Subcutaneous glucose electrode

• US 20020042090A1
• Filed: 11/29/2001
• Published: 04/11/2002
• Est. Priority Date: 03/04/1991
• Status: Active Grant

• Current Assignee: Therasense Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: Therasense Incorporated (Abbott Laboratories Incorporated)
• Inventors: Heller, Adam, Pishko, Michael V.
• Granted Patent: US 6,514,718 B2
• Time in Patent Office: Days
• US Class Current: 435/14
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: C12Q 1/006 for glucose
• CPC Class Codes: C12Q 1/54 involving glucose or galactose
• CPC Class Codes: Y10S 435/817 Enzyme or microbe electrode
• CPC Class Codes: Y10S 435/917 Aspergillus niger
• CPC Class Codes: Y10S 435/962 Prevention or removal of interfering materials or reactants or other treatment to enhance results, e.g. determining or preventing nonspecific binding

Abstract

A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow “one-point” in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.

Claims

1. An electrode comprising:

a non-corroding, conducting wire coated with an insulating polymer;

a recess at one end of said coated wire, forming a channel in the insulating polymer coat devoid of wire and bounded at one end by the wire and at an opposite end by the environment adjacent the coated wire;

a multilayered polymeric composition within said channel, the composition comprising;

a redox layer adjacent to and contacting said wire, the redox layer comprising a redox enzyme crosslinked to a redox polymer;

a biocompatable polymer layer adjacent to the environment outside the coated wire; and

an analyte diffusion limiting barrier layer positioned between said redox layer and said biocompatable layer.

3. A method for measuring glucose concentration in an animal comprising the steps of:

implanting subcutaneously in an animal the electrode of claim 1;

placing a second reference counter or combined reference and counter electrode on or in the skin of the animal;

connecting the electrodes through an electrical circuit; and

obtaining readings to measure glucose concentration.

4. The method of claim 3, wherein at least two electrodes of claim 1 are implanted subcutaneously in said animal, and wherein paired readings of said two electrodes that do not differ more than two standard deviations are accepted as correctly measuring the concentration of glucose.

7. The biosensor of claim 1, wherein said wire is coated along its length, but not at its tip, with an electrically insulating polymer containing less than 5% water by weight when in equilibrium with physiological body fluids.

8. The biosensor of claim 7, wherein said tip of the wire is recessed in the insulating polymer coat, forming a recessed channel having a length from tip of the sensor to the recessed wire of between approximately 20 μ

m and 1 mm.

9. The biosensor of claim 8, wherein said redox polymer is derived from poly(l-vinylimidazole) or a copolymer of (1-vinyl imidazole) bound to a metal ion selected from the group consisting of Os^3+/2+, Ru^3+/2+, and Fe^3+/2+.

10. The biosensor of claim 1, wherein the redox potential of said redox polymer is not more reducing than about −

0.15V and not more oxidizing than about +0.15V versus the standard calomel electrode in an aqueous solution at about pH 7.4.

11. The biosensor of claim 1 further comprising an interference eliminating layer comprising a peroxidase enzyme.

12. The biosensor of claim 1, wherein said redox enzyme catalyzes the oxidation of glucose.

13. The biosensor of claim 12, wherein said redox enzyme is glucose oxidase.

14. The biosensor of claim 13, wherein said redox enzyme is recombinant glucose oxidase.

15. The biosensor of claim 1, wherein said redox enzyme catalyzes the oxidation of lactate.

16. The biosensor of claim 11, wherein said interference eliminating layer further comprises an enzyme which catalyzes a hydrogen peroxide-generating reaction.

17. The biosensor of claim 7, wherein said insulating polymer is selected from the group consisting of polyimide, polyester, polyurethane, and perfluroinated polymer.

18. The biosensor of claim 1, further comprising a glucose flux limiting layer positioned between said sensing layer and said biocompatible layer, the glucose flux limiting layer comprising a polyanionic, polycationic, or zwitterionic polymer.

19. The biosensor of claim 1 wherein the outside diameter of the insulated wire is less than about 0.3 mm.

20. The biosensor of claim 1 wherein the redox enzyme and redox polymer are crosslinked.

23. A method for manufacturing the biosensor of claim 1, wherein said recessed channel is formed by electrolytic dissolution of part of the electrically conducting wire, with an oxidizing electrical potential of not less than 0.3 volts versus the standard calomel electrode being maintained on the dissolving wire, said wire being immersed in an aqueous solution containing at least one anion selected from the group consisting of CN⁻

, Cl⁻

, Br⁻

, and I⁻

at a concentration of at least approximately 0.1M.

24. A method for measuring the concentration of a biochemical in an animal comprising:

contacting body fluid of an animal the electrode of claim 1;

and

determining from the electrical signal generated at the electrode the concentration of biochemical in the body fluid.

30. A method for calibrating the implanted electrode of claim 1, comprising the steps of:

analyzing the concentration of the analyte to be measured by the electrode of claim 8 in one or more samples of fluid withdrawn from a patient, where the concentration of the chemical does not change substantially in the withdrawn samples;

relating the current generated by the electrode at the time the sample is withdrawn to the concentration of biochemical.

2. A method for producing an in vivo glucose biosensor comprising the steps of:

coating a non-corroding metal or carbon wire with a biocompatible insulating polymer containing less than 5% water when in equilibrium with physiological body fluids to form a coated wire;

etching said coated wire to form a recess at one end of said coated wire, said recess devoid of metal or carbon;

immobilizing within said recess, adjacent to said wire, a redox composition comprising glucose oxidase and a redox polymer;

overcoating contents of the recess with a biocoampatable polymer;

wherein said etched wire with said polymer overcoated recess and contents form a glucose biosensor having substantially no current output at zero glucose concentration, even in the presence of interfering eletroreactive species.

5. A biosensor comprising:

a non-corroding metal or carbon electrode;

a sensing layer adjacent to and in electrical contact with the electrode, the sensing layer comprising a redox polymer and a redox enzyme;

a biocompatable layer coating an outer surface of the electrode and sensing layer and adjacent to an environment outside the sensor, said biocompatable layer comprised of a biocompatable polymer containing not less than 20% water by weight when in equilibrium with physiological body fluids.

6. The biosensor of claim 5, wherein said electrode is part of an electrically conducting wire.

21. A method for manufacturing the biosensor of claim 6, comprising the steps of:

electrically charging droplets of an aqueous polymer;

applying a potential to the electrode such that the electrically charged droplets are attracted to said electrode; and

applying the charged droplets of polymer to the electrode to form a polymer coated electrode.

22. The method of claim 21, wherein the electrically charged droplets are applied to a non-insulated tip of an electrically insulated wire.

25. The method of claim 25, wherein said contacting is implanting the electrode subcutaneously.

26. The method of claim 25, wherein said subcutaneous tissue is blood.

27. The method of claim 24, wherein said biochemical is glucose.

28. The method of claim 24, wherein said biochemical is lactate.

29. The method of claim 24, wherein at least two electrodes are simultaneously implanted and wherein their readings are compared and accepted as valid only when they do not differ by more than two standard deviations, the standard deviations being calculated from paired measurements with a pair of implanted electrodes.