NO175457B - Objects having a blood compatible surface layer and method for equipping objects with such surface layer as well as using a coated substrate material for the manufacture of a medical object - Google Patents
Objects having a blood compatible surface layer and method for equipping objects with such surface layer as well as using a coated substrate material for the manufacture of a medical objectInfo
- Publication number
- NO175457B NO175457B NO900505A NO900505A NO175457B NO 175457 B NO175457 B NO 175457B NO 900505 A NO900505 A NO 900505A NO 900505 A NO900505 A NO 900505A NO 175457 B NO175457 B NO 175457B
- Authority
- NO
- Norway
- Prior art keywords
- blood
- surface layer
- hydrophobic
- objects
- compatible
- Prior art date
Links
- 239000008280 blood Substances 0.000 title claims description 23
- 210000004369 blood Anatomy 0.000 title claims description 23
- 239000002344 surface layer Substances 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 17
- 239000000463 material Substances 0.000 title claims description 9
- 239000000758 substrate Substances 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 229920000896 Ethulose Polymers 0.000 claims description 14
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 claims description 14
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 claims description 14
- 230000002209 hydrophobic effect Effects 0.000 claims description 14
- 238000005189 flocculation Methods 0.000 claims description 13
- 230000016615 flocculation Effects 0.000 claims description 13
- 239000011521 glass Substances 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 11
- 238000000576 coating method Methods 0.000 claims description 11
- 229920001600 hydrophobic polymer Polymers 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 230000005661 hydrophobic surface Effects 0.000 claims description 9
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 7
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 7
- -1 polytetrafluoroethylene Polymers 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 2
- 230000027455 binding Effects 0.000 description 8
- 238000009739 binding Methods 0.000 description 8
- 230000015271 coagulation Effects 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229920000669 heparin Polymers 0.000 description 6
- 229960002897 heparin Drugs 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 229940012952 fibrinogen Drugs 0.000 description 5
- 108010049003 Fibrinogen Proteins 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 229920002307 Dextran Polymers 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 102000007625 Hirudins Human genes 0.000 description 2
- 108010007267 Hirudins Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 229940006607 hirudin Drugs 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000004381 surface treatment Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- 101800003265 Beta-thromboglobulin Proteins 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 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 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 239000006087 Silane Coupling Agent Substances 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229920006321 anionic cellulose Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 102000007329 beta-Thromboglobulin Human genes 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000002091 cationic group Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000937 inactivator Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229920000831 ionic polymer Polymers 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920005992 thermoplastic resin Polymers 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/08—Polysaccharides
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
Description
Foreliggende oppfinnelse vedrører gjenstander som har et blodkompatibelt overflatelag og fremgangsmåter for å utstyre slike gjenstander med et slikt overflatelag, og spesielt for å tilveiebringe gjenstander som er nyttige innenfor medisin. Nærmere bestemt vedrører oppfinnelsen gjenstander som har minst en overflate av glass, metall eller en hydrofob polymer belagt med et blodkompatibelt overflatelag og fremgangsmåter for å utstyre gjenstander som har minst en overflate av glass, metall eller en hydrofob polymer med et belegg av et blodkompatibelt overflatelag, såvel som anvendelsen av substratmateriale av glass, metall eller hydrofob polymer, belagt med overflatelaget av en adsobert, vannoppløselig polymer som er gjort hydrofob, fortrinnsvis et ikke-protein for fremstilling av en medisinsk gjenstand som har en blodkompatibel overflate. The present invention relates to objects that have a blood-compatible surface layer and methods for equipping such objects with such a surface layer, and in particular for providing objects that are useful in medicine. More specifically, the invention relates to objects that have at least one surface of glass, metal or a hydrophobic polymer coated with a blood-compatible surface layer and methods for equipping objects that have at least one surface of glass, metal or a hydrophobic polymer with a coating of a blood-compatible surface layer, as well as the use of substrate material of glass, metal or hydrophobic polymer, coated with the surface layer of an adsorbed, water-soluble polymer which is made hydrophobic, preferably a non-protein for the production of a medical article having a blood-compatible surface.
