Method for determining analyte concentration using periodic temperature modulation and phase detection

• US 20040034291A1
• Filed: 02/27/2003
• Published: 02/19/2004
• Est. Priority Date: 03/12/1997
• Status: Abandoned Application

• Current Assignee: Bernhard B. Sterling, Daniel S. Goldberger, James R. Braig, Rick Trebino, Zheng Peng
• Original Assignee: Bernhard B. Sterling, Daniel S. Goldberger, James R. Braig, Rick Trebino, Zheng Peng
• Inventors: Braig, James R., Zheng, Peng, Sterling, Bernhard B., Goldberger, Daniel S., Trebino, Rick
• Application Number:
  US10/377,020
• Publication Number:
  US 20040034291A1
• Time in Patent Office: Days
• US Class Current: 600/316
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: G01N 21/35 using infrared light G01N21/39 takes precedence

Abstract

A method of determining the analyte concentration of a test sample is described. A temperature gradient is introduced in the test sample and infrared radiation detectors measure radiation at selected analyte absorbance peak and reference wavelengths. Reference and analytical signals are detected. In the presence of the selected analyte, parameter differences between reference and analytical signals are detectable. These parameter differences, having a relationship to analyte concentration, are measured, correlated, and processed to determine analyte concentration in the test sample. Accuracy is enhanced by inducing a periodically modulated temperature gradient in the test sample. The analytical and reference signals may be measured continuously and the parameter difference integrated over the measurement period to determine analyte concentration.

Claims

10. A method of spectroscopically analyzing a test sample utilizing a radiation detector and a means for inducing a thermal gradient in said sample, said method comprising the steps of:

a) providing a test sample;

b) inducing a thermal gradient in said test sample;

c) responsive to said inducing step, measuring at least one reference signal emitted by said sample;

d) further responsive to said inducing step, measuring at least one analytical signal emitted by said sample;

e) comparing said measured reference and said analytical signals to determine phase difference information between said analytical and reference signals;

f) using the magnitude of said phase difference to determine sample analyte concentration information; and

g) transmitting said concentration information, as an electrical signal for further processing.

11. A method as in claim 10 wherein said step of inducing a thermal gradient in said test sample comprises inducing and maintaining a periodically modulated thermal gradient in said test sample over a test period.

12. A method as in claim 11 wherein said step of comparing said measured reference and analytical signals includes making continuous measurements of said phase difference during the test period.

13. A method of determining the absolute or relative concentration of a chemical analyte in a medium, said method comprising the steps of:

a) inducing at least one periodically modulated thermal gradient into said medium;

b) responsive to said inducing step, measuring the radiation emitted from said medium at a predetermined wavelength related to said analyte, resulting in an analytical signal;

c) further responsive to said inducing step, measuring the radiation emitted from said medium at least one reference wavelength, resulting in at least one reference signal;

d) comparing the analytical signal with at least one of said at least one reference signal;

e) determining from said comparison, the phase difference between said analytical signal and said at least one reference signal to produce at least one phase signal; and

f) deducing from said at least one phase signal the concentration of said analytes in said medium.

14. A method as in claim 13 wherein said medium is a solid or a liquid or a gas, or a mixture of one or more of said solid or liquid or gas.

15. A method as in claim 13 wherein said medium is a biological material.

16. A method as in claim 13 wherein said medium is comprised of heterogeneous material.

17. A method as in claim 13 wherein the determination of absolute or relative concentration of a chemical analyte in said medium comprises a non-invasive determination of the analyte concentration.

18. A method as in claim 13 where the chemical analyte to be determined is selected from the group consisting of glucose, insulin, water, carbon dioxide, alcohol, blood oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins, albumin, urea, creatinine, white blood cells, red blood cells, hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, pharmaceuticals, cytochrome, various proteins and chromophores, microcalcifications, and hormones.

19. A method as in claim 13 wherein said step of measuring the radiation emitted from said medium at a predetermined wavelength related to said analyte is measured at an infrared radiation absorbance peak of said analyte.

