WO2017126612A1 - 半透膜及びその製造方法 - Google Patents
半透膜及びその製造方法 Download PDFInfo
- Publication number
- WO2017126612A1 WO2017126612A1 PCT/JP2017/001764 JP2017001764W WO2017126612A1 WO 2017126612 A1 WO2017126612 A1 WO 2017126612A1 JP 2017001764 W JP2017001764 W JP 2017001764W WO 2017126612 A1 WO2017126612 A1 WO 2017126612A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- semipermeable membrane
- cells
- complement
- albumin
- stock solution
- Prior art date
Links
- 239000012528 membrane Substances 0.000 title claims abstract description 249
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 230000035699 permeability Effects 0.000 claims abstract description 49
- 102000009027 Albumins Human genes 0.000 claims abstract description 43
- 108010088751 Albumins Proteins 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229920005989 resin Polymers 0.000 claims abstract description 30
- 239000011347 resin Substances 0.000 claims abstract description 30
- 230000000295 complement effect Effects 0.000 claims description 43
- 210000002966 serum Anatomy 0.000 claims description 41
- 239000011550 stock solution Substances 0.000 claims description 37
- 229920000642 polymer Polymers 0.000 claims description 28
- 238000005259 measurement Methods 0.000 claims description 27
- 102000004169 proteins and genes Human genes 0.000 claims description 24
- 108090000623 proteins and genes Proteins 0.000 claims description 24
- 239000000654 additive Substances 0.000 claims description 21
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 claims description 20
- 239000011148 porous material Substances 0.000 claims description 19
- 230000000996 additive effect Effects 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 13
- 230000024203 complement activation Effects 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 230000015271 coagulation Effects 0.000 claims description 8
- 238000005345 coagulation Methods 0.000 claims description 8
- 229920002492 poly(sulfone) Polymers 0.000 claims description 6
- 238000001179 sorption measurement Methods 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 4
- 229920003169 water-soluble polymer Polymers 0.000 claims description 4
- 239000004952 Polyamide Substances 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 238000006731 degradation reaction Methods 0.000 claims description 3
- 229920002239 polyacrylonitrile Polymers 0.000 claims description 3
- 229920002647 polyamide Polymers 0.000 claims description 3
- 229920000515 polycarbonate Polymers 0.000 claims description 3
- 239000004417 polycarbonate Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 28
- 230000007423 decrease Effects 0.000 abstract description 12
- 238000002834 transmittance Methods 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 71
- 210000000056 organ Anatomy 0.000 description 49
- 230000000052 comparative effect Effects 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000000463 material Substances 0.000 description 20
- -1 polyethylene terephthalate Polymers 0.000 description 20
- 238000000034 method Methods 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 230000004913 activation Effects 0.000 description 12
- 238000002054 transplantation Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 10
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 10
- 239000005977 Ethylene Substances 0.000 description 10
- 235000015097 nutrients Nutrition 0.000 description 10
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 9
- 239000004698 Polyethylene Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229920000573 polyethylene Polymers 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 230000003248 secreting effect Effects 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- 102000008100 Human Serum Albumin Human genes 0.000 description 7
- 108091006905 Human Serum Albumin Proteins 0.000 description 7
- 239000012237 artificial material Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 239000012510 hollow fiber Substances 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000008260 defense mechanism Effects 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 230000004727 humoral immunity Effects 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 4
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000003114 blood coagulation factor Substances 0.000 description 4
- 229940019700 blood coagulation factors Drugs 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 238000007654 immersion Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 108010062466 Enzyme Precursors Proteins 0.000 description 3
- 102000010911 Enzyme Precursors Human genes 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000007969 cellular immunity Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000004154 complement system Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 210000002660 insulin-secreting cell Anatomy 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 229920001748 polybutylene Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 229920001451 polypropylene glycol Polymers 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- 239000000592 Artificial Cell Substances 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 229920000392 Zymosan Polymers 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001112 coagulating effect Effects 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 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 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000007102 metabolic function Effects 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000016917 Complement C1 Human genes 0.000 description 1
- 108010028774 Complement C1 Proteins 0.000 description 1
- 108090000955 Complement C2 Proteins 0.000 description 1
- 108010028780 Complement C3 Proteins 0.000 description 1
- 108010028778 Complement C4 Proteins 0.000 description 1
- 108010028773 Complement C5 Proteins 0.000 description 1
- 108010028771 Complement C6 Proteins 0.000 description 1
- 108010028776 Complement C7 Proteins 0.000 description 1
- 108010028777 Complement C8 Proteins 0.000 description 1
- 108010027644 Complement C9 Proteins 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000001612 chondrocyte 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
- 238000012937 correction Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229920000359 diblock copolymer Polymers 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000004216 mammary stem cell Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001114 myogenic effect Effects 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 208000003068 pituitary dwarfism Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0016—Coagulation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/08—Polysaccharides
- B01D71/10—Cellulose; Modified cellulose
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/26—Polyalkenes
- B01D71/261—Polyethylene
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/38—Polyalkenylalcohols; Polyalkenylesters; Polyalkenylethers; Polyalkenylaldehydes; Polyalkenylketones; Polyalkenylacetals; Polyalkenylketals
- B01D71/381—Polyvinylalcohol
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
- B01D71/42—Polymers of nitriles, e.g. polyacrylonitrile
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/50—Polycarbonates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/56—Polyamides, e.g. polyester-amides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
- B01D71/68—Polysulfones; Polyethersulfones
Definitions
- the present invention relates to a semipermeable membrane and a method for producing the same.
- a bioartificial organ is a device intended to prevent or treat a patient's disease.
- a bioartificial organ provides cells with necessary metabolic functions by containing cells and biological tissues within itself.
- a bioartificial organ provides a patient with a biologically active factor that governs the metabolic functions of cells and biological tissues.
- Biologically active factors include hormones and proteins.
- bioartificial organs the types of cells constituting the bioartificial organ can be selected according to the type of disease to be treated.
- An example of a bioartificial organ is a bioartificial islet.
- Bioartificial islets contain insulin-secreting cells or a group of cells containing insulin-secreting cells.
- An example of the cell group is an islet.
- Bioartificial islets can be used to supply insulin hormone to patients who have difficulty or impossible to control blood glucose levels. For this reason, correction of a patient's blood glucose level is achieved.
- Another bioartificial organ produces blood coagulation factors as biologically active factors.
- Such a bioartificial organ has hepatocytes that produce blood coagulation factors.
- As blood coagulation factors there are factor VIII and factor XI.
- Such bioartificial organs are used for the treatment of hemophilia patients who exhibit blood coagulation disorders due to the lack of these blood coagulation factors.
- bioartificial organs produces growth hormone.
- Such bioartificial organs have human growth hormone (hGH) secreting cells.
- hGH human growth hormone
- Such bioartificial organs are used for the treatment of pituitary dwarfism caused by, for example, insufficient secretion of growth hormone.
- Another bioartificial organ contains cells that secrete parathyroid hormone. Such bioartificial organs can be used for the treatment of hypoparathyroidism. Another bioartificial organ contains cells that secrete erythropoietin. Such bioartificial organs can be used to treat anemia.
- a bioartificial organ is a device that is transplanted into a patient's body.
- the transplantation of a bioartificial organ has an advantage over the living organ transplantation.
- living organ transplantation may not be suitable for long-term efficacy maintenance. This is because, in living organ transplantation, the transplanted cells are rejected from the patient's body by the defense mechanism of the living body.
- As a defense mechanism of a living body acute rejection that occurs mainly by the latter half of the transplantation and chronic rejection that progresses in the following years. Such a problem also occurs in allogeneic transplantation.
- the defense mechanism of the living body functions by antibody proteins and complement proteins involved in humoral immunity and cellular immunity.
- antibody proteins and complement proteins involved in humoral immunity and cellular immunity.
- bioartificial organs have an immune isolation membrane as an artificial material.
- the immune isolation membrane can protect the cells constituting the bioartificial organ from humoral immunity and cellular immunity.
- bioartificial organ transplantation In living organ transplantation, there is a mismatch between supply and demand between donors and recipients. This is inevitable to avoid rejection. Compared with living organ transplantation, bioartificial organ transplantation does not greatly affect the suitability of transplantation due to mismatch problems. This is because the immune isolation membrane can protect the cells constituting the bioartificial organ from the defense mechanism of the living body, so that it is easy to prevent rejection. In addition, transplantation of a bioartificial organ does not require an immunosuppressive agent, or the prescription amount of the immunosuppressive agent is smaller than that of a living organ transplant.
- an immune isolation membrane having permselectivity has been searched for macromolecules such as proteins involved in humoral immunity.
- the immunoisolation membrane can sequester cells constituting the bioartificial organ from humoral immunity and cellular immunity due to permselectivity.
- Bioartificial organs come in various shapes including microcapsule types.
- a microcapsule-type bioartificial organ cells are encapsulated with an artificial material.
- an artificial material a film-like or gel-like polymer is used.
- the high molecular weight polymer protects cells contained in the microcapsule from the defense mechanism of the living body as an immunoisolating membrane.
- the molecular permeability can be controlled by devising the structure of the immunoisolation membrane. Control of molecular permeability is necessary for bioartificial organs to supply hormones and proteins secreted from cells to the living body, or to take in nutrients necessary for cell survival.
- Patent Document 1 discloses a cell transplant bag as one form of the shape of an immune isolation membrane. Such bags are made of polyethylene terephthalate (PET) mesh. Such a bag can be used to produce a bioartificial pancreas.
- PET polyethylene terephthalate
- Patent Document 2 discloses a module for an externally mounted bioartificial pancreas.
