Method and apparatus for the analysis of glucose in a biological matrix

• US 5,692,504 A
• Filed: 02/09/1996
• Issued: 12/02/1997
• Est. Priority Date: 11/04/1993
• Status: Expired due to Fees

• Current Assignee: Boehringer Mannheim GmbH (Roche Holding AG)
• Original Assignee: Boehringer Mannheim GmbH (Roche Holding AG)
• Inventors: Boecker, Dirk, Hein, Heinz-Michael, Haar, Hans-Peter, Essenpreis, Matthias
• Primary Examiner(s): Bahr, Jennifer
• Assistant Examiner(s): YARNELL, BRYAN KEITH
• Application Number:
  US08/592,303
• Time in Patent Office: 662 Days
• Field of Search: 128/633, 128/664-667, 356/39-41
• US Class Current: 600/316
• CPC Class Codes: A61B 2562/0242 for varying or adjusting the optical path length in the tissue
• 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 21/41 Refractivity; Phase-affecting properties, e.g. optical path length G01N21/21 takes precedence
• CPC Class Codes: G01N 21/47 Scattering, i.e. diffuse reflection G01N21/25, G01N21/41 take precedence G01N21/55 takes precedence
• CPC Class Codes: G01N 21/49 within a body or fluid
• CPC Class Codes: G01N 2201/0696 Pulsed

Abstract

Method and apparatus for the analytical determination of glucose concentration in a biological matrix, wherein in a detection step light from a light emitter is irradiated into the biological matrix as primary light via a boundary surface of the biological matrix and light emerging from the the biological matrix through a boundary surface is being detected by a light detector in order to determine a measurable physical light property which is changed by interaction with the biological matrix and which correlates with the glucose concentration of said matrix. The glucose concentration is ascertained in an evaluation step on the basis of said change of the physical light property determined in at least one detection step in comparison with a calibration. In order to achieve by such a method good analytical accuracy in reagent-free and non-invasive manner, for instance to observe the change of the concentration of the analyzed substance (monitoring) over an adequate time interval, a measurable parameter corresponding to the light transit-time within the biological matrix between a defined irradiation site and a defined detection site and correlating with the glucose concentration is determined in the detection step.

Claims

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

irradiating light from a light emitter as primary light through a boundary surface into the biological matrix;

detecting light emerging as secondary light from said matrix through said boundary surface by a light sensor in order to determine a measurable physical property of the light that is changed by interaction with the biological matrix, said measurable physical property correlating with the glucose concentration in the biological matrix; and

determining the glucose concentration based upon a measured change of the physical property compared to a calibration,

wherein the measurable physical property correlating with the glucose concentration is a parameter corresponding to a light transit-time inside the biological matrix between a defined irradiation site and a defined detection site.

2. A method according to claim 1, wherein a measurement distance between the irradiation site and the detection site is less than 4 cm, preferably less than 3 cm and especially-preferred less than 2 cm.

3. A method according to claim 1, wherein the parameter corresponding to the light transit-time is determined at a plurality of different measurement distances between the irradiation site and the detection site and in that in the evaluation step a dependence of the light transit-time on the measurement distance is used to determine the glucose concentration.

4. A method according to claim 1, wherein in the detection step a short pulse of primary light is irradiated into the biological matrix and the resulting pulse emerging at the detection site is detected in order to directly determine the transit time.

5. A method according to claim 4, wherein a pulse-width of the short pulse of primary-light is less than 1 ns.

6. A method according to claim 5, wherein the pulse width is less than 100 ps.

7. A method according to claim 5, wherein the pulse width is less than 20 ps.

8. A method according to claim 1, wherein the primary light is modulated with a high-frequency carrier frequency and wherein a phase-shift of the secondary light relative to the primary light is determined as the parameter corresponding to the transit time.

9. A method according to claim 8, wherein in the detection step a change in AC amplitude of the modulation of the secondary light is determined in relation to the AC amplitude of the modulation of the primary light and said change of AC amplitude is used additionally to the phase shift in the evaluation step to determine the .glucose concentration.

10. A method according to claim 8, wherein in the detection step the change of a DC amplitude of the secondary light is determined in relation to a DC amplitude of the primary light and said change of DC amplitude is used in addition to the phase shift in the evaluation step to determine the glucose concentration.

11. A method according to claim 8, wherein the carrier frequency is higher than 50 MHz.

12. A method according to claim 11, wherein the carrier frequency is higher than 200 MHz.

13. A method according to claim 8, wherein in the at least one detection step the primary light is modulated with a plurality of different carrier frequencies and in each case a respective phase shift of the secondary light is measured relative to the primary light as a measure of a mean optical path-length.

14. A method according to claim 8, wherein in at least one detection step the primary light is simultaneously irradiated at two different irradiation sites in such manner that light intensity waves propagating from the two irradiation sites through the biological matrix are superposed and a change of light detected at a defined detection site resulting from said superposition and depending on the light transit-time between the irradiation sites and the defined detection site determines the parameter corresponding to the transit-time in the detection step and is used in the evaluation step to ascertain the glucose concentration.

15. A method according to claim 14, wherein a relative phase and a relative intensity of the primary light irradiated at the two different irradiation sites are adjusted in such manner that the change detected at the detection site with changing glucose concentration is maximized.

16. A method according to claim 11, wherein a phase of the modulation of the primary light irradiated at the two different irradiation sites differ by approximately 180°

.

