Method and apparatus for non-invasive determination of glucose in body fluids

• US 6,517,482 B1
• Filed: 11/01/2000
• Issued: 02/11/2003
• Est. Priority Date: 04/23/1996
• Status: Expired due to Term

• Current Assignee: D.T.R. Dermal Therapy Research Inc.
• Original Assignee: Dermal Therapy (Barbados) Inc.
• Inventors: Ollmar, Stig, Wickett, Randall R., Elden, Harry Richardson
• Primary Examiner(s): Winakur, Eric F.
• Assistant Examiner(s): KREMER, MATTHEW J
• Application Number:
  US09/601,705
• Time in Patent Office: 832 Days
• Field of Search: 600/316, 600/347, 600/365, 600/547, 600/309
• US Class Current: 600/309
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/441 Skin evaluation, e.g. for skin disorder diagnosis

Abstract

A method and apparatus is disclosed for non-invasively determining glucose levels in a fluid of a subject, typically the blood glucose level. The impedance of skin tissue is measured and the measurement is used with impedance measurements previously correlated with directly determined glucose levels to determine the glucose level from the newly measured impedance. It is thus possible, to routinely non-invasively determine fluid glucose levels.

Claims

1. A method for non-invasively monitoring glucose in a body fluid of a subject, the method comprising:

measuring impedance between two electrodes in conductive contact with a skin surface of the subject at a plurality of frequencies wherein all said frequencies are in a range from about 10 Hz to about 5 MHZ; and

determining the amount of glucose in the body fluid based upon the measured impedance.

2. The method of claim 1, wherein the skin surface is treated with a saline solution prior to the measuring step, and the body fluid is blood.

3. The method of claim 1, wherein the subject is human and the body fluid is blood.

4. The method of claim 3, wherein determining the amount of glucose includes comparing the measured impedance with a predetermined relationship between impedance and blood glucose level.

5. The method of claim 4, including the step of determining the ratio of one or more pairs of measurements, and wherein determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s).

6. The method of claim 5, wherein the skin surface is located on the a volar forearm.

7. The method of claim 6, wherein an electrically conductive gel is applied to the skin to enhance conductive contact of the electrodes with the skin surface during the measuring step.

8. The method of claim 7, wherein the electrodes are in operative connection with a computer chip programmed to determined the amount of glucose in the body fluid based upon the measured impedance.

9. The method of claim 8, wherein an indicator is operatively connected to the computer chip for indication of the determined amount of glucose to the subject, and the indicator provides a visual display to the subject.

10. The method of claim 9, wherein the computer chip is operatively connected to an insulin pump and the computer chip is further programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

11. The method of claim 3, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

12. The method of claim 1 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a difference between first and second numbers obtained from first and second of said impedance measurements.

13. The method of claim 12, wherein said first number is the phase angle of the complex electrical impedance at the first frequency and said second number is the phase angle of the complex electrical impedance at the second frequency.

14. The method of claim 1, wherein determining the amount of glucose includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

15. The method of claim 1, wherein a saline solution is applied just prior to measuring impedance so as to render the stratum corneum more electrically transparent.

16. The method of claim 15, wherein said saline solution is a physiological saline solution.

17. The method of claim 16, wherein said saline solution is about 0.09% saline.

18. The method of claim 17, wherein said saline solution is applied against a measurement site for about a minute.

19. The method of claim 1, wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a ratio of first and second numbers obtained from first and second of said impedance measurements.

20. The method of claim 19 wherein each of said first and second numbers includes a component of said first and second impedance measurements, respectively.

21. The method of claim 20 wherein said first number is the real part of the complex electrical impedance at the first frequency and the second number is the magnitude of the complex electrical impedance at the second frequency.

22. The method of claim 20 wherein said first number is the imaginary part of the complex electrical impedance at the first frequency and the second number is magnitude of the complex electrical impedance at the second frequency.

23. The method of claim 20 wherein said first number is the magnitude of the complex electrical impedance at the first frequency and said second number is the magnitude of the complex electrical impedance at the second frequency.

24. A method for non-invasively monitoring glucose in a body fluid of a subject, the method comprising:

measuring impedance between two electrodes in conductive contact with a skin surface of the subject at a plurality of frequencies wherein at least one of the frequencies is below about 100 kHz; and

determining the amount of glucose in the body fluid based upon the measured impedance.

25. The method of claim 24, wherein the skin surface is treated with a saline solution prior to the measuring step, and the body fluid is blood.