- a hollow fiber made of a polymer semipermeable membrane is used.
- the polymer semipermeable membrane is made of an ethylene-vinyl alcohol copolymer.
- the film thickness and pore size of the hollow fiber are similar to those of a general artificial kidney dialysis membrane, plasma component separation membrane, or plasma separation membrane.
- Non-Patent Documents 1 and 2 disclose a bioartificial pancreas (BAP) produced by combining a device made of the above-mentioned semipermeable membrane transplanted into a body and a blood glucose-responsive insulin secreting cell. Yes.
- Patent Document 3 discloses a hollow fiber membrane made of a polymer semipermeable membrane having high permeability and high fractionation.
- the hollow fiber membrane is used for medical applications such as hemodialysis and plasma separation.
- An object of the present invention is to provide a semipermeable membrane for isolating cells from the external environment.
- An object of the present invention is to provide a semipermeable membrane that is resistant to a temporal decrease in the material permeability of a semipermeable membrane in a living body despite having high material permeability.
- a semipermeable membrane containing a resin, wherein the albumin permeability is 30% or more, and the amount of albumin adsorbed when the 1 cm square semipermeable membrane is immersed in a 0.1% albumin solution for 90 minutes A semipermeable membrane that is 10 ⁇ g / cm 2 or less.
- [5] The semipermeable membrane according to any one of [1] to [4], having a thickness of 50 ⁇ m or more and 200 ⁇ m or less.
- [6] The semipermeable membrane according to any one of [1] to [5], wherein an average pore diameter of at least one surface is 0.1 ⁇ m or more and 3 ⁇ m or less.
- the resin is any one of [1] to [6], wherein the resin is an ethylene-vinyl alcohol copolymer, and the semipermeable membrane contains 50% by mass or more of the ethylene-vinyl alcohol copolymer.
- Semipermeable membrane Semipermeable membrane.
- a bag comprising the semipermeable membrane according to any one of [1] to [8].
- the respective components are mixed so that the mass ratio is in the range of 7.5% to 25% by mass of the resin, 55% to 87.5% by mass of the solvent, and 5% to 20% by mass of the additive.
- a semi-permeable membrane production method wherein the resin comprises an ethylene-vinyl alcohol copolymer, a polysulfone polymer, a polyacrylonitrile polymer, a cellulose polymer, and a polyamide polymer.
- a polycarbonate polymer and the additive is a water-soluble polymer.
- the above components are heated and dissolved in the range of 50 ° C. to 120 ° C.
- the present invention it is possible to provide a semipermeable membrane that is resistant to a temporal decrease in the material permeability of the semipermeable membrane in a living body despite having high substance permeability. Therefore, according to the present invention, a semipermeable membrane having good biocompatibility can be provided.
- cell includes, but is not limited to, adherent cells and floating cells.
- Adherent cells refer to cells that proliferate by attaching to a carrier during cell culture.
- Suspension cells are cells that basically do not require attachment to a carrier for cell growth.
- Suspended cells include cells that can weakly adhere to a carrier.
- adherent cells examples include osteoblasts, chondrocytes, hematopoietic cells, epithelial cells (such as mammary epithelial cells), endothelial cells (such as vascular endothelial cells), epidermal cells, fibroblasts, mesenchymal cells, and cardiomyocytes.
- adherent cells include osteoblasts, chondrocytes, hematopoietic cells, epithelial cells (such as mammary epithelial cells), endothelial cells (such as vascular endothelial cells), epidermal cells, fibroblasts, mesenchymal cells, and cardiomyocytes.
- Myogenic cells smooth muscle cells, living skeletal muscle cells, human tumor cells, fiber cells, EB virus mutant cells, hepatocytes, kidney cells, bone marrow cells, macrophages, liver parenchymal cells, small intestinal cells, mammary cells, salivary gland cells , Thyroid cells, and skin cells, but are not limited to these.
- suspension cells include, but are not limited to, T cells, B cells, killer cells, lymphocytes, lymphoblasts, and pancreatic ⁇ cells.
- the cells may be aggregated with each other or differentiated. Aggregated cells may have an organ function.
- the cell may be a cell immediately after being collected from a living body or a cultured cell. Cells collected from a living body may form an organ.
- the semipermeable membrane according to the present invention can be produced, for example, by dissolving at least one kind of resin in a solvent and solidifying the dissolved resin.
- resin is not particularly limited.
- examples of such resins include resins such as ethylene-vinyl alcohol copolymers, polysulfone polymers, polyacrylonitrile polymers, cellulose polymers such as cellulose acetate, polyamide polymers, and polycarbonate polymers. Can do.
- the weight average molecular weight of these resins is preferably 10,000 or more.
- the content of the resin in the semipermeable membrane according to the present invention is preferably 50% by mass or more, more preferably 80% by mass or more, and further preferably 90% by mass or more.
- additives and solvents used for film formation may remain in the semipermeable membrane, but the content is preferably 50% by mass or less, more preferably 20% by mass or less. More preferably, it is 10 mass% or less.
- the semipermeable membrane according to the present invention is used for medical applications such as bioartificial organs, it is preferable to use an ethylene-vinyl alcohol copolymer or a polysulfone polymer as the resin.
- these resins are less likely to activate complement and are excellent in biocompatibility and chemical stability. Furthermore, these resins are difficult to biodegrade in vivo, and the amount of eluate generated is small.
- the ethylene-vinyl alcohol copolymer used in the present invention may be any of a random polymer, a block polymer and a graft polymer.
- the ethylene structural unit content in the ethylene-vinyl alcohol copolymer is preferably 10 mol% or more and 90 mol% or less. By making the content rate of an ethylene structural unit 10 mol% or more, it can suppress that a semipermeable membrane will activate a complement. In order to further suppress complement activation, the ethylene structural unit content is more preferably 30 mol% or more. By making the content rate of an ethylene structural unit 90 mol% or less, the fall of the softness
- the saponification degree of the ethylene-vinyl alcohol copolymer is preferably 95 mol% or more.
- the ethylene-vinyl alcohol copolymer is mainly composed of an ethylene structural unit and a vinyl alcohol structural unit.
- the ethylene-vinyl alcohol copolymer may contain other monomer structural units as structural units.
- the ethylene-vinyl alcohol copolymer may not contain other monomer structural units. Examples of other monomers include methacrylic acid, vinyl chloride, methyl methacrylate, and acrylonitrile.
- the content of other monomer structural units in the ethylene-vinyl alcohol copolymer can be appropriately adjusted within a range not impairing the gist of the present invention. Such a content is preferably in the range of 15 mol% or less.
- the thickness of the semipermeable membrane according to the present invention is preferably 50 ⁇ m or more and 200 ⁇ m or less. When the thickness is 50 ⁇ m or more, the strength of the semipermeable membrane can be increased. When the thickness is 200 ⁇ m or less, it is possible to provide a semipermeable membrane that easily adjusts the permeability of proteins such as albumin and the amount of water permeation to a desired range.
- the semipermeable membrane according to the present invention is a porous membrane provided with a plurality of minute holes.
- the average pore diameter of such holes is preferably 0.1 ⁇ m or more and 3 ⁇ m or less, more preferably 0.3 ⁇ m or more and 3 ⁇ m or less, and more preferably 0.5 ⁇ m or more and 2 ⁇ m or less.
- the hole diameter of each hole has a predetermined distribution. At this time, in order to prevent permeation of external cells and the like, it is preferable that the semipermeable membrane surface has no pores having a pore diameter of 20 ⁇ m or more.
- a semi-permeable membrane can be obtained by making a non-porous membrane by a known method and making a hole in the non-porous membrane by drilling.
- a semipermeable membrane can be produced by the following method.
- a resin, a solvent, and an additive are mixed and dissolved by heating in the range of 50 ° C. to 120 ° C., and the mixture of each component is used as a film forming stock solution.
- the film-forming stock solution is preferably maintained at a temperature of 20 to 95 ° C, more preferably 50 to 90 ° C.
- the film-forming stock solution is solidified at a temperature of 20 ° C. to 80 ° C. to form a film.
- a resin, an additive, and a solvent are mixed and dissolved by heating at 50 ° C. to 120 ° C., more preferably 50 ° C. to 80 ° C., to obtain a film forming stock solution.
- a film-forming stock solution heated to 20 ° C. to 95 ° C., more preferably 20 ° C. to 80 ° C. is applied to a plate-shaped molding tool.
- the film-forming stock solution on the molding tool is coagulated in a coagulation bath of 20 ° C. to 80 ° C., more preferably 20 ° C. to 60 ° C., and the additive and the solvent diffuse into the coagulation bath, so A permeable membrane is obtained.
- a purification step and a drying step can be appropriately provided.
- the mass ratio in the film forming stock solution is preferably 7.5% by mass to 25% by mass, and more preferably 10% by mass to 20% by mass.
- the solvent ratio is preferably 55% by mass to 87.5% by mass, and more preferably 60% by mass to 80% by mass.
- the ratio of the additive is preferably 5% by mass to 20% by mass. In order to promote the formation of the film, the additive ratio is preferably smaller than the resin ratio.
- the viscosity of the film-forming stock solution at 30 ° C. is preferably 1,000 mPa ⁇ s or more and 20,000 mPa ⁇ s or less, and more preferably 1,000 mPa ⁇ s or more and 10,000 mPa ⁇ s or less.
- the viscosity of the film-forming stock solution is less than 1,000 mPa ⁇ s or higher than 20,000 mPa ⁇ s, it is difficult to adjust the coagulation time of the film-forming stock solution, and film formation may be difficult. In addition, the membrane may be easily damaged after the stock solution is solidified.
