Method for analytically utilizing microfabricated sensors during wet-up

• US 5,112,455 A
• Filed: 07/20/1990
• Issued: 05/12/1992
• Est. Priority Date: 07/20/1990
• Status: Expired due to Term

• Current Assignee: i STAT Corporation (Abbott Laboratories Incorporated)
• Original Assignee: i STAT Corporation (Abbott Laboratories Incorporated)
• Inventors: Cozzette, Stephen N., Tirinato, Jody A., Holleritter, Lisa A., Smit, Nicolaas J., Davis, Graham, Zelin, Michael P., Lauks, Imants R., Wieck, Henry J., Piznik, Sylvia
• Primary Examiner(s): Niebling, John
• Assistant Examiner(s): Bell, Bruce F.
• Application Number:
  US07/555,976
• Time in Patent Office: 662 Days
• Field of Search: 204/153.12, 204/153.17, 204/153.1, 204/402, 204/406, 204/403, 204/400, 204/424
• US Class Current: 205/778
• CPC Class Codes: G01N 27/3274 Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration coding of calibration information G01N33/48771

Abstract

A method of determining the concentration of a preselected analyte species present in a sample fluid is disclosed, which method comprises: (a) providing an external computational means, a reference electrode and at least one substantially dry-stored sensor capable of exhibiting a response to changes in the concentration of a preselected analyte species before the sensor attains full equilibrated wet-up; (b) establishing electrical contact between the sensor, reference electrode and external computational means; (c) contacting the sensor and reference electrode with a calibrant fluid; (d) performing a first signal measurement in a first time window in the presence of the calibrant fluid; (e) displacing the calibrant fluid after performing the first signal measurement; (f) contacting the sensor and reference electrode with a sample fluid; (g) performing a second signal measurement in a second time window in the presence of the sample fluid; and (h) relating the first and second signal measurements to determine the concentration of the preselected analyte species in the sample fluid before said sensor attains full equilibrated wet-up. Alternative methods are disclosed further for collecting, relating and manipulating the results of the signal measurements to provide useful estimates of the analyte concentrations of interest.

Claims

1. A method of determining the concentration of a preselected analyte species present in a sample fluid comprising:

(a) providing an external computational means, a reference electrode and at least one substantially dry-stored microfabricated sensor capable of exhibiting a response to changes in the concentration of a preselected analyte species;

(b) establishing electrical contact between said sensor, reference electrode and external computational means;

(c) contacting said sensor and reference electrode with a calibrant fluid;

(d) performing a first signal measurement in a first time window in the presence of said calibrant fluid before said sensor attains full equilibrated wet-up;

(e) displacing said calibrant fluid after performing said first signal measurement;

(f) contacting said sensor and reference electrode with a sample fluid;

(g) performing a second signal measurement in a second time window in the presence of said sample fluid before said sensor attains full equilibrated wet-up; and

(h) relating said first and second signal measurements to determine the concentration of said preselected analyte species in said sample fluid.

6. The method of claim 1, 2 or 3 in which the order by which said sensor, reference electrode or array thereof is contacted with said calibrant and sample fluids is reversed.

7. The method of claim 6 in which said first and second signal measurements or sets thereof are performed in the presence of said sample and calibrant fluids, respectively.

12. The method of claim 1, 2, 3, 4 or 5 which further comprises providing a conductivity sensor capable of measuring the conductivity of a fluid in contact therewith.

13. The method of claim 1, 2 or 3 which further comprises performing a first conductivity measurement in the presence of said calibrant fluid.

15. The method of claim 13 which further comprises performing a second conductivity measurement in the presence of said sample fluid.

17. The method of claim 13 in which said first conductivity measurement is performed prior to performing said first signal measurement or set thereof.

19. The method of claim 15 in which said second conductivity measurement is performed after performing said second signal measurement or set thereof.

34. The method of claim 1, 2, 3, 4 or 5 in which said signal measurements or sets thereof are performed within about 2 minutes.

35. The method of claim 1, 2, 3, 4 or 5 in which the end of said first time window and the beginning of said second time window are separated by about three to about six seconds.

