルアクリ
ルアミド、アミノメチルアクリレート、アミノエチルア
クリレート、アミノイソプロピルアクリレート、ジアミ
ノメチルアクリレート、ジアミノエチルアクリレート、
ジアミノブチルアクリレート、メタアクリルアミド、Ｎ
、 Ｎ−、ジメチルメタクリルアミド、Ｎ、Ｎ−ジエ
チルメタクリルアミド、アミノメチルメタクリレート、
アミノエチルメタクリレート、ジアミノメチルメタクリ
レート、ジアミノエチルメタクリレート、メチルアクリ
レート、エチルアクリレート、イソプロピルアクリレー
ト、ブチルアクリレート、２−エチルへキシルアクリレ
ート、メチルメタクリレート、エチルメタクリレート、
ブチルメタクリレート、ヘキシルアクリレート、ヘキシ
ルメタクリレート、エチレン、プロピレン等がある。Examples of monomers copolymerizable with alkoxyalkyl (meth)acrylate include acrylamide, N, N-
Dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, diaminoethyl acrylate,
Diaminobutyl acrylate, methacrylamide, N
, N-, dimethyl methacrylamide, N, N-diethyl methacrylamide, aminomethyl methacrylate,
Aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate, methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate,
Examples include butyl methacrylate, hexyl acrylate, hexyl methacrylate, ethylene, propylene, etc.
これらの共重合性単量体は、得られる重合体の生体適合
性が損なわれない程度の量で使用される。These copolymerizable monomers are used in amounts that do not impair the biocompatibility of the resulting polymer.
メトキシアクリレートよりなるモノポリマーは吸水性と
ゴム弾性を有し、物性としては必ずしも優れていないた
め、改質剤としては使用できるものの、フィルムあるい
は中空糸膜などの成形体としての使用には問題かあった
。従って、メタクリレートやメチルメタクリレート４ど
のホモポリマーのガラス転位点が３００に以上の疎水性
単量体と共重合させることによって、ヤング率や強度な
どの物性が向上し、各種の成形体としても有用となる。A monopolymer made of methoxy acrylate has water absorption and rubber elasticity, but does not necessarily have excellent physical properties, so although it can be used as a modifier, it may be problematic to use it as a molded object such as a film or hollow fiber membrane. there were. Therefore, by copolymerizing a homopolymer such as methacrylate or methyl methacrylate 4 with a hydrophobic monomer having a glass transition point of 300 or higher, physical properties such as Young's modulus and strength can be improved, making it useful as a variety of molded products. Become.
また、共重合性単量体としては、分子内にヒドロキシル
基やカチオン性基を有しない単量体が、生体適合性を損
なわれにくいので好ましい。共重合体は、ランダム共重
合体、ブロック共重合体、グラフト共重合体のいずれで
もよく、ラジカル重合やイオン重合、マクロマーを利用
した重合等の公知の方法で使用できる。Further, as the copolymerizable monomer, a monomer having no hydroxyl group or cationic group in the molecule is preferable because biocompatibility is less likely to be impaired. The copolymer may be a random copolymer, a block copolymer, or a graft copolymer, and can be used by known methods such as radical polymerization, ionic polymerization, and polymerization using macromers.
共重合体より形成される表面を有する医用材料では、メ
トキシエチルアクリレートが有効に生体組織や体液と接
して使用されなければならない。In medical materials having a surface formed from a copolymer, methoxyethyl acrylate must be used effectively in contact with living tissues and body fluids.
例えば、ランダム共重合体の場合では、共重合する単量
体よりなるホモポリマーがポリメトキシエチルアクリレ
ートより親水性である場合、該単量体の比率は６０％以
下が好ましい。そのような単量体としては、アクリルア
ミド系誘導体のようにホモポリマーが水溶性である単量
体を例示できる。６０％を越えるとアルコキシアルキル
ジアクリレートによる効果が低下してしまうからである
。For example, in the case of a random copolymer, if a homopolymer consisting of monomers to be copolymerized is more hydrophilic than polymethoxyethyl acrylate, the ratio of the monomers is preferably 60% or less. Examples of such monomers include monomers whose homopolymers are water-soluble, such as acrylamide derivatives. This is because if it exceeds 60%, the effect of the alkoxyalkyl diacrylate will decrease.
