Electrochemical analyte measurement system

• US 6,083,710 A
• Filed: 06/16/1999
• Issued: 07/04/2000
• 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:
  US09/334,480
• Time in Patent Office: 384 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: 600/347
• 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 fiber configured and arranged for subcutaneous implantation of a portion of the fiber in a person and for acquisition of an analyte-containing sample of fluid from the person;

an electrochemical sensor configured and arranged for disposition in fluid communication with the fiber to receive the analyte-containing sample of fluid directly from the person, the electrochemical sensor comprising

a non-corroding working electrode, and

a sensing layer disposed on the non-corroding working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme.

2. The analyte measurement device of claim 1, wherein the sensing layer further comprises a non-leachable redox compound.

3. The analyte measurement device of claim 2, wherein the non-leachable redox compound comprises a redox polymer.

4. The analyte measurement device of claim 2, wherein the non-leachable redox compound comprises a transition metal complex.

5. The analyte measurement device of claim 1, wherein the electrochemical sensor further comprises an analyte flux limiting layer disposed over the sensing layer.

6. The analyte measurement device of claim 1, wherein the electrochemical sensor further comprises an interference eliminating layer disposed over the sensing layer.

7. The analyte measurement device of claim 1, wherein the electrochemical sensor further comprises a counter electrode.

8. The analyte measurement device of claim 1, wherein the electrochemical sensor further comprises a reference electrode.

9. The analyte measurement device of claim 1, wherein the electrochemical sensor further comprises a counter/reference electrode.

10. The analyte measurement device of claim 1, wherein the fiber comprises a microfiltration fiber.

11. The analyte measurement device of claim 10, further comprising a device to pull a sample through the microfiltration fiber to the electrochemical sensor.

12. The analyte measurement device of claim 11, further comprising an evacuated container to facilitate pulling the sample through the microfiltration fiber to the electrochemical sensor.

13. The analyte measurement device of claim 1, wherein the fiber comprises a microdialysis fiber.

14. The analyte measurement device of claim 13, further comprising a pump for use in conjunction with the microdialysis fiber to convey the analyte-containing sample of fluid to the electrochemical sensor.

15. The analyte measurement device of claim 1, wherein the non-leachable analyte-responsive enzyme comprises a glucose-responsive enzyme.

16. The analyte measurement device of claim 1, wherein the sensitivity of the sensor does not change by more than about ±

5% for 72 hours of operation at 37°

C.

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

5% for 8 hours of operation at 37°

C.

18. The analyte measurement device of claim 1, further comprising at least one alarm coupled to the electrochemical sensor.

19. The analyte measurement device of claim 18, wherein at least one of the at least one alarms is configured and arranged to activate if a signal generated by the electrochemical sensor is outside a predetermined range.

20. The analyte measurement device of claim 18, wherein at least one of the at least one alarms is configured and arranged to activate if a signal generated by the electrochemical sensor indicates at least one of (i) an analyte concentration above a predetermined concentration, and (ii) an analyte concentration below a predetermined concentration.

21. The analyte measurement device of claim 18, wherein at least one of the at least one alarms is configured and arranged to activate if a signal generated by the electrochemical sensor indicates at least one of hypoglycemia and hyperglycemia.

22. The analyte measurement device of claim 18, wherein the electrochemical sensor is configured and arranged for calibration using a single calibration sample from the person.

23. A method of measuring a concentration of an analyte in a sample, the method comprising steps of:

implanting a portion of a fiber into subcutaneous tissue of a person;

transporting an analyte-containing fluid directly from the person to an electrochemical sensor in fluid communication with the fiber;

generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode and a sensing layer disposed over the working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme; and

determining, from the electrical signal, a concentration of the analyte in the analyte-containing fluid.

24. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode and a sensing layer disposed over the working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme and a non-leachable redox compound.

25. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode and a sensing layer disposed over the working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme and a non-leachable redox polymer.

26. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode, a sensing layer disposed over the working electrode, and an analyte flux limiting layer disposed over the sensing layer, the sensing layer comprising a non-leachable, analyte-responsive enzyme.

27. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode, a sensing layer disposed over the working electrode, and an interference eliminating layer disposed over the sensing layer, the sensing layer comprising a non-leachable, analyte-responsive enzyme.

28. The method of claim 23, wherein the step of implanting a portion of a fiber comprises implanting a portion of a microfiltration fiber in a person.

29. The method of claim 28, further comprising pulling a sample through the microfiltration fiber to the electrochemical sensor.

30. The method of claim 29, wherein the step of pulling a sample comprising pulling a sample through the microfiltration fiber using an evacuated container.

31. The method of claim 23, wherein the step of implanting a portion of a fiber comprises implanting a portion of a microdialysis fiber in a person.

32. The method of claim 31, further comprising conveying a sample to the electrochemical sensor using a pump in conjunction with the microdialysis fiber.

33. The method of claim 23, wherein the step of determining a concentration of the analyte comprises measuring a current generated in the electrochemical sensor.

34. The method of claim 23, wherein the step of determining a concentration of the analyte comprises measuring an electrical potential in the electrochemical sensor.

35. The method of claim 23, wherein the step of determining a concentration of the analyte comprises measuring a charge used to electrolyze the analyte by the electrochemical sensor.

36. The method of claim 23, wherein the step of transporting an analyte-containing fluid comprises transporting, in a continuous manner, an analyte-containing fluid to the electrochemical sensor.

37. The method of claim 23, wherein the step of transporting an analyte-containing fluid comprises transporting, in a pulsed manner, an analyte-containing fluid to the electrochemical sensor.

38. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode and a sensing layer disposed over the working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme, wherein the sensitivity of the sensor does not change by more than about ±

5% for 72 hours of operation at 37°

C.

39. The method of claim 23, wherein the step of generating an electrical signal comprises generating an electrical signal in the electrochemical sensor, wherein the electrochemical sensor comprises a working electrode and a sensing layer disposed over the working electrode, the sensing layer comprising a non-leachable, analyte-responsive enzyme, wherein the sensitivity of the sensor does not change by more than about ±

5% for 8 hours of operation at 37°

C.

40. The method of claim 23, further comprising activating an alarm if the concentration of the analyte is outside a predetermined range.

41. The method of claim 23, further comprising activating an alarm if one of the following conditions is indicated:

(i) a concentration of the analyte in the analyte-containing fluid is above a predetermined concentration, and (ii) a concentration of the analyte in the analyte-containing fluid is below a predetermined concentration.

42. The method of claim 23, further comprising activating an alarm if one of the following conditions is indicated:

(i) hyperglycemia and (ii) hypoglycemia.

43. The method of claim 23, further comprising calibrating the electrochemical sensor.

44. The method of claim 43, wherein the step of calibrating the electrochemical sensor comprises

withdrawing a single calibration sample from the person,

assaying a concentration of an analyte in the single calibration sample, and

correlating the assayed concentration to at least one signal generated by the electrochemical sensor.