Process and device for determining an analyte contained in a scattering matrix

• US 5,962,852 A
• Filed: 07/28/1997
• Issued: 10/05/1999
• Est. Priority Date: 01/26/1996
• Status: Expired due to Term

• Current Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Original Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Inventors: Boecker, Dirk, Essenpreis, Matthias, Knuettel, Alexander
• Primary Examiner(s): Hannaher, Constantine
• Application Number:
  US08/875,349
• Time in Patent Office: 799 Days
• Field of Search: 356/345, 250/339.11
• US Class Current: 250/339.11
• CPC Class Codes: A61B 5/0066 Optical coherence imaging
• 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 21/49 within a body or fluid

Abstract

Method for determining an analyte in a scattering matrix. In a detection step detection measurements are made in which light is irradiated into the matrix as primary light and light leaving the scattering matrix is detected as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix. Information on the presence of the analyte in the matrix is determined in an evaluation step. The determination of optically weakly absorbing analytes against a strongly absorbing interference background is improved by the use of two selection methods for the depth selective detection of the secondary light in combination with one another. Primary light is focused by means of a primary light optically focussing element onto a region of focus lying in the matrix at a predetermined measuring depth and the region of focus is imaged by means of a secondary light optically focusing element onto a light entry aperture arranged in the light path of the secondary light to the detector. In addition to this first depth selection by a confocal arrangement, a second depth selection device is used to detect light reflected from a defined measuring depth as secondary light, with the measuring depth coinciding with the depth of focus.

Claims

1. Method for determining an analyte in a scattering, in particular biological, matrix, in which

in a detection step detection measurements are carried out in which light is irradiated through an interface limiting the scattering matrix as primary light into the matrix and light leaving the scattering matrix through the interface is detected by a detector as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix, said interaction including optical absorption and

in an evaluation step information on the presence of the analyte in the matrix is determined on the basis of a measured value of the measurement quantity measured in the detection step,

wherein, using a confocal measuring arrangement, a first depth selection means is provided such that the primary light is focussed by means of a primary light optically focussing element onto a region of focus lying in the matrix at a depth of focus below the interface,

the region of focus is imaged by means of a secondary light optically focussing element onto a light entry aperture arranged in the light path of the secondary light to the detector, the detection of the secondary light thereby being concentrated on the region of focus,

wherein for generating a measurement signal allowing a selective analysis of an analyte which causes only a small share of the optical absorption, light reflected from a defined measuring depth below the interface is detected selectively as secondary light by a second depth selection means, the defined measuring depth coinciding with the depth of focus, and wherein the analyte comprises glucose.

2. Method according to claim 1, wherein the measuring depth coinciding with the depth of focus is at least 0.3 mm and at most 1.5 mm.

3. Method according to claim 1, wherein the wavelength of the light in at least one of the detection measurements is between 2.0 μ

m and 2.4 μ

m.

4. Method according to claim 1, wherein at least two detection measurements are made with different light wavelengths.

5. Method according to claim 4, wherein in the evaluation step a quotient of the measured values at the two different wavelengths is obtained and the information on the presence of the analyte is determined on the basis of the quotient.

6. Method for determining an analyte in a scattering, in particular biological, matrix, in which

in a detection step detection measurements are carried out in which light is irradiated through an interface limiting the scattering matrix as primary light into the matrix and light leaving the scattering matrix through the interface is detected by a detector as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix, and

in an evaluation step information on the presence of the analyte in the matrix is determined on the basis of a measured value of the measurement quantity measured in the detection step,

the primary light being focussed by means of a primary light optically focussing element onto a region of focus lying in the matrix at a depth of focus below the interface, and

the region of focus being imaged by means of a secondary light optically focussing element onto a light entry aperture arranged in the light path of the secondary light to the detector, the detection of the secondary light thereby being concentrated on the region of focus,

wherein light reflected from a defined measuring depth below the interface is detected selectively as secondary light by means of a depth selection means, the defined measuring depth coinciding with the depth of focus, and wherein the primary light is focussed by means of an array of primary light optically focussing elements onto a plurality of regions of focus located at the same depth of focus below the interface and the plurality of the regions of focus is imaged by means of a corresponding number of secondary light optically focussing elements onto respective light entry apertures arranged in the light path to the detector.

