CA2383435A1 - Implantable glucose sensor - Google Patents
Implantable glucose sensor Download PDFInfo
- Publication number
- CA2383435A1 CA2383435A1 CA002383435A CA2383435A CA2383435A1 CA 2383435 A1 CA2383435 A1 CA 2383435A1 CA 002383435 A CA002383435 A CA 002383435A CA 2383435 A CA2383435 A CA 2383435A CA 2383435 A1 CA2383435 A1 CA 2383435A1
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- CA
- Canada
- Prior art keywords
- emulsion
- enzyme
- perfluoro
- sensor
- implantable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
- C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
Abstract
The sensitivity of enzyme-based polarographic electrodes to oxygen concentration can be significantly reduced or eliminated by providing an oxygen-reservoir in intimate contact with the oxidative enzyme. This is achieved by making a stabilized emulsion between the enzyme and a compound in which oxygen is extremely soluble. An aqueous glucose oxidase solution is emulsified with a perfluorocarbon liquid, and the resulting emulsion is stabilized by chemically crosslinking the mixture to form a gel. Thin layers of the emulsion are fabricated by spreading a layer of the liquid emulsion before gelation occurs. Additional carrier proteins such as albumin may be added to the enzyme prior to crosslinking to protect enzymatic activity and enhance gel strength.
Additional electron transport compounds may be added to further reduce sensitivity to oxygen concentration.
Additional electron transport compounds may be added to further reduce sensitivity to oxygen concentration.
Claims (26)
1. ~An implantable sensor for sensing a concentration of an organic substrate, the sensor comprising:
a conductive electrode; and a stabilized enzyme emulsion in contact with the electrode, the enzyme emulsion comprising:
an enzyme that quantitatively oxidizes the organic substrate;
a water immiscible oxygen dissolving compound emulsified into intimate contact with the enzyme to provide oxygen; and a protein crosslinking agent to crosslink and insolubilize the enzyme forming a stabilized gel comprising crosslinked protein and particles of the oxygen dissolving substance.
a conductive electrode; and a stabilized enzyme emulsion in contact with the electrode, the enzyme emulsion comprising:
an enzyme that quantitatively oxidizes the organic substrate;
a water immiscible oxygen dissolving compound emulsified into intimate contact with the enzyme to provide oxygen; and a protein crosslinking agent to crosslink and insolubilize the enzyme forming a stabilized gel comprising crosslinked protein and particles of the oxygen dissolving substance.
2. The implantable sensor of Claim 1 further comprising a semipermeable membrane covering the electrode with the enzyme emulsion sandwiched between the membrane and the electrode.
3. The implantable sensor of Claim 1, wherein the enzyme emulsion also contains an additional carrier protein.
4. The implantable sensor of Claim 3, wherein the additional carrier protein is selected from the group consisting of serum albumin and, gelatin.
5. The implantable sensor of Claim 1, wherein the oxygen dissolving substance is selected from the group consisting of perfluorocarbons, silicone oils, fluorosilicone oils, aromatic and aliphatic hydrocarbon oils or solids, carotenoids and steroids.
6. The implantable sensor of Claim 5, wherein the oxygen dissolving substance is a perfluorocarbon liquid selected from the group consisting of perfluorooctyl bromide, perfluorodichlorooctane, perfluorodecalin, perfluoroindane, perfluorophenanthrene, perfluorotetramethylcyclohexane, perfluoropolyalkylether oil, perfluoro-methyldecalin, perfluorodimethylethylcyclohexane, perfluorodimethyldecalin, perfluorotrimethyldecalin, perfluoroisopropyldecalin, perfluoropentamethyldecalin, perfluorodiisopropyl decalin, perfluorodiethyldecalin, perfluoromethyladamantane, perfluoro-dimethyladamantane, perfluoro-di-xylethane, and perfluoro-6,7 H-undec-6-ene.
7. The implantable sensor of Claim 1, wherein the crosslinking agent is selected from the group consisting of aldehydes, carbodiimides, imidoesters, pyrocarbonates, epoxides and N-hydroxysuccinimid esters.
8. The implantable sensor of Claim 1, wherein the oxidase enzyme is selected from the group consisting of cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactic acid oxidase, oxygen oxidoreductase, galactose oxidase, and glucose oxidase.
9. The implantable glucose sensor of Claim 1 further comprising an electron transport compound dissolved in the perfluorocarbon liquid.
10. The implantable glucose sensor of Claim 9, wherein the electron transport compound comprises ferrocene.
11. The implantable sensor of Claim 1, wherein the enzyme emulsion further comprises an antioxidant.
12. The implantable sensor of Claim 1, wherein the enzyme emulsion further comprises an antimicrobial agent.
13. The implantable sensor of Claim 1, wherein the enzyme emulsion further comprises an anti-inflammatory agent selected from the group consisting of steroids, lymphokines, and non-steroidal anti-inflammatory drugs.