一方、共重合する単量体が、アルキル（メタ）アクリレ
ートなどの疎水性単量体である場合、該単量体の比率は
９５％以下であることが好ましい。On the other hand, when the monomer to be copolymerized is a hydrophobic monomer such as alkyl (meth)acrylate, the ratio of the monomer is preferably 95% or less.
メトキシエチルアクリレートのほうがより親水性である
ため、生体組織との界面において、安定に存在しやす（
、少墓であっても効果を発現することとなる。Methoxyethyl acrylate is more hydrophilic, so it tends to exist stably at the interface with living tissues (
, the effect will be manifested even in small graves.
ブロック共重合体やグラフト共重合体の場合においても
同様の現象がより強く発現されるため、共重合する単量
体よりなるホモポリマーがポリメトキシエチルアクリレ
ートより親水性である場合、該単量体の比率は１０％以
下が好ましく、共重合する単量体が、アルキル（メタ）
アクリレートなどの疎水性単量体である場合、該単量体
の比率は９５％以下であることが好ましい。Similar phenomena are more strongly expressed in the case of block copolymers and graft copolymers, so if the homopolymer consisting of monomers to be copolymerized is more hydrophilic than polymethoxyethyl acrylate, the monomer The ratio of is preferably 10% or less, and the monomer to be copolymerized is alkyl (meth)
In the case of a hydrophobic monomer such as acrylate, the proportion of the monomer is preferably 95% or less.
このようにして得られるアルコキシアルギル（メタ）ア
クリレート重合体の数平均分子量は１ｏ、ｏｏｏ〜３０
０．０００、好ましくは３０゜０００〜１００，０００
である。The number average molecular weight of the alkoxyargyl (meth)acrylate polymer thus obtained is 1o, ooo to 30
0.000, preferably 30°000 to 100,000
It is.
本発明の生体適合性医用材料の形態としては、人工腎臓
用膜、血漿分離用膜、カテーテル、人工肺用膜、人工血
管、癒着防止膜、人工皮膚、創傷被覆材、インブラント
用材料、ＤＤＳ基材等を例示することができる。特に、
大量の血液と接する医療用分離膜や長期間組織と接する
創傷被覆材やインブラント用材料として好適に使用され
る。Forms of the biocompatible medical material of the present invention include membranes for artificial kidneys, membranes for plasma separation, catheters, membranes for artificial lungs, artificial blood vessels, anti-adhesion membranes, artificial skin, wound dressings, materials for implants, and DDS. A base material etc. can be illustrated. especially,
It is suitably used as a medical separation membrane that comes into contact with a large amount of blood, or as a material for wound dressings or implants that come into contact with tissues for a long period of time.
また、本発明の生体適合性医用材料は、一般式■で表わ
される繰返し単位を構成成分とする合成高分子を表面に
有していればよく、該合成高分子のみよりなる物品であ
る必要はない。これは、材料の表面構造が生体適合性と
密接な関係があるからである。したがって、基材の表面
に該材料を被覆したものでよい。基材の表面に該生体適
合性医療用材料を保持させる方法としては、被覆法が最
も一般的な方法であるが、放射線や紫外線によるグラフ
ト重合やプラズマ重合などにより保持することも可能で
ある。Furthermore, the biocompatible medical material of the present invention only needs to have a synthetic polymer having a repeating unit represented by the general formula (1) on its surface, and does not need to be an article made only of the synthetic polymer. do not have. This is because the surface structure of the material is closely related to its biocompatibility. Therefore, the material may be coated on the surface of the base material. The most common method for retaining the biocompatible medical material on the surface of a base material is a coating method, but it is also possible to retain it by graft polymerization using radiation or ultraviolet rays, plasma polymerization, or the like.
