JP7054689B2 - 人工肺の製造方法及び人工肺 - Google Patents
人工肺の製造方法及び人工肺 Download PDFInfo
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- JP7054689B2 JP7054689B2 JP2019505724A JP2019505724A JP7054689B2 JP 7054689 B2 JP7054689 B2 JP 7054689B2 JP 2019505724 A JP2019505724 A JP 2019505724A JP 2019505724 A JP2019505724 A JP 2019505724A JP 7054689 B2 JP7054689 B2 JP 7054689B2
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- Prior art keywords
- hollow fiber
- fiber membrane
- artificial lung
- polymer compound
- blood
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- LWMFAFLIWMPZSX-UHFFFAOYSA-N bis[2-(4,5-dihydro-1h-imidazol-2-yl)propan-2-yl]diazene Chemical compound N=1CCNC=1C(C)(C)N=NC(C)(C)C1=NCCN1 LWMFAFLIWMPZSX-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- NSGQRLUGQNBHLD-UHFFFAOYSA-N butan-2-yl butan-2-yloxycarbonyloxy carbonate Chemical compound CCC(C)OC(=O)OOC(=O)OC(C)CC NSGQRLUGQNBHLD-UHFFFAOYSA-N 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000010538 cationic polymerization reaction Methods 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000012986 chain transfer agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000000502 dialysis Methods 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
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 238000010828 elution Methods 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
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000012690 ionic polymerization Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 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
- QYZFTMMPKCOTAN-UHFFFAOYSA-N n-[2-(2-hydroxyethylamino)ethyl]-2-[[1-[2-(2-hydroxyethylamino)ethylamino]-2-methyl-1-oxopropan-2-yl]diazenyl]-2-methylpropanamide Chemical compound OCCNCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCNCCO QYZFTMMPKCOTAN-UHFFFAOYSA-N 0.000 description 1
- 238000006213 oxygenation reaction Methods 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
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002492 poly(sulfone) Polymers 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-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
