NO155089B - GOODS WITH A BIO-COMPATIBLE SURFACE LAYER AND PROCEDURE FOR AA SUPPLY GOODS WITH SUCH A SURFACE LAYER. - Google Patents
GOODS WITH A BIO-COMPATIBLE SURFACE LAYER AND PROCEDURE FOR AA SUPPLY GOODS WITH SUCH A SURFACE LAYER. Download PDFInfo
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- NO155089B NO155089B NO84840109A NO840109A NO155089B NO 155089 B NO155089 B NO 155089B NO 84840109 A NO84840109 A NO 84840109A NO 840109 A NO840109 A NO 840109A NO 155089 B NO155089 B NO 155089B
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- surface layer
- polysaccharide
- glass
- aluminum
- blood
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- 238000000034 method Methods 0.000 title claims description 21
- 239000002344 surface layer Substances 0.000 title claims description 21
- 229920001282 polysaccharide Polymers 0.000 claims description 21
- 239000005017 polysaccharide Substances 0.000 claims description 21
- 150000004676 glycans Chemical class 0.000 claims description 20
- 229920002307 Dextran Polymers 0.000 claims description 19
- 239000011521 glass Substances 0.000 claims description 19
- 210000004369 blood Anatomy 0.000 claims description 18
- 239000008280 blood Substances 0.000 claims description 18
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 17
- 229910052782 aluminium Inorganic materials 0.000 claims description 17
- 229920002379 silicone rubber Polymers 0.000 claims description 16
- 239000004945 silicone rubber Substances 0.000 claims description 16
- 229910052710 silicon Inorganic materials 0.000 claims description 11
- 239000010703 silicon Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 7
- 229910000077 silane Inorganic materials 0.000 claims description 7
- 125000003700 epoxy group Chemical group 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 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 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000015271 coagulation Effects 0.000 description 7
- 238000005345 coagulation Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 229920000669 heparin Polymers 0.000 description 7
- 229960002897 heparin Drugs 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 239000000499 gel Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 238000004851 dishwashing Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000005530 etching Methods 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004381 surface treatment Methods 0.000 description 2
- AZUXKVXMJOIAOF-UHFFFAOYSA-N 1-(2-hydroxypropoxy)propan-2-ol Chemical compound CC(O)COCC(C)O AZUXKVXMJOIAOF-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 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
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 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
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 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
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007978 cacodylate buffer Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- -1 dextran glycerol glycoside Chemical class 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 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 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000572 ellipsometry Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 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
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000000376 reactant Substances 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
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229920005992 thermoplastic resin Polymers 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- HQYALQRYBUJWDH-UHFFFAOYSA-N trimethoxy(propyl)silane Chemical compound CCC[Si](OC)(OC)OC HQYALQRYBUJWDH-UHFFFAOYSA-N 0.000 description 1
- BPSIOYPQMFLKFR-UHFFFAOYSA-N trimethoxy-[3-(oxiran-2-ylmethoxy)propyl]silane Chemical compound CO[Si](OC)(OC)CCCOCC1CO1 BPSIOYPQMFLKFR-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
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- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse vedrører gjenstander som utviser et biokompatibelt overflate og en fremgangsmåte for å forsyne gjenstander med et slikt overflatelag. Oppfinnelsen angår mer spesielt gjenstander som har minst en overflate av glass, silisium, aluminium eller silikongummi belagt med et biokompatibelt overflatelag og en fremgangsmåte for å forsyne gjenstander som utviser minst en overflate av glass, silisium, aluminium eller silikongummi med et biokompatibelt overflatelag. The present invention relates to objects that exhibit a biocompatible surface and a method for providing objects with such a surface layer. The invention relates more particularly to objects that have at least one surface of glass, silicon, aluminum or silicone rubber coated with a biocompatible surface layer and a method for providing objects that exhibit at least one surface of glass, silicon, aluminum or silicone rubber with a biocompatible surface layer.
Formålet med foreliggende oppfinnelse er å forsyne gjenstander som er nyttige innen medisinen med et biokompatibelt overflatelag. Dette betyr, f.eks. for gjenstander som skal anvendes i kontakt med blod, at gjenstanden som er fremmed for blodet behandles på en slik måte at den ikke induserer koagulering eller dannelse av tromboser. The purpose of the present invention is to provide objects that are useful in medicine with a biocompatible surface layer. This means, e.g. for objects to be used in contact with blood, that the object which is foreign to the blood is treated in such a way that it does not induce coagulation or the formation of thrombi.
