System for non-invasive measurement of glucose in humans

• US 6,574,490 B2
• Filed: 04/11/2001
• Issued: 06/03/2003
• Est. Priority Date: 04/11/2001
• Status: Expired due to Term

• Current Assignee: Rio Grande Medical Technologies Incorporated
• Original Assignee: Rio Grande Medical Technologies Incorporated
• Inventors: Maynard, John D., Johnson, Robert D., Abbink, Russell E.
• Primary Examiner(s): Walberg, Teresa
• Assistant Examiner(s): FUQUA, SHAWNTINA T
• Application Number:
  US09/832,585
• Publication Number:
  US 20030023152A1
• Time in Patent Office: 783 Days
• Field of Search: 600/310, 600/314-316, 600/322-328, 600/339, 600/341, 600/473, 600/476, 600/478, 356/39-41
• US Class Current: 600/316
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• 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: G01J 3/02 Details
• CPC Class Codes: G01J 3/0216 using light concentrators or collectors or condensers
• CPC Class Codes: G01J 3/0218 using optical fibers
• CPC Class Codes: G01J 3/10 Arrangements of light sources specially adapted for spectrometry or colorimetry

Abstract

An apparatus and method for non-invasive measurement of glucose in human tissue by quantitative infrared spectroscopy to clinically relevant levels of precision and accuracy. The system includes six subsystems optimized to contend with the complexities of the tissue spectrum, high signal-to-noise ratio and photometric accuracy requirements, tissue sampling errors, calibration maintenance problems, and calibration transfer problems. The six subsystems include an illumination subsystem, a tissue sampling subsystem, a calibration maintenance subsystem, an FTIR spectrometer subsystem, a data acquisition subsystem, and a computing subsystem.

Claims

1. An apparatus for non-invasive measurement of glucose in human tissue by quantitative near infrared spectroscopy comprising:

an illumination subsystem which generates near infrared light;

a tissue sampling subsystem optically coupled to said illumination subsystem which receives at least a portion of said infrared light, said tissue sampling subsystem including means for irradiating human tissue with at least a portion of said received infrared light and collecting at least a portion of said light diffusely reflected from said human tissue;

a calibration maintenance subsystem selectively optically coupled to said tissue sampling subsystem for receiving at least a portion of said infrared light and diffusely reflecting a portion thereof;

an FTIR spectrometer subsystem selectively optically coupled to said tissue sampling subsystem to receive at least a portion of said light diffusely reflected from said tissue or selectively optically coupled to said calibration maintenance subsystem to receive at least a portion of said infrared light diffusely reflected therefrom, said FTIR spectrometer subsystem including a spectrometer that creates an interferogram, said FTIR spectrometer subsystem further including a detector which receives the interferogram and converts said interferogram to an electrical representation;

a data acquisition subsystem which receives the electrical representation of the interferogram, said data acquisition subsystem including means for amplifying and filtering said electrical representation and converting a resulting electrical signal to its digital representation; and

a computing subsystem for receiving said digital representation and further including means for determining glucose concentration in human tissue from said digital representation, wherein in combination said subsystems provide a clinically relevant level of glucose measurement precision and accuracy.

2. The apparatus of claim 1, wherein said apparatus provides a clinically relevant level of glucose measurement precision and accuracy, including 80% or more predictions on a single subject within a physiological range of glucose falling in the “

A”

region of a Clark Error Grid when compared to a reference measurement.

3. The apparatus of claim 1, wherein said calibration maintenance subsystem comprises a reference sample which receives a portion of said infrared light and reflects a portion thereof and produces a spectrum similar to a representative human tissue sample.

4. The apparatus of claim 3, wherein the representative human tissue sample includes multiple samples from multiple subjects.

5. The apparatus of claim 4, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 30 or less over a spectral range of 4,200 cm⁻

1 to 7,200 cm<sup>−

1</sup>.