26. The method of claim 24, wherein the subject is human and the body fluid is blood.

27. The method of claim 26, wherein determining the amount of glucose includes comparing the measured impedance with a predetermined relationship between impedance and blood glucose level.

28. The method of claim 27, including the step of determining the ratio of one or more pairs of measurements, and wherein determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s).

29. The method of claim 28, wherein the skin surface is located on a volar forearm.

30. The method of claim 29, wherein an electrically conductive gel is applied to the skin to enhance conductive contact of the electrodes with the skin surface during the measuring step.

31. The method of claim 30, wherein the electrodes are in operative connection with a computer chip programmed to determine the amount of glucose in the body fluid based upon the measured impedance.

32. The method of claim 31, wherein an indicator is operatively connected to the computer chip for indication of the determined amount of glucose to the subject, and the indicator provides a visual display to the subject.

33. The method of claim 32, wherein the computer chip is operatively connected to an insulin pump and the computer chip is further programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

34. The method of claim 26, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

35. The method of claim 24 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a ration of first and second numbers obtained from first and second of said impedance measurements.

36. The method of claim 35 wherein each of said first and second numbers includes a component of said first and second impedance measurements, respectively.

37. The method of claim 36 wherein said first number is the real part of the complex electrical impedance at the first frequency and the second number is the magnitude of the complex electrical impedance at the second frequency.

38. The method of claim 36 wherein said first number is the imaginary part of the complex electrical impedance at the first frequency and the second number is magnitude of the complex electrical impedance at the second frequency.

39. The method of claim 36 wherein said first number is the magnitude of the complex electrical impedance at the first frequency and said second number is the magnitude of the complex electrical impedance at the second frequency.

40. The method of claim 24 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a difference between first and second numbers obtained from first and second of said impedance measurements.

41. The method of claim 40, wherein said first number is the phase angle of the complex electrical impedance at the first frequency and said second number is the phase angle of the complex electrical impedance at the second frequency.

42. The method of claim 24, wherein determining the amount of glucose includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

43. The method of claim 24, wherein a saline solution is applied just prior to measuring impedance so as to render the stratum corneum more electrically transparent.

44. The method of claim 43, wherein said saline solution is a physiological saline solution.

45. The method of claim 44, wherein said saline solution is about 0.9% saline.

46. The method of claim 45, wherein said saline solution is applied against a measurement site for about a minute.

47. A method for non-invasively monitoring glucose in a body fluid of a subject, the method comprising:

measuring impedance between two electrodes in conductive contact with a skin surface of the subject at a plurality of frequencies wherein at least one of the frequencies is about 20 kHz; and

determining the amount of glucose in the body fluid based upon the measured impedance.

48. The method of claim 47, wherein the skin surface is treated with a saline solution prior to the measuring step, and the body fluid is blood.

49. The method of claim 47, wherein the subject is human and the body fluid is blood.

50. The method of claim 49, wherein determining the amount of glucose includes comparing the measured impedance with a predetermined relationship between impedance and blood glucose level.

51. The method of claim 50, including the step of determining the ratio of one or more pairs of measurements, and wherein determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s).

52. The method of claim 51, wherein the skin surface is located on a volar forearm.

53. The method of claim 52, wherein an electrically conductive gel is applied to the skin to enhance conductive contact of the electrodes with the skin surface during the measuring step.

54. The method of claim 53, wherein the electrodes are in operative connection with a computer chip programmed to determine the amount of glucose in the body fluid based upon the measured impedance.

55. The method of claim 54, wherein an indicator is operatively connected to the computer chip for indication of the determined amount of glucose to the subject, and the indicator provides a visual display to the subject.

56. The method of claim 55, wherein the computer chip is operatively connected to an insulin pump and the computer chip is further programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

57. The method of claim 49, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

58. The method of claim 47 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a ratio of first and second numbers obtained from first and second of said impedance measurements.

59. The method of claim 58 wherein each of said first and second numbers includes a component of said first and second impedance measurements, respectively.

60. The method of claim 59 wherein said first number is the real part of the complex electrical impedance at the fist frequency and the second number is the magnitude of the complex electrical impedance at the second frequency.

61. The method of claim 59 wherein said first number is the imaginary part of the complex electrical impedance at the first frequency and the second number is magnitude of the complex electrical impedance at the second frequency.

62. The method of claim 59 wherein said first number is the magnitude of the complex electrical impedance at the first frequency and said second number is the magnitude of the complex electrical impedance at the second frequency.