被覆法を行なう場合には、前記アルコキシアルキル（メ
タ）アクリレート重合体の溶液を浸漬法、スプレー法、
フローコーター法等公知の方法により被覆し、ついで乾
燥することにより行なわれる。When performing the coating method, a solution of the alkoxyalkyl (meth)acrylate polymer is applied by dipping, spraying,
This is carried out by coating by a known method such as a flow coater method and then drying.
その膜厚は１μｍ以上であれば充分であり、好ましくは
１＋＋＋＋ａ以下である。It is sufficient that the film thickness is 1 μm or more, and preferably 1++++a or less.
プラズマグラフト重合により基材の表面に前記アルコキ
シアルキル（メタ）アクリレート重合体層を形成するに
は、１０−３〜１０Ｔｏｒｒ、好ましくは１０−２〜Ｉ
Ｔｏｒｒの減圧下にアルゴン、窒素、空気、種々のモ
ノマー等の雰囲気下に低温プラズマを１〜３００秒間、
好ましくは２〜３０秒間照射したのち、前記単量体を供
給してプラズマ開始重合を行なうことにより行なわれる
。In order to form the alkoxyalkyl (meth)acrylate polymer layer on the surface of the substrate by plasma graft polymerization, the pressure is 10-3 to 10 Torr, preferably 10-2 to I
Low-temperature plasma is applied for 1 to 300 seconds in an atmosphere of argon, nitrogen, air, various monomers, etc. under a reduced pressure of Torr.
Preferably, after irradiation for 2 to 30 seconds, the monomer is supplied to perform plasma-initiated polymerization.
基材としては、目的とする人工臓器ないし医療用具によ
り異なるが、例えばポリエチレン、ポリプロピレン、ポ
リ塩化ビニル、ポリ塩化ビニリデン、ポリフッ化ビニリ
デン、ポリテトラフルオロエチレン、ハロゲン化ポリオ
レフィン、ポリエチレンテレフタレート、ポリブチレン
テレフタレート、ポリカーボネート等がある。The base material varies depending on the intended artificial organ or medical device, but examples include polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, polyvinylidene fluoride, polytetrafluoroethylene, halogenated polyolefin, polyethylene terephthalate, polybutylene terephthalate, Polycarbonate, etc.
本発明の生体適合性医用材料において、アルコキシアル
キルアクリレートは、分子内に極性基としてエーテル結
合とエステル結合を有しているだけであり、これらの極
性基は窒素原子（アミノ基、イミノ基）やカルボキシル
基などと異なり、生体成分と強い静電的相互作用を持た
ないため、組織や体液に対して活性が低く、また、適度
な親水性で大きな疎水基を持たないため、疎水性相互作
用も小さくなり、このため優れた生体適合性を発現する
ものと推測される。例えば１、合成高分子材料表面と体
液中のタンパク質との接触を考えると、なるべ（タンパ
ク質の吸着変性や活性化が起こらない表面が好ましく、
物質量に働く大きな相互作用である疎水性相互作用や静
電的相互作用を小さくすることが有用であると考えられ
ており、このことからも本発明の医用材料は好適な表面
構造となり得る。In the biocompatible medical material of the present invention, the alkoxyalkyl acrylate only has an ether bond and an ester bond as polar groups in the molecule, and these polar groups include nitrogen atoms (amino groups, imino groups) and Unlike carboxyl groups, etc., it does not have strong electrostatic interactions with biological components, so it has low activity against tissues and body fluids.It is also moderately hydrophilic and does not have large hydrophobic groups, so it does not have hydrophobic interactions. It is presumed that this results in excellent biocompatibility. For example, 1. When considering the contact between the surface of a synthetic polymer material and proteins in body fluids, it is preferable to have a surface that does not adsorb, denature, or activate proteins;
It is believed that it is useful to reduce hydrophobic interactions and electrostatic interactions, which are major interactions that affect the amount of substances, and this also allows the medical material of the present invention to have a suitable surface structure.
また、本発明の医用材料の表面は、水酸基が存在するこ
とな（、適度の親水性を有しているので、血液浄化等の
膜素材として血液と接して使用した場合、補体系の活性
化や血小板の粘着が軽微となり、優れた血液適合性を発
現することとなる。In addition, the surface of the medical material of the present invention has no hydroxyl groups (and has moderate hydrophilicity, so when used in contact with blood as a membrane material for blood purification etc., it can activate the complement system. The adhesion of blood and platelets becomes slight, resulting in excellent blood compatibility.
