Device and method of calibrating and testing a sensor for in vivo measurement of an analyte

• US 6,275,717 B1
• Filed: 06/23/1998
• Issued: 08/14/2001
• Est. Priority Date: 06/16/1997
• Status: Expired due to Term

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Katz, Moshe George, Gross, Joseph, Reingewirtz, Meir
• Primary Examiner(s): O'Connor, Cary
• Assistant Examiner(s): Natnithithadha, Navin
• Application Number:
  US09/102,840
• Time in Patent Office: 1,148 Days
• Field of Search: 600/309, 600/345-346, 600/347-348, 600/354, 600/355, 600/353, 600/358, 600/362, 600/365-366
• US Class Current: 600/345
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: A61B 5/6848 Needles
• CPC Class Codes: C12Q 1/006 for glucose

Abstract

A method of calibrating an analyte sensor in vivo, by providing a first predetermined stimulus to the sensor when the sensor is applied to a subject to produce a first sensor signal, measuring the first sensor signal, and determining a calibration function based on the first measured sensor signal resulting from the predetermined stimulus. The calibration function, when applied to further signals received from the sensor, can be used to provide a calibrated output.

Claims

1. A method of calibrating an analyte sensor in vivo, comprising the steps of:

(a) providing a first predetermined stimulus to the sensor when the sensor is applied to a subject to produce a first sensor signal;

(b) measuring the first sensor signal; and

(c) determining a calibration function based on the first measured sensor signal resulting from the predetermined stimulus,

whereby the calibration function when applied to further signals received from the sensor can be used to provide a calibrated output.

2. A method according to claim 1, wherein the first predetermined stimulus is generated by providing a supply of material to which the sensor is sensitive, such that the material stimulates the sensor when the sensor is applied to a subject.

3. A method according to claim 2, wherein the material is provided in the vicinity of the sensor in a form in which it is soluble in biological fluids present in the area of the subject to which the sensor is applied.

4. A method according to claim 2, wherein the material comprises an analyte or a precursor or derivative thereof.

5. A method according to claim 1, wherein the predetermined stimulus is adapted to saturate the sensor such that the first signal is a maximum signal.

6. A method according to claim 1, further comprising the steps of providing a second predetermined stimulus to the sensor so as to produce a second sensor signal and measuring the second sensor signal, such that the determination of the calibration function is based on the first and second measured sensor signals.

7. A method according to claim 6, wherein the second sensor signal is a base line signal measured when substantially no analyte is in the vicinity of the sensor.

8. A method according to claim 7, wherein the second predetermined stimulus is provided by consuming substantially all of the analyte in the vicinity of the sensor.

9. A method according to claim 8, wherein the analyte is measured by the sensor by means of an electrochemical reaction, with the sensor forming part of an electrical circuit, and wherein the analyte is consumed by providing a current through the circuit which causes the analyte to undergo the electrochemical reaction, with the measurement of the second sensor signal being carried out shortly after the analyte is consumed.

10. A method according to claim 6, wherein the first and second signals constitute known points on a measured performance curve describing the measured performance of the sensor, and wherein the calibration function correlates the measured performance curve with a theoretical sensor performance curve for which there is stored a calibrated output, such that any further sensor signal measurement from the sensor can be calibrated by correlating the point on the measured performance curve to which the measurement relates with a corresponding point on the theoretical sensor performance curve, and hence with the corresponding calibrated output.

11. A method according to claim 10, wherein the known points on a curve describing the measured performance of the sensor are endpoints of the curve.

12. A method according to claim 1, wherein the analyte is glucose.

13. A method of measuring an analyte in vivo comprising the steps of applying a sensor to a subject, calibrating the sensor according to the method of claim 1, and providing a calibrated output of any further measurements made by the sensor based on the calibration function.

58. A device for measuring an analyte in vivo comprising means for applying a sensor to a subject, means for calibrating the sensor according to the method of claim 1, and means for providing a calibrated output of any further measurements made by the sensor based on the calibration function.

14. A device for the in vivo measurement of an analyte, comprising:

(a) an in vivo sensor for measuring the analyte and providing a signal in response to the measurement of the analyte;

(b) means for providing a first predetermined stimulus to the sensor when the sensor is applied to a subject so as to produce a first sensor signal; and

(c) electronic circuitry associated with the sensor for receiving the signal and providing a calibrated output based on the signal, wherein the electronic circuitry includes means for determining a calibration function for the sensor based on the first measured sensor signal resulting from the predetermined stimulus;

such that the function when applied to further signals received from the sensor can be used to provide a calibrated output.