7. Method according to claim 6, wherein the primary light is focussed onto at least ten different regions of focus.

8. A method as recited in claim 6, wherein at least two detection measurements are made with different light wavelengths.

9. A method as recited in claim 8, wherein in the evaluation step, a quotient of the measured values at the two different wavelengths is obtained, and the information on the presence of the analyte is determined on the basis of the quotient.

10. Method for determining an analyte in a scattering, in particular biological, matrix, in which

in a detection step detection measurements are carried out in which light is irradiated through an interface limiting the scattering matrix as primary light into the matrix and light leaving the scattering matrix through the interface is detected by a detector as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix, and

in an evaluation step information on the presence of the analyte in the matrix is determined on the basis of a measured value of the measurement quantity measured in the detection step,

the primary light being focussed by means of a primary light optically focussing element onto a region of focus lying in the matrix at a depth of focus below the interface, and

the region of focus being imaged by means of a secondary light optically focussing element onto a light entry aperture arranged in the light path of the secondary light to the detector, the detection of the secondary light thereby being concentrated on the region of focus,

wherein light reflected from a defined measuring depth below the interface is detected selectively as secondary light by means of a depth selection means, the defined measuring depth coinciding with the depth of focus, and wherein at least two detection measurements are made, in which the measuring depth coinciding with the depth of focus is different.

11. Method according to claim 10, wherein the measuring depth coinciding with the depth of focus differs by at least 0.3 mm in the at least two detection measurements.

12. A method as recited in claim 10, wherein at least two detection measurements are made with different light wavelengths.

13. A method as recited in claim 12, wherein in the evaluation step, a quotient of the measured values at the two different wavelengths is obtained, and the information on the presence of the analyte is determined on the basis of the quotient.

14. Method for determining an analyte in a scattering, in particular biological, matrix, in which

in a detection step detection measurements are carried out in which light is irradiated through an interface limiting the scattering matrix as primary light into the matrix and light leaving the scattering matrix through the interface is detected by a detector as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix, and

in an evaluation step information on the presence of the analyte in the matrix is determined on the basis of a measured value of the measurement quantity measured in the detection step,

the primary light being focussed by means of a primary light optically focussing element onto a region of focus lying in the matrix at a depth of focus below the interface, and

the region of focus being imaged by means of a secondary light optically focussing element onto a light entry aperture arranged in the light path of the secondary light to the detector, the detection of the secondary light thereby being concentrated on the region of focus,

wherein light reflected from a defined measuring depth below the interface is detected selectively as secondary light by means of a depth selection means, the defined measuring depth coinciding with the depth of focus, and wherein the measuring step comprises providing means for performing a low coherence reflectometric measurement as the depth selection means.

15. A method as recited in claim 14, wherein at least two detection measurements are made with different light wavelengths.

16. A method as recited in claim 15, wherein in the evaluation step, a quotient of the measured values at the two different wavelengths is obtained, and the information on the presence of the analyte is determined on the basis of the quotient.

17. Method for determining an analyte in a scattering, in particular biological, matrix, in which

in a detection step detection measurements are carried out in which light is irradiated through an interface limiting the scattering matrix as primary light into the matrix and light leaving the scattering matrix through the interface is detected by a detector as secondary light, in order to determine as a measurement quantity a measurable physical property of the light which is variable due to the interaction of the light with the matrix, and

in an evaluation step information on the presence of the analyte in the matrix is determined on the basis of a measured value of the measurement quantity measured in the detection step,

the primary light being focussed by means of a primary light optically focussing element onto a region of focus lying in the matrix at a depth of focus below the interface, and

the region of focus being imaged by means of a secondary light optically focussing element onto a light entry aperture arranged in the light path of the secondary light to the detector, the detection of the secondary light thereby being concentrated on the region of focus,

wherein light reflected from a defined measuring depth below the interface is detected selectively as secondary light by means of a depth selection means, the defined measuring depth coinciding with the depth of focus, and wherein the measuring step comprises providing means for irradiating the primary light in a form of a short light pulse and the secondary light is measured within a defined time window, as the depth selection means.

