Method and apparatus for determining glucose concentration in a biological sample

• US 5,710,630 A
• Filed: 10/10/1995
• Issued: 01/20/1998
• Est. Priority Date: 05/05/1994
• Status: Expired due to Fees

• Current Assignee: Boehringer Mannheim GmbH (Roche Holding AG)
• Original Assignee: Boehringer Mannheim GmbH (Roche Holding AG)
• Inventors: Boecker, Dirk, Essenpreis, Matthias, Knuettel, Alexander
• Primary Examiner(s): Turner, Samuel A.
• Application Number:
  US08/530,241
• Time in Patent Office: 833 Days
• Field of Search: 356/345, 356/39, 356/346, 128/633, 250/343, 250/227.27
• US Class Current: 356/479
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: G01N 21/314 with comparison of measurements at specific and non-specific wavelengths dual wavelength spectrometry G01J3/427
• CPC Class Codes: G01N 21/45 using interferometric methods; using Schlieren methods
• CPC Class Codes: G01N 21/49 within a body or fluid

Abstract

A method for the analytical determination of the glucose concentration in a biological sample. In a detection step, light is irradiated into the sample and the light emerging therefrom after interaction with the sample emerges therefrom is detected in order to measure a physical light property affected by said interaction. The glucose concentration is determined from this measurement in an evaluation step. To provide a method for determining glucose in reagent-free and non-invasive manner, the invention proposes that a portion of the light emitted by the light source be guided along a reference light path of defined optical path length to the photodetector, that the total measuring light path also has a defined optical length and that the measuring light path after it has traversed the sample is so combined with the reference light path that the measuring light and the reference light interfere with each other. The photodetector measures an interference signal used in the evaluation step to determine the glucose concentration.

Claims

1. A method for analytically determining a concentration of glucose in a biological sample, said method comprising the steps of:

irradiating light along a primary-side measuring light path into the biological sample;

guiding secondary light emerging from the sample along a secondary-side measuring light path to a photodetector;

detecting the secondary light with the photodetector, the photodetector providing a signal representative of the secondary light,

wherein a first portion of the primary light emitted by the light source is guided to the photodetector along a total measuring light path which includes the primary-side measuring light path, an interior light path in which the light travels inside the sample, and the secondary-side measuring light path, wherein a second portion of the primary light emitted by the light source is guided along a reference light path to the photodetector, said reference light path not including an interior light path in which the light travels inside the sample, and wherein the secondary-side measuring light path and the reference light path are combined whereby the secondary light and the reference light interfere with each other such that the photodetector detects an interference signal, said method further comprising the step of

determining the glucose concentration based on the signal provided in the detecting step, wherein a factor in the determining of the glucose concentration is an optical light path length of the interior light path inside the sample derived from said interference signal.

2. Method according to claim 1, wherein the optical path length of at least one of the light paths is modulated by a modulating signal and the interference signal is evaluated using the modulation signal.

3. Method according to claim 2, wherein at least two detection steps are performed with two different measuring-light wavelengths to determine a glucose concentration and wherein the wavelength-dependency of the interference signal is used in an evaluation step for said determination.

4. Method according to claim 3, wherein the optical path length of the reference light path is variable and is set to a plurality of lengths, wherein the light source emits a broadband spectrum and in that the wavelength-dependency is determined by means of a Fourier-Transform-Spectroscopy procedure.

5. Method according to claim 1, wherein the light on the reference light path is reflected by a light reflecting optical component into the opposite direction.

6. Method according to claim 1, wherein the optical path length of at least one of the light paths is variable and is set to a plurality of different lengths.

7. Method according to claim 6, wherein the optical path length of the reference light path is variable and is set to a plurality of lengths.

8. Method according to claim 7, wherein the optical path length is varied by moving a reflecting optical element.

9. Method according to claim 6, wherein the optical light path length is varied in an oscillating manner.

10. Method according to claim 1, wherein the light source emits light of a short length of coherence of at most 50μ

.

11. A method according to claim 10, wherein the short length of coherence is no greater than 10μ

.

12. Method according to claim 10, wherein the primary-side measuring light path and the secondary-side measuring light path run in the same half-space defined by a boundary surface of the sample, whereby the light reflected by the sample enters the secondary-side measuring light path.

13. Method according to claim 12, wherein the primary-side measuring light path and the secondary-side measuring light path partially coincide and wherein an optic coupler is used to split the primary-side sample light path and the reference light path and to combine the secondary-side measuring light path and the reference light path.

14. Method according to claim 12, wherein in order to determine a glucose concentration, several different relations of the path lengths of the total measuring light path in relation to the reference light path are set, where the optical path length of the reference light path is larger than the sum of the optical path lengths of the primary-side measuring light path and the secondary-side measuring light path, whereby the interference signal corresponds to reflections at different depths in the sample.

15. Method according to claim 14, wherein the glucose concentration is determined from the intensity of the interference signal on the set relation of the optical path lengths.

16. Method according to claim 12, wherein the measuring light is irradiated through the eye cornea into the anterior chamber and is detected following reflection in the eye by means of the light emerging through the cornea whereby the sample light path runs from an irradiation site at the cornea through the anterior chamber up to a reflection site and from there to an exit site at the cornea.

17. Method according to claim 16, wherein interferograms of two reflections in the eye are measured, the site of a first reflection being in front of the anterior chamber and the site of the second reflection being located behind the anterior chamber and the glucose concentration is determined in the evaluation step from the two interferograms.

18. Method according to claim 17, wherein the site of the first reflection is located at the boundary surface of the eye cornea wetted by the aqueous humor.

19. Method according to claim 17, wherein the site of the second reflection is located at the boundary of the anterior chamber facing the eye ball.