15. A device according to claim 14, wherein the means for providing a first predetermined stimulus to the sensor comprises a supply of material associated with the sensor such when the sensor is applied to a subject, the sensor is sensitive to the material.

16. A device according to claim 15, wherein the supply of material is associated with a permeable protective coating provided on the sensor.

17. A device according to claim 15, wherein the supply of material is provided in an amount sufficient to saturate the sensor and thereby generate a maximum signal which can be used to calibrate the sensor.

18. A device according to claim 15, wherein the sensor comprises an element which is adapted to be inserted subcutaneously, intradermally, intravenously or by surgical implantation into the subject, and wherein the supply of material is provided on the sensor in soluble form.

19. A device according to claim 15, further comprising a housing having a lower surface for application to the skin of a subject, wherein the sensor is in the form of a needle extending from the housing such that the sensor penetrates the skin of the subject when the device is applied thereto.

20. A device according to claim 15, wherein means are provided for generating a base line signal corresponding to the signal obtained when substantially no analyte is present in the vicinity of the needle, and wherein the base line signal is used to calibrate the sensor.

21. A device according to claim 20, wherein the means for generating a base line signal comprises a voltage generator which forms part of the electronic circuitry, and wherein the base line signal is provided by passing a current in the vicinity of the needle which eliminates the analyte or a chemical substance used in the measurement of the analyte.

22. A device according to claim 15, wherein the analyte is glucose.

41. A device according to claim 14, further comprising means for delivering a substance to the subject in response to the measured analyte values.

44. A device according to claim 41, wherein the substance is a medicament suitable to correct a condition in the patient for which the analyte is an indicating agent.

23. A method for the in vivo testing of an analyte sensor which is provided to a subject as an electrode of an electrical circuit, comprising the steps of:

(a) applying a potential to the electrode and varying the electrode potential so as to cause the electrode current to undergo at least part of a cycle which exhibits hysteresis;

(b) measuring and recording a plurality of current values on the hysteresis cycle;

(c) calculating a characteristic point on the hysteresis curve from the plurality of current values; and

(e) comparing the characteristic point with a stored value and determining from this comparison whether the sensor meets a predetermined condition.

24. A method according to claim 23, wherein the characteristic point is a nodal point on the hysteresis curve.

25. A method according to claim 23, wherein the nodal point is defined as a voltage for which the current value is independent of the analyte concentration in the vicinity of the sensor when the sensor is operating correctly.

26. A method according to claim 23, wherein steps (a)-(e) are repeated periodically.

27. A method according to claim 23, wherein an initial iteration of steps (a)-(d) yields a value for the characteristic point which is stored for comparative subsequent use.

28. A method according to claim 27, wherein the initial iteration is repeated a plurality of times shortly after the sensor has been applied to the subject, and wherein a supply of the analyte to be measured is provided to the sensor in varying concentrations during the repetition of the iterations.

29. A method according to claim 28, wherein the analyte is supplied on the sensor in such a manner that it is released upon application of the sensor to the subject, and wherein the varying concentrations of analyte are achieved by consuming the analyte in a reaction or allowing the analyte to diffuse within the body of the subject.

30. A method according to claim 23, further comprising the step of providing an indicator if it is determined that the sensor does not meet the predetermined condition.

31. A method according to claim 30, wherein the indicator comprises an audible alarm.

32. A device for the in vivo measurement of an analyte, comprising:

(a) an in vivo sensor for measuring the analyte and providing a signal in response to the measurement of the analyte;

(b) electronic circuitry associated with the sensor for receiving the signal and providing a calibrated output based on the signal;

(c) an electrical circuit in which the sensor acts as an electrode, the electrical circuit comprising means for energizing the electrode to a predetermined potential and for measuring and recording the resultant current through the electrode;

(d) means for varying the electrode potential so as to cause the current to undergo at least part of a hysteresis cycle;

(e) means for calculating a characteristic point on the hysteresis curve from the recorded current measurements; and

(f) means for comparing the characteristic point with a stored value and for determining from this comparison whether the sensor meets a predetermined condition.

33. A device according to claim 32, wherein the characteristic point is a nodal point on the hysteresis curve.

34. A device according to claim 32, wherein the nodal point is defined as a voltage for which the current value on the hysteresis curve is independent of the analyte concentration in the vicinity of the sensor when the sensor is functioning correctly.

