Device for monitoring of physiological analytes

• US 6,594,514 B2
• Filed: 12/20/2001
• Issued: 07/15/2003
• Est. Priority Date: 05/13/1998
• Status: Expired due to Term

• Current Assignee: LifeScan IP Holdings, LLC
• Original Assignee: Cygnus, Inc. (Johnson & Johnson)
• Inventors: Chiang, Chia-Ming, Jona, Janan, Berner, Bret, Potts, Russell O., Tamada, Janet A., Tierney, Michael J., Garrison, Michael D.
• Primary Examiner(s): Hindenburg, Max F.
• Assistant Examiner(s): Natnithithadha, Navin
• Application Number:
  US10/026,086
• Publication Number:
  US 20020091312A1
• Time in Patent Office: 572 Days
• Field of Search: 600/347, 600/345, 600/346, 600/365, 600/309, 600/300
• 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 5/150022 for capillary blood or interstitial fluid
• CPC Class Codes: A61B 5/150091 by electricity
• CPC Class Codes: A61B 5/157 Devices characterised by integrated means for measuring characteristics of blood
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: C12Q 1/006 for glucose

Abstract

Methods and devices are provided for measuring the concentration of target chemical analytes present in a biological system. Device configuration and/or measurement techniques are employed in order to reduce the effect of interfering species on sensor sensitivity. One important application of the invention involves a method and device for monitoring blood glucose values.

Claims

1. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

a device for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising a sensor; and

one or more microprocessors programmed to control;

(i) said device for extracting a sample from the biological system, said sample comprising the analyte;

(ii) said device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system; and

(iii) a process for selectively favoring analyte-specific signal components over signal components due to interfering species, said process selected from the group consisting of (a) a differential signal process that subtracts non-analyte signal components from a measurement signal, (b) a delay that is performed between extracting the sample and sensing extracted analyte, (c) a selective electrochemical detection process that is performed during sensing, (d) a purge that is performed after sensing, (e) a charge segregation, and (f) any combination of (a) through (e);

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

2. The method of claim 1, wherein said process (iii) comprises the differential signal process, and the differential signal process comprises:

dividing an extracted sample comprising the analyte into a first sample portion and a second sample portion;

contacting the first sample portion with the sensor to obtain a first signal that predominantly comprises signal components due to interfering species and background variations;

contacting the second sample portion with the sensor to obtain a measurement signal that comprises analyte-specific signal components; and

subtracting the first signal from the measurement signal to obtain a signal that is specifically related to the analyte.

3. The method of claim 2, wherein said contacting the second sample portion with the sensor comprises contacting the second sample portion with an enzyme that reacts with the analyte to provide an analyte-specific signal.

4. The method of claim 3, wherein the enzyme comprises glucose oxidase and the analyte is blood glucose.

5. The method of claim 1, wherein said process (iii) comprises the differential signal process, and the differential signal process comprises:

extracting first and second samples, wherein at least the second sample contains extracted analyte;

contacting the first sample with the sensor to obtain a first signal that predominantly comprises signal components due to interfering species and background variations;

contacting the second sample with the sensor to obtain a measurement signal that comprises analyte-specific signal components; and

subtracting the first signal from the measurement signal to obtain a signal that is specifically related to the analyte.

6. The method of claim 5, wherein said contacting the second sample with the sensor comprises contacting the second sample with an enzyme that reacts with the extracted analyte to provide an analyte-specific signal.

7. The method of claim 6, wherein the enzyme comprises glucose oxidase and the analyte is blood glucose.

8. The method of claim 1, wherein said process (iii) comprises the selective electrochemical detection process, said selective electrochemical detection process comprising

contacting the extracted sample with an electrochemical biosensor electrode that is maintained at a lowered potential in order to selectively detect analyte-specific signal components over signal components due to interfering species.

9. The method of claim 8, wherein the selective electrochemical detection process comprises maintaining the biosensor electrode at a potential of about 0.5V or less.

10. The method of claim 1, wherein said process (iii) comprises the purge, wherein said purge comprises operating the sensor for a sufficient period of time to substantially remove residual signal components from the sensor after the sensing has been carried out.

11. The method of claim 10, wherein said sensor comprises a biosensor electrode and said biosensor electrode is operated at a potential of about 0.6V or greater during the purge.

12. The method of claim 1, wherein the analyte is blood glucose.

13. The method of claim 1, wherein said process (iii) comprises the charge segregation, said charge segregation comprising collecting certain interfering species preferentially at the anode.

14. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

an iontophoretic device, comprising first and second iontophoretic electrodes, for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising first and second sensor elements;

first and second reservoirs; and

one or more microprocessors programmed to control a measurement cycle comprising (i) operating the first iontophoretic electrode as an iontophoretic cathode and the second iontophoretic electrode as an iontophoretic anode during a first phase of an extraction, wherein said first iontophoretic electrode is in contact with the first reservoir and the second iontophoretic electrode is in contact with the second reservoir, (ii) operating the first sensor element that is in contact with the first reservoir during a first phase of a sensing to obtain a first signal, (iii) purging residual signal from said first and second reservoirs in a purge, (iv) operating the second iontophoretic electrode as an iontophoretic cathode and the first iontophoretic electrode as an iontophoretic anode during a second phase of the extraction, and (v) operating the second sensor element that is in contact with the second reservoir during a second phase of the sensing to obtain a second signal, wherein at least one of said first and second signals comprises an analyte-specific signal component;

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

15. The method of claim 14, wherein the first and second sensor elements are respectively first and second electrochemical biosensor electrodes.

16. The method of claim 15, wherein the second biosensor electrode is operated at a potential of about 0.5V or less during the second phase of the sensing.

17. The method of claim 14, wherein the purge comprises operating the second biosensor electrode for a sufficient period of time to substantially remove signal components from the second collection reservoir.

18. The method of claim 17, wherein the second biosensor electrode is operated at a potential of about 0.6V or greater during the purge.

19. The method of claim 14, wherein the measurement cycle further comprises a delay between the second phase of the extraction and the second phase of the sensing.

20. The method of claim 15, wherein the second collection reservoir comprises an enzyme that reacts with extracted analyte to provide an analyte-specific electrochemical signal component in the second signal.

21. The method of claim 20, wherein the first collection reservoir does not comprise an enzyme that reacts with extracted analyte to provide an analyte-specific electrochemical signal, the first signal predominantly contains signal components due to interfering species and background variations, and the first signal is subtracted from the second signal to obtain a signal that is specifically related to the analyte.

22. The method of claim 15, wherein the first and second collection reservoirs comprise an enzyme that reacts with extracted analyte to respectively provide an analyte-specific electrochemical signal component in the first and second signals.

23. The method of claim 14, wherein the measurement cycle is repeated at least once.

24. The method of claim 23, further comprising a second purge for purging residual signal from said first and second reservoirs after (v).

25. The method of claim 14, wherein the analyte is blood glucose.

26. The method of claim 20, wherein the analyte is blood glucose and the enzyme comprises glucose oxidase.

27. The method of claim 22, wherein the analyte is blood glucose and the enzyme comprises glucose oxidase.

28. The method of claim 14, wherein the measurement cycle comprises the charge segregation, said charge segregation comprising collecting certain interfering species preferentially at the anode.

29. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

an iontophoretic device, comprising first and second iontophoretic electrodes, for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising first, second, and third sensor elements;

first, second, and third reservoirs; and

one or more microprocessors programmed to control a measurement cycle comprising

(i) operating the first iontophoretic electrode as an iontophoretic cathode during a first phase of an extraction, wherein the first iontophoretic electrode is in contact with the first reservoir, (ii) operating the first sensor element that is in contact with the first reservoir during a first phase of a sensing to obtain a first signal, (iii) operating the second iontophoretic electrode as an iontophoretic cathode during a second phase of the extraction, wherein the second iontophoretic electrode is in contact with the second reservoir, (iv) operating the second sensor element that is in contact with the second reservoir during a second phase of the sensing to obtain a second signal, wherein at least one of said first and second signals comprises an analyte-specific signal component, (v) operating the third sensor element that is in contact with the third collection reservoir to obtain a blank signal, wherein the third collection reservoir uses a passive transdermal sampling system to collect substances that diffuse from or are secreted by the biological system, and (vi) subtracting said blank signal from said signal comprising the analyte-specific signal component to provide an analyte-specific signal;

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

30. The method of claim 29, said measurement cycle further comprises (vii) subtracting said blank signal from said second signal to provide an analyte-specific signal.

31. The method of claim 29, wherein said measurement cycle is repeated at least once.

32. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

an iontophoretic device, comprising first, second, and third iontophoretic electrodes, for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising first and second sensor elements;

first and second reservoirs; and

one or more microprocessors programmed to control a measurement cycle comprising

(i) operating the first iontophoretic electrode as an iontophoretic cathode during an extraction, wherein said first iontophoretic electrode is in contact with the first reservoir, (ii) operating the first sensor element that is in contact with the first reservoir during a sensing to obtain an active signal, (iii) operating the second iontophoretic electrode as an iontophoretic cathode during the extraction wherein the second iontophoretic electrode is in contact with the second reservoir, (iv) operating the second sensor element that is in contact with the second reservoir during the sensing to obtain a blank signal, (v) operating the third iontophoretic electrode as the iontophoretic anode during each extraction, and (vi) subtracting said blank signal from said active signal to provide an analyte-specific signal;

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

33. The method of claim 32, wherein the first collection reservoir comprises an enzyme that reacts with extracted analyte to provide an analyte-specific signal.