Tidligere kjent teknikk for å utstyre gjenstander nyttige innen medisin med et blodkompatibelt overflatelag innbefattet ofte en endring i overflateenergien for materialet. En forbedring i egenskapene for forskjellige materialer er oppnådd ved å modifisere overflatelagene, enten til en mer hydrofob karakter eller til en mer hydrofil karakter. Tilveiebringelse av hydrofobe egenskaper for overflatelaget, f.eks. ved metylisering av en glassoverflate, resulterer i en reduksjon av effektiviteten for det overflateaktiverte koaguleringssystemet til blodet. Imidlertid er proteiner, såsom fibrinogen, bundet relativt fast til en slik overflate, og til dette proteinlaget kan visse celler, trombocyttene, bindes og aktiveres hvoretter koagulering startes selv om den forløper langsomt. Hydrofile overflater, f.eks. hydrolysert nylon eller oksydert aluminium, har gitt redusert binding av celler, men det overflateaktiverte koaguleringssystemet forhindres ikke ved disse overflatene. Anvendelse av disse overflatene i kontakt med blod forutsetter tilsatsen av anti-koaguleringsmidler, f.eks. heparin til blodet. Prior art for providing articles useful in medicine with a blood-compatible surface layer often involved a change in the surface energy of the material. An improvement in the properties of different materials has been achieved by modifying the surface layers, either to a more hydrophobic character or to a more hydrophilic character. Providing hydrophobic properties to the surface layer, e.g. by methylation of a glass surface, results in a reduction of the efficiency of the surface-activated coagulation system of the blood. However, proteins, such as fibrinogen, are bound relatively firmly to such a surface, and to this protein layer certain cells, the platelets, can be bound and activated, after which coagulation is started, even if it proceeds slowly. Hydrophilic surfaces, e.g. hydrolyzed nylon or oxidized aluminium, have resulted in reduced attachment of cells, but the surface-activated coagulation system is not prevented by these surfaces. Use of these surfaces in contact with blood requires the addition of anti-coagulants, e.g. heparin to the blood.
En annen overflatebehandlingsteknikk ifølge teknikkens stand for å forebygge koagulering omfatter binding av anti-koaguleringsmidler i overflatelaget. Eeparin har hovedsakelig vært benyttet med denne teknikken. Heparin er et heksoseamin-heksuronsyrepolysakkarid som er sulfatert og har syre-egenskaper, det vil si heparin er en organisk syre. Ifølge DE-A-21 54 542 impregneres gjenstander av en organisk termoplastisk harpiks først med et amino-silan-koblings-middel, og den derved behandlede gjenstanden behandles så med en syreoppløsning av heparinsalt for å oppnå binding av heparin i overflatelaget ved hjelp av ioniske bindinger. Overflater behandlet på denne måten med heparin har vist seg å redusere koaguleringsreaksjonen. En betydelig ulempe ved disse overflatene er imidlertid at heparinbehandlingen ikke forhindrer vedhenget av trombocytter som er et stort problem i f.eks. hjerte-lungemaskiner. Another surface treatment technique according to the state of the art to prevent coagulation involves binding anti-coagulants in the surface layer. Eeparin has mainly been used with this technique. Heparin is a hexoseamine-hexuronic acid polysaccharide that is sulfated and has acid properties, i.e. heparin is an organic acid. According to DE-A-21 54 542, articles of an organic thermoplastic resin are first impregnated with an amino-silane coupling agent, and the thereby treated article is then treated with an acid solution of heparin salt to achieve binding of heparin in the surface layer by means of ionic bindings. Surfaces treated in this way with heparin have been shown to reduce the clotting reaction. However, a significant disadvantage of these surfaces is that the heparin treatment does not prevent the attachment of platelets, which is a major problem in e.g. heart-lung machines.
På det tiende årlige møtet av Society for Biomaterials (Washington D.C., 27. april 1984) ble det beskrevet at polyetylenglykol-overflater på kvarts minimaliserer protein-adsorpsjon. Fremgangsmåter for kovalent binding av polyetylenglykol til overflater er tidligere beskrevet, f.eks. i W086/02087. Polyion-komplekser dannet mellom et kationisk og et anionisk cellulosederivat er også funnet å ha gode blodkompatibiliteter (Ito, H. et al., J. Appl. Polym. Sei., bind 32 (1986) 3413). Fremgangsmåter for kovalent binding av av vannoppløselige polymerer til overflater er også beskrevet, f.eks. i EP 166 998. At the Tenth Annual Meeting of the Society for Biomaterials (Washington D.C., April 27, 1984), it was described that polyethylene glycol surfaces on quartz minimize protein adsorption. Methods for covalently binding polyethylene glycol to surfaces have previously been described, e.g. in W086/02087. Polyion complexes formed between a cationic and an anionic cellulose derivative have also been found to have good blood compatibilities (Ito, H. et al., J. Appl. Polym. Sei., vol. 32 (1986) 3413). Methods for covalent binding of water-soluble polymers to surfaces are also described, e.g. in EP 166 998.
