Electrochemical analyte measurement system

• US 6,121,009 A
• Filed: 07/16/1999
• Issued: 09/19/2000
• Est. Priority Date: 12/02/1993
• Status: Expired due to Term

• Current Assignee: Therasense Incorporated (Abbott Laboratories)
• Original Assignee: E. Heller & Company
• Inventors: Heller, Adam, Pishko, Michael V.
• Primary Examiner(s): Leary, Louise N.
• Application Number:
  US09/356,102
• Time in Patent Office: 431 Days
• Field of Search: 435/14, 435/28, 435/26, 435/24, 435/288, 435/291, 435/817, 204/403, 204/157.15, 204/153.1, 429/111, 429/40, 373/80
• 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 analyte measurement system comprising:

a plurality of non-corroding, analyte-responsive working electrodes, each of the working electrodes adapted for subcutaneous implantation in an animal;

at least one counter electrode;

non-leachable, analyte-responsive enzyme disposed on each of the working electrodes; and

a device to compare signals generated at two or more of the plurality of working electrodes in response to electrolysis of an analyte.

2. The analyte measurement system of claim 1, wherein at least one of the at least one counter electrodes is adapted for disposition on the skin of the animal.

3. The analyte measurement system of claim 1, further comprising non-leachable redox compound disposed on each of the working electrodes to facilitate electrolysis of analyte.

4. The analyte measurement system of claim 3, wherein the enzyme and the redox compound are non-leachable by fluids in the body of the animal at a pH between about 6.5 and about 7.8.

5. The analyte measurement system of claim 3, wherein the redox compound comprises a redox polymer.

6. The analyte measurement system of claim 5, wherein the redox polymer is crosslinked with the enzyme.

7. The analyte measurement system of claim 1, further comprising a biocompatible layer disposed over the non-leachable, analyte-sensitive redox enzyme of at least one of the working electrodes.

8. The analyte measurement system of claim 1, further comprising an analyte flux limiting layer disposed over the non-leachable, analyte-sensitive redox enzyme of at least one of the working electrodes.

9. The analyte measurement system of claim 1, further comprising an interference eliminating layer disposed over the non-leachable, analyte-sensitive redox enzyme of at least one of the working electrodes.

10. The analyte measurement system of claim 1, wherein the analyte measurement system is configured and arranged to only accept signals that are within one standard deviation of each other.

11. The analyte measurement system of claim 1, further comprising an alarm coupled to the device.

12. The analyte measurement system of claim 11, wherein the alarm is configured and arranged to trigger if the signals from the working electrodes indicates that a level of analyte is outside a prescribed range.

13. The analyte measurement system of claim 11, wherein the alarm is configured and arranged to trigger if the signals compared by the device differ by more than a predetermined value.

14. The analyte measurement system of claim 11, wherein the alarm is configured and arranged to trigger if the signals compared by the device differ by more than a predetermined value for at least a predetermined period of time.

15. The analyte measurement system of claim 11, wherein the alarm is configured and arranged to trigger if the signals compared by the device differ by more than one standard deviation for at least ten minutes.

16. The analyte measurement system of claim 1, further comprising a bipotentiostat to apply a potential between the plurality of working electrodes and the at least one counter electrode.

17. The analyte measurement system of claim 1, wherein the sensitivity of the analyte measurement system does not change by more than about ±

5% for 72 hours of operation at 37°

C.

18. The analyte measurement system of claim 1, wherein the sensitivity of the analyte measurement system does not change by more than about ±

5% for 8 hours of operation at 37°

C.

19. The analyte measurement system of claim 1, wherein the analyte measurement system is configured and arranged for determining a concentration of glucose and the enzyme is a glucose-responsive enzyme.

20. A method of determining a concentration of an analyte in a human, the method comprising steps of:

subcutaneously implanting a plurality of non-corroding, analyte-responsive working electrode with non-leachable, analyte-responsive enzyme disposed on each of the working electrodes;

disposing at least one counter electrode proximate to at least one of the working electrodes;

generating a signal at each of the electrodes in response to the analyte;

comparing the signals from at least two of the working electrodes; and

accepting those signals that do not differ by more than a prescribed amount.