14. An implantable glucose sensor for sensing a concentration of glucose, the sensor comprising:
a metal electrode; and a stabilized enzyme emulsion in contact with the electrode, the enzyme emulsion comprising:
a solution of glucose oxidase protein for oxidizing glucose to quantitatively produce hydrogen peroxide;
a perfluorocarbon liquid emulsified with the glucose oxidase; and a crosslinking agent to crosslink covalently said protein to form a stabilized gel comprising crosslinked protein and particles of the perfluorocarbon liquid.
a metal electrode; and a stabilized enzyme emulsion in contact with the electrode, the enzyme emulsion comprising:
a solution of glucose oxidase protein for oxidizing glucose to quantitatively produce hydrogen peroxide;
a perfluorocarbon liquid emulsified with the glucose oxidase; and a crosslinking agent to crosslink covalently said protein to form a stabilized gel comprising crosslinked protein and particles of the perfluorocarbon liquid.
15. The implantable glucose sensor of Claim 14 further comprising a semipermeable membrane covering the electrode with the enzyme emulsion in contact with a first surface of the membrane and sandwiched between the membrane and the electrode and with body fluids or cells in contact with a second surface of the semipermeable membrane.
16. The implantable sensor of Claim 14, wherein the oxygen dissolving substance is selected from the group consisting of perfluorocarbons, silicone oils, fluorosilicone oils, aromatic and aliphatic hydrocarbon oils or solids, carotenoids and steroids.
17. The implantable sensor of Claim 16, wherein the oxygen dissolving substance is a perfluorocarbon liquid selected from the group consisting of perfluorooctyl bromide, perfluorodichlorooctane, perfluorodecalin, perfluoroindane, perfluorophenanthrene, perfluorotetramethylcyclohexane, perfluoropolyalkylether oil, perfluoro-methyldecalin, perfluorodimethylethylcyclohexane, perfluorodimethyldecalin, perfluorotrimethyldecalin, perfluoroisopropyldecalin, perfluoropentamethyldecalin, perfluorodiisopropyl decalin, perfluorodiethyldecalin, perfluoromethyladamantane, perfluoro-dimethyladamantane, perfluoro-di-xylethane, and perfluoro-6,7 H-undec-6-ene.
18. The implantable glucose sensor of Claim 14 further comprising an electron transport compound dissolved in the perfluorocarbon liquid.
19. The implantable glucose sensor of Claim 18, wherein the electron transport compound comprises ferrocene.
20. A method for producing a stabilized enzyme emulsion for use with a polarographic or amperometric sensor comprising the steps of:
making an aqueous solution of a water soluble enzyme that oxidizes an organic substrate to produce hydrogen peroxide;
emulsifying a volume of a water immiscible oxygen dissolving substance into the aqueous solution to form an emulsion;
contacting the emulsion with a protein crosslinking agent; and spreading a mixture of the protein crosslinking agent and the emulsion into a uniform layer whereby the emulsion becomes crosslinked to form a solid gel.
making an aqueous solution of a water soluble enzyme that oxidizes an organic substrate to produce hydrogen peroxide;
emulsifying a volume of a water immiscible oxygen dissolving substance into the aqueous solution to form an emulsion;
contacting the emulsion with a protein crosslinking agent; and spreading a mixture of the protein crosslinking agent and the emulsion into a uniform layer whereby the emulsion becomes crosslinked to form a solid gel.
21. The method of Claim 20, wherein to the emulsion is contacted with a carrier protein prior to contacting with the protein crosslinking agent.
22. The method of Claim 21, wherein the aqueous solution contains the carrier protein and the water soluble enzyme is added to the emulsion prior to contacting with the protein crosslinking agent.
23. The method of Claim 20, wherein the oxygen dissolving substance is selected from the group consisting of perfluorocarbons, silicone oils, fluorosilicone oils, aromatic and aliphatic hydrocarbon oils or solids, carotenoids and steroids.
24. The method of Claim 23, wherein the oxygen dissolving substance is a perfluorocarbon liquid selected from the group consisting of perfluorooctyl bromide, perfluorodichlorooctane, perfluorodecalin, perfluoroindane, perfluorophenanthrene, perfluorotetramethylcyclohexane, perfluoropolyalkylether oil, perfluoromethyldecalin, perfluorodimethylethylcyclohexane, perfluorodimethyldecalin, perfluoro-trimethyldecalin, perfluoroisopropyldecalin, perfluoropentamethyldecalin, perfluorodiisopropyl decalin, perfluorodiethyldecalin, perfluoro-methyladamantane, perfluorodimethyladamantane, perfluoro-di-xylethane, and perfluoro-6,7 H-undec-6-ene.
25. A method for producing a stabilized enzyme emulsion for use with a polarographic sensor comprising the steps of:
making an aqueous solution of a carrier protein;
emulsifying a volume of a perfluorocarbon liquid into the aqueous solution to form an emulsion;
contacting the emulsion with a water soluble enzyme that oxidizes an organic substrate to produce hydrogen peroxide to form a mixture;
contacting the mixture with a protein crosslinking agent; and spreading a mixture of the protein crosslinking agent and the emulsion into a uniform layer whereby the emulsion~
becomes crosslinked to form a solid gel.
making an aqueous solution of a carrier protein;
emulsifying a volume of a perfluorocarbon liquid into the aqueous solution to form an emulsion;
contacting the emulsion with a water soluble enzyme that oxidizes an organic substrate to produce hydrogen peroxide to form a mixture;
contacting the mixture with a protein crosslinking agent; and spreading a mixture of the protein crosslinking agent and the emulsion into a uniform layer whereby the emulsion~
becomes crosslinked to form a solid gel.