Det er kjent at vannbindende geler, f.eks. polyhydroksyalkyl-metakrylat, reduserer adsorpsjonen av proteiner og gir et lavt vedheng til celler (Hoffman et al., Ann. N.Y. Acad. Sei., bind 283 (1977) 372). Disse egenskapene antas å ha sin årsak i det faktum at geler som inneholder vann gir en lav overflateenergi i grenseflaten til blodet. Den tidligere kjente teknikken for fremstilling av vannbindende geler hemmes imidlertid ved ulemper, såsom komplisert fremstil-lingsteknikk og ufullstendig polymerisasjon, hvilket resulterer i lekkasje av toksiske monomerer. En gel-lignende blanding av sakkarose og glukose innbefattet i en matriks av polysakkaridet dekstran eller dekstrin, benyttes ifølge tidligere kjent teknikk som et rør for sammenføyningen av blodkar. Blandingen bør ha den virkningen at ingen toksisitet for pasienten finner sted slik at Implantatet oppløses i blodet etter en viss tid. Det er kjent at det nøytrale polysakkaridet dekstran er blandbart med blod uten å fremkalle noen koaguleringsreaksjon. Dekstran har vært benyttet som et overflatebelegg på glass, aluminium og silikongummi og det er vist å redusere blodkoagulering under blodkontakt med disse overflatene som beskrevet i W083/03977. It is known that water-binding gels, e.g. polyhydroxyalkyl methacrylate, reduces the adsorption of proteins and provides a low attachment to cells (Hoffman et al., Ann. N.Y. Acad. Sei., vol. 283 (1977) 372). These properties are believed to be due to the fact that gels containing water provide a low surface energy at the blood interface. However, the previously known technique for producing water-binding gels is hampered by disadvantages, such as complicated production technique and incomplete polymerization, which results in leakage of toxic monomers. A gel-like mixture of sucrose and glucose contained in a matrix of the polysaccharide dextran or dextrin is used according to prior art as a tube for joining blood vessels. The mixture should have the effect that no toxicity for the patient takes place so that the Implant dissolves in the blood after a certain time. It is known that the neutral polysaccharide dextran is miscible with blood without causing any coagulation reaction. Dextran has been used as a surface coating on glass, aluminum and silicone rubber and it has been shown to reduce blood coagulation during blood contact with these surfaces as described in WO83/03977.
Adhesjonen av blodkomponenter til overflater i kontakt med blod kan reduseres ved foradsorpsjon av albumin på hydrofobe overflater (Mosher, D.F. i "Interaction of blood with natural and artificial surfaces", Ed. Salzman, E.W. Dekker Inc. 1981). Det adsorberte albuminet danner ikke et stabilt belegg, men desorberes under kontakt med blod og koagulering induseres, om enn med en lavere hastighet. The adhesion of blood components to surfaces in contact with blood can be reduced by preadsorption of albumin on hydrophobic surfaces (Mosher, D.F. in "Interaction of blood with natural and artificial surfaces", Ed. Salzman, E.W. Dekker Inc. 1981). The adsorbed albumin does not form a stable coating, but is desorbed in contact with blood and coagulation is induced, albeit at a lower rate.
Formålet med foreliggende oppfinnelse er å utstyre gjenstander som er nyttige innenfor medisin med et blodkompatibelt oveflatelag. Dette betyr, for gjenstander som er ment for anvendelse i kontakt med blod, at gjenstanden som er fremmed for blodet behandles på en slik måte at den ikke induserer koagulering eller dannelsen av tromboser. The purpose of the present invention is to equip objects that are useful in medicine with a blood-compatible surface layer. This means, for articles intended for use in contact with blood, that the article foreign to the blood is treated in such a way that it does not induce coagulation or the formation of thrombi.
Foreliggende oppfinnelse tilveiebringer teknikk for over-flatebehandling av materiale som er viktig for medisinsk teknologi, såsom glass, metall og hydrofobe polymerer (f.eks. polytetrafluoretylen (PTFE)). The present invention provides a technique for the surface treatment of material that is important for medical technology, such as glass, metal and hydrophobic polymers (e.g. polytetrafluoroethylene (PTFE)).