63. The method of claim 47 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a difference between first and second numbers obtained from first and second of said impedance measurements.

64. The method of claim 63, wherein said first number is the phase angle of the complex electrical impedance at the first frequency and said second number is the phase angle of the complex electrical impedance at the second frequency.

65. The method of claim 47, wherein determining the amount of glucose includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

66. The method of claim 47, wherein a saline solution is applied just prior to measuring impedance so as to render the stratum corneum more electrically transparent.

67. The method of claim 66, wherein said saline solution is a physiological saline solution.

68. The method of claim 67, wherein said saline solution is about 0.9% saline.

69. The method of claim 68, wherein said saline solution is applied against a measurement site for about a minute.

70. A method for non-invasively monitoring glucose in a body fluid of a subject, the method comprising:

treating a surface of the skin of the subject with a saline solution and wiping the treated surface to reduce variability that may be introduced into impedance measurements by the stratum corneum;

measuring impedance between two electrodes in conductive contact with the skin surface; and

determining the amount of glucose in the body fluid based upon the measured impedance.

71. The method of claim 70 wherein said saline solution is applied just prior to measuring impedance so as to render the stratum corneum more electrically transparent.

72. The method of claim 70 wherein the body fluid is blood and the subject is human.

74. The method of claim 70, including measuring impedance at a plurality of frequencies, determining the ratio of one or more pairs of measurements and wherein determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s).

75. The method of claim 74 wherein the skin surface is located on a volar forearm.

76. The method of claim 70 wherein an electrically conductive gel is applied to the skin to enhance conductive contact of the electrodes with the skin surface during the measuring step.

77. The method of claim 76, wherein the electrodes are in operative connection with a computer chip programmed to determine the amount of glucose in the body fluid based upon the measured impedance.

78. The method of claim 77, wherein an indicator is operatively connected to the computer chip for indication of the determined amount of glucose to the subject, and the indicator provides a visual display to the subject.

79. The method of claim 78, wherein the computer chip is operatively connected to an insulin pump and the computer chip is further programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

80. The method of claim 70, wherein the electrode are spaced between about 0.2 mm and about 2 cm from each other.

81. The method of claim 70 wherein determining the amount of glucose includes measuring impedance at two frequencies.

82. The method of claim 81 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a ratio of first and second numbers obtained from first and second of said impedance measurements.

83. The method of claim 82 wherein each of said first and second numbers includes a component of said first and second impedance measurements, respectively.

84. The method of claim 83 wherein said first number is the real part of the complex electrical impedance at the first frequency and the second number is the magnitude of the complex electrical impedance at the second frequency.

85. The method of claim 83 wherein said first number is the imaginary part of the complex electrical impedance at the first frequency and the second number is magnitude of the complex electrical impedance at the second frequency.

86. The method of claim 83 wherein said first number is the magnitude of the complex electrical impedance at the first frequency and said second number is the magnitude of the complex electrical impedance at the second frequency.

87. The method of claim 81 wherein determining the amount of glucose further includes determining a predetermined index, the index comprising a difference between first and second numbers obtained from first and second of said impedance measurements.

88. The method of claim 87 wherein said first number is the phase angle of the complex electrical impedance at the first frequency and said second number is the phase angle of the complex electrical impedance at the second frequency.

89. The method claim 70 wherein determining the amount of glucose includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

90. The method of claim 70, wherein said saline solution is a physiological saline solution.

91. The method of claim 70, wherein said saline solution is about 0.9% saline.

92. The method of claim 70, wherein said saline solution is applied against a measurement site for about a minute.

73. The method of 72 wherein determining the amount of glucose includes comparing the measured impedance with a predetermined relationship between impedance and blood glucose level.

93. An apparatus for non-invasive monitoring of glucose in a body fluid of a subject, the apparatus comprising:

means for measuring impedance of skin tissue, at a plurality of frequencies wherein all said frequencies are in a range from about 10 Hz to about 5 MHZ, in response to a voltage applied thereto; and

a microprocessor operatively connected to the means for measuring impedance, for determining the amount of glucose in the body fluid based upon the impedance measurement.

94. The apparatus of claim 93, wherein said means for measuring impedance of skin tissue includes a pair of spaced apart electrodes for electrically conductive contact with a skin surface.

95. The apparatus of claim 94, wherein said microprocessor is programmed to compare the measured impedance with a predetermined correlation between impedance and blood glucose level.