18. A method as recited in claim 17, wherein at least two detection measurements are made with different light wavelengths.

19. A method as recited in claim 18, wherein in the evaluation step, a quotient of the measured values at the two different wavelengths is obtained, and the information on the presence of the analyte is determined on the basis of the quotient.

20. Apparatus for determining an analyte in a scattering matrix, said apparatus comprising:

a measuring head with a sample contact surface adapted to be placed against an interface of the scattering matrix,

light irradiating means with a light transmitter for irradiating primary light into the scattering matrix through the sample contact surface and the interface,

detection means with a detector for detecting secondary light leaving the scattering matrix through the interface and the sample contact surface and

evaluation means for deriving the information on the presence of the analyte in the matrix from the measuring signal of the detector,

in which the irradiation means and the detection means each comprise, an optically focussing element, a primary light optically focussing element of the irradiation means focusses the primary light onto a region of focus lying in the matrix at a depth of focus below the interface, and a secondary light optically focussing element of the detection means images the region of focus onto a light entry aperture arranged in the light path of the secondary light to the detector, whereby the detection of the secondary light is concentrated on the region of focus,

wherein an additional depth selection means is provided for selectively detecting light as secondary light reflected from a defined measuring depth, the measuring depth coinciding with the depth of focus, wherein said apparatus performs

a detection step wherein detection measurements are carried out in which light is irradiated through the interface as the primary light into the matrix, and the secondary light is detected by the detector leaving the matrix, to determine a measurable physical property of the light which is variable due to interaction of the light with the matrix as a measurement quantity, and

an evaluation step wherein information on presence of the analyte in the matrix is determined based upon a measured value of the measurement quantity measured in the detection step, with the primary light being focused by the primary light optically focussing element onto the region of focus lying in the matrix at the depth of focus below the interface, with the region of focus being imaged by the secondary light optical focussing element onto the light entry aperture arranged in the light path of the secondary light to the detector, with the detection of the secondary light being concentrated on the region of focus, and wherein the light reflected from the defined measuring depths below the interface is detected selectively as secondary light by the additional depth selection means, with the defined depth coinciding with the depth of focus.

21. Apparatus according to claim 20, wherein the diameter of the light entry aperture is less than 0.1 mm.

22. Apparatus according to claim 20, wherein both the irradiation means and the detection means comprise an array of optically focussing elements by means of which the primary light is focussed onto a plurality of regions of focus and the plurality of the regions of focus is imaged onto respective light entry apertures in front of a detector.

23. Apparatus according to claim 22, wherein the array of optically focussing elements is a microlens array.

24. Apparatus according to claim 22, wherein a plurality of detectors is integrated monolithically on a semiconductor chip.

25. Apparatus according to any one of claim 22, wherein a plurality of light transmitters is integrated monolithically on a semiconductor chip.

26. Apparatus according to claim 20, wherein the primary light optically focussing element and the secondary light optical focussing element comprise the same optically focussing element forming part both of the irradiation means and of the detection means, so that the optical axis of the primary light and the optical axis of the secondary light coincide between the optically focussing element and the region of focus, and on the side of the focussing element facing away from the matrix a beam splitter is disposed by means of which the secondary light is branched to the detector.

27. Apparatus according to claim 20, wherein the irradiation means and the detection means comprise separate optically focussing elements, wherein the optical axis, on which the primary light is irradiated into the matrix, and the optical axis, on which the secondary light is detected, are different.

28. Apparatus according to claim 20, wherein it includes as the depth selection means a low coherence reflectometric measuring device.

29. Apparatus according to claim 20, wherein it includes as the depth selection means a device for irradiating the primary light in the form of a short light pulse and for measuring the secondary light within a defined time window.