- the viscosity of the film-forming stock solution at 30 ° C. can be measured using a BL-type viscometer or a BH-type viscometer under conditions of a rotor rotational speed of 6 rpm and a temperature of 30 ° C.
- the solvent constituting the film forming stock solution is not particularly limited as long as it is a good solvent for the resin used for film formation.
- Examples thereof include dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), dimethylacetamide (DMAc), and the like, or a mixed solvent containing these as components.
- DMSO dimethyl sulfoxide
- DMF dimethylformamide
- DMAc dimethylacetamide
- DMSO dimethyl sulfoxide
- DMSO dimethyl sulfoxide
- DMSO dimethyl sulfoxide
- the additive constituting the film-forming stock solution is preferably a water-soluble polymer.
- a surfactant can be used as an additive.
- the surfactant is preferably a polymer surfactant.
- the average pore diameter of the semipermeable membrane can be adjusted by adjusting the type and amount of the additive.
- the viscosity of the film-forming stock solution can be adjusted.
- the phase separation temperature (LST, Land Surface Temperature) of the film-forming stock solution can be adjusted.
- the polymer surfactant has a molecular weight of 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000 and 9,000 or more. Refers to a surfactant.
- the surface active function may be nonionic, anionic, or cationic. Of these, nonionic polymer surfactants are preferred.
- Nonionic polymer surfactants include, for example, the following: polymers represented by polyethylene glycol, polyethylene oxide, polypropylene glycol, and polypropylene oxide; polyethylene glycol-polypropylene glycol, polyethylene glycol-polytetramethylene glycol , Polyethylene glycol-polybutylene glycol, and diblock or random copolymers represented by polyethylene glycol-polypentylene glycol; polyethylene glycol-polypropylene glycol-polyethylene glycol, polyethylene glycol-polytetramethylene glycol-polyethylene glycol , Polyethylene glycol-polybutylene glycol-polyethylene glycol And a triblock copolymer represented by polyethylene glycol-polypentylene glycol-polyethylene glycol; polypropylene glycol-sulfate sodium salt, polytetramethylene glycol-sulfate sodium salt, polybutylene glycol-sulfate sodium salt, and Polypentylene glycol-s
- water-soluble polymers that can be used as additives can be mentioned.
- examples thereof include polysaccharides represented by various known vinyl alcohol polymers, starch, carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and dextran.
- the semipermeable membrane according to the present invention contains a resin. It is preferable that the surface of the semipermeable membrane hardly activates serum complement. The fact that the surface of the semipermeable membrane hardly activates complement is expressed based on the following evaluation method.
- ⁇ Method A Evaluation Based on Serum Complement Value (CH50) Measurement> Contact the semipermeable membrane with fresh human serum. At this time, if the rate of decrease in serum complement value (CH50) is 25% or less, the surface of the semipermeable membrane is evaluated to be difficult to activate complement. Serum complement titers are proportional to the total amount of complement C1, C2, C3, C4, C5, C6, C7, C8 and C9 remaining without being activated. The degree of complement activation can be evaluated based on the serum complement value.
- ⁇ Method B Evaluation Based on Measurement of Individual Complement Activity>
- Complements in the blood usually exist as inactive enzyme precursors.
- the enzyme precursor is activated by being stimulated by a foreign substance that has entered the body.
- the enzyme precursor is partially decomposed by activation to generate a partial decomposition product. Partially decomposed products are eliminated or form a complex. Therefore, when the semipermeable membrane behaves as a foreign substance, the surface of the semipermeable membrane activates complement. It can be evaluated by the following evaluation method.
- the increase in activity is calculated based on the measurement of the amount of each complement in fresh human serum in contact with the membrane.
- the complement to be measured is preferably one or more complements of C1, C2, C3, C4, C5, C6, C7, C8 and C9, and one or more complements of C3 and C4. More preferably it is.
- the increase in activity is calculated based on the measurement of the amount of protein (partially decomposed product) produced by decomposing the complement.
- the protein (partially decomposed product) released from the complement to be measured is preferably one or more of C1r, C1q, C2b, C3a, C4a and C5a, and the protein released from the complement is C3a. And more preferably one or more of C5a.
- C3a and C5a have an action of attracting inflammatory leukocytes.
- C3a can be effectively used as an indicator of initiation of complement system activation.
- the increase in activity is calculated based on a measurement of the amount of the complement complex.
- the complex to be measured is preferably formed by binding of complements to each other when the complements are activated.
- the complex is preferably SC5b-9. SC5b-9 is the final product of the complement system activation reaction.
- a semipermeable membrane having a predetermined size is immersed in a predetermined amount of fresh human serum.
- the volume of serum is 1 mL per cm 2 surface area of the semipermeable membrane.
- the inner surface of the incubation container is preferably previously blocked with albumin.
- fresh human serum (positive control) to which a predetermined amount of zymosan is added instead of a semipermeable membrane is prepared. These are incubated for 90 minutes at 37 ° C. with agitation.
- EDTA disodium ethylenediaminetetraacetate
- the amount of complement in serum is measured.
- the amount of complement in serum may be the amount of protein produced by degradation of complement.
- the measurement can be performed by the ELIZA method.
- X be the amount (mass) of complement of serum immersed in a semipermeable membrane.
- the complement amount (mass) of serum without the semipermeable membrane immersed therein is defined as Xmin.
- the amount of complement (mass) of serum to which zymozan was added is defined as Xmax.
- the activation rate is calculated according to the following formula.
- Activation rate (%) ⁇ (X-Xmin) / (Xmax-Xmin) ⁇ x 100
- the surface of the semipermeable membrane according to the present invention hardly adsorbs protein.
- the fact that the surface of the semipermeable membrane hardly adsorbs proteins can be evaluated based on the following evaluation method using albumin.
- albumin adsorption amount to the semi-permeable membrane is equal to 10 [mu] g / cm 2 or less, the surface of the semipermeable membrane is evaluated as hardly adsorbs proteins. Furthermore, it is more preferable that the albumin adsorption amount is not more than any one of 9, 8, 7, 6, 5, 4, 3, 2 , and 1 ⁇ g / cm 2 .
- the albumin adsorption amount can be adjusted by selecting a resin used for producing the semipermeable membrane. When the surface of the semipermeable membrane is difficult to adsorb proteins, it can be evaluated that the material permeability of the semipermeable membrane can be prevented from decreasing with time and the biocompatibility is high.
- the semipermeable membrane according to the present invention has high water permeability.
- the water permeability of the semipermeable membrane is determined by the amount of water per unit area and per unit time of the semipermeable membrane when distilled water at 25 ° C. is sucked through the semipermeable membrane at a negative pressure of 3 ⁇ 0.2 kPa ⁇ L / (M 2 ⁇ h) ⁇ . If the water permeation amount is 1,000 ⁇ L / (m 2 ⁇ hr) ⁇ or more, it is evaluated that the water permeability of the semipermeable membrane is high.
- the amount of water permeation is preferably 2000 ⁇ L / (m 2 ⁇ hr) ⁇ or more.
- the permeation amount of such water is preferably 20,000 ⁇ L / (m 2 ⁇ h) ⁇ or less, more preferably 15,000 ⁇ L / (m 2 ⁇ h) ⁇ or less, particularly preferably 10,000 ⁇ L / (m 2 ⁇ hr) ⁇ or less.
- the permeability of albumin of the semipermeable membrane according to the present invention is 30% or more, preferably 40% or more, and more preferably 50% or more.
- the albumin permeability of the semipermeable membrane is preferably 90% or less, more preferably 80% or less.
- the albumin permeability is used as an indicator of the substance permeability of the semipermeable membrane.
- transmittance of various proteins other than albumin can also be evaluated indirectly.
- permeability of various amino acids such as glutamine, glucose, hormones, vitamins and the like can be indirectly evaluated. These substances desirably penetrate the semipermeable membrane of the present invention.
- the permeability of albumin can be measured by the following method.
- a semi-permeable membrane of a predetermined size is folded in half and the two sides are melt bonded to produce a bag-like member with one side not bonded.
- a bag is formed from the bag-shaped member by injecting a predetermined amount of the human albumin solution into the bag-shaped member and then melting and bonding one unbonded side of the bag-shaped member to close the seal. .
- the bag containing the human albumin solution is immersed in a predetermined volume, for example, 10 mL of Hanks buffer solution present in a predetermined volume, for example, a 15 mL tube. Shake the tube at 37 ° C. for 30 minutes. After 30 minutes, collect the Hanks buffer on the outside of the bag.
- the albumin concentration in the collected Hanks buffer is measured by the ELISA method.
- the measurement by ELISA method may be carried out using HumanHAlbumin ELISA Quantitation Set (Bethyl Laboratories, Inc.).
- the transmittance can be calculated by the following equation. Let Xn be the permeation amount (mass) of albumin transferred from the bag to the Hanks buffer. Let Xmax be the amount (mass) of aluminum bumine equal to the amount injected into the bag.
- FIG. 1 shows an embodiment of a bag formed of a semipermeable membrane 10 according to the present invention.
- a base material 11 and desired cells 12 for fixing cells are placed in a bag.
- the cells 12 are sealed with a bag.
- the bag is a member provided with a region closed by a semipermeable membrane.
- the bag can be produced, for example, by the method described in the column of [Substance permeability of substance (albumin)].
- the semipermeable membrane 10 permeates nutrients 15 necessary for the cells 12.
- the nutrient is, for example, an amino acid or a substance adsorbed on albumin.
- the nutrient 15 moves from the external environment toward the inside of the bag.
- the semipermeable membrane 10 permeates the secretory substance 16 that has exited from the cells 12.
