Monitoring of physiological analytes

• US 20030195403A1
• Filed: 05/14/2003
• Published: 10/16/2003
• Est. Priority Date: 05/13/1998
• Status: Active Grant

• Current Assignee: LifeScan IP Holdings, LLC
• Original Assignee: Cygnus, Inc. (Johnson & Johnson)
• Inventors: Berner, Bret, Potts, Russell O., Chiang, Chia-Ming, Jona, Janan, Tamada, Janet A., Tierney, Michael J., Garrison, Michael D.
• Granted Patent: US 6,850,790 B2
• Time in Patent Office: Days
• 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 for measuring the concentration of an analyte present in a biological system, said method comprising

a measurement cycle which comprises an extraction step in which a sample containing the analyte is transdermally extracted from the biological system using a sampling system that is in operative contact with a skin or mucosal surface of said biological system, and

a sensing step in which the extracted sample is contacted with sensor means to obtain a measurement signal that is related to analyte concentration,

wherein said measurement cycle further comprises 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 which subtracts non-analyte signal components from the measurement signal, (b) a delay step which is performed between the extraction and sensing steps, (c) a selective electrochemical detection process which is performed during the sensing step, (d) a purge step which is performed after the sensing step, (e) a charge segregation step, and (f) any combination thereof.

2. The method of claim 1, wherein the differential signal process comprises:

(a) dividing the extracted sample into first and second sample portions;

(b) contacting the first sample portion with said sensor means to obtain a first signal which predominantly comprises signal components due to interfering species and background variations;

(c) contacting the second sample portion with said sensor means to obtain the measurement signal which comprises analyte-specific signal components; and

(d) subtracting the first signal from the measurement signal to obtain a signal which is specifically related to the analyte.

3. The method of claim 2, wherein step (c) entails contacting the second sample portion with an enzyme which reacts with the extracted analyte to provide an analyte-specific signal.

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

5. The method of claim 1, wherein the differential signal process comprises:

(a) extracting first and second samples in the extraction step, wherein at least the second sample contains extracted analyte;

(b) contacting the first sample with said sensor means to obtain a first signal which predominantly comprises signal components due to interfering species and background variations;

(c) contacting the second sample with said sensor means to obtain the measurement signal which comprises analyte-specific signal components; and

(d) subtracting the first signal from the measurement signal to obtain a signal which is specifically related to the analyte.

6. The method of claim 5, wherein step (c) entails contacting the second sample with an enzyme which reacts with the extracted analyte to provide an analyte-specific signal.

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

8. The method of claim 1, wherein the selective electrochemical detection process comprises contacting the extracted sample with an electrochemical biosensor electrode which 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 biosensor electrode is maintained at a potential of about 0.5V or less.

10. The method of claim 1, wherein the sample is extracted into a collection reservoir which is in operative contact with the sampling system.

11. The method of claim 10, wherein the sensor means comprises an electrochemical biosensor electrode which is in contact with the collection reservoir.

12. The method of claim 11, wherein the extraction and sensing steps are repeated while the sampling system is maintained in contact with the biological system to provide for continual or continuous measurement of the analyte.

13. The method of claim 12, wherein the purge step comprises operating the biosensor electrode for a sufficient period of time to substantially remove residual signal components from the collection reservoir after a sensing step has been carried out.

14. The method of claim 13, wherein the biosensor electrode is operated at a potential of about 0.6V or greater during the purge step.

15. The method of claim 1, wherein the analyte is transdermally extracted from the biological system using iontophoresis.

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

17. The method of claim 1, wherein the extraction step comprises a charge segregation step wherein certain interfering species are preferentially collected at the anode.

18. The method of claim 1, wherein said biological system includes skin, and said extracting of analyte from the biological system further comprises enhancement of skin permeability by pricking the skin with micro-needles.