21. The method of claim 20, wherein the step of disposing at least one counter electrode comprises disposing a single counter electrode proximate to all of the working electrodes.

22. The method of claim 20, wherein the step of disposing at least one counter electrode comprises disposing at least one counter electrode on the skin of the human proximate to at least one of the working electrodes.

23. The method of claim 20, wherein the step of subcutaneously implanting a plurality of non-corroding, analyte-responsive working electrodes comprises subcutaneously implanting a plurality of non-corroding, analyte-responsive working electrode with non-leachable, analyte-responsive enzyme and non-leachable redox compound disposed on each of the working electrodes.

24. The method of claim 20, wherein the step of subcutaneously implanting a plurality of non-corroding, analyte-responsive working electrodes comprises subcutaneously implanting a plurality of non-corroding, analyte-responsive working electrode with non-leachable, analyte-responsive enzyme and non-leachable redox polymer disposed on each of the working electrodes.

25. The method of claim 20, wherein the step of generating a signal comprises measuring the signal continuously.

26. The method of claim 20, wherein the step of generating a signal comprises measuring the signal intermittently.

27. The method of claim 20, further comprising determining a concentration of the analyte in the human from the signals generated at the working electrodes.

28. The method of claim 27, further comprising activating an alarm if the concentration of the analyte is outside a prescribed range.

29. The method of claim 27, wherein the step of determining the concentration of the analyte comprises determining the concentration of the analyte in the human using only those signals that only differ by no more than a predetermined amount.

30. The method of claim 20, wherein the step of comparing the signals comprises activating an alarm if the signals form the at least two of the working electrodes differ by more than a predetermined amount.

31. The method of claim 20, wherein the step of comparing the signals comprises activating an alarm if the signals from the at least two of the working electrodes differ by more than a predetermined amount for more than a predetermined period of time.

32. The method of claim 20, wherein the step of comparing the signals comprises activating an alarm if the signals from the at least two of the working electrodes differ by more than one standard deviation for ten minutes.

33. The method of claim 20, further comprising calibrating the working electrodes by single point, in vivo calibration using a calibration sample from the human.

34. An electrochemical sensor, comprising:

at least one non-corroding electrode configured and arranged for implantation in an animal; and

an analyte-responsive sensing layer disposed on at least one non-corroding electrodes;

wherein the electrochemical sensor is configured and arranged for single point, in vivo calibration of the sensor using a calibration sample from the animal.

35. The electrochemical sensor of claim 34, wherein the analyte-responsive sensing layer comprises a non-leachable redox compound.

36. The electrochemical sensor of claim 35, wherein the non-leachable redox compound comprises a redox polymer.

37. The electrochemical sensor of claim 34, wherein the analyte-responsive sensing layer comprises a non-leachable enzyme.

38. The electrochemical sensor of claim 34, further comprising a barrier layer disposed over the sensing layer of at least one of the at least one non-corroding electrodes to slow a rate of permeation of interferents to the sensing layer.

39. The electrochemical sensor of claim 38, wherein the barrier layer comprises a polyanionic polymer.

40. The electrochemical sensor of claim 34, further comprising an interferent eliminating layer disposed over the sensing layer.

41. The electrochemical sensor of claim 40, wherein the interferent eliminating layer comprises a peroxide-generating enzyme.

42. The electrochemical sensor of claim 34, further comprising an analyte flux limiting layer disposed over the sensing layer of at least one of the at least one non-corroding electrodes.

43. The electrochemical sensor of claim 34, further comprising a biocompatible layer disposed over the sensing layer of at least one of the at least one non-corroding electrodes.

44. The electrochemical sensor of claim 34, wherein the electrochemical sensor is configured and arranged to have a baseline current of less than 0.5 nA in absence of the analyte.

45. The electrochemical sensor of claim 34, wherein the electrochemical sensor is configured and arranged to have a noise level of less than 10 pA.

46. The electrochemical sensor of claim 34, wherein the electrochemical sensor is configured and arranged to generate a signal of at least 3 nA at 2 mM glucose concentration.

47. The electrochemical sensor of claim 34, wherein the electrochemical sensor is configured and arranged for subcutaneous implantation in the animal.

48. The electrochemical sensor of claim 34, wherein the at least one working electrode is configured and arranged for implantation in a human.