- the secretory substance 16 moves from the inside of the bag toward the external environment.
- the base material 11 suppresses aggregation of cells and uniformly disperses the cells in the bag. Moreover, the humoral immunity is suppressed by the base material 11.
- Examples of the base material 11 include non-woven fabrics, sheets, and gels that serve as cell scaffolds, which are made of a material having good biocompatibility or a biodegradable material.
- the semipermeable membrane 10 constituting the bag has pores large enough to pass through the nutrients 15 and the secretory material 16, while external cells including leukocytes 18 containing phagocytic cells. Does not pass through. For this reason, spreading
- the semipermeable membrane 10 contributes to maintaining the function of the bioartificial organ for a long period of time.
- the semipermeable membrane of the present invention can be used as various members in addition to the above bag.
- a semipermeable membrane can be processed into a cylindrical member using one or more semipermeable membranes.
- it can be set as the bag-shaped member by which the semipermeable membrane was processed and only 1 side was open
- it can be set as a new member by combining the member which consists of a semipermeable membrane, and another member.
- the semipermeable membrane may be subjected to a surface treatment according to the use.
- the semipermeable membrane of the present invention and various members made therefrom can be widely used for medical applications other than bioartificial organs, drug discovery research applications, and the like.
- the stock solution Prepares the stock solution. Put all the following materials into a pressure test tube. The total material was 12 g.
- the material is an ethylene-vinyl alcohol copolymer (made by Kuraray Co., Ltd., Kuraray Eval (registered trademark) G110B, an ethylene structural unit content of 47 mol%, a saponification degree of 98 mol%, and EVOH-1 in this specification. ), Dimethyl sulfoxide (DMSO) as a solvent and polyethylene oxide (PEO, molecular weight of about 60,000) as an additive, and the mass ratio thereof was 15:75:10.
- DMSO Dimethyl sulfoxide
- PEO polyethylene oxide
- the pressure test tube was capped and the material was sealed. The temperature in the test tube was set to 90 ° C.
- a film forming stock solution at 80 ° C. was hung on one end of the glass plate.
- the stock solution on the glass plate was uniformly stretched with a glass rod. 5.
- the sample was left in the atmosphere at room temperature (25 ° C.) for 1 minute. 6).
- the glass plate coated with the stock solution was immersed in a coagulation bath containing warm water at 30 ° C. 7).
- a semipermeable membrane was formed by the addition of the additive and solvent in the membrane-forming stock solution into the coagulation bath and the resin component coagulating.
- Ten minutes after the start of immersion the semipermeable membrane was peeled off from the glass plate in water. 8).
- the four sides of the semipermeable membrane were fixed by sandwiching the semipermeable membrane between two rectangular metal frames in water and fixing two portions on each side. 9.
- the semipermeable membrane was transferred to 30 ° C. warm water and immersed in water overnight. 10. The semipermeable membrane was removed from the water. The semipermeable membrane was transferred to a mixture of acetone and water. The volume ratio of acetone and water was 8/2 and the temperature was 25 ° C. The semipermeable membrane was immersed in the mixed solution for 15 minutes. 11. The semipermeable membrane was removed from the mixed solution. The semipermeable membrane was transferred to acetone and immersed in acetone at 25 ° C. for 15 minutes. 12 The semipermeable membrane was taken out from acetone and allowed to stand in the atmosphere at room temperature (25 ° C.) for 1 hour. 13. The semipermeable membrane was dried in a drier set at 40 ° C. for 1 hour to obtain a semipermeable membrane having a long side of 150 mm ⁇ short side of 120 mm ⁇ thickness of 100 ⁇ m.
- Example 2 the above 2.
- the ratio of the masses of EVOH-1, DMSO and PEO shown in Table 2 was changed to 20:12:68.
- Example 5 the above 1.
- the mass ratio of EVOH-1, DMSO, and PEO shown in Table 2 was changed to 10: 7.5: 82.5.
- Example 6 the above 1. Was changed to polyethylene glycol (PEG, molecular weight of about 20,000).
- Example 7 the above 1.
- EVOH-1 represented by the formula (1) is an ethylene-vinyl alcohol copolymer (Kuraray Co., Ltd., Kuraray Eval (registered trademark) F101B, ethylene structural unit content: 32 mol%, saponification degree: 98 mol%.
- EVOH- Changed to 2 Each composition was changed as shown in Table 1.
- Example 8 the above 1.
- EVOH-1 is changed to polysulfone-based polymer (PS) (manufactured by Amoco, UDEL P-1700), the additive is changed to polyethylene oxide (PEO, molecular weight 60,000), and the solvent is dimethylacetamide (DMAc). ).
- PS polysulfone-based polymer
- PEO polyethylene oxide
- DMAc dimethylacetamide
- Each composition was changed as shown in Table 1.
- Example 9 the above 1.
- EVOH-1 shown in the formula was changed to an ethylene-vinyl alcohol copolymer (ethylene structural unit content 9 mol%, saponification
- Comparative Example 1 the above 1.
- the mass ratio of EVOH-1, DMSO and PEO shown in Fig. 1 was changed to 15: 85: 0.
- Comparative Example 2 the above 1.
- the mass ratio of EVOH-1, DMSO, and PEO shown in Table 2 was changed to 10:20:30.
- Comparative Example 3 a semipermeable membrane was prepared in accordance with Example 3 of JP-A No. 2001-314736. That is, the above 1.
- the additives shown in Table 1 were changed to water and lithium chloride. Each composition was changed as shown in Table 1.
- Comparative Example 4 a semipermeable membrane was produced in accordance with Example 4 of JP-A No. 2001-314736. That is, the above 1.
- EVOH-1 shown in the following is changed to polysulfone polymer (PS) (Amoco, UDEL P-1700), and additives are polyethylene glycol (PEG, molecular weight 600) and polyvinylpyrrolidone (PVP) (BASF, K -90) and the solvent was changed to dimethylacetamide (DMAc).
- PS polysulfone polymer
- PEG polyethylene glycol
- PVP polyvinylpyrrolidone
- DMAc dimethylacetamide
- Serum complement value, individual complement activity, and albumin adsorption were measured using the semipermeable membrane. The measuring method is shown below.
- Serum complement value (CH50) can be measured using a commercially available measuring reagent.
- the measuring reagent include Complement Value-HA Test Wako manufactured by Wako Pure Chemical Industries, Ltd. and Immunoturbidimetric Test CH50 Auto (KW) manufactured by Nippon BCG Manufacturing Co., Ltd.
- the reduction rate of serum complement value (CH50) of fresh human serum (complement value reduction rate) by the semipermeable membrane according to Examples 1 to 8 and Comparative Examples 1 and 3 to 5 was 25% or less. For this reason, it was evaluated that the surface of the semipermeable membrane hardly activates complement.
- Method B Measurement of individual complement activity
- the measurement of the activity of individual complements was performed using a Human OPtEIA ELISA Set C3a (Cat. No 550499) from BD Biosciences.
- the measurement target is protein C3a desorbed from complement.
- C3a can be used effectively as an indicator of initiation of complement system activation.
- the semipermeable membrane according to each example and comparative example was cut and separated into pieces of 10 mm ⁇ 10 mm without changing the thickness. 2.
- the separated semipermeable membrane was immersed in ethanol at 25 ° C. for 30 minutes or more to expel bubbles in the holes of the semipermeable membrane. Subsequently, it was washed with PBS ( ⁇ ).
- PBS (-) refers to PBS (phosphate buffered saline) free of magnesium and calcium.
- a semipermeable membrane separated into a test tube and 2.0 mL of fresh human serum were added.
- the ratio of the semipermeable membrane to the serum was 1 (cm 2 / mL) (the area of the thickness portion was neglected because it was very small).
- the inner surface of the test tube was previously blocked with albumin before use. 4).
- fresh human serum without an individualized semipermeable membrane was similarly placed in a test tube.
- fresh human serum without singulated semipermeable membrane but containing 20 mg of zymosan (Z4350-1G from SIGMA) was added to a test tube. These tubes were warmed with agitation and incubated at 37 ° C. for 90 minutes. 5. The separated semipermeable membrane was pulled up from the test tube.
- the activity of complement in each serum was measured. The measurement was performed using an ELISA kit of BD Bioscience, part number 550499. Measurement was performed according to the protocol attached to the kit. 6).
- the activation rate was determined by the following formula.
- the value of complement activity (mass of C3a) in fresh human serum containing individualized semipermeable membranes according to Examples and Comparative Examples was defined as Xn.
- the value of the negative control activity was defined as Xmin.
- the value of the positive control activity was defined as Xmax.
- the activation rate can be calculated by the following formula.
- the activation rate (complement activation rate) of individual complements in serum, that is, C3a, by the semipermeable membranes according to Examples 1 to 8 and Comparative Examples 1 and 3 to 5 was 30% or less. For this reason, it was evaluated that the surface of the semipermeable membrane hardly activates complement.
- the amount of albumin adsorbed on the semipermeable membrane separated into pieces was calculated.
- the measurement was performed by the ELISA method.
- Measurement by ELISA was performed using a Human Albumin ELISA Quantitation Set (Bethyl Laboratories, Inc.).
- the amount of albumin adsorbed to the semipermeable membranes according to Examples 1 to 9 and Comparative Examples 1 and 3 to 5 was 10 ⁇ g / cm 2 or less. For this reason, it was evaluated that the surface of the semipermeable membrane hardly adsorbs proteins.
- a spacer was placed on the lower part, a semipermeable membrane was placed on the spacer, and an upper part was placed on the semipermeable membrane.
- the upper part and the lower part were clamped and fixed.