さらには、水酸基に起用した水素結合による生体成分と
の相互作用、吸着タンパクの変性なども起こらなくなる
。Furthermore, interactions with biological components and denaturation of adsorbed proteins due to hydrogen bonds in hydroxyl groups will no longer occur.
また、メトキシエチル（メタ）アクリレートやエトキシ
エチル（メタ）アクリレートなどのアルコキシアルキル
（メタ）アクリレートは、適度の親水性と吸水性（メト
キンエチルアクリレートでは吸水率４．１％）を有して
いるので、薄い膜状に成形した場合、創傷部の適度な蒸
散と保温が要求される創傷被覆材として優れたものとな
ることができる。In addition, alkoxyalkyl (meth)acrylates such as methoxyethyl (meth)acrylate and ethoxyethyl (meth)acrylate have moderate hydrophilicity and water absorption (methoxyethyl acrylate has a water absorption rate of 4.1%). Therefore, when formed into a thin film, it can be an excellent wound dressing material that requires appropriate evaporation and heat retention of the wound area.
（実施例）
実施例１
ポリプロピレンフィルム（二村化学株式会社製、ＦＯＰ
＃６０、厚さ６０μｍ）の表面をプラズマ処理（乾燥空
気で１． ０Ｔｏｒｒ、 ３０秒）した後、メトキシエ
チルアクリレートを２０重量部含むメタノール溶液中に
アゾビスイソブチルニトリル（０，５重合部）を開始剤
として、５０℃、３時間重合して得られたポリメトキシ
エチルアクリレートを上記ポリプロピレンフィルムの表
面にコーティングすることにより、メトキシエチルアク
リレートをコーティングしたフィルムを作製した。(Example) Example 1 Polypropylene film (manufactured by Futamura Chemical Co., Ltd., FOP
#60, thickness 60 μm) was subjected to plasma treatment (dry air at 1.0 Torr for 30 seconds), and then azobisisobutylnitrile (0.5 polymerization parts) was added to a methanol solution containing 20 parts by weight of methoxyethyl acrylate. A film coated with methoxyethyl acrylate was prepared by coating the surface of the polypropylene film with polymethoxyethyl acrylate obtained by polymerization at 50° C. for 3 hours as an initiator.
このようにして得られたフィルムをラット背部と腹腔に
埋入し、２週問および４週間後に上記フィルムを取り出
して生体適合性を観察したところ、組織や異物反応かほ
とんど認められず、優れた生体適合性を示した。The film obtained in this manner was implanted into the back and abdominal cavity of rats, and after 2 and 4 weeks, the film was removed and biocompatibility was observed. Showed biocompatibility.
実施例２〜３および比較例１〜４
ポリプロピレンフィルムの表面にアルゴン低温プラズマ
を０ 、 Ｉ Ｔｏｒｒ、約１５秒間照射した後、第
１表に示した単量体と接触させてグラフト鎖を形成させ
た。Examples 2 to 3 and Comparative Examples 1 to 4 After irradiating the surface of a polypropylene film with argon low temperature plasma at 0 and I Torr for about 15 seconds, it was brought into contact with the monomers shown in Table 1 to form graft chains. Ta.
得られた材料表面について、実施例１と同様にして、生
体適合性試験を行った。A biocompatibility test was conducted on the surface of the obtained material in the same manner as in Example 1.
なお、比較例４は、ポリエチレンイミンと錯体を形成さ
せた後試験に供した。In Comparative Example 4, a complex was formed with polyethyleneimine and then tested.
結果を１表に示す。The results are shown in Table 1.