Tidligere teknikk for å forsyne gjenstander som er nyttige innen medisinen med et biokompatibelt overflatelag, omfat-ter ofte en forandring av materialets overflateenergi. Previous techniques for providing objects that are useful in medicine with a biocompatible surface layer often involve a change in the material's surface energy.
En forbedring av egenskapene til forskjellige materialer An improvement in the properties of different materials
har blitt oppnådd ved å modifisere overflatelagene enten til en mer hydrofob karakter eller til en mer hydrofil karakter. Hydrofobisering av overflatelaget, f.eks. ved metylisering av en glassoverflate, resulterer i en minsking av effektiviteten hos blodets overflateaktiverte koaguleringssystem. Proteiner slik som fibrinogen bindes imidlertid relativt sterkt til slike overflater og til dette proteinlag 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 vist redusert binding av celler, men det overflateaktiverte koaguleringssystem hindres ikke ved disse overflatene. Bruken av disse overflater i kontakt med blod innebærer således tilsetning av anti-koaguleringsmidler, f.eks. heparin til blodet. have been achieved by modifying the surface layers either to a more hydrophobic character or to a more hydrophilic character. Hydrophobization of the surface layer, e.g. by methylation of a glass surface, results in a decrease in the efficiency of the blood's surface-activated coagulation system. However, proteins such as fibrinogen bind relatively strongly to such surfaces 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 shown reduced binding of cells, but the surface-activated coagulation system is not hindered by these surfaces. The use of these surfaces in contact with blood thus involves the addition of anti-coagulants, e.g. heparin to the blood.
En annen tidligere overflatebehandlingsteknikk for hindring av koagulering innbefatter binding av antikoagulerings-midler i overflatelaget. Heparin har hovedsakelig blitt benyttet med denne teknikk. Heparin er et heksoseamin-heksuronsyrepolysakkarid som er sulfatert og har sure egenskaper, dvs. heparin er en organisk syre. Ifølge DE-A-21 54 542 blir gjenstander av en organisk termoplastisk harpiks først impregnert med et aminosilan-koplingsmiddel og den således behandlede gjenstand reageres deretter med en sur oppløsning av et heparinsalt for binding av heparin i overflatelaget ved hjelp av ioniske bindinger. Overflater som er behandlet på denne måte med heparin har vist seg å redusere koaguleringsreaksjonen. En betydelig ulempe hos disse overflater er imidlertid at heparinbehand-lingen ikke hindrer vedhefting av trombocytter som er et stort problem i f.eks. hjerte-lungemaskiner. Another prior surface treatment technique for preventing coagulation involves binding anticoagulants into the surface layer. Heparin has mainly been used with this technique. Heparin is a hexoseamine-hexuronic acid polysaccharide that is sulfated and has acidic 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 aminosilane coupling agent and the thus treated article is then reacted with an acidic solution of a heparin salt to bind heparin in the surface layer by means of ionic bonds. Surfaces treated in this way with heparin have been shown to reduce the clotting reaction. A significant disadvantage of these surfaces, however, is that the heparin treatment does not prevent adhesion of platelets, which is a major problem in e.g. heart-lung machines.
Det er også kjent at vannbindende geler, f.eks. polyhydroksy-alkylmetakrylat, reduserer adsorpsjonen av proteiner og har en lav adhesivitet til celler (Hoffman et al. Ann. It is also known that water-binding gels, e.g. polyhydroxy-alkyl methacrylate, reduces the adsorption of proteins and has a low adhesiveness to cells (Hoffman et al. Ann.