Foreliggende oppfinnelse tilveiebringer en gjenstand som har minst en hydrofob overflate av glass, metall eller en hydrofob polymer belagt med et blodkompatibelt overflatelag, kjennetegnet ved at det blodkompatible overflatelaget består av en adsorbert etylhydroksyetylcellulose som er gjort hydrofob og som har en flokkuleringstemperatur på 35-40°C. The present invention provides an object which has at least one hydrophobic surface of glass, metal or a hydrophobic polymer coated with a blood-compatible surface layer, characterized in that the blood-compatible surface layer consists of an adsorbed ethylhydroxyethylcellulose which has been rendered hydrophobic and which has a flocculation temperature of 35-40° C.
Oppfinnelsen omfatter videre en fremgangsmåte for tilveiebringelse av gjenstander som har minst en hydrofob overflate av glass, metall eller en hydrofob polymer med et belegg av et blodkompatibelt overflatelag, kjennetegnet ved at nevnte overflate av gjenstanden, etter å være gjort hydrofob når dette er påkrevet, eksponeres mot en oppløsning av etylhydroksyetylcellulose som har en flokkuleringstemperatur på 35-40°C, ved en temperatur under flokkuleringstemperaturen. The invention further comprises a method for providing objects which have at least one hydrophobic surface of glass, metal or a hydrophobic polymer with a coating of a blood-compatible surface layer, characterized in that said surface of the object, after being rendered hydrophobic when required, is exposed against a solution of ethyl hydroxyethyl cellulose which has a flocculation temperature of 35-40°C, at a temperature below the flocculation temperature.
Substratoverflaten må være hydrofob før belegging. For metaller eller metalloksyder kan dette oppnås ved metylisering med silaner. The substrate surface must be hydrophobic before coating. For metals or metal oxides, this can be achieved by methylation with silanes.
Etylhydroksyetylcellulosen som er gjort hydrofob, som benyttes i foreliggende oppfinnelse, er begrenset oppløselige i vann, avhengig av graden av hydrofobering. The ethyl hydroxyethyl cellulose which has been rendered hydrophobic, which is used in the present invention, is limited in water solubility, depending on the degree of hydrophobicisation.
Etylhydroksyetylcellulosen som anvendes ved foreliggende oppfinnelse er kjennetegnet ved den egenskapen at den har evnen til å adsorberes ved hydrofobe overflater. Hydrofo-beringen av polymeren kan utføres ved binding av hydrokarboner til polymer-ryggraden. Eksempler på slike hydrokarboner er alkylgrupper, benzylgrupper eller alkylengrupper. Hydro-foberingen gjør polymeren delvis uoppløselig i vann med en flokkulering over en viss temperatur eller over en viss ionestyrke. The ethyl hydroxyethyl cellulose used in the present invention is characterized by the property that it has the ability to be adsorbed on hydrophobic surfaces. Hydrophobing of the polymer can be carried out by binding hydrocarbons to the polymer backbone. Examples of such hydrocarbons are alkyl groups, benzyl groups or alkylene groups. The hydrophobing makes the polymer partially insoluble in water with a flocculation above a certain temperature or above a certain ionic strength.
Substratoverflaten eksponeres mot en oppløsning av etylhydroksyetylcellulosen ved en temperatur under flokkuleringstemperaturen og ved en saltkonsentrasjon under flokkuler-ingskonsentrasjonen. Etylhydroksyetylcellulosen som er gjort hydrofob adsorberes sterkt til hydrofobe overflater. Etylhydroksyetylcellulosen har en flokkuleringstemperatur på 35-40°C. The substrate surface is exposed to a solution of the ethyl hydroxyethyl cellulose at a temperature below the flocculation temperature and at a salt concentration below the flocculation concentration. The ethyl hydroxyethyl cellulose which has been made hydrophobic is strongly adsorbed to hydrophobic surfaces. The ethyl hydroxyethyl cellulose has a flocculation temperature of 35-40°C.
Den behandlende overflaten viser seg å være biologisk inert og overflater behandlet på denne måten gir redusert adsorpsjon av proteiner, vedheng av celler og koagulering. Den adsorberte polymeren blir ikke utvekslet med plasmaproteiner. The treating surface turns out to be biologically inert and surfaces treated in this way result in reduced adsorption of proteins, attachment of cells and coagulation. The adsorbed polymer is not exchanged with plasma proteins.