実施例２
実施例３
比較例１
比較例２
比較例３
比較例４
メト牛／エチルアクリレート
メトキノブチルアクリレート
ジメチルアクリル了；ト
ビニルピリジン
エチルアクリレート
メタクリル酸
非常に弱い
非常に弱い
中
強
やや弱い
強
実施例４および比較例５〜６
血液との適合性を調べるために、表２に示した材料につ
いて、血小板の粘着テストを行った。すなわち、クエン
酸ナトリウムで抗凝固した人新鮮多血小板血漿と材料表
面とを３０分間接触させ、生理食塩水でリンスし、グル
タルアルデヒドで固定した後、０．１ｍｍ２に粘着した
血小板数を電子顕微鏡で観察した。血小板の形態変化の
進行度により１→２→３−４型に分類して、ＭＳ（モル
フォロジカルスコア）を以下のように定義して血液との
適合性の評価を行った。Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Methyl acrylate Methyl acrylate Methoxybutyl acrylate Dimethyl acrylic; Tovinylpyridine Ethyl acrylate Methacrylic acid Very weak Very weak Medium strong Moderately weak Strong Example 4 and Comparative Examples 5-6 In order to examine compatibility with blood, the materials shown in Table 2 were subjected to a platelet adhesion test. Specifically, fresh human platelet-rich plasma anticoagulated with sodium citrate was brought into contact with the surface of the material for 30 minutes, rinsed with physiological saline, and fixed with glutaraldehyde. Observed. The compatibility with blood was evaluated by classifying platelets into types 1→2→3-4 according to the degree of progression of platelet morphological change, and defining MS (morphological score) as follows.
ＭＳ＝ｎ、Ｘｌ十ｎ２ Ｘ２＋ｎ３ｘ３＋ｎ４ｘ４（ｎ
、は１型の血小板数、ｎ２は２型の血小板数、ｎ３は３
型の血小板数、ｎ４は４型の血小板数）結果を第２表に
示す。これより、ポリメトキシエチルアクリレート表面
は、ＭＳが小さく、血小板の粘着が抑制されていたこと
が示される。MS=n, Xl+n2 X2+n3x3+n4x4(n
, is the number of type 1 platelets, n2 is the number of type 2 platelets, n3 is 3
n4 is the number of type 4 platelets) The results are shown in Table 2. This shows that the MS of the polymethoxyethyl acrylate surface was small, and the adhesion of platelets was suppressed.
第２表
実施例４
実施例５
比較例１
比較例２
比較例３
比較例４
比較例５
ボリハ牛ジエチルアクリレート表面
ポリメトキ／ブチルアクリレ−）表面
ポリエチルメタクリレート表面
ポリビニルピリジン表面
ポリエチル了クリレート表面
ボップロとレン表面
ポリメチルメタクリレート表面
実施例６および比較例７〜８
補体系の活性化について調べるために、メトキシエチル
アクリレートよりなる重合体を表面に有する孔径０．４
５μｍのポリプロピレン多孔質膜（実施例５）を実施例
２と同様の方法を用いてプラズマグラフト法により作製
した。Table 2 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Polymethacrylate surface Polymethoxy/butyl acrylate surface Polyethyl methacrylate surface Polyvinyl pyridine surface Polyethyl acrylate surface Boppro and Ren surfaces Polymethyl methacrylate surface Example 6 and Comparative Examples 7 to 8 In order to investigate the activation of the complement system, a pore size of 0.4 with a polymer made of methoxyethyl acrylate on the surface was used.
A 5 μm polypropylene porous membrane (Example 5) was produced by plasma grafting using the same method as in Example 2.
このようして得られｊ：多孔質膜を用いて入断鮮血を濾
過して、濾液の血漿中に含まれる補体系の活性化成分で
あるＣ３ａの定量を行った。The fresh blood thus obtained was filtered using a porous membrane, and C3a, which is an activating component of the complement system, contained in the plasma of the filtrate was quantified.
また、比較例として、孔径０．４５μｍのアトパンチツ
ク■製セルロースアセテート膜（比較例６）とポリプロ
ピレン膜（比較例７）についても？ＪｊｌＪ定［７た。Also, as a comparative example, a cellulose acetate membrane (Comparative Example 6) and a polypropylene membrane (Comparative Example 7) made by Atopanchiku ■ with a pore size of 0.45 μm are also considered. JjlJ set [7].
結果を以下に示す。The results are shown below.