New York Acad. Sei., Vol. 283 (1977) 372). Disse egenskaper anses å skyldes det faktum at geler inneholdende vann gir en lav overflateenergi i grenseflaten mot blodet. Den tidligere teknikk for fremstilling av vannbindende geler forrringes imidlertid av ulemper slik som komplisert frem-stillingsteknikk og ufullstendig polymerisasjon, hvilket resulterer i lekkasje av toksiske monomerer. En gellignende blanding av sakkarose og glykose innbefattet i en matrise av polysakkaridet dekstran eller dekstrin anvendes ifølge tidligere kjent teknikk som et rør for tilslutning av blod-kar. Denne blanding bør ha den virkning at det ikke opp-trer noen toksisitet for pasienten og at implantatet opp-løses i blodet etter en viss tid. Det er kjent at det nøytrale polysakkariddekstran er blandbart med blod uten å utløse noen koaguleringsreaksjon. New York Acad. Sei., Vol. 283 (1977) 372). These properties are considered to be due to the fact that gels containing water give a low surface energy at the interface with the blood. However, the previous technique for producing water-binding gels is marred by disadvantages such as complicated production techniques 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 connecting blood vessels. This mixture should have the effect that no toxicity occurs for the patient and that the implant dissolves in the blood after a certain time. It is known that the neutral polysaccharide dextran is miscible with blood without triggering any coagulation reaction.
Foreliggende oppfinnelse kombinerer egenskapen til vannbindende geler med den lave toksisitet til polysakkarider samtidig som den frembyr teknikk for overflatebehandling av materialet som er viktig for medisinsk teknologi, slik som glass, silisium, aluminium og silikongummi. (Betegnel-sen "glass" som er benyttet her og i kravene er også ment å skulle innbefatte kvarts.) The present invention combines the property of water-binding gels with the low toxicity of polysaccharides while simultaneously providing a technique for surface treatment of the material that is important for medical technology, such as glass, silicon, aluminum and silicone rubber. (The term "glass" used here and in the requirements is also intended to include quartz.)
Gjenstanden ifølge oppfinnelsen som utviser minst en overflate av glass, silisium, aluminium eller silikongummi belagt med et biokompatibelt lag, er kjennetegnet ved at det biokompatible lag består av et polysakkarid inneholdende minst en hydroksylgruppe, hvilket polysakkarid er kovalent bundet til nevnte overflate av glass, silisium, aluminium eller silikongummi hos gjenstanden ved hjelp av et silan. The object according to the invention, which exhibits at least one surface of glass, silicon, aluminum or silicone rubber coated with a biocompatible layer, is characterized in that the biocompatible layer consists of a polysaccharide containing at least one hydroxyl group, which polysaccharide is covalently bound to said surface of glass, silicon , aluminum or silicone rubber at the object using a silane.
Fremgangsmåten ifølge foreliggende oppfinnelse for å forsyne gjenstander som utviser minst en overflate av glass, silisium, aluminium eller silikongummi med et biokompatibelt overflatelag, er kjennetegnet ved at overflaten på gjenstanden, etter oksydasjon derav etter behov, omsettes med et silan inneholdende minst en epoksygruppe og at den således behandlede overflate omsettes med et polysakkarid inneholdende minst en hydroksylgruppe. The method according to the present invention for providing objects that exhibit at least one surface of glass, silicon, aluminum or silicone rubber with a biocompatible surface layer is characterized in that the surface of the object, after oxidation thereof as required, is reacted with a silane containing at least one epoxy group and that the thus treated surface is reacted with a polysaccharide containing at least one hydroxyl group.
Silanet kan være et alkoksysilan (R-Si(OCH^)^) eller et klorsilan (R-SiCl^), i hvilke formler R representerer en The silane can be an alkoxysilane (R-Si(OCH^)^) or a chlorosilane (R-SiCl^), in which formulas R represents a
epoksygruppe epoxy group
som er koplet til silisiumatomet which is connected to the silicon atom
via en hydrokarbonkjede (i de fleste tilfeller propyl). via a hydrocarbon chain (in most cases propyl).
