Subcutaneous glucose electrode

• US 6,162,611 A
• Filed: 01/03/2000
• Issued: 12/19/2000
• Est. Priority Date: 12/02/1993
• Status: Expired due to Term

• Current Assignee: Therasense Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: E. Heller & Company
• Inventors: Heller, Adam, Pishko, Michael V.
• Primary Examiner(s): Leary, Louise N.
• Application Number:
  US09/477,053
• Time in Patent Office: 351 Days
• Field of Search: 435/14, 435/28, 435/4, 435/25, 435/289.1, 435/817, 436/63, 436/149
• 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. A method of using an analyte-responsive electrochemical sensor, the method comprising steps of:

(a) implanting an analyte-responsive electrochemical sensor into a patient;

(b) determining, using a device other than the analyte-responsive electrochemical sensor, at least one analyte concentration value for the patient to generate a single calibration value;

(c) obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor; and

(d) correlating the calibration value to the output signal to provide a single point, in vivo calibration of the electrochemical sensor.

2. The method of claim 1 wherein the correlating step comprises correlating the calibration value to the output signal to provide a single point, in vivo calibration that is based on a linear relationship between the output signal of the electrochemical sensor and the analyte concentration.

3. The method of claim 1 wherein the step of obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor comprises intermittently obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor.

4. The method of claim 1 wherein the step of obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor comprises continuously obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor.

5. The method of claim 1 wherein the analyte-responsive electrochemical sensor generates a baseline current of less than 0.5 nA.

6. The method of claim 1 wherein the step of correlating the calibration value to the output signal to provide a single point, in vivo calibration of the electrochemical sensor comprises correlating the calibration value to the output signal using a baseline of approximately nil at 0 mM analyte.

7. The method of claim 1 wherein the step of correlating the calibration value to the output signal to provide a single point, in vivo calibration of the electrochemical sensor comprises correlating the calibration value to the output signal using a baseline current of less than 0.5 nA at 0 mM analyte.

8. A method of using an analyte-responsive electrochemical sensor, the method comprising steps of:

(a) implanting an analyte-responsive electrochemical sensor into a patient, the analyte-responsive electrochemical sensor comprising;

(i) at least one non-corroding electrode; and

(ii) a sensing layer disposed over the electrode;

(b) determining, using a device other than the analyte-responsive electrochemical sensor, at least one analyte concentration value for the patient to generate a single calibration value;

(c) obtaining an output signal related to the analyte concentration from the analyte-responsive electrochemical sensor; and

(d) correlating the calibration value to the output signal to provide a single point, in vivo calibration of the electrochemical sensor.

9. The method of claim 8 wherein the analyte-responsive electrochemical sensor further comprises an analyte flux limiting layer disposed over the sensing layer.

10. The method of claim 9 wherein the analyte flux limiting layer comprises an electrically insulating polymer.

11. The method of claim 8 wherein the analyte-responsive electrochemical sensor further comprises an interferant eliminating layer disposed over the sensing layer.

12. The method of claim 11 wherein the interferant eliminating layer comprises a peroxidase.

13. The method of claim 12 wherein the interferant eliminating layer further comprises lactate oxidase.

14. The method of claim 8 wherein the analyte-responsive electrochemical sensor further comprises a biocompatible layer disposed over the sensing layer.

15. The method of claim 14 wherein the biocompatible layer comprises a hydrogel.

16. The method of claim 8 wherein the sensing layer comprises an analyte-responsive enzyme.

17. The method of claim 8 wherein the sensing layer comprises a non-leachable redox mediator.

18. A method of using a glucose-responsive electrochemical sensor, the method comprising steps of:

(a) implanting a glucose-responsive electrochemical sensor into a patient, the glucose-responsive electrochemical sensor comprising;

(i) at least one non-corroding electrode;

(ii) a sensing layer disposed over the electrode, the sensing layer comprising a glucose-responsive enzyme; and

(iii) an interferant eliminating layer disposed over the sensing layer;

(b) determining, using a device other than the glucose-responsive electrochemical sensor, at least one glucose concentration value for the patient to generate a single calibration value;

(c) obtaining an output signal related to the glucose concentration from the glucose-responsive electrochemical sensor; and

(d) correlating the calibration value to the output signal to provide a single point, in vivo calibration of the electrochemical sensor.