36. The method of claim 1, 2, 3, 4 or 5 in which the end of said first time window and the beginning of said second time window are separated by no more than about ten seconds.

37. The method of claim 1, 2, 3, 4 or 5 in which the duration of said time windows is about five to about fifteen seconds.

39. The method of claim 1, 2, or 3 in which the displacement of said calibrant fluid is carried out by the introduction of said sample fluid.

40. The method of claim 39 in which the displacement of said calibrant fluid with said sample fluid is carried out with an air segment separating said fluids.

43. The method of claim 1 in which performing said signal measurements comprises acquiring a preselected number of data points over the time period of said time windows.

44. The method of claim 43 in which acquiring said data points comprises:

(a) collecting a first preselected fraction of said data points in a first sliding window, which first sliding window comprises a corresponding fraction of said time window; and

(b) collecting additional preselected fractions of said data points in subsequent sliding windows until every data point in said time window is included in at least one sliding window.

45. The method of claim 44 in which said first and subsequent sliding windows are of equal duration.

46. The method of claim 44 in which said first and additional preselected fractions contain an equal number of data points.

47. The method of claim 44 in which collecting additional fractions of said data points comprises including at least one new point of data in said first sliding window to form a subsequent sliding window.

48. The method of claim 44 in which collecting additional fractions of said data points comprises removing at least the earliest point of data collected in said first sliding window and adding to the remaining points of data at least one new point of data to form a subsequent sliding window.

49. The method of claim 44 which further comprises designating one of said preselected fractions as forming a basis set of data points and determining its characteristics.

50. The method of claim 49 which further comprises comparing the characteristics of said basis set of data points with the characteristics of the remaining preselected fractions.

51. The method of claim 50 in which one of said characteristics includes the slope of each preselected fraction in its respective sliding window.

52. The method of claim 50 which further comprises detecting the presence of aberrant data points on the basis of such comparisons.

53. The method of claim 52 which further comprises counteracting the deleterious effects of said aberrant data points if the presence of such points has been detected.

54. The method of claim 53 in which counteracting the deleterious effects of said aberrant data points comprises performing a step selected from the group consisting of utilizing median filter techniques, eliminating the data points which lie outside the desired range and interpolating the remaining data points, utilizing digital filter techniques or discarding the sliding window which contains said aberrant data points.

55. The method of claim 1 which further comprises comparing the slope of the data points in a particular time window to a range of expected values to determine the integrity of the corresponding signal measurement.

56. The method of claim 1 which further comprises comparing the difference between the slope of the data points in said first time window and the slope of the data points in said second time window to a range of preselected limiting values to determine the integrity of said signal measurements.

57. The method of claim 1 which further comprises comparing the mean value of the data points in a particular time window to a range of expected values to determine the integrity of said signal measurement.

58. The method of claim 1 which further comprises comparing the deviation of the data points in a particular time window from the linear interpolation of said data points to a range of preselected limiting values to determine the integrity of said signal measurement.

59. The method of claim 1, 2, 3, 4 or 5 in which relating said signal measurements comprises:

(a) interpolating the data points in said first time window;

(b) interpolating the data points in said second time window;

(c) extrapolating said first time window interpolation forward to a position located between said first and second time windows;

(d) extrapolating said second time window interpolation backward to said position; and

(e) calculating the ratio of the values obtained from said extrapolations, from which ratio the concentration of said preselected analyte species can be determined.

62. The method of claim 1, 2, 3, 4 or 5 in which at least two signal measurements are performed in each of said first and second time windows, one of said signal measurements being carried out at a first applied potential and the other being carried out at a second applied potential.

63. The method of claim 62 in which said signal measurement includes measuring the current.

64. The method of claim 62 in which said first and second applied potentials lie in the range of about 100 to about 300 mV.

65. The method of claim 62 in which one of said signal measurements in said first time window is carried out at an applied potential of about 125 mV and the other measurement is carried out at about 225 mV.

66. The method of claim 65 in which one of said signal measurements in said second time window is carried out at an applied potential of about 225 mV and the other measurement is carried out at about 125 mV.

67. The method of claim 62 which further comprises determining the slope of the line defined by at least two points on a signal versus applied potential curve, which points are obtained from said signal measurements performed at each of said time windows.