6. The apparatus of claim 4, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 30 or less using discrete wavelengths, in wavenumbers (cm⁻

1) selected from the group consisting of;

4196, 4227, 4273, 4281, 4304, 4320, 4335, 4366, 4389, 4436, 4451, 4459, 4497, 4528, 4559, 4613, 4690, 4775, 4829, 4860, 4883, 4922, 5014, 5091, 5176, 5230, 5269, 5299, 5315, 5338, 5369, 5392, 5454, 5469, 5477, 5515, 5585, 5623, 5662, 5701, 5731, 5755, 5785, 5809, 5839, 5893, 5924, 5947, 6001, 6094, 6163, 6187, 6287, 6318, 6349, 6449, 6472, 6557, 6595, 6673, 6696, 6935, 6973, 7004, 7043, 7066, 7205, and combinations thereof.

7. The apparatus of claim 4, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 30 or less over a spectral range of 4,440 cm⁻

1 to 4,800 cm<sup>−

1</sup> and 5,440 cm<sup>−

1</sup> to 6,400 cm<sup>−

1</sup>.

8. The apparatus of claim 4, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue spectra, of 30 or less over a spectral range of 4,200 cm⁻

1 to 7,200 cm<sup>−

1</sup>.

9. The apparatus of claim 4, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue spectra, of 30 or less using discrete wavelengths, in wavenumbers (cm⁻

1) selected from the group consisting of;

4196, 4227, 4273, 4281, 4304, 4320, 4335, 4366, 4389, 4436, 4451, 4459, 4497, 4528, 4559, 4613, 4690, 4775, 4829, 4860, 4883, 4922, 5014, 5091, 5176, 5230, 5269, 5299, 5315, 5338, 5369, 5392, 5454, 5469, 5477, 5515, 5585, 5623, 5662, 5701, 5731, 5755, 5785, 5809, 5839, 5893, 5924, 5947, 6001, 6094, 6163, 6187, 6287, 6318, 6349, 6449, 6472, 6557, 6595, 6673, 6696, 6935, 6973, 7004, 7043, 7066, 7205, and combinations thereof.

10. The apparatus of claim 4, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue sample spectra, of 30 or less over a spectral range of 4,440 cm⁻

1 to 4,800 cm<sup>−

1</sup> and 5,440 cm<sup>−

1</sup> to 6,400 cm<sup>−

1</sup>.

11. The apparatus of claim 3, wherein the representative human tissue sample is from a single subject.

12. The apparatus of claim 11, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 1500 or less over a spectral range of 4,200 cm⁻

1 to 7,200 cm<sup>−

1</sup>.

13. The apparatus of claim 8, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 1500 or less using discrete wavelengths, in wavenumbers (cm⁻

1) selected from the group consisting of;

4196, 4227, 4273, 4281, 4304, 4320, 4335, 4366, 4389, 4436, 4451, 4459, 4497, 4528, 4559, 4613, 4690, 4775, 4829, 4860, 4883, 4922, 5014, 5091, 5176, 5230, 5269, 5299, 5315, 5338, 5369, 5392, 5454, 5469, 5477, 5515, 5585, 5623, 5662, 5701, 5731, 5755, 5785, 5809, 5839, 5893, 5924, 5947, 6001, 6094, 6163, 6187, 6287, 6318, 6349, 6449, 6472, 6557, 6595, 6673, 6696, 6935, 6973, 7004, 7043, 7066, 7205, and combinations thereof.

14. The apparatus of claim 11, wherein the reference sample has a spectral similarity ratio, when compared with the representative human tissue sample spectra, of 7500 or less over a spectral range of 4,440 cm⁻

1 to 4,800 cm<sup>−

1</sup> and 5,440 cm<sup>−

1</sup> to 6,400 cm<sup>−

1</sup>.

15. The apparatus of claim 11, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue sample spectra, of 4500 or less over a spectral range of 4,200 cm⁻

1 to 7,200 cm<sup>−

1</sup>.