Det hydrolyserte silan danner et aktivt silan (R-Si(OH)^), The hydrolyzed silane forms an active silane (R-Si(OH)^),
som reagerer med uorganiske forbindelser, som har hydroksyl-grupper ved deres overflate. Eksempler på slike materialer er glass, silisium, oksydert aluminium og oksydert silikongummi, hvilke materialer etter hydratisering oppnår hydrok-sylgrupper i overflatelaget. Reaksjonen mellom det uorganiske stoff i overflatelaget og silanolen representerer tidligere kjent teknikk (Dow Corning Product Bulletin 23-181. C 1980) og denne reaksjon forløper på følgende måte: which react with inorganic compounds, which have hydroxyl groups at their surface. Examples of such materials are glass, silicon, oxidized aluminum and oxidized silicone rubber, which materials after hydration obtain hydroxyl groups in the surface layer. The reaction between the inorganic substance in the surface layer and the silanol represents previously known technology (Dow Corning Product Bulletin 23-181. C 1980) and this reaction proceeds as follows:
hvoretter silanolen polymeriseres lateralt after which the silanol is polymerized laterally
Sluttresultatet er en overflate som er belagt med den funksjonelle gruppen i silanolen. Polysakkaridet kan deretter i et annet trinn koples til overflaten. I følgende eksempel beskrives reaksjonen mellom polysakkaridet P og en silani-sert overflate, idet den funksjonelle gruppen R er en epoksygruppe som angitt ovenfor. Polysakkaridet P bindes til epoksygruppen via hydroksylgruppene i polysakkaridet ifølge reaksj onen: The end result is a surface that is coated with the functional group in the silanol. The polysaccharide can then be linked to the surface in another step. In the following example, the reaction between the polysaccharide P and a silanized surface is described, the functional group R being an epoxy group as indicated above. The polysaccharide P is bound to the epoxy group via the hydroxyl groups in the polysaccharide according to the reaction:
Optimale betingelser for denne reaksjon har tidligere blitt undersøkt (se Sundberg og Porath, J. Chromatogr. 90 (1974) 87) . Optimal conditions for this reaction have previously been investigated (see Sundberg and Porath, J. Chromatogr. 90 (1974) 87).
Ifølge et trekk ved oppfinnelsen kan polysakkaridet P være nøytralt. Ifølge et annet trekk ved oppfinnelsen kan polysakkaridet være et polysakkarid som forekommer i naturen, slik som dekstran, eller et syntetisk polysakkarid fremstilt, f.eks. ved polymerisasjon av mono- eller disakkarider ved hjelp av kjemiske reaktanter slik som epiklorhydrin. Dekstranet kan være etyl-, hydroksyetyl- eller 2-hydroksy-propyleter av dekstran eller dekstranglyserolglykosid eller hydrodekstran (dvs. dekstran hvis reduserende ende-grupper er redusert til alkoholgrupper) eller hydroksyl-gruppeholdige hydrofile derivater av dekstran eller delvis nedbrutt dekstran. According to one feature of the invention, the polysaccharide P can be neutral. According to another feature of the invention, the polysaccharide can be a polysaccharide that occurs in nature, such as dextran, or a synthetic polysaccharide produced, e.g. by polymerization of mono- or disaccharides using chemical reactants such as epichlorohydrin. The dextran can be ethyl, hydroxyethyl or 2-hydroxypropyl ether of dextran or dextran glycerol glycoside or hydrodextran (i.e. dextran whose reducing end groups have been reduced to alcohol groups) or hydroxyl group-containing hydrophilic derivatives of dextran or partially degraded dextran.
Etter bindingen til overflatelaget kan polysakkaridet bli ytterligere polymerisert slik at det oppnås et tykkere lag. Denne polymerisasjon er beskrevet i SE-A-169 293. After binding to the surface layer, the polysaccharide can be further polymerized so that a thicker layer is obtained. This polymerization is described in SE-A-169,293.
Den behandlede overflaten blir biologisk inert og overflater behandlet på denne måten gir redusert absorpsjon av proteiner, vedhefting av celler og koagulering. Fremgangsmåten ifølge foreliggende oppfinnelse kan anvendes innen mange forskjellige områder. Således benyttes det i hjerte-lungemaskiner mange detaljer som er laget av aluminium. Overflatene som kommer i kontakt med blod er lette å oksydere til aluminiumoksyd for deretter å bli behandlet ifølge foreliggende fremgangsmåte. Denne fremgangsmåte kan anvendes på andre mekaniske detaljer som er beregnet for kontakt med blod, f.eks. i dialyseappara-ter . The treated surface becomes biologically inert and surfaces treated in this way reduce absorption of proteins, adhesion of cells and coagulation. The method according to the present invention can be used in many different areas. Thus, heart-lung machines use many details that are made of aluminium. The surfaces that come into contact with blood are easily oxidized to aluminum oxide and then treated according to the present method. This method can be applied to other mechanical details that are intended for contact with blood, e.g. in dialysis machines.