濾液巾のＣ３ａ濃度・′分離前血葉巾のＣ３ａｆｆｉｉ
実施例６１．５
比較例６ ２１．２
比較例７５，６
実施例７〜９
創傷被覆膜や医療用膜のような膜状物を作製するために
はある程度の強度が要求され、他のモノマーとの共重合
が必要となることがあるが、アルコキシアルキルアクリ
レートは、他のアクリル系モノマーやスチレン、エチレ
ン等と共重合することが知られている。例えば、メトキ
シエチルアクリレートを薄い膜状に成形して強度を持た
せるためには、エチルメタクリレートなどの疎水性でガ
ラス転位点の高いポリマーと共重合させるとよい。C3a concentration in filtrate width・'C3affii in blood lobe width before separation
Example 61.5 Comparative Example 6 21.2 Comparative Examples 75, 6 Examples 7 to 9 A certain degree of strength is required to produce membrane-like materials such as wound covering membranes and medical membranes, and other Although copolymerization with monomers may be required, alkoxyalkyl acrylates are known to copolymerize with other acrylic monomers, styrene, ethylene, etc. For example, in order to form methoxyethyl acrylate into a thin film with strength, it is preferable to copolymerize it with a hydrophobic polymer having a high glass transition point, such as ethyl methacrylate.
膜状に成形するには、キャスティング法や湿式紡糸法等
の方法でよく、形状も平膜状、中空糸状を問わない。In order to form a membrane, a method such as a casting method or a wet spinning method may be used, and the shape does not matter whether it is a flat membrane or a hollow fiber.
以下に、膜状物の作製についての実施例を示す。Examples regarding the production of a film-like material are shown below.
メトキシエチルアクリレートとエチルメタクリレート（
２： １）をブタノール中で、ベンゾインパーオキシド
（０，１重量％）を開始剤として重合させた。得られた
ポリマー溶液をガラス板上にキャストし、溶媒を蒸発乾
固してメトキンエチルアクリレートを構成成分とした膜
（実施例７）を得た。Methoxyethyl acrylate and ethyl methacrylate (
2: 1) was polymerized in butanol using benzoin peroxide (0.1% by weight) as an initiator. The obtained polymer solution was cast on a glass plate, and the solvent was evaporated to dryness to obtain a film containing metquinethyl acrylate as a constituent component (Example 7).
メトキシエチルアクリレートとエチルメタクリレート（
１： ２）をベンゼン中で、ベンゾインパーオキシド（
０，１重量％）を開始剤として重合させた。得られたポ
リマー溶液をガラス板上にキャストし、溶媒を蒸発乾固
してメトキシエチルアクリレートを構成成分とした膜（
実施例８）を得た。Methoxyethyl acrylate and ethyl methacrylate (
1:2) in benzene, benzoin peroxide (
0.1% by weight) as an initiator. The obtained polymer solution was cast on a glass plate, and the solvent was evaporated to dryness to form a film containing methoxyethyl acrylate as a constituent (
Example 8) was obtained.
メトキシエチルアクリレートとメチルメタクリレート（
１： ５）をベンゼン中で、ベンゾインパーオキシド（
０，１重量％）を開始剤として重合させた。得られたポ
リマー溶液をガラス板上にキャストし、溶媒を蒸発乾固
してメトキンエチルアクリレートを構成成分とした膜（
実施例９）を得た。Methoxyethyl acrylate and methyl methacrylate (
1:5) in benzene, benzoin peroxide (
0.1% by weight) as an initiator. The obtained polymer solution was cast on a glass plate, and the solvent was evaporated to dryness to form a film containing metquinethyl acrylate as a constituent (
Example 9) was obtained.
実施例７〜９の膜について、実施例４と同様にして血小
板の粘着テストを行った。The membranes of Examples 7 to 9 were subjected to a platelet adhesion test in the same manner as in Example 4.
結果を以下に示す。これより、粘着した血小板はほとん
ど観察されなかった。The results are shown below. From this, almost no adherent platelets were observed.