34. The method of claim 32, wherein said measurement cycle is repeated at least once.

35. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

an iontophoretic device, comprising first, second, and third iontophoretic electrodes, for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising first and second sensor elements;

first and second reservoirs; and

one or more microprocessors programmed to control a measurement cycle comprising

(i) operating the first iontophoretic electrode as an iontophoretic cathode during an extraction wherein the first iontophoretic electrode is in contact with the first reservoir, (ii) operating the first sensor element that is in contact with the first reservoir during a sensing to obtain a first analyte-specific signal, (iii) operating the second iontophoretic electrode as an iontophoretic cathode during the extraction wherein the second iontophoretic electrode is in contact with the second reservoir, (iv) operating the second sensor element that is in contact with the second reservoir during the sensing to obtain a second analyte-specific signal, and (v) operating the third iontophoretic electrode as an iontophoretic anode during the extractions;

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

36. The method of claim 35, wherein the first and second collection reservoirs contain an enzyme that reacts with extracted analyte to provide the analyte-specific signal.

37. The method of claim 35, wherein said measurement cycle is repeated at least once.

38. A method of making a device for measuring a concentration of an analyte present in a biological system, said method comprising,

combining operatively:

an iontophoretic device for extracting a sample from the biological system, said sample comprising the analyte;

a device for sensing an extracted analyte to obtain a measurement signal that is related to analyte amount or concentration in the biological system, said device comprising a sensor; and

one or more microprocessors programmed to control a measurement cycle comprising (i) operating the iontophoretic device for extracting a sample from the biological system, said sample comprising the analyte, (ii) operating the device for sensing the analyte in the extracted sample to obtain a measurement signal that is related to the analyte amount or concentration in the biological system, and (iii) a process for selectively favoring analyte-specific signal components over signal components due to interfering species, said process selected from the group consisting of (a) a differential signal process that subtracts non-analyte signal components from a measurement signal, (b) a delay that is performed between extracting the sample and sensing extracted analyte, (c) a selective electrochemical detection process that is performed during sensing, (d) a purge that is performed after sensing, (e) a charge segregation, and (f) any combination of (a) through (e);

wherein said operatively combining makes the device for measuring the concentration of the analyte present in the biological system.

39. The method of claim 38, wherein said process (iii) comprises the differential signal process, and the differential signal process comprises:

dividing an extracted sample comprising the analyte into a first sample portion and a second sample portion;

contacting the first sample portion with the sensor to obtain a first signal that predominantly comprises signal components due to interfering species and background variations;

contacting the second sample portion with the sensor to obtain a measurement signal that comprises analyte-specific signal components; and

subtracting the first signal from the measurement signal to obtain a signal that is specifically related to the analyte.

40. The method of claim 39, wherein said contacting the second sample portion with the sensor comprises contacting the second sample portion with an enzyme that reacts with the analyte to provide an analyte-specific signal.

41. The method of claim 40, wherein the enzyme comprises glucose oxidase and the analyte is blood glucose.

42. The method of claim 38, wherein said process (iii) comprises the differential signal process, and the differential signal process comprises:

extracting a first sample and a second sample, wherein at least the second sample contains extracted analyte;

contacting the first sample with the sensor to obtain a first signal that predominantly comprises signal components due to interfering species and background variations;

contacting the second sample with the sensor to obtain a measurement signal that comprises analyte-specific signal components; and

subtracting the first signal from the measurement signal to obtain a signal that is specifically related to the analyte.

43. The method of claim 42, wherein said contacting the second sample with the sensor comprises contacting the second sample with an enzyme that reacts with the extracted analyte to provide an analyte-specific signal.

44. The method of claim 43, wherein the enzyme comprises glucose oxidase and the analyte is blood glucose.

45. The method of claim 38, wherein said process (iii) comprises the selective electrochemical detection process, said selective electrochemical detection process comprising

contacting the extracted sample with an electrochemical biosensor electrode that is maintained at a lowered potential in order to selectively detect analyte-specific signal components over signal components due to interfering species.

46. The method of claim 45, wherein the selective electrochemical detection process comprises maintaining the biosensor electrode at a potential of about 0.5V or less.

47. The method of claim 38, wherein said process (iii) comprises the purge, said purge comprising operating the sensor for a sufficient period of time to substantially remove residual signal components from the sensor after the sensing has been carried out.

48. The method of claim 47, wherein said sensor comprises a biosensor electrode and said biosensor electrode is operated at a potential of about 0.6V or greater during the purge.

49. The method of claim 48, wherein the analyte is blood glucose.

50. The method of claim 48, wherein the measurement cycle comprises the charge segregation, said charge segregation comprising collecting certain interfering species preferentially at the anode.

51. The method of claim 48, wherein said measurement cycle is repeated at least once.