- the lower part was connected to a suction bottle. 5.
- 11 mL of distilled water was placed in the upper part of the calibrated filter holder. 6).
- the aspirator was operated, and the lower part side where the semipermeable membrane was not in contact with distilled water was decompressed.
- the water temperature at this time was 25 ° C., and the negative pressure was 3 ⁇ 0.2 kPa. 7).
- the water permeability of the semipermeable membrane is represented by the permeation amount of water ⁇ L / (m 2 ⁇ hr) ⁇ per effective unit area and unit time of the membrane attached to the filter holder at the above negative pressure.
- four semipermeable membranes were prepared, and the measurement was performed four times. The average value was used as a representative value as a water permeability value.
- the permeation amount of water was 5 mL / (3.14 cm 2. 22.9 sec), that is, 2,500 L / (m 2 ⁇ hr) rounded to the first digit.
- the water permeability of the semipermeable membranes of Examples and Comparative Examples is as shown in Table 1, and the water permeability of the semipermeable membranes according to Examples 1 to 9 was 1,000 L / (m 2 ⁇ hr) or more. . For this reason, the semipermeable membrane was evaluated as having high water permeability.
- the bag containing the albumin solution was immersed in 10 mL of Hanks buffer in a 15 mL tube and shaken at 37 ° C. for 30 minutes. 5. One hour later, Hanks buffer solution outside the bag was collected. 6). The albumin concentration in the collected Hanks buffer was measured by ELISA. Measurement by ELISA was performed using a Human Albumin ELISA Quantitation Set (Bethyl Laboratories, Inc.). 7). The transmittance was determined by the following formula.
- the albumin permeation amount transferred from the bag to the Hanks buffer was defined as Xn.
- the amount of aluminum bumine injected into the bag was taken as Xmax. That is, Xmax is 400 ng at 20 mg / L ⁇ 200 ⁇ L.
- the albumin permeability of the semipermeable membranes according to Examples 1 to 9 was 30% or more. For this reason, the semipermeable membrane was evaluated as having high permeability to substances such as proteins.
- the pore diameter of the semipermeable membrane was measured by observing the surface of the semipermeable membrane. One surface of the semipermeable membrane was photographed with a scanning electron microscope at a magnification of 2,000, and after photographing, 30 holes, that is, voids were randomly selected, and the diameter of each void was measured. The average of the measured values was taken as the average pore diameter of the semipermeable membrane.
- the surface of the semipermeable membrane according to the example was difficult to adsorb albumin, that is, protein. Therefore, it was suggested that the semipermeable membrane according to the example has good biocompatibility. Further, the surface of the semipermeable membrane according to the example was difficult to activate complement. Therefore, it was suggested that the membrane according to the example suppresses a decrease in the material permeability of the semipermeable membrane in the living body over time. Moreover, from the measurement of the albumin permeability, it was found that the semipermeable membrane according to the example had pores large enough to penetrate nutrients and secretory substances. Therefore, it was suggested that the semipermeable membrane of the present invention is excellent in substance permeability. Moreover, the semipermeable membrane of the present invention was excellent in water permeability.
- the semipermeable membranes according to Comparative Examples 1, 3, and 4 have a small average pore diameter, and are inferior in water permeability and permeability of nutrients and secretory substances. Moreover, the semipermeable membrane according to Comparative Example 2 could not produce a uniform membrane and was inferior in durability. In addition, the semipermeable membrane which concerns on the comparative example 2 is characterized by the ratio of the resin in a film-forming stock solution being low.
- the semipermeable membrane according to Comparative Example 5 had a low albumin permeability. This is because the semipermeable membrane according to Comparative Example 5 is made of the same material as the semipermeable membrane according to Example 1, but the semipermeable membrane according to Comparative Example 5 is the semipermeable membrane according to Example 1. Because it is thicker.
- the semipermeable membrane according to Example 9 was easier to activate complement than the semipermeable membranes according to Examples 1 to 8. This is because an ethylene-vinyl alcohol copolymer having a low content of ethylene structural units was used for the semipermeable membrane according to Example 9, so that the semipermeable membrane according to Example 9 was relatively adsorbed with albumin. Because it was easy.
- the semipermeable membranes of the present invention shown in Examples 1 to 9 have high substance permeability, they are resistant to a decrease in the substance permeability of the semipermeable membrane in vivo over time. Have. Therefore, the semipermeable membrane of the present invention has good biocompatibility.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Manufacturing & Machinery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
[2] 前記半透膜を通して負圧3±0.2kPaで水を吸引したとき、水の透過量が1,000L/(m2・時)以上で表される、[1]の半透膜。
[3] 前記半透膜と血清とを接触させたとき、前記半透膜による、血清中の補体価(CH50)の減少が25%以下である、[1]又は[2]の半透膜。
[4] 前記半透膜と血清とを接触させたとき、前記半透膜による、血清中の補体の活性の増加が30%以下であり、
前記活性の増加は、C1、C2、C3、C4、C5、C6、C7、C8及びC9の内、一以上の補体の量、前記補体が分解されて生じたタンパク質の量、並びに前記補体の複合体の内、一以上のものの測定の量に基づき、算出されたものである、[1]~[3]のいずれかの半透膜。
[5] 厚さが50μm以上、200μm以下である、[1]~[4]のいずれかの半透膜。
[6] 少なくとも一面の平均孔径が0.1μm以上、3μm以下である、[1]~[5]のいずれかの半透膜。
[7] 前記樹脂はエチレン-ビニルアルコール系共重合体であり、前記半透膜は前記エチレン-ビニルアルコール系共重合体を50質量%以上含有する、[1]~[6]のいずれかの半透膜。
[8] 細胞を外部環境から隔離するための、[1]~[7]のいずれかの半透膜。