17. A method according to claim 14, wherein the detection site is located between two bounding straight lines each passing through one irradiation site and each perpendicular to a connecting straight line between said two irradiation sites.

18. A method according to claim 17, wherein the detection site is located within a bounding circle passing through both irradiation sites.

19. A method according to claim 14, wherein the two different irradiation sites are located at different measurement distances to the detection site.

20. A method according to claim 14, wherein the biological matrix is a tissue of a mammal, including a human, wherein one of the irradiation sites is selected in such manner that a substantial blood vessel is in the light path to the detection site, whereas the second irradiation site is selected in such a way that no comparably large blood vessel is in its light path to the detection site.

21. A method according to claim 1, wherein the wavelength of the primary light is between 400 and 2,500 nm.

22. A method according to claim 21, wherein the primary-light wavelength is between 750 and 850 nm.

23. A method according to claim 22, wherein the primary-light wavelength is between 780 and 825 nm.

24. A method according to claim 22, wherein the primary-light wavelength is between 800 and 805 nm.

25. A method according to claim 21, wherein the primary-light wavelength is between 1,150 and 1,350 nm.

26. A method according to claim 25, wherein the primary-light wavelength is between 1200 and 1300 nm.

27. A method according to claim 21, wherein the primary-light wavelength is between 1,600 and 1,800 nm.

28. A method according to claim 27, wherein the primary-light wavelength is between 1630 and 1770 nm.

29. A method according to claim 27, wherein the primary-light wavelength is between 1630 and 1670 nm.

30. A method according to claim 27, wherein the primary-light wavelength is between 1730 and 1770 nm.

31. A method according to claim 1, wherein the wavelength of the primary light is selected within a range wherein the absorption of an aqueous glucose solution presents little dependence on the glucose concentration.

32. A method according to claim 1, wherein temperature of the detection site is measured and is taken into account in the evaluation step.

33. A method according to claim 32, wherein the temperature of the detection site is measured without contact.

34. A method according to claim 1, wherein a detection-site temperature is kept constant.

35. A method according to claim 1, wherein the biological matrix is a biological liquid, in particular blood.

36. A method according to claim 1, wherein biological matrix is a biological tissue.

37. A method according to claim 36, wherein the biological matrix is skin tissue, in particular at a finger pad, an abdominal wall, a nail bed, a lip, a tongue, a human inner upper arm, or sclera tissue.

38. Apparatus for determining a glucose concentration in a biological matrix, comprising:

a measuring head to be placed against a boundary surface of the biological matrix,

irradiation means with a primary light emitter for irradiating primary light through a boundary surface into the biological matrix, detection means for detecting secondary light emerging from said biological matrix through said boundary surface and for determining a physical property of the light that is changed by interaction with the biological matrix, said property correlating with the glucose concentration in the biological matrix, and

evaluation means for determining the glucose concentration from the detected physical property of the light,

wherein the detection means comprise means for measuring a parameter corresponding to a light transit-time along a measurement light path within the biological matrix between a defined irradiation site, and a defined detection site as a physical property of the light which correlates with the glucose concentration.

39. Apparatus according to claim 38, wherein the irradiation means comprise a measurement frequency generator and a driver stage controlling the primary light emitter thereby to modulate the primary light with a high-frequency carrier frequency, and in that the means for measuring a parameter corresonding to the light transit-time in the biological matrix comprise a phase measurement device for determining a phase shift of the secondary light relative to the primary light as a parameter correlating with the light transit-time.

40. Apparatus according to claim 39, wherein the phase-measurement device comprises means for determining an AC amplitude of the secondary light in relation to an AC amplitude of the primary light.

41. Apparatus according to claim 39, wherein the phase measurement device comprises means for determining a DC amplitude of the secondary light in relation to a DC amplitude of the primary light.

42. Apparatus according to claim 39, wherein the driver stage and the primary light emitter are enclosed in an electromagnetically insulating housing.

43. Apparatus according to claim 42, wherein the measurement frequency generator also is enclosed in an electromagnetically insulating housing.

44. Apparatus according to claim 42, wherein the phase measurement device comprises a second frequency generator which is also enclosed inside an electromagnetically insulating housing.

45. Apparatus according to claim 39, wherein the phase measurement device comprises a signal mixer receiving the output signal from a light sensor and in that the signal path between the light sensor and the signal mixer is minimized.

46. Apparatus according to claim 45, wherein the light sensor and the signal mixer are jointly integrated on the same semiconductor substrate.

47. Apparatus according to claim 46, wherein the signal mixer is a FET mixer and the light sensor is directly connected to the gate of the FET mixer.

48. Apparatus according to claim 46, wherein the light sensor is a photodiode and in that the photodiode is a part of the signal mixer.

49. Apparatus according to claim 38, wherein the means for measuring a parameter corresponding to the light transit-time along the measurement light path within the biological matrix comprise an optical reference light path which is adapted to the measurement light path regarding light transit-time and light intensity attenuation, wherein the measurement light is optically switchable between a sample light path comprising the measurement light path and the reference light path.

50. Apparatus according to claim 39, wherein the phase measurement device comprises a first and a second measuring frequency generator oscillating at a constant differential frequency wherein the differential frequency between the frequencies of the first measuring frequency generator and the second measuring frequency generator is predetermined by means of a difference-frequency generator and the frequency of the second measuring frequency generator is regulated on the basis of the predetermined differential frequency in such manner that the second measuring frequency generator follows the frequency fluctuations of the first measuring frequency generator at a constant differential frequency.