Katetere av silikongummi kan også behandles ved hjelp av fremgangsmåten ifølge oppfinnelsen. I dette tilfellet må silikongummien først gjøres reaktiv ved oksydasjon av et tynt overflatelag. Dette bevirkes ved hjelp av en etse-prosess som medfører at overflatelaget oksyderes i et oksygenplasma ved et lavt trykk. Denne prosess resulterer ikke i noen svekkelse av materialets egenskaper. Etter etsingen blir overflaten hydrofil og reaktiv overfor silaner og den kan behandles ved hjelp av fremgangsmåten ifølge oppfinnelsen. Silicone rubber catheters can also be treated using the method according to the invention. In this case, the silicone rubber must first be made reactive by oxidation of a thin surface layer. This is achieved by means of an etching process which means that the surface layer is oxidized in an oxygen plasma at a low pressure. This process does not result in any weakening of the material's properties. After etching, the surface becomes hydrophilic and reactive towards silanes and it can be treated using the method according to the invention.
Oppfinnelsen kan også anvendes i andre forbindelser, f.eks. for behandling av gjenstander av aluminium, glass eller silikongummi for prøvetaking og/eller lagring av blod. The invention can also be used in other compounds, e.g. for the treatment of objects made of aluminium, glass or silicone rubber for sampling and/or storage of blood.
Oppfinnelsen vil i det følgende bli illustrert ved en rekke arbeidseksempler, men er ikke begrenset til disse og således er modifikasjoner naturligvis mulige innenfor grensene for kravene. In what follows, the invention will be illustrated by a number of working examples, but is not limited to these and thus modifications are naturally possible within the limits of the requirements.
Eksempel 1 Example 1
a) Et stykke silikongummi med en størrelse på 4 x 4 cm og en tykkelse på 2 mm, ble behandlet med en 10% (v/v) a) A piece of silicone rubber with a size of 4 x 4 cm and a thickness of 2 mm was treated with a 10% (v/v)
oppløsning av konvensjonelle detergenter for manuell oppvask og ble deretter skyllet grundig med rennende destillert vann. Stykket ble deretter etset i en oksygenplasma, 300 millibar 0^, 100 W, i 3 minutter og deretter umiddelbart nedsenket i vann. b) Stykket av silikongummi ble tatt opp fra vannet og dets overflater ble blåst slik at synlig vann forsvant hvoretter det umiddelb art ble nedsenket i en 5% (vekt/vol) oppløsning av 3-glysidoksypropyltrimetoksysilan (epoksy-silan) i propanol i 10 minutter. Stykket av silikongummi var fullstendig dekket av oppløsningen. solution of conventional detergents for manual dishwashing and was then rinsed thoroughly with running distilled water. The piece was then etched in an oxygen plasma, 300 millibar 0^, 100 W, for 3 minutes and then immediately immersed in water. b) The piece of silicone rubber was taken up from the water and its surfaces were blown so that visible water disappeared after which it was immediately immersed in a 5% (w/v) solution of 3-glycidoxypropyltrimethoxysilane (epoxy-silane) in propanol for 10 minutes . The piece of silicone rubber was completely covered by the solution.
Deretter ble stykket tørket i en ovn ved 60°C til tilsyne-latende tørrhet, vasket i destillert vann og blåst tørt. Overflaten var nå hydrofob. The piece was then dried in an oven at 60°C to apparent dryness, washed in distilled water and blown dry. The surface was now hydrophobic.
c) Stykket behandlet ifølge b) ble neddyppet i en 20% (vekt/vol) oppløsning av dekstran med en gjennomsnittlig c) The piece treated according to b) was immersed in a 20% (w/v) solution of dextran with an average
molekylvekt (M ) på 2.000.000 i destillert vann og fikk reagere i 20 timer ved romtemperatur. Overflaten var nå hydrofil. molecular weight (M) of 2,000,000 in distilled water and allowed to react for 20 hours at room temperature. The surface was now hydrophilic.