35. A device according to claim 32, further comprising a memory for storing the value of a characteristic point determined on an initial iteration of measurements of current values.

36. A device according to claim 32, further comprising means for providing an alarm if it is determined that the sensor does not meet the predetermined condition.

42. A device according to claim 32 further comprising means for delivering a substance to the subject in response to the measured analyte values.

45. A device according to claim 42, wherein the substance is a medicament suitable to correct a condition in the patient for which the analyte is an indicating agent.

37. A method for the in vivo measurement of an analyte, comprising:

(a) providing an in vivo sensor, which acts as an electrode of an electrical circuit, to a subject for measuring the analyte, wherein the operation of the sensor is dependent on a reaction in which oxygen is required;

(b) passing a voltage through the electrode, the voltage being of a magnitude and duration sufficient to cause the electrolysis of a chemical species present in the vicinity of the sensor so as to generate oxygen;

(c) measuring the signal produced by the sensor in response to the oxygen-dependent reaction; and

(d) repeating steps (b) and (c) periodically.

38. A method according to claim 37, wherein water is the chemical species present in the vicinity of the sensor which is electrolyzed to provide oxygen.

39. A method according to claim 37, wherein step (b) continues for a duration sufficient to generate oxygen in an excess stoichiometric ratio relative to the analyte being measured at the sensor.

40. A device for the in vivo measurement of an analyte, comprising:

(a) an in vivo sensor for measuring the analyte and providing a signal in response to the measurement of the analyte, wherein the operation of the sensor is dependent on a reaction in which oxygen is required;

(b) electronic circuitry associated with the sensor for receiving the signal and providing a calibrated output based on the signal;

(c) an electrical circuit in which the sensor acts as an electrode, the electrical circuit comprising means for energizing the electrode to a voltage which is of a magnitude and duration sufficient to cause the electrolysis of a chemical species present in the vicinity of the sensor to provide oxygen; and

(d) means for alternately generating oxygen by electrolysis and measuring the analyte by allowing the generated oxygen to take part in the reaction.

43. A device according to claim 40 further comprising means for delivering a substance to the subject in response to the measured analyte values.

46. A device according to claim 43, wherein the substance is a medicament suitable to correct a condition in the patient for which the analyte is an indicating agent.

47. A device for calibrating an analyte sensor in vivo, comprising:

(a) a sensor for application to a subject;

(b) means for providing a first predetermined stimulus to the sensor to produce a first sensor signal;

(c) means for measuring the first sensor signal; and

(d) means for determining a calibration function based on the first measured sensor signal resulting from the predetermined stimulus,

whereby the calibration function when applied to further signals received from the sensor can be used to provide a calibrated output.

48. A device according to claim 47, wherein the means for providing the first predetermined stimulus comprises a supply of material to which the sensor is sensitive, such that the material stimulates the sensor when the sensor is applied to a subject.

49. A device according to claim 48, wherein the material is soluble in biological fluids present in the area of the subject to which the sensor is applied.

50. A device according to claim 47, wherein the material comprises an analyte or a precursor or derivative thereof.

51. A device according to claim 47, wherein the predetermined stimulus is adapted to saturate the sensor such that the first signal is a maximum signal.

52. A device according to claim 47, further comprising means for providing a second predetermined stimulus to the sensor so as to produce a second sensor signal and means for measuring the second sensor signal, such that the means for determination of the calibration function determines a calibration function based on the first and second measured sensor signals.

53. A device according to claim 52, wherein the second sensor signal is a base line signal measured when substantially no analyte is in the vicinity of the sensor.

54. A device according to claim 52, wherein the second predetermined stimulus is provided by consuming substantially all of the analyte in the vicinity of the sensor.

55. A device according to claim 47, wherein the first and second signals constitute known points on a measured performance curve describing the measured performance of the sensor, and wherein the calibration function correlates the measured performance curve with a theoretical sensor performance curve for which there is stored a calibrated output, such that any further sensor signal measurement from the sensor can be calibrated by correlating the point on the measured performance curve to which the measurement relates with a corresponding point on the theoretical sensor performance curve, and hence with the corresponding calibrated output.

56. A device according to claim 55, wherein the known points on a curve describing the measured performance of the sensor are endpoints of the curve.

57. A device according to claim 47, wherein the analyte is glucose.

59. A sensor for use in a device according to claim 47.