[9] [1]~[8]のいずれかの半透膜からなる、バッグ。
[10] 質量比が、樹脂7.5質量%~25質量%、溶媒55質量%~87.5質量%、及び添加剤5質量%~20質量%の範囲となるように各成分を混合して製膜原液を得る、半透膜の製造方法であって、前記樹脂は、エチレン-ビニルアルコール系共重合体、ポリスルホン系重合体、ポリアクリロニトリル系重合体、セルロース系重合体、ポリアミド系重合体、及びポリカーボネート系重合体の少なくともいずれか一つであり、前記添加剤は、水溶性高分子である、半透膜の製造方法。
[11] 前記各成分を、50℃~120℃の範囲で加温溶解することで、前記製膜原液を得て、前記製膜原液を20℃~95℃に保持して、次いで20℃~80℃の温度で前記製膜原液を凝固させる、[10]の半透膜の製造方法。
[12] 前記製膜原液の凝固が凝固浴で行われる、[11]の半透膜の製造方法。
本発明に係る半透膜は、例えば、少なくとも一種類以上の樹脂を溶媒に溶解させ、溶解した樹脂を凝固させることで作製することができる。かかる樹脂は特に限定されるものではない。かかる樹脂として、例えば、エチレン-ビニルアルコール系共重合体、ポリスルホン系重合体、ポリアクリロニトリル系重合体、酢酸セルロースなどのセルロース系重合体、ポリアミド系重合体、ポリカーボネート系重合体などの樹脂を用いることができる。これらの樹脂の重量平均分子量は1万以上であることが好ましい。
本発明に係る半透膜の厚さは50μm以上、200μm以下であることが好ましい。厚さが50μm以上であることで、半透膜の強度を高めることができる。厚さが200μm以下であることで、アルブミンなどのタンパク質の透過率や、水の透過量を所望の範囲に調整しやすい半透膜を提供することができる。
本発明に係る半透膜は、微小な孔が複数設けられている多孔膜である。かかる孔の平均孔径は0.1μm以上、3μm以下であることが好ましく、0.3μm以上、3μm以下であることがさらに好ましく、0.5μm以上、2μm以下であることがより好ましい。平均孔径がかかる下限を有することで、タンパク質の透過率や、水の透過量を高めることができる。また平均孔径がかかる上限を有することで、外部細胞等の透過を抑制することができる。また、半透膜において、各孔の孔径は所定の分布を有する。このとき、外部細胞等の透過を防止するために、半透膜表面に孔径が20μm以上の孔が無いことが好ましい。
本発明に係る半透膜の製膜方法に特に制限は無い。例えば、公知の方法で無孔膜を作製するとともに、かかる無孔膜に対してドリル加工により孔を開けることで半透膜を得ることができる。また、例えば以下の方法で半透膜を製造することもできる。
30℃における製膜原液の粘度は1,000mPa・s以上20,000mPa・s以下であることが好ましく、1,000mPa・s以上10,000mPa・s以下であることがより好ましい。
製膜原液の30℃における粘度は、BL型粘度計又はBH型粘度計を用いて、ロータ回転数6rpm、温度30℃の条件で測定できる。
製膜原液を構成する溶媒は、製膜に用いる樹脂の良溶媒であれば、特に限定されない。例えば、ジメチルスルホキシド(DMSO)、N,N-ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMAc)等、あるいはこれらを成分とする混合溶媒を挙げることができる。製膜性や毒性が低いという観点から、なかでもジメチルスルホキシド(DMSO)が好ましい。
製膜原液を構成する添加剤は、水溶性高分子であることが好ましい。例えば、一般的に界面活性剤と呼ばれるものを添加剤として使用できる。界面活性剤は高分子界面活性剤であることが好ましい。添加剤の種類や量を調整することで、半透膜の孔の平均孔径を調節することができる。また、製膜原液の粘度を調整することができる。また、製膜原液の相分離温度(LST、Land Surface Temperature)を調整することができる。
本発明に係る半透膜は樹脂を含有する。半透膜の表面は血清中の補体を活性化しにくいことが好ましい。半透膜の表面が補体を活性化しにくいことは以下の評価方法に基づき表される。
半透膜と新鮮ヒト血清とを接触させる。この時、血清補体価(CH50)の減少率が25%以下であれば、半透膜の表面は補体を活性化しにくいと評価される。血清補体価は、活性化を受けることなく残存している補体C1、C2、C3、C4、C5、C6、C7、C8及びC9の総量に比例する。血清補体価に基づき補体の活性化の度合いを評価することができる。
血液中の補体は通常、不活性な酵素前駆体として存在する。酵素前駆体は体内に侵入した異物により刺激を受けることで活性化する。酵素前駆体は活性化により部分的に分解され、部分分解物を生成する。部分分解物は脱離するか又は複合体を形成する。したがって、半透膜が異物として振る舞う場合には、半透膜の表面が補体を活性化する。以下の評価方法により評価できる。
まず所定の大きさの半透膜を所定量の新鮮ヒト血清に浸漬する。半透膜の表面積1cm2当たり血清の体積を1mLとする。ここで孔により生じた膜内部の表面積は無視してもよい。以下同様である。半透膜と血清とを撹拌しながら37℃で90分間インキュベートする。インキュベート用の容器の内面は予めアルブミンでブロッキングしておくことが好ましい。リファレンスとして半透膜を浸漬させない新鮮ヒト血清(陰性コントロール)も用意する。また半透膜に換えて所定量のザイモザンを添加した新鮮ヒト血清(陽性コントロール)も用意する。これらを撹拌しながら37℃で90分間インキュベートする。
本発明に係る半透膜の表面はタンパク質を吸着しにくいことが好ましい。半透膜の表面がタンパク質を吸着しにくいことは、以下のアルブミンを用いた評価方法に基づき評価することができる。
本発明に係る半透膜の透水性は高い。半透膜の透水性は、半透膜を通して負圧3±0.2kPaで25℃の蒸留水を吸引したときの、半透膜の単位面積当たり及び単位時間当たりの水の透過量{L/(m2・時)}により評価する。かかる水の透過量が1,000{L/(m2・時)}以上であれば半透膜の透水性が高いと評価する。かかる水の透過量は2000{L/(m2・時)}以上であることが好ましい。またかかる水の透過量は、好ましくは20,000{L/(m2・時)}以下、さらに好ましくは15,000{L/(m2・時)}以下、特に好ましくは10,000{L/(m2・時)}以下である。
本発明に係る半透膜のアルブミンの透過率は30%以上、好ましくは40%以上、さらに好ましくは50%以上である。また半透膜のアルブミンの透過率は好ましくは90%以下、さらに好ましくは80%以下である。本実施形態ではアルブミンの透過率を半透膜の物質透過性の指標として用いる。これにより、アルブミン以外の各種タンパク質の透過性も間接的に評価できる。またグルタミン等の各種アミノ酸、グルコース、ホルモン、ビタミン等の透過性も間接的に評価できる。これらの物質は、本発明の半透膜を透過することが望ましい。アルブミンの透過率は次の方法で測定できる。
本発明に係る半透膜は細胞を外部環境から隔離するために用いることができる。図1は本発明に係る半透膜10で形成されたバッグの一態様を示す。バッグ中に細胞を固定するための基材11および所望の細胞12が入れられている。細胞12はバッグによって密閉されている。ここで、バッグとは、半透膜により閉じられた領域が設けられた部材である。バッグは、例えば、[物質(アルブミン)の透過性]の欄で述べた方法で作製できる。また、複数枚の半透膜を用いてバッグを作製しても良い。
発明者らは従来の体内埋め込み式のバイオ人工臓器に以下の課題があることを見出した。すなわち細胞を封入したバッグ及びバッグに封入された細胞をバイオ人工臓器として生体内に移植するとバッグ表面に生体中のタンパク質が付着する。また、そのタンパク質を足場として細胞が接着し、バッグ表面に細胞の層が形成される。このためバッグの物質透過性が低下する。物質透過性の低下によりバッグ内の細胞が分泌する物質の放出が抑制されるだけでなく、バッグ内の細胞が外部環境から十分な栄養分を受けられなくなる。このためバイオ人工臓器の機能を長期間維持することは難しい。
なお、本発明は上記実施の形態に限られたものではなく、趣旨を逸脱しない範囲で適宜変更することが可能である。
各実施例及び比較例において、以下に示す実施例1の方法を基本として半透膜を作製する。製膜原液の組成及び凝固液の組成を変えることで 、孔径及び内部構造の異なる半透膜(多孔膜)を得ることができる。各実施例及び比較例において、実施例1から変更する点は後述する。
2.熱風乾燥機を調整することで、製膜原液の温度を80℃に調整した。
3.成形器具としてガラス板を用いた。ホットプレート上にガラス板を設置し、ガラス板の表面が30℃になるようにホットプレートの温度を調節した。製膜時の厚み調整のため、ガラス板の一方端と他方端にテープを貼った。
4.ガラス板の一方端に80℃の製膜原液を垂らした。ガラス板上の製膜原液をガラス棒で均一に引き伸ばした。
5.大気中、室温(25℃)環境下で1分間放置した。
6.製膜原液が塗布されたガラス板を30℃の温水が入った凝固浴に浸漬した。
7.製膜原液のうち添加剤及び溶媒が凝固浴中に拡散し、さらに樹脂成分が凝固することで半透膜が生じた。浸漬開始から10分後、水中にてガラス板から半透膜を剥がした。
8.水中にて半透膜を二枚の四角形の金枠で挟み、さらに、それぞれの辺で二箇所ずつ固定することで、半透膜の四辺を固定した。
9.浸漬開始から15分後、半透膜を30℃の温水に移し、一晩水に浸漬した。
10.半透膜を水から取り出した。半透膜をアセトン及び水の混合液に移した。アセトン及び水の体積比は8/2で、温度は25℃であった。半透膜を15分間、当該混合液に浸漬した。
11.半透膜を混合液から取り出した。半透膜をアセトンに移し、15分間25℃のアセトンに浸漬した。
12.半透膜をアセトンから取り出し、大気中、室温(25℃)環境下で1時間静置した。
13.半透膜を40℃に設定した乾燥機中で一時間乾燥することで、長辺150mm×短辺120mm×厚み100μmの半透膜を得た。
実施例3においては、上記6.に示す凝固浴の温度を60℃に変更した。
実施例4においては、上記1.に示すEVOH-1、DMSO及びPEOの質量の比を20:12:68に変更した。
実施例5においては、上記1.に示すEVOH-1、DMSO及びPEOの質量の比を10:7.5:82.5に変更した。
実施例6においては、上記1.に示す添加剤をポリエチレングリコール(PEG、分子量約20,000)に変更した。
実施例7においては、上記1.に示すEVOH-1をエチレン-ビニルアルコール系共重合体(株式会社クラレ製、クラレエバール(登録商標)F101B、エチレン構造単位の含有率32モル%、けん化度98モル%、本明細書においてEVOH-2)に変更した。また、各組成を表1のように変更した。
実施例8においては、上記1.に示すEVOH-1をポリスルホン系重合体(PS)(アモコ社製、UDEL P-1700)に変更し、添加剤をポリエチレンオキサイド(PEO、分子量60,000)に変更し、溶媒をジメチルアセトアミド(DMAc)に変更した。また、各組成を表1のように変更した。
実施例9においては、上記1.に示すEVOH-1をエチレン-ビニルアルコール系共重合体(エチレン構造単位の含有率9モル%、けん化度98モル%、本明細書においてEVOH-3)に変更した。また、各組成を表1のように変更した。
比較例2においては、上記1.に示すEVOH-1、DMSO及びPEOの質量の比を10:20:30に変更した。
比較例3においては、特開2001-314736号公報の実施例3に準拠して半透膜を作製した。すなわち、上記1.に示す添加剤を水および塩化リチウムに変更した。また、各組成を表1のように変更した。
比較例4においては、特開2001-314736号公報の実施例4に準拠して半透膜を作製した。すなわち、上記1.に示すEVOH-1をポリスルホン系重合体(PS)(アモコ社製、UDEL P-1700)に変更し、添加剤をポリエチレングリコール(PEG、分子量600)およびポリビニルピロリドン(PVP)(BASF社製、K-90)に変更し、溶媒をジメチルアセトアミド(DMAc)に変更した。また、各組成を表1のように変更した。
比較例5においては、上記3.の操作で厚み調整用のテープの高さを調整し、厚みが300μmである半透膜を得た。
血清補体価(CH50)の測定は市販の測定試薬を用いて行うことができる。測定試薬としては例えば、和光純薬株式会社の補体価-HAテストワコー及び日本ビーシージー製造株式会社の免疫比濁テストCH50オート(KW)がある。
個別の補体の活性の測定は、BD Biosciences社のHuman OPtEIA ELISA Set C3a(Cat.No 550499)を用いて行った。かかる測定では、測定対象となるのは、補体から脱離するタンパク質C3aとなる。C3aは補体系の活性化の開始の指標として有効に利用できる。
2.個片化した半透膜を25℃のエタノールに30分以上浸漬し、半透膜の孔内の気泡を追い出した。次いでPBS(-)で洗浄した。PBS(-)の用語はマグネシウム及びカルシウムの含まれていないPBS(リン酸緩衝生理食塩水)を表す。
3.試験管に個片化した半透膜と、新鮮ヒト血清を2.0mL入れた。半透膜と血清との比(半透膜の表面積/血清の体積)は1(cm2/mL)とした(厚み部分の面積は微小のため無視している)。なお、試験管の内面はあらかじめアルブミンでブロッキングして使用した。