Fremgangsmåten ifølge foreliggende oppfinnelse kan anvendes innenfor mange felter. Følgelig benyttes i hjerte-lungemaskiner mange detaljer som er fremstilt av aluminium som lett kan behandles med metyl-silan for å gi en hydrofob overflate. The method according to the present invention can be used in many fields. Consequently, heart-lung machines use many details made of aluminum which can be easily treated with methyl-silane to give a hydrophobic surface.
Fremgangsmåten ifølge foreliggende oppfinnelse er ideelt egnet for behandling av venekatetere. Disse er ofte fremstilt i PTFE og dette materialet er normalt ikke blodkompatibelt. For dette materialet er det også vanskelig å finne egnede prosesser for kovalent kobling av hydrofile polymerer. The method according to the present invention is ideally suited for the treatment of venous catheters. These are often made of PTFE and this material is not normally blood compatible. For this material, it is also difficult to find suitable processes for covalently linking hydrophilic polymers.
Oppfinnelsen omfatter videre anvendelse av et substratmateriale av glass, metall eller hydrofob polymer belagt med et overflatelag bestående av en adsorbert etylhydroksyetylcellulose som er gjort hydrofob og som har en flokkuleringstemperatur på 35-40°C for fremstilling av en medisinsk gjenstand som har en blodkompatibel overflate. The invention further comprises the use of a substrate material of glass, metal or hydrophobic polymer coated with a surface layer consisting of an adsorbed ethyl hydroxyethyl cellulose which has been rendered hydrophobic and which has a flocculation temperature of 35-40°C for the production of a medical object which has a blood-compatible surface.
Oppfinnelsen kan også anvendes i andre sammenhenger, f.eks. for behandling av gjenstander av hydrofob plast for prøve-taking og/eller lagring av blod. The invention can also be used in other contexts, e.g. for the treatment of objects made of hydrophobic plastic for sampling and/or storage of blood.
Oppfinnelsen skal i det følgende illustreres ved hjelp av et arbeidseksempel. In what follows, the invention will be illustrated using a working example.
Arbeldseksempel Working example
Beleggingsfremgangsmåte Coating procedure
a) Polymeren renses og isoleres ved gjentatt varmeflok-kulering og sentrifugering. b) Et polytetrafluoretylen-rør (teflon), diameter 3 mm, og et polyuretan-rør, diameter 3 mm, ble neddykket i en a) The polymer is purified and isolated by repeated heat flocculation and centrifugation. b) A polytetrafluoroethylene tube (Teflon), diameter 3 mm, and a polyurethane tube, diameter 3 mm, were immersed in a
oppløsning av etylhydroksyetylcellulose (EHEC, 1 g/l, fremstilt ifølge US-patent nr. 3 926 951) i destillert vann i 20 timer ved romtemperatur. Rørene ble renset i saltvann I 1 minutt. solution of ethyl hydroxyethyl cellulose (EHEC, 1 g/l, prepared according to US patent no. 3,926,951) in distilled water for 20 hours at room temperature. The tubes were cleaned in saline for 1 minute.
Eksperimentelle tester Experimental tests
To forskjellige tester ble utført. Inkubering med en oppløsning av fibrinogen ved høy konsentrasjon ble utført for å detektere utvekslingsreaksjoner mellom polymeren og plasmaprotein. Inkubering med fullblod etterfulgt av måling av frigitt tromboglobulin ble benyttet for å måle stabili-teten av polymerbelegget og aktiveringen av plater ved overflaten. Two different tests were performed. Incubation with a solution of fibrinogen at high concentration was performed to detect exchange reactions between the polymer and plasma protein. Incubation with whole blood followed by measurement of released thromboglobulin was used to measure the stability of the polymer coating and the activation of plaques at the surface.
Fibrinogen adsorpsjon Fibrinogen adsorption
a) Belagte og ubelagte rør ble inkubert i en oppløsning av humant fibrinogen (1 g/l) i saltvann i 30 minutter ved a) Coated and uncoated tubes were incubated in a solution of human fibrinogen (1 g/l) in saline for 30 min at
romtemperatur. room temperature.
b) Rørene ble renset i saltvann i 10 sekunder. b) The tubes were cleaned in salt water for 10 seconds.
c) Inkubering i anti-fibrinogenantiserum fortynnet 1:1000 i 1 time ved romtemperatur. d) Inkubering med peroksydase-konjugerte antistoffer i 30 minutter. e) Inkubering i en oppløsning av ortofenylendiamin (0,5 g/l) og 0,01 % E202 i 0,1M citratbuffer, pH=4,5. f) Tilsats av 2M H2SO4 og avlesning av absorbans ved X=450 nm. c) Incubation in anti-fibrinogen antiserum diluted 1:1000 for 1 hour at room temperature. d) Incubation with peroxidase-conjugated antibodies for 30 minutes. e) Incubation in a solution of orthophenylenediamine (0.5 g/l) and 0.01% E2O2 in 0.1M citrate buffer, pH=4.5. f) Addition of 2M H2SO4 and reading of absorbance at X=450 nm.