96. The apparatus of claim 95, including means for measuring impedance at a plurality of frequencies of said applied voltage, wherein said microprocessor is further programmed to determine the ratio of one or more pairs of the impedance measurements and means for comparing the determined ratio(s) with corresponding predetermined ratio(s) to determine the amount of glucose in the body fluid.

97. The apparatus of claim 94, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

98. The apparatus of claim 94, including a case having means for mounting the apparatus on a forearm of a human subject with the electrodes in said electrically conductive contact with a skin surface of the subject.

99. The apparatus of claim 93, further comprising an indicator operatively connected to the microprocessor for indication of the determined amount of glucose.

100. The apparatus of claim 99, wherein the indicator provides a visual display.

101. The apparatus of claim 99, wherein the microprocessor is operatively connected to an insulin pump and includes means to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

102. The apparatus of claim 93, further comprising:

means for calibrating the apparatus against a directly measured glucose level of a said subject.

103. The apparatus of claim 93, wherein the microprocessor is programmed to determine the glucose level of a subject based on the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

104. An apparatus for non-invasive monitoring of glucose in a body fluid of a subject, the apparatus comprising:

means for measuring impedance of skin tissue, at a plurality of frequencies wherein at least one of the frequencies is below about 100 kHz, in response to a voltage supplied thereto; and

a microprocessor operatively connected to the means for measuring impedance, for determining the amount of glucose in the body fluid based upon the impedance measurement.

105. The apparatus of claim 104, wherein said means for measuring impedance of skin tissue includes a pair of spaced apart electrodes for electrically conductive contact with a skin surface.

106. The apparatus of claim 105, wherein said microprocessor is programmed to compare the measured impedance with a predetermined correlation between impedance and blood glucose level.

107. The apparatus of claim 106, including means for measuring impedance at a plurality of frequencies of said applied voltage, wherein said microprocessor is further programmed to determine the ratio of one or more pairs of the impedance measurements and means for comparing the determined ratio(s) with corresponding predetermined ratio(s) to determine the amount of glucose in the body fluid.

108. The apparatus of claim 105, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

109. The apparatus of claim 105, including a case having means for mounting the apparatus on a forearm of a human subject with the electrodes in said electrically conductive contact with a skin surface of the subject.

110. The apparatus of claim 104, further comprising an indicator operatively connected to the microprocessor for indication of the determined amount of glucose.

111. The apparatus of claim 110, wherein the indicator provides a visual display.

112. The apparatus of claim 110, wherein the microprocessor is operatively connected to an insulin pump and includes means to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

113. The apparatus of claim 104, further comprising:

means for calibrating the apparatus against a directly measured glucose level of a said subject.

114. The apparatus of claim 104, wherein the microprocessor is programmed to determine the glucose level of a subject based on the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.

115. An apparatus for non-invasive monitoring of glucose in a body fluid of a subject, the apparatus comprising:

means for measuring impedance of skin tissue, at a plurality of frequencies wherein at least one of the frequencies is about 20 kHz, in response to a voltage applied thereto; and

a microprocessor operatively connected to the means for measuring impedance, for determining the amount of glucose in the body fluid based upon the impedance measurement.

116. The apparatus of claim 115, wherein said means for measuring impedance of skin tissue includes a pair of spaced apart electrodes for electrically conductive contact with a skin surface.

117. The apparatus of claim 116, wherein said microprocessor is programmed to compare the measured impedance with a predetermined correlation between impedance and blood glucose level.

118. The apparatus of claim 117, including means for measuring impedance at a plurality of frequencies of said applied voltage, wherein said microprocessor is further programmed to determine the ratio of one or more pairs of the impedance measurements and means for comparing the determined ratio(s) with corresponding predetermined ratio(s) to determine the amount of glucose in the body fluid.

119. The apparatus of claim 116, including a case having means for mounting the apparatus on a forearm of a human subject with the electrodes in said electrically conductive contact with a skin surface of the subject.

120. The apparatus of claim 115, further comprising an indicator operatively connected to the microprocessor for indication of the determined amount of glucose.

121. The apparatus of claim 120, wherein the indicator provides a visual display.

122. The apparatus of claim 120, wherein the microprocessor is operatively connected to an insulin pump and includes means to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose.

123. The apparatus of claim 116, wherein the electrodes are spaced between about 0.2 mm and about 2 cm from each other.

124. The apparatus of claim 115, further comprising:

means for calibrating the apparatus against a directly measured glucose level of a said subject.

125. The apparatus of claim 115, wherein the microprocessor is programmed to determine the glucose level of a subject based on the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.