Eksempel 2 Example 2
a) Et dekkglass ble behandlet med dikromat-svovelsyre og grundig skyllet med rennende destillert vann. b) Dekkglasset behandlet ifølge a) ble reagert med 3-glysid- a) A coverslip was treated with dichromate-sulfuric acid and thoroughly rinsed with running distilled water. b) The coverslip treated according to a) was reacted with 3-glycid-
oksypropyldimetoksysilan ifølge eksempel 1 b) ovenfor. oxypropyldimethoxysilane according to example 1 b) above.
c) Dekkglasset behandlet ifølge b) ble neddyppet i en 40% (vekt/vol) oppløsning av dekstran med en gjennomsnittlig c) The coverslip treated according to b) was immersed in a 40% (w/v) solution of dextran with an average
molekylvekt (M ) på 200.000 i destillert vann og fikk reagere i 20 timer ved romtemperatur. Den oppnådde overflaten var hydrofil. Tykkelsen på det påførte lag var 2 nanometer som bestemt ved ellipsometri. molecular weight (M) of 200,000 in distilled water and allowed to react for 20 hours at room temperature. The surface obtained was hydrophilic. The thickness of the applied layer was 2 nanometers as determined by ellipsometry.
Eksempel 3 Example 3
a) Et stykke aluminium med dimensjonen 2 x 4 cm og en tykkelse på 1 mm ble behandlet med en 10% (v/v) oppløsning av a) A piece of aluminum with dimensions of 2 x 4 cm and a thickness of 1 mm was treated with a 10% (v/v) solution of
konvensjonelle detergenter for manuell oppvask og ble deretter skyllet med destillert vann natten over. conventional detergents for manual dishwashing and were then rinsed with distilled water overnight.
b) Et stykke aluminium behandlet ifølge a) ble reagert med 3-glysidoksydpropyltrimetoksysilan ved anvendelse b) A piece of aluminum treated according to a) was reacted with 3-glycidoxide propyltrimethoxysilane in use
av metoden beskrevet i eksempel lb) ovenfor. of the method described in example lb) above.
c) Stykket av aluminium behandlet ifølge b) ble nedsenket i en 20% (vekt/vol) oppløsning av dekstran med en gjennomsnittlig molekylvekt (M ) på 200.000 i destillert vann og fikk reagere i 2 0 timer ved romtemperatur. Den oppnådde overflaten var hydrofil. c) The piece of aluminum treated according to b) was immersed in a 20% (w/v) solution of dextran with an average molecular weight (M ) of 200,000 in distilled water and allowed to react for 20 hours at room temperature. The surface obtained was hydrophilic.
Eksempel A Biokompatibilitetstest Example A Biocompatibility Test
Dekkglass behandlet analogt med eksempel 2, men ved benyttelse av en 20% (vekt/vol) oppløsning av et dekstranmateriale med en gjennomsnittlig molekylvekt (M ) på 2.000.000 i trinn c) ble benyttet som en gjenstand ifølge oppfinnelsen i dette forsøket. Tykkelsen på dekstranlaget var 5 nanometer. De dekstranbelagte dekkglassene ble fuktet og pre-inkubert i et fuktet kammer ved 37°C fulgt av den eksperi-mentelle inkubering med blod. Inkubering ble foretatt i 10 minutter ved 37°C med ubehandlet rotteblod oppnådd ved snitt i eterbedøvede rotter. Ubehandlede dekkglass og metyliserte glass (Elwing, H. og Stenberg, M; J. Immunol. Meth. 44 (1981) 343-345) ble benyttet som positive kontroller for klumpdannelse og blodplateadhesjon. Etter inkubering ble klumpene oppdelt i to halvdeler med et barberblad. Coverslips treated analogously to example 2, but using a 20% (w/v) solution of a dextran material with an average molecular weight (M) of 2,000,000 in step c) were used as an object according to the invention in this experiment. The thickness of the dextran layer was 5 nanometers. The dextran-coated coverslips were moistened and pre-incubated in a humidified chamber at 37°C followed by the experimental incubation with blood. Incubation was carried out for 10 minutes at 37°C with untreated rat blood obtained by incision in ether-anesthetized rats. Untreated coverslips and methylated slides (Elwing, H. and Stenberg, M; J. Immunol. Meth. 44 (1981) 343-345) were used as positive controls for clumping and platelet adhesion. After incubation, the clumps were divided into two halves with a razor blade.