16. The apparatus of claim 11, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue sample spectra, of 3000 or less using discrete wavelengths, in wavenumbers (cm⁻

1) selected from the group consisting of;

4196, 4227, 4273, 4281, 4304, 4320, 4335, 4366, 4389, 4436, 4451, 4459, 4497, 4528, 4559, 4613, 4690, 4775, 4829, 4860, 4883, 4922, 5014, 5091, 5176, 5230, 5269, 5299, 5315, 5338, 5369, 5392, 5454, 5469, 5477, 5515, 5585, 5623, 5662, 5701, 5731, 5755, 5785, 5809, 5839, 5893, 5924, 5947, 6001, 6094, 6163, 6187, 6287, 6318, 6349, 6449, 6472, 6557, 6595, 6673, 6696, 6935, 6973, 7004, 7043, 7066, 7205, and combinations thereof.

17. The apparatus of claim 11, wherein the reference sample has a regression weighted spectral similarity ratio, when compared to the representative human tissue sample spectra, of 9000 or less over a spectral range of 4,440 cm⁻

1 to 4,800 cm<sup>−

1</sup> and 5,440 cm<sup>−

1</sup> to 6,400 cm<sup>−

1</sup>.

18. The apparatus of claim 3, wherein the reference sample has a spatial similarity, expressed in terms of standard deviation, of 0.079 or less.

19. The apparatus of claim 3, wherein the reference sample has an angular similarity, expressed in terms of standard deviation, of 0.051 or less.

20. An apparatus for non-invasive measurement of glucose in human tissue by quantitative near infrared spectroscopy comprising:

an illumination subsystem which generates near infrared light, said illumination subsystem including a light homogenizer positioned to receive at least a portion of said infrared light;

a tissue sampling subsystem optically coupled to said illumination subsystem which receives at least a portion of said infrared light exiting said light homogenizer, said tissue sampling subsystem including means for irradiating human tissue with at least a portion of said received infrared light and collecting at least a portion of said light diffusely reflected from human tissue;

an FTIR spectrometer subsystem selectively optically coupled to said tissue sampling subsystem to receive at least a portion of said light diffusely reflected from said tissue, said FTIR spectrometer subsystem including a spectrometer that creates an interferogram, said FTIR spectrometer subsystem further including a detector which receives the interferogram and converts said interferogram to an electrical representation;

a data acquisition subsystem which receives the electrical representation of the interferogram, said data acquisition subsystem including means for amplifying and filtering said electrical representation and converting a resulting electrical signal to its digital representation; and

a computing subsystem for receiving said digital representation and further including means for determining glucose concentration in human tissue from said digital representation, wherein in combination said subsystems provide a clinically relevant level of glucose prediction precision and accuracy.

21. The apparatus of claim 20, wherein said apparatus provides a clinically relevant level of glucose measurement precision and accuracy, including 80% or more predictions on a single subject within a physiological range of glucose falling in the “

A”

region of a Clark Error Grid when compared to a reference measurement.

22. The apparatus of claim 20, wherein said light homogenizer comprises a light pipe.

23. The apparatus of claim 22, wherein said light pipe has a polygonal cross section.

24. The apparatus of claim 20, wherein said light pipe includes one or more bends to achieve angular homogenization.

25. The apparatus of claim 20, wherein angular homogenization is achieved, at least in part by passing the radiation through a glass diffuser.

26. The apparatus of claim 22, wherein said light pipe includes a diffusely reflective coating on the interior surface thereof.

27. The apparatus of claim 20, wherein said illumination subsystem further comprises a filament which generates said light and said light homogenizer sufficiently homogenizes said light so that light which contacts the human tissue has a spatial and angular distribution which is repeatable through a one-millimeter vertical translation of the filament resulting in a standard deviation of less than 0.053 in spatial distribution and a standard deviation of less than 0.044 in angular distribution.