20. A method as in claim 19 wherein said step of measuring the radiation emitted from said medium at least one reference wavelength is measured at wavelengths which bracket said infrared radiation absorbance peak of said analyte.

21. A method as in claim 13 wherein said step of measuring the radiation emitted from said medium at said at least one reference wavelength is measured at wavelengths where the infrared radiation absorbance of said medium is high.

22. A method as in claim 13 wherein said step of measuring the radiation emitted from said medium at said at least one reference wavelength is measured at wavelengths where the infrared radiation transmission of said medium is high.

23. A method as in claim 13 wherein said step of inducing at least one periodically modulated thermal gradient into said medium comprises inducing the periodic gradient at a single driving frequency.

24. A method as in claim 13 wherein said step of inducing at least one periodically modulated thermal gradient into said medium comprises inducing two periodic gradients at two different driving frequencies.

25. A method as in claim 13 wherein said step of comparing the analytical signal with said at least one reference signal includes continuously comparing said signals over a measurement period.

26. A method as in claim 13 wherein said step of comparing the analytical signal with said at least one reference signal includes intermittently comparing said signals over a measurement period.

27. A method as in claim 13 wherein said step of comparing the analytical signal with said at least one reference signal includes comparing said analytical signal and said reference signals a their respective zero-crossings.

28. A method of determining the absolute or relative concentration of a chemical analyte in a medium, said method comprising the steps of:

a) inducing a shallow temperature gradient in said medium using a first driving frequency;

b) inducing a deep temperature gradient in said medium using a second driving frequency;

c) responsive to said step of inducing a shallow temperature gradient, measuring a shallow analytical signal and at least one shallow reference signal;

d) responsive to said step of inducing a deep temperature gradient, measuring a deep analytical signal and at least one deep reference signal;

e) comparing the shallow analytical signal with said at least one shallow reference signal;

f) comparing the deep analytical signal with said at least one deep reference signal;

g) determining from the comparison of said shallow signals, a parameter difference between said shallow analytical signal and said at least one shallow reference signal to produce at least one shallow parameter difference signal;

h) determining from the comparison of said deep signals, the parameter difference between said deep analytical signal and said at least one deep reference signal to produce at least one deep parameter difference signal;

i) analyzing said at least one shallow parameter difference signal together with said at least one deep parameter difference signal to determine a combined parameter difference signal; and

j) deducing from said combined parameter difference signal, the concentration of said analytes in said medium.

29. A method as in claim 28 wherein said parameter difference includes a phase difference.

30. A method of determining the absolute or relative concentration of blood glucose in a human or animal subject, said method comprising the steps of:

a) providing a human or animal test subject;

b) inducing two periodic thermal gradients in the skin of said test subject, a first gradient being driven at a first frequency and a second gradient being driven at a second frequency, said second gradient driving frequency being greater than said first gradient driving frequency, whereby said second frequency providing a second gradient which extends to the shallower regions of the skin and said first frequency providing a first gradient which extends deeper into the skin than said second gradient;

c) responsive to said inducing of the first gradient, measuring the radiation emitted from the deeper regions of the skin at a glucose absorbance peak wavelength, resulting in a first analytical signal and at one or more one reference wavelengths, resulting in a first reference signal;

d) responsive to said inducing of the second gradient, measuring the radiation emitted from the shallower regions of the skin at a glucose absorbance peak wavelength, resulting in a second analytical signal and at one or more one reference wavelengths, resulting in a second reference signal;

e) comparing the first analytical signal with said one or more first reference signals to determine a the phase differences between said first analytical signal and said first reference signals producing at least one first phase signal;

f) comparing the second analytical signal with said one or more second reference signals to determine a the phase differences between said second analytical signal and said second reference signals producing at least one second phase signal;

g) analyzing said at least one first phase signal together with said at least one second phase signal to determine a combined phase signal; and

j) deducing from said combined phase signal, the blood glucose concentration in said test subject.

k) transmitting said blood glucose concentration information, as an electrical signal, for further processing.