En halvdel ble forsiktig fjernet og glassene ble skyllet One half was carefully removed and the glasses were rinsed
i fosfatbufferet saltoppløsning (0,05M fosfatbuffer pH in phosphate-buffered saline (0.05M phosphate buffer pH
7,4) i 5-10 sekunder med en strøm av 1,5-2 liter/min. Fiksering ble foretatt i 0,15M kakodylatbuffer pH 7,4 med 7.4) for 5-10 seconds with a flow of 1.5-2 litres/min. Fixation was carried out in 0.15 M cacodylate buffer pH 7.4 with
3% glutaraldehyd i 2 timer, fulgt av dehydratisering i etanol og tørking i luft eller i en tørker med kritisk punkt. Prøvestykket ble belagt med gull og undersøkt i et JEOL 100 cx skannerende elektronmikroskop ved en aksele-rerende spenning på 2 0 kV. 3% glutaraldehyde for 2 hours, followed by dehydration in ethanol and drying in air or in a critical point dryer. The sample was coated with gold and examined in a JEOL 100 cx scanning electron microscope at an accelerating voltage of 20 kV.
Resultater Results
Ved slutten av inkubasjonstiden hadde blodprøvene klumpet By the end of the incubation period, the blood samples had clotted
seg mot ubehandlet glass og mot metylisert glass. Blod inkubert på dekstranbelagte glass ifølge oppfinnelsen viste sammenhopninger av klumper mens størstedelen forble flyt-ende. Klumpene vedheftet ikke til overflaten og syntes å være fremkalt i blod/luft-grenseflaten. Ved undersøkelse i det skannerende elektronmikroskop ble det funnet at grenseflaten mellom ubehandlet glass og tromben besto av fibrin-forankrede erytrocytter og blodplater. Hydrofobt, metylisert glass fremkalte på den annen side et begynnelses-lag av vedheftende, aktiverte blodplater på hvilke andre blodceller festet seg. Fibrintråder ble nesten ikke funnet nær overflaten, men kunne ses inne i tromben. Dekstranbelagte glassoverflater ifølge oppfinnelsen fremkalte ikke trombedannelse. Ved undersøkelse i SEM-apparatet ble det funnet at mer enn 90% av overflatearealet var fritt for celler og fibrin. Spredte enkelt-erytrocytter og blodplater kunne ses. Det runde utseende til blodplatene på den dekstranbelagte overflaten sto i skarp kontrast til den mer avlange og flate form til blodplatene som kunne ses på den hydrofobe overflaten, hvilket indikerer at de runde cellene var vedheftet til, men ikke aktivert av den dekstranbelagte overflaten . against untreated glass and against methylated glass. Blood incubated on dextran-coated slides according to the invention showed aggregations of clots while the majority remained fluid. The clumps did not adhere to the surface and appeared to be formed at the blood/air interface. When examined in the scanning electron microscope, it was found that the interface between untreated glass and the thrombus consisted of fibrin-anchored erythrocytes and platelets. Hydrophobic, methylated glass, on the other hand, induced an initial layer of adherent, activated platelets onto which other blood cells adhered. Fibrin threads were hardly found near the surface, but could be seen inside the thrombus. Dextran-coated glass surfaces according to the invention did not induce thrombus formation. When examined in the SEM apparatus, it was found that more than 90% of the surface area was free of cells and fibrin. Scattered single erythrocytes and platelets could be seen. The round appearance of the platelets on the dextran-coated surface contrasted sharply with the more elongated and flattened shape of the platelets seen on the hydrophobic surface, indicating that the round cells were attached to, but not activated by, the dextran-coated surface.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8203029 | 1982-05-14 | ||
| PCT/SE1983/000191 WO1983003977A1 (en) | 1982-05-14 | 1983-05-13 | Articles exhibiting a biocompatible surface layer and process for providing articles with such a surface layer |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO840109L NO840109L (en) | 1984-01-12 |
| NO155089B true NO155089B (en) | 1986-11-03 |
| NO155089C NO155089C (en) | 1987-02-11 |
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ID=26658179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO840109A NO155089C (en) | 1982-05-14 | 1984-01-12 | GOODS WITH A BIO-COMPATIBLE SURFACE LAYER AND PROCEDURE FOR AA SUPPLY GOODS WITH SUCH A SURFACE LAYER. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO155089C (en) |
-
1984
- 1984-01-12 NO NO840109A patent/NO155089C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO840109L (en) | 1984-01-12 |
| NO155089C (en) | 1987-02-11 |
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