19. A method for measuring the concentration of an analyte present in a biological system, said method comprising

a measurement cycle which comprises transdermally extracting the analyte from the biological system in an extraction step using an iontophoretic sampling system that is in operative contact with a skin or mucosal surface of said biological system, and contacting the extracted analyte with a sensor means in a sensing step to obtain a detectable signal which is specifically related to the analyte, wherein:

(a) the sampling system comprises (i) a first collection reservoir containing an ionically conductive medium, a first iontophoretic sampling means for extracting substances including the analyte from the biological system into the first collection reservoir to obtain a concentration of the analyte, and a first sensor element, wherein said first sampling means and said first sensor element are in operative contact with the first collection reservoir; and

(ii) a second collection reservoir containing an ionically conductive medium, a second iontophoretic sampling means for extracting substances including the analyte from the biological system into the second collection reservoir, and a second sensor element, wherein said second sampling means and said second sensor element are in operative contact with the second collection reservoir; and

(b) the measurement cycle comprises (i) operating the first iontophoretic sampling means as an iontophoretic cathode during a first phase of the extraction step, (ii) detecting substances extracted into the first reservoir with the first sensor element during a first phase of the sensing step to obtain a first signal, (iii) purging residual signal from the sampling system in a purging step, (iv) operating the second iontophoretic sampling means as an iontophoretic cathode during a second phase of the extraction step, and (v) detecting substances extracted into the second reservoir with the second sensor element during a second phase of the sensing step to obtain a second signal, wherein at least one of said first and second signals comprises an analyte-specific signal component.

20. The method of claim 19, wherein the first and second sensor elements are respectively first and second electrochemical biosensor electrodes.

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

22. The method of claim 20, wherein the second biosensor electrode is operated at a potential of about 0.5V or less during the second phase of the sensing step.

23. The method of claim 19, wherein the purge step comprises operating the second biosensor electrode for a sufficient period of time to substantially remove signal components from the second collection reservoir.

24. The method of claim 23, wherein the second biosensor electrode is operated at a potential of about 0.6V or greater during the purge step.

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

26. The method of claim 21, wherein the first collection reservoir does not contain the enzyme, 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 which is specifically related to the analyte.

27. The method of claim 20, wherein the first and second collection reservoirs contain an enzyme which reacts with extracted analyte to respectively provide an analyte-specific electrochemical signal component in the first and second signals.

28. The method of claim 19, wherein the measurement cycle is repeated at least once while the sampling system is maintained in contact with the biological system to provide for continual or continuous measurement of the analyte.

29. The method of claim 28 further comprising a second purging step for purging residual signal from the sampling system after step (e).

30. The method of claim 21, wherein the analyte is blood glucose and the enzyme is glucose oxidase.

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

32. The method of claim 19, wherein the measurement cycle comprises a charge segregation step wherein certain interfering species preferentially collect at the anode.

33. The method of claim 19, wherein said biological system includes skin, and said extracting of analyte. from the biological system further comprises enhancement of skin permeability by pricking the skin with micro-needles.

34. A method for measuring the concentration of an analyte present in a biological system, said method comprising:

(a) transdermally extracting the analyte from the biological system in an extraction step using an iontophoretic sampling system that comprises first and second collection reservoirs which are respectively in operative contact with first and second iontophoretic sampling means and a skin or mucosal surface of said biological system, wherein the first and second iontophoretic sampling means extract substances including the analyte from the biological system into the first and second collection reservoirs, and the first iontophoretic sampling means is operated as a cathode during the extraction step;

(b) passively collecting substances which diffuse from, or are secreted by the biological system into a third collection reservoir using a passive transdermal sampling system that is in operative contact with a skin or mucosal surface of the biological system;

(c) contacting the analyte extracted into the first collection reservoir with sensing means in a sensing step to obtain an active signal;

(d) contacting the substances collected into the third collection reservoir with sensing means in the sensing step to obtain a blank signal; and

(e) subtracting the blank signal from the active signal to provide an analyte-specific signal.

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

(a) transdermally extracting the analyte from the biological system in an extraction step using an iontophoretic sampling system that comprises first, second, and third collection reservoirs which are respectively in operative contact with first, second, and third iontophoretic sampling means and a skin or mucosal surface of said biological system, wherein said first, second, and third iontophoretic sampling means respectively extract substances including the analyte from the biological system into the first, second, and third collection reservoirs, and the first and second iontophoretic sampling means are operated as cathodes during the extraction step;

(b) contacting the analyte extracted into the first collection reservoir with sensing means in a sensing step to obtain an active signal;

(c) contacting the substances extracted into the second collection reservoir with sensing means in the sensing step to obtain a blank signal; and

(d) subtracting the blank signal from the active signal to provide an analyte-specific signal.