ＭＳ
実施例７６
実施例８ １４
実施例９ １１
例えば、実施例９で得られたメトキシエチルアクリレー
トとメチルメタクリレートの共重合体をメタノールに溶
解させ、塩化カルシウム：メタノール：水＝１：１：８
の組成の凝固浴にキャストすることにより、メトキシエ
チルアクリレートを含む重合体よりなる膜状物を得るこ
とができる。MS Example 76 Example 8 14 Example 9 11 For example, the copolymer of methoxyethyl acrylate and methyl methacrylate obtained in Example 9 was dissolved in methanol, and calcium chloride:methanol:water=1:1:8
By casting in a coagulation bath having the composition, a film-like material made of a polymer containing methoxyethyl acrylate can be obtained.
このようにして得られる膜状物は、創傷被覆膜や血漿分
離膜、あるいは人工腎臓用膜として有用である。The membrane thus obtained is useful as a wound covering membrane, a plasma separation membrane, or a membrane for artificial kidneys.
（発明の効果）
以上述べたように、本発明は、一般式１で表わされる繰
返し単位を構成とする合成高分子を表面に有することを
特徴とする生体組織や体液と接して使用される生体適合
性医用材料であるから、血液、体液、生体組織と接触し
た際に、血小板の粘着や活性化が軽微で、また補体系の
活性化が軽微であり、さらに生体組織との親和性に優れ
ているという利点があり、このため、人工腎臓用膜、血
漿分離膜、カテーテル、人工肺用膜、人工血管、人工皮
膚等の人工臓器ないしは医療用具の材料として極めて有
用である。(Effects of the Invention) As described above, the present invention provides a method for use in a living body that is used in contact with living tissue or body fluid, and is characterized by having a synthetic polymer having a repeating unit represented by the general formula 1 on its surface. Because it is a compatible medical material, when it comes into contact with blood, body fluids, and living tissues, it has minimal adhesion and activation of platelets, minimal activation of the complement system, and has excellent compatibility with living tissues. Therefore, it is extremely useful as a material for artificial organs or medical devices such as membranes for artificial kidneys, plasma separation membranes, catheters, membranes for artificial lungs, artificial blood vessels, and artificial skin.
Claims (1)
する合成高分子を表面に有することを特徴とする生体組
織や体液と接して使用される生体適合性医用材料。 ▲数式、化学式、表等があります▼（ I ） （ただし、式中、Ｒ＾１は炭素数１〜４のアルキレン、
Ｒ＾２は炭素数１〜４のアルキルであり、またＲ＾３は
ＨまたはＣＨ＿３をそれぞれ表す）（２）メトキシエチ
ル（メタ）アクリレートを主成分とする合成高分子を表
面に有することを特徴とする請求項１に記載の生体組織
や体液と接して使用される生体適合性医用材料。(1) A biocompatible medical material used in contact with biological tissue or body fluid, characterized by having a synthetic polymer containing a repeating unit represented by general formula I on its surface. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, R^1 is alkylene with 1 to 4 carbon atoms,
(R^2 is alkyl having 1 to 4 carbon atoms, and R^3 represents H or CH_3, respectively) (2) Characterized by having a synthetic polymer mainly composed of methoxyethyl (meth)acrylate on the surface. The biocompatible medical material according to claim 1, which is used in contact with living tissue or body fluid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2280031A JP2806510B2 (en) | 1990-10-18 | 1990-10-18 | Artificial organ membrane or medical device |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2280031A JP2806510B2 (en) | 1990-10-18 | 1990-10-18 | Artificial organ membrane or medical device |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04152952A true JPH04152952A (en) | 1992-05-26 |
| JP2806510B2 JP2806510B2 (en) | 1998-09-30 |
Family
ID=17619336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2280031A Expired - Fee Related JP2806510B2 (en) | 1990-10-18 | 1990-10-18 | Artificial organ membrane or medical device |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2806510B2 (en) |
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| JPS56140927A (en) * | 1980-04-07 | 1981-11-04 | Nitto Electric Ind Co Ltd | Medical member |
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| JPS56140927A (en) * | 1980-04-07 | 1981-11-04 | Nitto Electric Ind Co Ltd | Medical member |
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