4.陰性コントロール用に、個片化した半透膜を入れていない新鮮ヒト血清を同様に試験管に入れた。陽性コントロール用に、個片化した半透膜を入れていないが20mgのザイモザン(SIGMA製 Z4350-1G)を添加した新鮮ヒト血清を試験管に入れた。これらの試験管を撹拌しながら加温して90分間37℃でインキュベートした。
5.試験管から個片化した半透膜を引き上げた。各血清中の補体の活性を測定した。測定はBD Bioscience社の品番550499のELISAキットを使用して行った。同キットに付属のプロトコルに従い測定を行った。
6.活性化率を以下の式により求めた。実施例および比較例に係る個片化した半透膜を入れた新鮮ヒト血清中の補体の活性の値(C3aの質量)をXnとした。陰性コントロールの活性の値をXminとした。陽性コントロールの活性の値をXmaxとした。活性化率は以下の式で算出できる。
1.各実施例及び比較例に係る半透膜を切断して、厚みはそのままで10mm×10mmの大きさに個片化した。個片化した半透膜を25℃のエタノールに30分以上浸漬した。次いでPBS(-)で洗浄した。
2.個片化した膜をヒトアルブミン(SIGMA製 A1653-10G)溶液に浸漬した。アルブミン溶液の濃度は0.1%(1mg/mL)で、温度は30℃で、溶液の体積は2.4mLとした。浸漬は90分間行った。
3.浸漬後、溶液中から個片化した半透膜を取り出した。
4.残された溶液中のアルブミンの濃度を測定することで、個片化した半透膜へのアルブミン吸着量を算出した。測定はELISA法で行った。ELISA法による測定はHuman Albumin ELISA Quantitation Set(Bethyl Laboratories,Inc.)を用いて実施した。
実施例1~9及び比較例1、3~5に係る半透膜へのアルブミン吸着量は10μg/cm2以下であった。このため当該半透膜の表面はタンパク質を吸着しにくいと評価された。
1.各実施例及び比較例に係る半透膜を切断することで、厚みはそのままで3cm×3cmの大きさに個片化した。
2.個片化した膜を25℃のエタノールに30分以上浸漬した。
3.その後、個片化した膜を30℃の蒸留水に30分以上浸漬した。
4.上記膜を目盛付きフィルターホルダー(FILTER HOLDER:ADVANTEC製25 mm、フィルター面積3.14 cm2)に装着した。フィルターホルダーは下部部品、スペーサー、上部部品及びクリップからなる。上部部品は外枠及び半透膜の支えとして機能する部品である。下部部品の上にスペーサーを置き、スペーサーの上に半透膜、半透膜の上に上部部品を置いた。上部部品と下部部品とをクリップで挟み固定した。下部部品は、吸引瓶に接続した。
5.目盛付きフィルターホルダーの上部部品内に11mLの蒸留水を入れた。
6.目盛付きフィルターホルダーにアスピレーターを接続した後、アスピレーターを稼働し、半透膜が蒸留水と接していない下部部品側を減圧した。このときの水温は25℃、負圧の大きさは3±0.2kPaとした。
7.上部部品内の蒸留水の体積が10mLから5mLになった時間を記録した。当該時間が10分以上であった場合は、減圧開始後10分間での水の濾過量を記録した。
8.半透膜の透水性を上記負圧における、フィルターホルダーに装着された膜の実効単位面積当たり及び単位時間当たりの水の透過量{L/(m2・時)}で表す。各実施例及び比較例において、4枚の半透膜を用意し、測定を4回行った。その平均値を代表値として透水性の値とした。
1.各実施例および比較例に係る半透膜を切断することで、厚みはそのままで、短辺25mm×長辺40mmの大きさに個片化した。個片化した半透膜を25℃のエタノールに30分以上浸漬し、次いでPBS(-)で洗浄した。
2.長辺部を折り曲げ、ヒートシーラーで、もとの長辺部2辺を各々溶融接着し、もとの短辺部が解放されている袋状の部材を作製した。
3.当該部材内部に20mg/Lのヒトアルブミン溶液を200μL注入し、もとの短辺部をヒートシーラーで封じてバッグを作製した。
4.前記アルブミン溶液入りのバッグを15mLチューブ内のハンクス緩衝液10mLに浸漬し、37℃で30分間振とうした。
5.一時間後、バッグ外側のハンクス緩衝液を採取した。
6.採取したハンクス緩衝液内のアルブミン濃度をELISA法により測定した。ELISA法による測定はHuman Albumin ELISA Quantitation Set(Bethyl Laboratories,Inc.)を用いて実施した。
7.透過率を以下の式により求めた。バッグからハンクス緩衝液に移行したアルブミン透過量をXnとした。バッグに注入したアルミブミン量をXmaxとした。Xmaxはすなわち、20mg/L×200μLで、400ngである。
膜厚を膜厚計で測定し、製膜された半透膜の四隅における測定値の平均をその半透膜の膜厚とした。各実施例及び比較例の膜の膜厚を表1に示す。
半透膜の孔の孔径は半透膜の表面を観察することで測定した。半透膜の一方の表面を走査型電子顕微鏡にて倍率2,000倍で写真撮影し、撮影後、無作為に30個の孔、すなわち空隙を選択し、各空隙の直径を測定した。測定値の平均を半透膜の孔の平均孔径とした。
上述の通り、実施例に係る半透膜の表面はアルブミン、すなわちタンパク質を吸着しにくかった。したがって実施例に係る半透膜は生体適合性が良好であることが示唆された。また実施例にかかる半透膜の表面は補体を活性化しにくかった。したがって実施例に係る膜は生体内における半透膜の物質透過性の経時的な低下を抑制することが示唆された。また、アルブミンの透過率の測定から、実施例に係る半透膜は、栄養分や分泌物質を透過するのに十分な大きさの孔を有することが分かった。したがって本発明の半透膜は物質透過性に優れることが示唆された。また、本発明の半透膜は透水性にも優れていた。
Claims (12)
- 樹脂を含有する半透膜であって、アルブミンの透過率が30%以上であり、1cm角の前記半透膜を0.1%アルブミン溶液に90分浸漬した時のアルブミン吸着量が10μg/cm2以下である半透膜。
- 前記半透膜を通して負圧3±0.2kPaで水を吸引したとき、水の透過量が1,000L/(m2・時)以上で表される、請求項1に記載の半透膜。
- 前記半透膜と血清とを接触させたとき、前記半透膜による、血清中の補体価(CH50)の減少が25%以下である、請求項1又は2に記載の半透膜。
- 前記半透膜と血清とを接触させたとき、前記半透膜による、血清中の補体の活性の増加が30%以下であり、
前記活性の増加は、C1、C2、C3、C4、C5、C6、C7、C8及びC9の内、一以上の補体の量、前記補体が分解されて生じたタンパク質の量、並びに前記補体の複合体の内、一以上のものの測定の量に基づき、算出されたものである、請求項1~3のいずれかに記載の半透膜。 - 厚さが50μm以上、200μm以下である、請求項1~4のいずれかに記載の半透膜。
- 少なくとも一面の平均孔径が0.1μm以上、3μm以下である、請求項1~5のいずれかに記載の半透膜。
- 前記樹脂はエチレン-ビニルアルコール系共重合体であり、前記半透膜は前記エチレン-ビニルアルコール系共重合体を50質量%以上含有する、請求項1~6のいずれかに記載の半透膜。
- 細胞を外部環境から隔離するための、請求項1~7のいずれかに記載の半透膜。
- 請求項1~8のいずれかに記載の半透膜からなる、バッグ。
- 質量比が、樹脂7.5質量%~25質量%、溶媒55質量%~87.5質量%、及び添加剤5質量%~20質量%の範囲となるように各成分を混合して製膜原液を得る、半透膜の製造方法であって、前記樹脂は、エチレン-ビニルアルコール系共重合体、ポリスルホン系重合体、ポリアクリロニトリル系重合体、セルロース系重合体、ポリアミド系重合体、及びポリカーボネート系重合体の少なくともいずれか一つであり、前記添加剤は、水溶性高分子である、半透膜の製造方法。
- 前記各成分を、50℃~120℃の範囲で加温溶解することで、前記製膜原液を得て、前記製膜原液を20℃~95℃に保持して、次いで20℃~80℃の温度で前記製膜原液を凝固させる、請求項10に記載の半透膜の製造方法。
- 前記製膜原液の凝固が凝固浴で行われる、請求項11に記載の半透膜の製造方法。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/070,989 US11058795B2 (en) | 2016-01-19 | 2017-01-19 | Semipermeable membrane and method of manufacturing the same |
EP17741489.3A EP3406271B1 (en) | 2016-01-19 | 2017-01-19 | Bag consisting of semipermeable membrane |
JP2017562893A JP7023717B2 (ja) | 2016-01-19 | 2017-01-19 | 半透膜及びその製造方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016007721 | 2016-01-19 | ||
JP2016-007721 | 2016-01-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017126612A1 true WO2017126612A1 (ja) | 2017-07-27 |
Family
ID=59362734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2017/001764 WO2017126612A1 (ja) | 2016-01-19 | 2017-01-19 | 半透膜及びその製造方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US11058795B2 (ja) |
EP (1) | EP3406271B1 (ja) |
JP (1) | JP7023717B2 (ja) |
WO (1) | WO2017126612A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017196150A (ja) * | 2016-04-27 | 2017-11-02 | 株式会社クラレ | 移植用デバイス及びバイオ人工臓器 |
CN111050815A (zh) * | 2017-08-30 | 2020-04-21 | 富士胶片株式会社 | 血管新生剂及其制造方法 |
US11439960B2 (en) | 2017-08-30 | 2022-09-13 | Fujifilm Corporation | Cell transplant device and method of manufacturing the same |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111686595A (zh) * | 2019-03-13 | 2020-09-22 | 西陇科学股份有限公司 | 原位改性结合相分离技术制备高性能亲水改性聚丙烯腈膜的方法 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54118697A (en) * | 1978-03-06 | 1979-09-14 | Kuraray Co | Membrane for treating body fluids |
JPS61276561A (ja) * | 1985-05-31 | 1986-12-06 | 株式会社クラレ | 血液処理装置 |
JPH05293344A (ja) * | 1992-04-20 | 1993-11-09 | Kuraray Co Ltd | エチレンビニルアルコール系共重合体中空糸膜の製造法 |
JPH11169693A (ja) * | 1997-12-09 | 1999-06-29 | Kuraray Co Ltd | 製膜溶液及び製膜方法 |
JP2001299908A (ja) | 2000-04-26 | 2001-10-30 | Yasuhiko Tabata | 細胞移植用バッグ及び人工膵臓 |
JP2001314736A (ja) | 2000-05-12 | 2001-11-13 | Kuraray Co Ltd | 製膜原液および中空糸膜の製造方法 |
JP2003010654A (ja) * | 2001-04-24 | 2003-01-14 | Kuraray Co Ltd | 中空糸膜の製造方法 |
JP2004275718A (ja) | 2003-02-26 | 2004-10-07 | Kuraray Medical Inc | バイオ人工膵臓用モジュール及びバイオ人工膵臓 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2935097A1 (de) * | 1978-09-07 | 1980-03-20 | Kuraray Co | Aethylen/vinylalkohol-copolymermembran |
DE3829766A1 (de) * | 1988-09-01 | 1990-03-22 | Akzo Gmbh | Verfahren zur herstellung von membranen |
US5962544A (en) * | 1995-12-07 | 1999-10-05 | 3M | Microporous materials of ethylene-vinyl alcohol copolymer and methods for making same |