36. The method of claim 35, wherein the first collection reservoir contains an enzyme which reacts with extracted analyte to provide an analyte-specific signal.

37. A method for measuring the concentration of an analyte present in a biological system, said method comprising:

(a) transdermally extracting the analyte from the biological system in an extraction step using an iontophoretic sampling system that comprises first, second, and third collection reservoirs which are respectively in operative contact with first, second, and third iontophoretic sampling means and a skin or mucosal surface of said biological system, wherein said first, second, and third iontophoretic sampling means respectively extract substances including the analyte from the biological system into the first, second, and third collection reservoirs, and the first and second iontophoretic sampling means are operated as cathodes during the extraction step; and

(b) contacting the analyte extracted into the first and second collection reservoirs with sensing means in a sensing step to obtain multiple analyte-specific signals.

38. The method of claim 37, wherein the first and second collection reservoirs contain an enzyme which reacts with extracted analyte to provide an analyte-specific signal.

39. A sampling system for measuring an analyte present in a biological system, said system comprising, in operative combination:

(a) iontophoretic sampling means for transdermally extracting the analyte from the biological system across a skin or mucosal surface of said biological system;

(b) sensing means in operative contact with the analyte extracted by the sampling means, wherein said sensing means obtains a detectable signal from the extracted analyte and said signal is specifically related to the analyte; and

(c) microprocessor means in operative communication with the sampling means and the sensing means, wherein said microprocessor means controls said sampling and sensing means to provide a measurement cycle in which analyte-specific signal components are detected in the substantial absence of signal components due to interfering species.

40. The sampling system of claim 39, wherein:

(a) said sampling system comprises (i) a first collection reservoir containing an ionically conductive medium, a first iontophoretic sampling means for extracting substances including the analyte from the biological system into the first collection reservoir, and a first sensor element, wherein said first sampling means and said first sensor element are in operative contact with the first collection reservoir; and

(ii) a second collection reservoir containing an ionically conductive medium, a second iontophoretic sampling means for extracting substances including the analyte from the biological system into the second collection reservoir, and a second sensor element, wherein said second sampling means and said second sensor element are in operative contact with the second collection reservoir; and

(b) the microprocessor controls a measurement cycle which entails (i) operating the first iontophoretic sampling means as an iontophoretic cathode during a first phase of the extraction step, (ii) detecting substances extracted into the first reservoir with the first sensor element during a first phase of the sensing step to obtain a first signal, (iii) purging residual signal from the sampling system in a purging step, (iv) operating the second iontophoretic sampling means as an iontophoretic cathode during a second phase of the extraction step, and (v) detecting substances extracted into the second reservoir with the second sensor element during a second phase of the sensing step to obtain a second signal, wherein at least one of said first and second signals comprises an analyte-specific signal component.

41. The sampling system of claim 40, wherein the first and second sensor elements are respectively first and second electrochemical biosensor electrodes.

42. The sampling system of claim 41, wherein the second collection reservoir contains an enzyme which reacts with extracted analyte to provide an analyte-specific electrochemical signal component in the second signal.

43. The sampling system of claim 42, wherein the analyte is blood glucose and the enzyme is glucose oxidase.

44. The sampling system of claim 41, wherein the first and second collection reservoirs contain an enzyme which reacts with extracted analyte to respectively provide an analyte-specific electrochemical signal component in the first and second signals.

45. The sampling system of claim 44, wherein the analyte is blood glucose and the enzyme is glucose oxidase.

46. The sampling system of claim 39, wherein the measurement cycle comprises a charge segregation step wherein sensing takes place at the cathode and certain interfering species preferentially collect at the anode.

47. Use of the sampling system of claim 40 to continually or continuously measure an analyte present in a biological system.