19. A method of using an analyte-responsive electrochemical sensor, the method comprising steps of:

(a) implanting an analyte-responsive electrochemical sensor into a patient;

(b) assaying a body fluid of the patient, using a device other than the analyte-responsive electrochemical sensor, to obtain at least one analyte concentration value for the patient, and generating a single calibration value from the at least one analyte concentration value;

(c) obtaining an output signal related to the analyte concentration from the anaylte-responsive electrochemical sensor; and

(d) correlating the calibration value to the output signal to provide a linear calibration curve based on a single point, in vivo calibration of the electrochemical sensor.

20. A method of using a glucose-responsive electrochemical sensor, the method comprising steps of:

(a) subcutaneously implanting a glucose-responsive electrochemical sensor into a patient;

(b) determining, using a device other than the glucose-responsive electrochemical sensor, a calibration value;

(c) obtaining an output signal related to the glucose concentration from the glucose-responsive electrochemical sensor; and

(d) correlating the calibration value to the output signal to provide a calibration of the electrochemical sensor based on a fixed baseline value at 0 mM glucose.

21. The method of claim 20 wherein the step of determining, using a device other than the glucose-responsive electrochemical sensor, a calibration value comprises determining a single calibration value.

22. The method of claim 20 wherein the step of obtaining an output signal comprises obtaining a plurality of output signals from the glucose-responsive electrochemical sensor, and wherein the correlating step comprises, after obtaining the plurality of output signals, correlating the calibration value to one or more of the output signals obtained at approximately the same time as the calibration value to provide a calibration of the electrochemical sensor for at least the plurality of output signals.

23. The method of claim 20 wherein the sensor comprises at least one working electrode, the at least one working electrode comprising an glucose-responsive sensing layer disposed thereon.

24. The method of claim 23, wherein the sensing layer comprises a non-leachable redox mediator.

25. The method of claim 23, wherein the sensing layer comprises a glucose-responsive enzyme.

26. The method of claim 25, wherein the glucose-responsive enzyme comprises glucose oxidase, glucose dehydrogenase, or mixtures thereof.

27. The method of claim 25, wherein the glucose-responsive enzyme is non-leachable.

28. The method of claim 23, wherein at least one working electrode further comprises a barrier layer disposed over the sensing layer to at least slow a rate of permeation of interferents.

29. The method of claim 28, wherein the barrier layer comprises a polyanionic polymer.

30. The method of claim 23, wherein at least one working electrode further comprises an interferent eliminating layer disposed over the sensing layer.

31. The method of claim 30, wherein the interferent eliminating layer comprises a peroxide-generating enzyme.

32. The method of claim 23, wherein at least one working electrode further comprises, disposed over the sensing layer, a glucose flux limiting layer to limit diffusion of glucose.

33. The method of claim 23, wherein at least one working electrode further comprises a biocompatible layer disposed over the sensing layer.

34. The method of claim 33, wherein the biocompatible layer is bound to the sensing layer.

35. The method of claim 34, wherein the biocompatible layer is indirectly bound to the sensing layer via an intermediate layer between the biocompatible layer and the sensing layer.

36. The method of claim 35, wherein the intermediate layer comprises at least one of an interferent eliminating layer and a glucose flux limiting layer.

37. The method of claim 34, wherein the biocompatible layer is chemically bound to the sensing layer.

38. The method of claim 34, wherein the biocompatible layer is crosslinked with the sensing layer.

39. The method of claim 33, wherein the biocompatible layer comprises a hydrogel.

40. The method of claim 33, wherein the biocompatible layer comprises at least one material selected from the group consisting of hydrophilic polyurethanes, poly(vinyl alcohol), and polyHEMA membranes.

41. The method of claim 33, wherein the biocompatible layer comprises polyethylene oxide.

42. The method of claim 23, wherein at least one working electrode is configured and arranged to provide a substantially constant signal output in absence of glucose.

43. The method of claim 23, wherein at least one working electrode is configured and arranged to have a baseline current of less than 0.5 nA in absence of glucose.

44. The method of claim 23, wherein at least one working electrode is configured and arranged to have a noise level of less than 10 pA.

45. The method of claim 23, wherein at least one working electrode is configured and arranged to generate a signal of at least 3 nA at 2 mM glucose.

46. The method of claim 23, wherein the glucose-responsive sensing layer defines, on the working electrode, a working surface having an area of no more than 0.05 mm².

47. The method of claim 23, wherein correlating the calibration value comprises correlating the calibration value to the output signals generated by at least two working electrodes of the electrochemical sensor.

48. The method of claim 47, further comprising comparing signals generated at each of the working electrodes and accepting those signals that do not differ by more than a predetermined degree.

49. The method of claim 20, further comprising disposing a reference or counter/reference electrode on the skin of the animal.