US6793820B1 (en) | 1999-01-21 | 2004-09-21 | Ebara Corporation | Ethylene-vinyl alcohol hollow fiber membranes |
DE10239658A1 (de) * | 2002-05-06 | 2003-11-20 | Klaus-Peter Priebe | Vorrichtung zur Bluttrennung |
JP4985271B2 (ja) * | 2006-09-29 | 2012-07-25 | 東レ株式会社 | 多孔質膜およびその製造方法 |
JP2011526830A (ja) * | 2008-06-30 | 2011-10-20 | スリーエム イノベイティブ プロパティズ カンパニー | 再湿潤可能な非対称な膜の形成方法 |
ES2926504T3 (es) * | 2014-02-06 | 2022-10-26 | Gambro Lundia Ab | Membrana para purificación sanguínea |
-
2017
- 2017-01-19 JP JP2017562893A patent/JP7023717B2/ja active Active
- 2017-01-19 WO PCT/JP2017/001764 patent/WO2017126612A1/ja active Application Filing
- 2017-01-19 US US16/070,989 patent/US11058795B2/en active Active
- 2017-01-19 EP EP17741489.3A patent/EP3406271B1/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54118697A (en) * | 1978-03-06 | 1979-09-14 | Kuraray Co | Membrane for treating body fluids |
JPS61276561A (ja) * | 1985-05-31 | 1986-12-06 | 株式会社クラレ | 血液処理装置 |
JPH05293344A (ja) * | 1992-04-20 | 1993-11-09 | Kuraray Co Ltd | エチレンビニルアルコール系共重合体中空糸膜の製造法 |
JPH11169693A (ja) * | 1997-12-09 | 1999-06-29 | Kuraray Co Ltd | 製膜溶液及び製膜方法 |
JP2001299908A (ja) | 2000-04-26 | 2001-10-30 | Yasuhiko Tabata | 細胞移植用バッグ及び人工膵臓 |
JP2001314736A (ja) | 2000-05-12 | 2001-11-13 | Kuraray Co Ltd | 製膜原液および中空糸膜の製造方法 |
JP2003010654A (ja) * | 2001-04-24 | 2003-01-14 | Kuraray Co Ltd | 中空糸膜の製造方法 |
JP2004275718A (ja) | 2003-02-26 | 2004-10-07 | Kuraray Medical Inc | バイオ人工膵臓用モジュール及びバイオ人工膵臓 |
Non-Patent Citations (5)
Title |
---|
KOBAYASHI, NAOYA,: ""body-implantable bioartificial pancreas,"", 19 December 2011 (2011-12-19), Retrieved from the Internet <URL:http://www.jst.go.jp/chiiki/ikusei/seika/h22/h22_hiroshima01.pdf> |
NAKAJI, SHUHEI: ""development of novel treatment of diabetes with implantable bioartificial pancreas,"", 15 January 2016 (2016-01-15), Retrieved from the Internet <URL:http://renkei.office.ous.ac.jp/wp-content/uploads/2012/01/C-5.pdf> |
See also references of EP3406271A4 |
TAKEMURA, S ET AL.: "New aspects of the complement system", JPN J CLIN IMMUN, vol. 11, no. 2, 1988, pages 93 - 98, XP055573539, ISSN: 0911-4300 * |
YUASA, T ET AL.: "Neovascularization induced around an artificial device implanted in the abdomen by the use of gelatinized fibroblast growth factor 2", CELL TRANSPLANTATIO N, vol. 18, no. 5-6, 2009, pages 683 - 688, XP055532886 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017196150A (ja) * | 2016-04-27 | 2017-11-02 | 株式会社クラレ | 移植用デバイス及びバイオ人工臓器 |
CN111050815A (zh) * | 2017-08-30 | 2020-04-21 | 富士胶片株式会社 | 血管新生剂及其制造方法 |
US11439960B2 (en) | 2017-08-30 | 2022-09-13 | Fujifilm Corporation | Cell transplant device and method of manufacturing the same |
US11471564B2 (en) * | 2017-08-30 | 2022-10-18 | Fujifilm Corporation | Angiogenic agent and method of manufacturing the same |
Also Published As
Publication number | Publication date |
---|---|
JPWO2017126612A1 (ja) | 2018-11-08 |
EP3406271B1 (en) | 2024-04-17 |
EP3406271A1 (en) | 2018-11-28 |
US11058795B2 (en) | 2021-07-13 |
JP7023717B2 (ja) | 2022-02-22 |
EP3406271A4 (en) | 2019-09-25 |
US20190015547A1 (en) | 2019-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109913400B (zh) | 人工组织前体及制备其的方法 | |
WO2017126612A1 (ja) | 半透膜及びその製造方法 | |
US8435751B2 (en) | Membrane for cell expansion | |
DE69633189T2 (de) | Fester Träger zur Verwendung in der Zellkultivierung, insbesondere für die Kultivierung von Leberzellen, Bioreaktor, welcher den festen Träger enthält, und die Verwendung davon in einem biologisch-künstlichen Lebersystem | |
US8999167B2 (en) | Composite porous membrane and process for producing the same | |
Bettahalli et al. | Development of poly (l-lactic acid) hollow fiber membranes for artificial vasculature in tissue engineering scaffolds | |
WO2020070484A1 (en) | Membrane | |
US20180161478A1 (en) | Barrier membrane used in periodontitis treatment and a production method thereof | |
Gentile et al. | Polymer science for macroencapsulation of cells for central nervous system transplantation | |
JP2004501700A (ja) | 連通セルを用いた三次元構造を有する生体適合性ポリマー、その調製方法、および医薬ならびに手術における適用 | |
Verma et al. | Functionally coated polyethersulfone hollow fiber membranes: A substrate for enhanced HepG2/C3A functions | |
JP6920681B2 (ja) | 移植用デバイス及びその製造方法並びにバイオ人工臓器の製造方法 | |
JP4847129B2 (ja) | 創傷治癒促進材 | |
Jiang et al. | Superhydrophobic polydimethylsiloxane dip-coated polycaprolactone electrospun membrane for extracorporeal membrane oxygenation | |
Waheed et al. | Green synthesized nano-cellulose polyethylene imine-based biological membrane | |
JP2001200089A (ja) | 親水性細孔膜 | |
WO2003034945A1 (fr) | Vaisseau artificiel et procede de realisation | |
Ran et al. | Constructing an anisotropic triple-pass tubular framework within a lyophilized porous gelatin scaffold using dexamethasone-loaded functionalized Whatman paper to reinforce its mechanical strength and promote Osteogenesis | |
KR102189850B1 (ko) | 생리활성인자가 탑재된 고분자-세포 혼합 스페로이드 및 이의 제조방법 | |
EP1177829B1 (de) | Mit Blut und Gewebe verträgliche Membranen aus P(AN/NVP)-Misch-polymeren und deren Anwendung im medizinischen Bereich | |
US20240148936A1 (en) | Scaffold for tissue regeneration, particularly for bone regeneration, and manufacturing method thereof | |
WO2023012823A1 (en) | Electrospun microfibrous porous stretchable membranes and the method of preparation thereof | |
Groth et al. | Biomedical Application of Membranes in Bioartificial Organs and Tissue Engineering | |
Buruiana | 10 Potential Biomedical | |
KR20200112255A (ko) | 2중 성장인자가 탑재된 조직공학용 pcl 기반 소구경 인공혈관 및 이의 제조방법 |
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: 17741489 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017562893 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2017741489 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2017741489 Country of ref document: EP Effective date: 20180820 |