26. The method of Claim 25, wherein the oxygen dissolving substance is a perfluorocarbon liquid selected from the group consisting of perfluorooctyl bromide, perfluorodichlorooctane, perfluorodecalin, perfluoroindane, perfluorophenanthrene, perfluorotetramethylcyclohexane, perfluoropolyalkylether oil, perfluoromethyldecalin, perfluorodimethylethylcyclohexane, perfluorodimethyldecalin, perfluoro-trimethyldecalin, perfluoroisopropyldecalin, perfluoropentamethyldecalin, perfluorodiisopropyl decalin, perfluorodiethyldecalin, perfluoro-methyladamantane, perfluorodimethyladamantane, perfluoro-di-xylethane, and perfluoro-6,7 H-undec-6-ene.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/395,466 US6343225B1 (en) | 1999-09-14 | 1999-09-14 | Implantable glucose sensor |
US09/395,466 | 1999-09-14 | ||
PCT/US2000/040888 WO2001020019A2 (en) | 1999-09-14 | 2000-09-13 | Implantable glucose sensor |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2383435A1 true CA2383435A1 (en) | 2001-03-22 |
CA2383435C CA2383435C (en) | 2009-11-17 |
Family
ID=23563162
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002383435A Expired - Fee Related CA2383435C (en) | 1999-09-14 | 2000-09-13 | Implantable glucose sensor |
Country Status (8)
Country | Link |
---|---|
US (2) | US6343225B1 (en) |
EP (1) | EP1214586B1 (en) |
JP (1) | JP4981225B2 (en) |
AT (1) | ATE462132T1 (en) |
AU (1) | AU2112001A (en) |
CA (1) | CA2383435C (en) |
DE (1) | DE60044064D1 (en) |
WO (1) | WO2001020019A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111511404A (en) * | 2017-12-21 | 2020-08-07 | 美国西门子医学诊断股份有限公司 | Compositions comprising stabilized oxygen and methods of forming the same |
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US5914026A (en) * | 1997-01-06 | 1999-06-22 | Implanted Biosystems Inc. | Implantable sensor employing an auxiliary electrode |
US6081736A (en) * | 1997-10-20 | 2000-06-27 | Alfred E. Mann Foundation | Implantable enzyme-based monitoring systems adapted for long term use |
US6030827A (en) * | 1998-01-23 | 2000-02-29 | I-Stat Corporation | Microfabricated aperture-based sensor |
US6343225B1 (en) * | 1999-09-14 | 2002-01-29 | Implanted Biosystems, Inc. | Implantable glucose sensor |
-
1999
- 1999-09-14 US US09/395,466 patent/US6343225B1/en not_active Expired - Lifetime
-
2000
- 2000-09-13 JP JP2001523790A patent/JP4981225B2/en not_active Expired - Fee Related
- 2000-09-13 DE DE60044064T patent/DE60044064D1/en not_active Expired - Lifetime
- 2000-09-13 EP EP00984516A patent/EP1214586B1/en not_active Expired - Lifetime
- 2000-09-13 CA CA002383435A patent/CA2383435C/en not_active Expired - Fee Related
- 2000-09-13 WO PCT/US2000/040888 patent/WO2001020019A2/en active Application Filing
- 2000-09-13 AU AU21120/01A patent/AU2112001A/en not_active Abandoned
- 2000-09-13 AT AT00984516T patent/ATE462132T1/en not_active IP Right Cessation
-
2002
- 2002-01-28 US US10/058,453 patent/US6815186B2/en not_active Expired - Lifetime
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111511404A (en) * | 2017-12-21 | 2020-08-07 | 美国西门子医学诊断股份有限公司 | Compositions comprising stabilized oxygen and methods of forming the same |
CN111511404B (en) * | 2017-12-21 | 2023-10-03 | 美国西门子医学诊断股份有限公司 | Composition comprising stable oxygen and method of forming the same |
Also Published As
Publication number | Publication date |
---|---|
ATE462132T1 (en) | 2010-04-15 |
US6343225B1 (en) | 2002-01-29 |
JP4981225B2 (en) | 2012-07-18 |
EP1214586A2 (en) | 2002-06-19 |
DE60044064D1 (en) | 2010-05-06 |
EP1214586B1 (en) | 2010-03-24 |
JP2003513230A (en) | 2003-04-08 |
WO2001020019A9 (en) | 2002-08-29 |
US20020068860A1 (en) | 2002-06-06 |
AU2112001A (en) | 2001-04-17 |
WO2001020019A3 (en) | 2002-01-17 |
CA2383435C (en) | 2009-11-17 |
US6815186B2 (en) | 2004-11-09 |
WO2001020019A2 (en) | 2001-03-22 |
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