- NHARPDSAXCBDDR-UHFFFAOYSA-N propyl 2-methylprop-2-enoate Chemical compound CCCOC(=O)C(C)=C NHARPDSAXCBDDR-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- OPQYOFWUFGEMRZ-UHFFFAOYSA-N tert-butyl 2,2-dimethylpropaneperoxoate Chemical compound CC(C)(C)OOC(=O)C(C)(C)C OPQYOFWUFGEMRZ-UHFFFAOYSA-N 0.000 description 1
- VNJISVYSDHJQFR-UHFFFAOYSA-N tert-butyl 4,4-dimethylpentaneperoxoate Chemical compound CC(C)(C)CCC(=O)OOC(C)(C)C VNJISVYSDHJQFR-UHFFFAOYSA-N 0.000 description 1
- NMOALOSNPWTWRH-UHFFFAOYSA-N tert-butyl 7,7-dimethyloctaneperoxoate Chemical compound CC(C)(C)CCCCCC(=O)OOC(C)(C)C NMOALOSNPWTWRH-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Description
前記外表面及び前記内表面のいずれか一方を、抗血栓性高分子化合物を含むコロイド溶液と接触させ、他方の表面側に炭酸ガスを流通させる工程を有する、人工肺の製造方法に関する。本発明によれば、中空糸膜に対する抗血栓性高分子材料(抗血栓性高分子化合物)のコート量を増加させた人工肺を製造できる。
本発明に係る人工肺の製造方法は、外表面と、内腔を形成する内表面と、前記外表面と前記内表面とを連通する開口部と、を有する複数のガス交換用多孔質中空糸膜を有する人工肺の製造方法であって、前記外表面及び前記内表面のいずれか一方を、抗血栓性高分子化合物を含むコロイド溶液と接触させ、他方の表面側に炭酸ガスを流通させる工程を有する。
本工程では、中空糸膜の外表面又は内表面に塗布するための、コロイド溶液を調製する。上述のように、本発明に係る方法において用いられるコロイド溶液は、抗血栓性高分子化合物を含む。
本発明において用いられる抗血栓性高分子化合物は、中空糸膜に塗布されることにより、人工肺に抗血栓性を付与する化合物である。
で示されるアルコキシアルキル(メタ)アクリレート由来の構成単位を有すると好ましい。上記の式(I)で示される構成単位を有する化合物は、抗血栓性生体適合性(血小板の粘着/付着の抑制・防止効果、及び血小板の活性化の抑制・防止効果)、特に血小板の粘着/付着の抑制・防止効果に優れる。ゆえに、上記構成単位を有する化合物を用いることにより、抗血栓性生体適合性(血小板の粘着/付着の抑制・防止効果、及び血小板の活性化の抑制・防止効果)、特に血小板の粘着/付着の抑制・防止効果に優れた人工肺を製造することが可能となる。
抗血栓性高分子化合物を含む溶液(コロイド溶液)の調製に使用される溶媒は、抗血栓性高分子化合物を適度に分散させてコロイド溶液を調製することができるものであれば特に制限されない。中空糸膜の細孔の外表面又は内表面(酸素含有ガスが流れる側の表面)までのコロイド溶液の浸透をより有効に防止する観点から、溶媒が水を含むことが好ましい。ここで、水は、純水、イオン交換水又は蒸留水であると好ましく、なかでも、蒸留水であると好ましい。
次に、上記の通り調製したコロイド溶液を、中空糸膜の外表面又は内表面に塗布(被覆)する。具体的には、人工肺(例えば、後述する図1又は図3のような構造のもの)を組み立てた後、上記工程(1)において調製したコロイド溶液を中空糸膜の外表面及び内表面のいずれか一方と接触させ(又は流通させ)、他方の表面側に炭酸ガスを流通させることによって、中空糸膜の外表面又は内表面(すなわち、血液接触部)を、抗血栓性高分子化合物で被覆する。これにより、中空糸膜の外表面又は内表面に抗血栓性高分子化合物を含む塗膜を形成する。また、中空糸膜に対するコロイド溶液の塗布は、コロイド溶液を中空糸膜の外表面及び内表面のいずれか一方と接触させ(又は流通させ)、他方の表面側に炭酸ガスを流通させる限りにおいては、人工肺の組立前に行ってもよい。
本発明に係る人工肺の製造方法によれば、中空糸膜の外表面又は内表面に、十分な量の抗血栓性高分子化合物を含む被膜を形成することができる。すなわち、本発明の一形態によると、外表面と、内腔を形成する内表面と、前記外表面と前記内表面とを連通する開口部と、を有する複数のガス交換用多孔質中空糸膜を有する人工肺であって、前記外表面及び前記内表面のいずれか一方に、抗血栓性高分子化合物を10mg/m2表面以上100mg/m2表面以下の量で含む被膜を有する、人工肺が提供される。当該被膜中の抗血栓性高分子化合物の量は、15mg/m2表面以上60mg/m2表面以下であることがより好ましい。抗血栓性高分子化合物のコート量が10mg/m2表面以上であれば、抗血栓性に優れた人工肺が得られる。一方、コート量の上限は特に制限されないが、100mg/m2以下であると好ましい。かようなコート量であれば、抗血栓性高分子化合物を含む被膜が厚すぎることによるガス交換能の低下が抑制され、ガス交換能にも優れた人工肺が得られる。なお、上記コート量は、下記実施例に記載の方法によって測定される値を採用する。