20. Method according to claim 19, wherein the site of the second reflection is located at the lens surface of the eye lens.

21. Method according to claim 1, wherein the temperature of the biological sample is measured and taken into account in the evaluation step for the determination of the glucose concentration.

22. Method according to claim 1, wherein the biological sample is a biological fluid.

23. A method according to claim 22, wherein the biological fluid comprises blood.

24. Method according to claim 1, wherein the biological sample is a biological tissue.

25. Method according to claim 24, wherein the biological tissue is one of a finger pad, an upper abdominal wall, a nail bed, a lip, a tongue, an inner upper arm of a human, tissue of the sclera and a retina.

26. Method according to claim 1, wherein the biological sample includes the aqueous humor of the anterior chamber of the eye.

27. A method for analytically determining a concentration of glucose as recited in claim 1, wherein said step of determining glucose concentration is based upon a change of an optical path length inside the sample in relation to a given geometrical path length.

28. Glucose-measuring apparatus for the analytical determination of the concentration of glucose in a biological sample, said apparatus comprising:

a light source for emitting measuring light;

light-irradiation means having a light aperture by means of which the measuring light is irradiated through a boundary surface of the sample into said sample;

a primary-side measuring light path from the light emitter to the boundary surface,

light detection means for detecting light emerging from the sample at a boundary surface after interaction with the sample; and

a secondary-side measuring light path from the boundary surface where the measuring light emerges from the sample to a photodetector,

wherein a reference light path of defined optical length is provided for guiding light from the light source to the photodetector, and wherein an optic coupler is positioned in the secondary-side measuring light path by means of which the secondary-side measuring light path and the reference light path are combined in such manner that they are incident at the same point on the photodetector, thereby generating an interference signal, said apparatus further comprising

means for determining the glucose concentration based on a signal provided by the light detection means, wherein a factor in determining the glucose concentration is an optical light path length of the secondary-side measuring light path inside the sample derived from the interference signal.

29. Glucose measuring apparatus according to claim 28, wherein the light is guided at least along a part of the light paths in single mode optical fibers.

30. Glucose measuring apparatus according to claim 28, wherein the light source (10) is a light emitting diode.

31. A glucose measuring apparatus according to claim 30, wherein the light emitting diode comprises a superluminescent diode.

32. Glucose measuring apparatus according to claim 28, wherein the primary-side measuring light path and the secondary-side measuring light path partly coincide and pass through the same components.

33. Glucose measuring apparatus according to claim 28, wherein the reference light path comprises a reflecting optical component which is movable along the optical axis for adjusting the optical path length thereof.

34. A method for analytically determining a concentration of glucose in a biological sample, said method comprising the steps of:

irradiating light along a primary-side measuring light path into the biological sample;

guiding secondary light emerging from the sample along a secondary-side measuring light path to a photodetector;

detecting the secondary light with the photodetector, the photodetector providing a signal representative of the secondary light,

wherein a first portion of the primary light emitted by the light source is guided to the photodetector along a total measuring light path which includes the primary-side measuring light path, an interior light path in which the light travels inside the sample, and the secondary-side measuring light path, wherein a second portion of the primary light emitted by the light source is guided along a reference light path to the photodetector, said reference light path not including an interior light path in which the light travels inside the sample, wherein the optical path length of at least one of the light paths is variable and is set to a plurality of different lengths, wherein the primary-side measuring light path and the secondary-side measuring light path run in a same half-space defined by a boundary surface of the sample, such that the light reflected by the sample enters the secondary-side measuring light path, wherein the light on the reference light path is reflected by a light reflecting optical component in an opposite direction, and wherein the secondary-side measuring light path and the reference light path are combined such that the secondary light and the reference light interfere with each other such that the photodetector detects an interference signal, said method further comprising the step of

determining the glucose concentration based on the signal provided in the detecting step, wherein a factor in said determining of the glucose concentration is an optical light path length of the interior light path inside the sample derived from said interference signal, wherein said determining step includes setting of a plurality of different relations of the path lengths of the total measuring light path in relation to the reference light path, wherein the optical path length of the reference light path is larger than the sum of the optical path lengths of the primary-side measuring light path and the secondary-side measuring light path, whereby the interference signal corresponds to reflections at different depths in the sample, and determining the glucose concentration from the dependence of the intensity of the interference signal on the set relation of the optical path lengths.

35. A method according to claim 34, wherein the optical path length of at least one of the light paths is modulated by a modulating signal, and the interference signal is evaluated using the modulation signal.

36. A method according to claim 35, wherein at least two detection steps are performed with two different measuring-light wavelengths to determine a glucose concentration, and wherein the wavelength-dependency of the interference signal is used in an evaluation step for said determination.

37. A method according to claim 34, wherein the optical path length of the reference light path is variable, and is set to a plurality of lengths.

38. A method according to claim 37, wherein the optical path length is varied by moving the reflecting optical component.

39. A method according to claim 34, wherein the optical light path length is varied in an oscillating manner.

40. A method according to claim 34, wherein the light source emits light of a short length of coherence of no greater than 50μ

.

41. A method according to claim 40, wherein said short length of coherence is no greater than 10μ

.

42. A method according to claim 34, wherein an optic coupler is used to split the primary-side sample light path and the reference light path and to combine the secondary-side measuring light path and the reference light path.

43. A method according to claim 34, wherein the temperature of the biological sample is measured and taken into account in the evaluation step for the determination of the glucose concentration.

44. A method according to claim 34, wherein the biological sample is a biological fluid.

45. A method according to claim 34, wherein the biological sample is a biological tissue.

46. A method according to claim 45, wherein the biological tissue is one of a finger pad, an upper abdominal wall, a nail bed, a lip, a tongue, an inner upper arm of a human, tissue of the sclera, and a retina.