28. The apparatus of claim 20, wherein said illumination subsystem further comprises a light source including a filament generating said light, wherein the light contacting the human tissue has a spatial and angular distribution which is repeatable through a one-millimeter rotational translation of the filament resulting in a standard deviation of less than 0.050 in spatial distribution and a standard deviation of less than 0.066 in angular distribution.

29. The apparatus of claim 20, wherein the illumination subsystem includes a light source and the light homogenizer produces sufficient angular and spatial homogenization so that the inverse multivariate signal-to-noise value is about 60 or less when the light source is changed in the illumination subsystem.

30. The apparatus of claim 20, wherein the illumination subsystem includes a light source that comprise a tungsten-halogen lamp.

31. The apparatus of claim 20, wherein said light generated by said illumination subsystem possesses a band of wavelengths within the infrared regions of the electromagnetic spectrum.

32. The apparatus of claim 31, wherein the illumination subsystem further comprises means for concentrating the radiation emitted by the radiation source emitter.

33. The apparatus of claim 20, wherein the sampling subsystem comprises means for channeling at least a portion of the light exiting the light homogenizer to the human tissue.

34. The apparatus of claim 33, wherein the channeling means is at least one fiber optic wire.

35. The apparatus of claim 33, wherein the channeling means is at least one mirror.

36. The apparatus of claim 33, wherein the channeling means is at least one optic lens.

37. An apparatus for non-invasive measurement of glucose in human tissue by quantitative near infrared spectroscopy comprising:

an illumination subsystem which generates near infrared light including means for angularly and spatially homogenizing at least a portion of said light;

a tissue sampling subsystem optically coupled to said illumination subsystem which receives at least a portion of said infrared light, said tissue sampling subsystem including means for irradiating human tissue with at least a portion of said received infrared light and collecting at least a portion of said light diffusely reflected from said human tissue, said tissue sampling subsystem including at least one input element which transfers said light to said human tissue and at least one output element which receives light from said tissue, wherein said input element and said output element are spaced apart by a gap of about 100 μ

m or greater;

a calibration maintenance subsystem selectively optically coupled to said tissue sampling subsystem for receiving at least a portion of said infrared light and diffusely reflecting a portion thereof, said calibration maintenance subsystem including a reference sample having optical properties similar to a representative human tissue sample;

an FTIR spectrometer subsystem selectively optically coupled to said tissue sampling subsystem to receive at least a portion of said light diffusely reflected from said tissue or selectively optically coupled to said calibration maintenance subsystem to receive at least a portion of said infrared light diffusely reflected therefrom, said FTIR spectrometer subsystem including a spectrometer that creates an interferogram, said FTIR spectrometer subsystem further including a detector which receives the interferogram and converts said interferogram to an electrical representation, said detector that is sensitive to light in the 1.2 to 2.5 μ

m region of the spectrum;

a data acquisition subsystem with a minimum SNR of 100 dbc which receives the electrical representation of the interferogram, said data acquisition subsystem including means for amplifying and filtering said electrical representation and an analog-to-digital converter for converting the resulting electrical signal to its digital representation; and

a computing subsystem for receiving said digital representation and further including means for determining glucose concentration in human tissue from said digital representation, wherein in combination said subsystems provide a clinically relevant level of precision and accuracy.

38. The apparatus of claim 37, wherein said apparatus provides a clinically relevant level of glucose measurement precision and accuracy, including 80% or more predictions on a single subject within a physiological range of glucose falling in the “

A”

region of a Clark Error Grid when compared to a reference measurement.

39. The apparatus of claim 37, wherein said detector is a thermo-electrically cooled, extended range InGaAs detector that is sensitive to light in the 1.2 to 2.5 μ

m region of the spectrum.33.

40. The apparatus of claim 37, wherein said input element and said output element comprise, at least in part, optical fibers.