製造例1:重量平均分子量42万のPMEAの合成
2-メトキシエチルアクリレート(MEA)80g(0.61mol)をメタノール115gに溶解し、四ツ口フラスコに入れ、50℃でN2バブリングを1時間行い、モノマー溶液を調製した。別途、2,2’-アゾビス(4-メトキシ-2,4-ジメチルバレロニトリル)(V-70、和光純薬工業(株)製)0.08gをメタノール5gに溶解して、重合開始剤溶液を調製した。次に、この重合開始剤溶液をモノマー溶液に添加し、50℃で5時間重合反応を行った。所定時間重合後、重合溶液をエタノールに滴下し、析出した重合体(PMEA)を回収した。なお、回収した重合体の重量平均分子量を測定したところ、420,000であった。
実施例1-1:PMEA濃度0.1質量%のコート液
上記製造例1で合成したPMEA(重量平均分子量=42万)0.4gを、20gのメタノールに溶解した。別の容器に蒸留水370gを添加し、スターラーで撹拌しながら、上記PMEAのメタノール溶液を20g/分の添加速度で添加した。その後、25℃で10分間撹拌し、白濁したコート液(1)を得た。コート液(1)は、PMEAのコロイドが分散されたコロイド液であった。
実施例1-1において用いたPMEAの量を1.2gへと変更したこと以外は、実施例1-1と同様にしてコート液(2)を得た。コート液(2)は、PMEAのコロイドが分散されたコロイド液であった。
実施例2-1
内径が195μm、外径が295μm、肉厚が50μm、空孔率が約35体積%、外表面の孔径(すなわち、開口部の平均直径)が80nmの多孔質ポリプロピレン製のガス交換用多孔質中空糸膜が巻きつけられた、膜面積(中空糸膜の外表面の面積)が0.5m2である血液外部灌流型中空糸膜人工肺(a)を作製した。
上記実施例2-1において炭酸ガスの流通時間を10分間へと変更したこと以外は、実施例2-1と同様にして血液外部灌流型中空糸膜人工肺(2)を製造した。なお、このようにして得られた血液外部灌流型中空糸膜人工肺(2)(以下、単に「人工肺(2)」とも称する)を製造した。
上記実施例2-1において炭酸ガスの流通時間を60分間へと変更したこと以外は、実施例2-1と同様にして血液外部灌流型中空糸膜人工肺(3)を製造した。なお、このようにして得られた血液外部灌流型中空糸膜人工肺(3)(以下、単に「人工肺(3)」とも称する)を製造した。
上記実施例2-1においてコート液(1)を人工肺(a)の血液流路に充填した状態で、ガス流通側(内表面側)から炭酸ガスを流通させずに2分間静置したこと以外は、実施例1-1と同様にして血液外部灌流型中空糸膜人工肺(4)を製造した。なお、このようにして得られた血液外部灌流型中空糸膜人工肺(4)(以下、単に「人工肺(4)」とも称する)を製造した。
上記比較例2-1において用いたコート液(1)をコート液(2)へと変更したこと以外は比較例2-1と同様にして血液外部灌流型中空糸膜人工肺(5)を製造した。なお、このようにして得られた血液外部灌流型中空糸膜人工肺(5)(以下、単に「人工肺(5)」とも称する)を製造した。
上記実施例2-1~2-3の人工肺(1)~(3)及び比較例2-1~2-2の人工肺(4)~(5)について、下記方法によって、PMEAのコート量を測定した。
上記実施例2-1及び比較例2-1で得られた人工肺(1)及び人工肺(4)について、下記方法に従って、抗血栓性を評価した。
2…ハウジング、
3…中空糸膜、
3a…外面層、
3a’…外表面、
3b…内部層、
3c…内面層、
3c’…内表面、
3d…通路、
3e…開口部、
4,5…隔壁、
6…血液流入口、
7…血液流出口、
8…ガス流入口、
10…ガス流入側ヘッダー、
11…ガス流出側ヘッダー、
12…血液室、
14…ガス流出室、
18…抗血栓性高分子化合物、
17…血液室、
20…中空糸膜外部血液灌流型人工肺、
32…血液流通用開口、
31…内側筒状部材、
22…筒状中空糸膜束、
23…ハウジング、
25,26…隔壁、
28…血液流入口、
29a,29b…血液流出口、
24…ガス流入口、
27…ガス流出口。
Claims (6)
- 外表面と、内腔を形成する内表面と、前記外表面と前記内表面とを連通する開口部と、を有する複数のガス交換用多孔質中空糸膜を有する人工肺の製造方法であって、
前記外表面及び前記内表面のいずれか一方を、抗血栓性高分子化合物を含むコロイド溶液と接触させ、他方の表面側に炭酸ガスを流通させる工程を有する、人工肺の製造方法。 - 前記工程において、前記炭酸ガスを、前記コロイド溶液1gに対して、50mL以上5000mL以下流通させる、請求項1に記載の人工肺の製造方法。
- 前記コロイド溶液は、抗血栓性高分子化合物を0.01質量%以上含む、請求項1又は2に記載の人工肺の製造方法。
- 前記工程において、前記外表面を、抗血栓性高分子化合物を含むコロイド溶液と接触させ、前記内表面側に炭酸ガスを流通させる、請求項1~3のいずれか1項に記載の人工肺の製造方法。
- 前記抗血栓性高分子化合物の重量平均分子量は、200,000を超えて800,000未満である、請求項1~5のいずれか1項に記載の人工肺の製造方法。
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