68. The method of claim 67 in which relating said signal measurements involves comparing the slopes of said lines obtained from said time windows to determine the concentration of said preselected analyte species.

2. A method of determining the concentration of a preselected analyte species present in a sample fluid comprising:

(a) providing at least one microfabricated potentiometric sensor sensitive to changes in the concentration of a preselected analyte species, a reference electrode capable of sustaining a well-behaved reference potential for a period of time sufficient to permit the completion of at least two signal measurement before said sensor attains full equilibrated wet-up and external computational means,

which sensor and reference electrode have been stored substantially dry;

(b) establishing electrical contact between said sensor, reference electrode and external computational means;

(c) contacting said sensor and reference electrode with a calibrant fluid;

(d) performing a first signal measurement in a first time window in the presence of said calibrant fluid before said sensor attains full equilibrated wet-up;

(e) displacing said calibrant fluid after performing said first signal measurement;

(f) contacting said sensor and said reference electrode with a sample fluid;

(g) performing a second signal measurement in a second time window in the presence of said sample fluid before said sensor attains full equilibrated wet-up; and

(h) relating said first and second signal measurements to determine the concentration of said preselected analyte species in said sample fluid.

60. The method of claims 2 or 3 in which said calibrant fluid is comprised of an aqueous liquid or a wet gas.

3. A method of determining the concentration of a plurality of different preselected analyte species present in a sample fluid comprising:

(a) providing an array of microfabricated potentiometric and amperometric sensors, each sensitive to changes in the concentration of different preselected analyte species, and external computational means,

which array comprises individual sensors and at least two reference electrodes capable of sustaining a well-behaved reference potential for a period of time sufficient to permit the completion of at least two sets of signal measurements before said sensors attain full equilibrated wet-up, one reference electrode being connected to said potentiometric sensors when the other reference electrode is connected to said amperometric sensors, and each of which sensors has been stored substantially dry;

(b) establishing electrical contact between said array of sensors and external computational means;

(c) contacting said array of sensors with a calibrant fluid;

(d) performing a first set of signal measurements in a first time window in the presence of said calibrant fluid before said sensor attains full equilibrated wet-up;

(e) displacing said calibrant fluid after performing said first set of signal measurements;

(f) contacting said array of sensors with a sample fluid;

(g) performing a second set of signal measurements in a second time window in the presence of said sample fluid before said sensor attains full equilibrated wet-up; and

(h) relating said first and second sets of signal measurements to determine the concentration of a plurality of the different preselected analyte species in said sample fluid.

21. The method of claim 3 or 4 which further comprises activating said amperometric sensor or array thereof.

22. The method of claim 21 in which activating said amperometric sensor comprises subjecting said amperometric sensor to a series of potential changes in the presence of said calibrant or first fluid.

23. The method of claim 22 in which said potential changes comprises cycling the applied potential between values of opposite sign relative to said reference electrode.

24. The method of claim 22 in which said series of potential changes includes a first group which comprises at least ten repetitions of a cycle in which the applied potential is maintained at a first value and then is switched to a second value of equal magnitude but of opposite sign as said first value.

25. The method of claim 24 in which said series of potential changes further includes a second group which comprises at least five repetitions of a cycle in which the applied potential is maintained at a first value and then is switched to a second value of equal magnitude but of opposite sign as said first value.

26. The method of claim 25 in which said series of potential changes further includes a third group which comprises at least five repetitions of a cycle in which the applied potential is maintained at a first value and then is switched to a second value of equal magnitude but of opposite sign as said first value.

27. The method of claim 24 in which the application of said first group is commenced within about one second after said calibrant or first fluid comes into contact with said amperometric sensor.

28. The method of claim 25 in which the application of said second group is commenced within about twelve seconds after said calibrant or first fluid comes into contact with said amperometric sensor.

29. The method of claim 26 in which the application of said third group is commenced within about twenty seconds after said calibrant or first fluid comes into contact with said amperometric sensor.

30. The method of claim 25 in which said first value for said first and second groups is about +1000 mV.

31. The method of claim 26 in which said first value for said third group is within double the magnitude of the operating potential of said amperometric sensor.