41. The apparatus of claim 40, wherein said optical fibers have ends potted into a cluster ferrule which is mounted in said sampling head.

42. The apparatus of claim 37, wherein said cradle includes a base having an opening therethrough in which said sample head is disposed.

43. The apparatus of claim 42, wherein said means for positioning human tissue relative to said sampling surface comprises a bracket extending upward from said base which references an elbow of a subject'"'"'s arm disposed thereon.

44. The apparatus of claim 43, wherein said cradle further includes an adjustable hand rest spaced longitudinally from said bracket along said base.

45. The apparatus of claim 44, further including means for raising and lowering said cradle to form and reform the tissue interface.

46. The apparatus of claim 37, wherein the input element surface area is at least seven times greater than the output element surface area.

47. An apparatus for non-invasive measurement of glucose in human tissue by quantitative near-infrared spectroscopy comprising:

an illumination subsystem which generates near-infrared light;

a tissue sampling subsystem optically coupled to said illumination subsystem which receives at least a portion of said infrared light generated by said illumination subsystem, said tissue sampling subsystem including means for irradiating human tissue with at least a portion of said received infrared light and collecting at least a portion of said light diffusely reflected from human tissue, said means for irradiating human tissue including at least one input element which transfers said light to said human tissue and at least one output element which receives light from said tissue;

an FTIR spectrometer subsystem selectively optically coupled to said tissue sampling subsystem to receive at least a portion of said light diffusely reflected from said tissue, said FTIR spectrometer subsystem including a spectrometer that creates an interferogram, said FTIR spectrometer subsystem further including a detector which receives the interferogram and converts said interferogram to an electrical representation, said detector that is sensitive to light in the 1.2 to 2.5 μ

m region of the spectrum;

a data acquisition subsystem which receives the electrical representation of the interferogram, said data acquisition subsystem including means for amplifying and filtering said electrical representation and converting a resulting electrical signal to its digital representation; and

a computing subsystem for receiving said digital representation and further including means for determining glucose concentration in human tissue from said digital representation, wherein in combination said subsystems provide a clinically relevant level of precision and accuracy.

48. The apparatus of claim 47, wherein said detector is a thermo-electrically cooled, extended range InGaAs detector that is sensitive to light in the 1.2 to 2.5 μ

m region of the spectrum.

49. The apparatus of claim 47, wherein said apparatus provides a clinically relevant level of glucose measurement precision and accuracy, including 80% or more predictions on a single subject within a physiological range of glucose falling in the “

A”

region of a Clark Error Grid when compared to a reference method.

50. An apparatus for non-invasive measurement of glucose in human tissue by quantitative near-infrared spectroscopy comprising:

an illumination subsystem which generates near-infrared light;

a tissue sampling subsystem optically coupled to said illumination subsystem which receives at least a portion of said infrared light generated by said illumination subsystem, said tissue sampling subsystem including means for irradiating human tissue with at least a portion of said received infrared light and collecting at least a portion of said light diffusely reflected from human tissue, said means for irradiating human tissue including at least one input element which transfers said light to said human tissue and at least one output element which receives light from said tissue;

an FTIR spectrometer subsystem selectively optically coupled to said tissue sampling subsystem to receive at least a portion of said light diffusely reflected from said tissue, said FTIR spectrometer subsystem including a spectrometer that creates an interferogram, said FTIR spectrometer subsystem further including a detector which receives the interferogram and converts said interferogram to an electrical representation;

a data acquisition subsystem with a minimum SNR of 100 dbc which receives the electrical representation of the interferogram, said data acquisition subsystem including means for amplifying and filtering said electrical representation and converting a resulting electrical signal to its digital representation and an analog-to-digital converter for converting a resulting electrical signal to its digital representation; and

a computing subsystem for receiving said digital representation and further including means for determining glucose concentration in human tissue from said digital representation, wherein in combination said subsystems provide a clinically relevant level of precision and accuracy.