1. A method of analyzing a test sample utilizing a radiation detector, a data processing means, and a means for inducing a thermal gradient in said sample, said method comprising the steps of:

a) providing a test sample;

b) inducing a thermal gradient in said test sample;

c) responsive to said inducing step, measuring at least one reference signal emitted by said sample;

d) further responsive to said inducing step, measuring at least one analytical signal emitted by said sample;

e) comparing said reference and analytical signals to determine parameter information; and

f) transmitting said parameter information, as an electrical signal for further processing.

2. A method as in claim 1 wherein said step (e) of comparing said reference and analytical signals to determine parameter information includes comparing said reference and analytical signals to determine phase difference information between said analytical and reference signals.

3. A method as in claim 2 wherein said step of comparing phase difference information includes the step of deducing the analyte concentration of said sample based on said phase difference information.

4. A method as in claim 3 wherein said step of deducing the analyte concentration includes correlating said phase information with known information regarding analyte concentration and phase.

5. A method as in claim 2 wherein said at least one analytical signal is measured at one or more predefined wavelengths.

6. A method as in claim 3 wherein said predefined wavelength intervals are defined by analyte absorbance peaks.

7. A method as in claim 2 wherein said at least one reference signal is measured at one or more predefined wavelength intervals.

8. A method as in claim 7 wherein said predefined wavelength intervals are defined by the absorbance properties of the sample media.

9. A method as in claim 1 wherein said step of inducing a thermal gradient in said test sample includes inducing a periodic thermal gradient in said test sample.

31. A method as in claim 30 wherein said first gradient driving frequency is at about 1 hertz and said second gradient driving frequency is at about 3 hertz.

33. A method as in claim 30 wherein said first and second phase signals are sequentially implemented resulting in an alternating frequency pattern in said combined phase signal.

34. A method as in claim 30 wherein said step of measuring the radiation emitted from the skin at least one reference wavelength is measured at wavelengths which bracket said glucose absorbance peak wavelength.

35. A method as in claim 30 wherein said step of measuring the radiation emitted from the skin at least one reference wavelength is measured at wavelengths which is near said glucose absorbance peak wavelength.

36. A method as in claim 30 wherein said step of measuring the radiation emitted from the skin at said at least one reference wavelength is measured at wavelengths where the infrared radiation absorbance of the skin is high.

37. A method as in claim 36 wherein said radiation is measured in the range of about 2.2 μ

m to about 3.8 μ

m.

38. A method as in claim 36 wherein said radiation is measured in the range of about 5.5 μ

m to about 6.5 μ

m.

39. A method as in claim 30 wherein said step of measuring the radiation emitted from the skin at said at least one reference wavelength is measured at wavelengths where the infrared radiation transmission of said medium is high.

40. A method as in claim 38 wherein said radiation is measured in the range of about 3.8 μ

m to about 4.8 μ

m.

41. A method as in claim 38 wherein said radiation is measured in the range of about 7 μ

m to about 11 μ

m.

33-1. A method as in claim 30 wherein said first and second phase signals are implemented simultaneously resulting in said first and second phase signals being superimposed in a combined phase signal.

42. A method of determining the absolute or relative concentration of a chemical analyte in a medium, said method comprising the steps of:

a) inducing at least one thermal gradient into said medium;

b) responsive to said inducing step, measuring the radiation emitted from said medium at a predetermined wavelength related to said analyte, resulting in an analytical signal;

c) further responsive to said inducing step, measuring the radiation emitted from said medium at least one reference wavelength, resulting in at least one reference signal;

d) comparing the analytical signal with at least one of said at least one reference, signals;

e) determining from said comparison, a parameter between said analytical signal and said at least one reference signal; and

f) deducing from said parameter the concentration of said analytes in said medium.

43. A method as in claim 42 wherein said step of inducing at least one thermal gradient into said medium includes inducing a periodically modulated temperature gradient.