Blodkompatibilitetstest Blood compatibility test
a) Veneblod (18 ml) ble tatt fra en frisk donor i 2,0 ml av en oppløsning av hirudin i saltvann (500 IE/ml) (hirudin a) Venous blood (18 ml) was taken from a healthy donor in 2.0 ml of a solution of hirudin in saline (500 IU/ml) (hirudin
er en trombin-inaktivator). is a thrombin inactivator).
b) Blodet ble fylt i belagte og ubelagte rør og fikk inkubere i 2 timer ved romtemperatur. c) 1 ml blod ble tatt inn i en sprøyte inneholdende 0,2 ml "diatube" og blandingen ble sentrifugert ved 5000 g i 30 b) The blood was filled into coated and uncoated tubes and allowed to incubate for 2 hours at room temperature. c) 1 ml of blood was taken into a syringe containing 0.2 ml "diatube" and the mixture was centrifuged at 5000 g for 30
minutter ved +3°C. minutes at +3°C.
d) Supernatanten ble samlet og mengden P-tromboglobulin ble bestemt ved anvendelse av et kommersielt sett (Diagnostica d) The supernatant was collected and the amount of β-thromboglobulin was determined using a commercial kit (Diagnostica
Stago). Stago).
Resultater Results
Resultatene fra de ovenfor omtalte testene er gjengitt i The results from the above-mentioned tests are reproduced in
tabellene I og II. Tabell I viser at mengden av fibrinogen adsorbert på rørene reduseres ved belegging med etylhydroksyetylcellulose. Tabell II viser at mengden av 3-tromboglobulin frigitt fra platene under inkubering med blod også reduseres ved belegging med etylhydroksyetylcellulose. tables I and II. Table I shows that the amount of fibrinogen adsorbed on the tubes is reduced by coating with ethyl hydroxyethyl cellulose. Table II shows that the amount of 3-thromboglobulin released from the plates during incubation with blood is also reduced by coating with ethyl hydroxyethyl cellulose.
Claims (8)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8703310A SE8703310D0 (en) | 1987-08-26 | 1987-08-26 | ARTICLES EXHIBITING A BLOOD COMPATIBLE SURFACE LAYER AND PROCESS FOR PROVIDING ARTICLES WITH SUCH A SURFACE LAYER |
| PCT/SE1988/000421 WO1989001791A1 (en) | 1987-08-26 | 1988-08-18 | Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO900505D0 NO900505D0 (en) | 1990-02-02 |
| NO900505L NO900505L (en) | 1990-02-02 |
| NO175457B true NO175457B (en) | 1994-07-11 |
| NO175457C NO175457C (en) | 1994-10-19 |
Family
ID=26659924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO900505A NO175457C (en) | 1987-08-26 | 1990-02-02 | Objects having a blood compatible surface layer and method for equipping objects with such surface layer as well as using a coated substrate material for the manufacture of a medical object |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU625391B2 (en) |
| NO (1) | NO175457C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU616212B2 (en) * | 1987-09-21 | 1991-10-24 | Terumo Kabushiki Kaisha | Medical instrument and production thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1208557A (en) * | 1982-09-29 | 1986-07-29 | George B. Marks | Antibacterial attachment |
| JPS60202702A (en) * | 1984-03-26 | 1985-10-14 | Showa Denko Kk | Dialysis membrane |
-
1988
- 1988-08-18 AU AU23178/88A patent/AU625391B2/en not_active Ceased
-
1990
- 1990-02-02 NO NO900505A patent/NO175457C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO900505D0 (en) | 1990-02-02 |
| AU625391B2 (en) | 1992-07-09 |
| NO900505L (en) | 1990-02-02 |
| AU2317888A (en) | 1989-03-31 |
| NO175457C (en) | 1994-10-19 |
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