32. The method of claim 3 which further comprises:

providing a conductivity sensor capable of measuring the conductivity of a fluid in contact therewith,

activating said amperometric sensor in the presence of said calibrant fluid, and

performing a first conductivity measurement in the presence of said calibrant fluid, after activating said amperometric sensor but before performing any set of signal measurements.

33. The method of claim 32 which further comprises performing a second conductivity measurement in the presence of said sample fluid, after performing all sets of signal measurements.

38. The method of claim 3 in which one of said reference electrodes is replaced with a counter electrode,

that the remaining reference electrode is available to both of said potentiometric and amperometric sensors and said counter electrode is dedicated to said amperometric sensors.

61. The method of claim 22 in which said potential changes are applied in the form of pulses, incremental steps, sine waves, linear sweeps or combinations thereof.

4. A method of determining the ratio of the concentrations of a preselected analyte species present in two fluids comprising:

(a) providing at least one microfabricated amperometric sensor sensitive to changes in the concentration of a preselected analyte species, a reference electrode capable of sustaining a well-behaved reference potential for a period of time sufficient to permit the completion of at least two signal measurements before said sensors attain full equilibrated wet-up and external computational means,

which sensor and reference electrode have been stored substantially dry;

(b) establishing electrical contact between said sensor, reference electrode and external computational means;

(c) contacting said sensor and reference electrode with a first fluid;

(d) performing a first signal measurement in a first time window in the presence of said first fluid before said sensor attains full equilibrated wet-up;

(e) displacing said first fluid after performing said first signal measurement;

(f) contacting said sensor and said reference electrode with a second fluid;

(g) performing a second signal measurement in a second time window in the presence of said second fluid before said sensor attains full equilibrated wet-up; and

(h) relating said first and second signal measurements to determine the ratio of the concentrations of said preselected analyte species in said first and second fluids.

8. The method of claim 4 or 5 in which said first fluid is a calibrant fluid.

9. The method of claim 8 in which said second fluid is sample fluid.

10. The method of claim 4 or 5 in which said first fluid is sample fluid.

11. The method of claim 10 in which said second fluid is calibrant

14. The method of claim 4 or 5 which further comprises performing a first conductivity measurement in the presence of said first fluid.

16. The method of claim 14 which further comprises performing a second conductivity measurement in the presence of said second fluid.

18. The method of claim 14 in which said first conductivity measurement is performed prior to performing said first signal measurement.

20. The method of claim 16 in which said second conductivity measurement is performed after performing said second signal measurement.

41. The method of claim 4 or 5 in which the displacement of said first fluid is carried out by the introduction of said second fluid.

42. The method of claim 41 in which the displacement of said first fluid with said second fluid is carried out with an air segment separating said fluids.

5. A method of determining the ratio of the concentrations of a preselected analyte species present in two fluids comprising:

(a) providing at least one dry-stored microfabricated sensor capable of exhibiting a response to changes in the concentration of a preselected analyte species, which response is fast relative to the monotonic wet-up behavior of said sensor when contacted with a fluid;

(b) providing a dry-stored microfabricated reference electrode capable of sustaining a well-behaved reference potential for a period of time sufficient to permit the completion of at least two signal measurements before said sensor attains fully equilibrated wet-up and exhibiting a monotonic wet-up behavior which is similar to that exhibited by said sensor when contacted with a fluid;

(c) establishing electrical contact between said sensor, reference electrode and external computational means;

(d) contacting said sensor and reference electrode with a first fluid;

(e) performing a first signal measurement in a preselected first tie window in the presence of said first fluid before said sensor and reference electrode attain full equilibrated wet-up;

(f) displacing said first fluid after performing said first signal measurement;

(g) contacting said sensor and reference electrode with a second fluid;

(h) performing a second signal measurement in a preselected second time window in the presence of said second fluid before said sensor and reference electrode attain full equilibrated wet-up;

(i) relating the first and second signal measurements to determine the ratio of the concentrations of said analyte species in said first and second fluids by a computational method which distinguishes the relatively fast response of the sensor to changes in the concentration of said preselected analyte from the slower monotonic wet-up behavior of said sensor and reference electrode.