METHOD AND DEVICE FOR ANALYTE MEASUREMENT

Abstract

A device for non-invasively measuring concentration of one or more analytes in a living subject or a biological sample, wherein the device includes several light sources, a system for controlling the timing and intensity of the light source outputs, a system for passing the light through the subject or sample, a system for measuring the amount of light transmitted, and a system for relating the measurement to the concentration of the analyte in question. The light sources are narrow band sources at different wavelengths, and are capable of being rapidly switched between two levels of intensity. The actual number of light sources required and the wavelengths of the sources are dependent upon the specific analyte being measured.

Description

FIG. 1 is a block diagram according to an embodiment of the invention.

FIG. 2A illustrates one embodiment of a system for controlling the light levels for the light sources.

FIG. 2B illustrates an alternate embodiment of a system for controlling light levels for the light sources.

FIG. 3A illustrates one embodiment of a system for combining the several light beams and focusing them onto the sample under test.

FIG. 3B illustrates another embodiment of a system for combining and focusing the light beams.

FIG. 3C illustrates another view of the embodiment of the system in FIG. 3B.

FIG. 4A illustrates one embodiment of a system for focusing the light beam onto a detector.

FIG. 4B illustrates another embodiment of a system for focusing the light beam onto the detector.

FIG. 4C illustrates yet another embodiment of a system for focusing the light beam onto a detector.

FIG. 5A illustrates an embodiment of a system for digitizing the signal output from a detector.

FIG. 5B illustrates an alternate embodiment of a system for digitizing the signal output from a detector.

FIG. 5C illustrates another alternative embodiment of a system for digitizing the signal output from a detector.

FIG. 5D illustrates an embodiment of a system for measuring the temperature of light sources.

FIG. 6 illustrates absorption spectra for three different analytes.

FIG. 7 illustrates the relationships of the various software elements to an embodiment of the invention.

FIG. 8A illustrates the relationship between a calibration experiment and the modules involved in removing nuisance variation from data.

FIG. 8B illustrates the method of light source duplication for biological calibration.

FIG. 8C illustrates one embodiment of a prediction module for the internal temperatures of the light sources.

Claims

1. An apparatus for measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the apparatus comprising: a light generation module adapted to generate a plurality of light wavelength bands each band of a narrow wavelength;the light generation module adapted to switch each of the plurality of light wavelength bands between two or more predetermined intensities;a light combination module adapted to combine the plurality of light bands into a narrow beam;a focusing module adapted to direct the narrow beam onto the sample;a light detection module adapted to detect light from the apparatus having passed through or reflected from the sample;a measurement module adapted to measure the intensity of the light which has passed through or reflected from the sample; anda determination module adapted to determine the concentration of the target analyte based on the intensity of the light which has passed through or reflected from the sample.

2. The apparatus of claim 1, wherein the light generation module further comprises a plurality of light sources, each of the plurality of light sources adapted to generate one or more of the plurality of light bands.

3. The apparatus of claim 2, wherein the light generation module further comprises a light intensity control module adapted to control the average or instantaneous intensity of the plurality of light bands.

4. The apparatus of claim 3, wherein the light intensity control module is further adapted to control the intensity of each of the plurality of light bands.

5. The apparatus of claim 2, wherein the plurality of light bands further comprises at least two sets of light bands such that when the narrow beam passes through or is reflected from the sample, the difference between the average intensities of the two sets of light bands is a function of the concentration of the target analyte in the sample and is independent of the concentration of the alternate analytes in the sample.

6. The apparatus of claim 2, wherein the light generation module is further adapted to switch each of the plurality of light sources between the two predetermined intensities in a synchronous manner such that at any given time each of the plurality of light sources are at a same predetermined intensity level.

7. The apparatus of claim 1, wherein the determination module is further adapted to determine the concentration of the target analyte in a composition of analytes wherein the target analyte absorbs at least one of the plurality of light bands in a manner different than the alternate analytes.

8. The apparatus of claim 7, wherein the composition is at least one of (1) a living organism; (2) a material of biologic origin; and (3) an agricultural product.

9. The apparatus of claim 1, wherein the target analyte is glucose and wherein the sample is a part of a human body.

10. The apparatus of claim 1, wherein each of the plurality of light sources are at least one of a: (1) a light emitting diode (LED); (2) a laser generator; (3) a superluminescent diode; and (4) a thin film infrared generator.

11. The apparatus of claim 1, wherein each of the plurality of light sources further includes an optical bandpass filter.

12. The apparatus of claim 1, wherein the light combination module is a fiber optic assembly.

13. The apparatus of claim 1, wherein the focusing module is implemented by a non-imaging concentrator.

14. The apparatus of claim 2, wherein the light detection module is further adapted to generate an electrical signal proportional to the light passing through or reflected from the sample.

15. The apparatus of claim 14, wherein the measurement module is further adapted to identify and measure the electrical signal using the switching pattern used by the light generation module to switch each of the plurality of light sources between two or more predetermined intensities.

16. The apparatus of claim 2, wherein the light generation module is further adapted to monitor internal temperature of at least one of the plurality of light sources and to calibrate output of the plurality of light sources according to their internal temperatures.

17. An apparatus for measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the apparatus comprising: a light generation module adapted to generate a plurality of light wavelength bands each band of a narrow wavelength;wherein the light generation module further comprises a plurality of light sources, each of the plurality of light sources adapted to generate one or more of the plurality of light bands;wherein the light generation module is further adapted to monitor the internal temperature of at least one of the plurality of light sources using at least one of: (1) a thermocouple; (2) a thermistor; and (3) a voltage drop measurement apparatus adapted to measure voltage drop across a semiconductor junction of the at least one of the plurality of light sources; andwherein the light generation module is further adapted to calibrate output of the plurality of light sources according to their internal temperatures.

18. The apparatus of claim 17, further comprising: a light combination module adapted to combine the plurality of light bands into a narrow beam;a focusing module adapted to direct the narrow beam onto the sample;a light detection module adapted to detect light from the apparatus having passed through or reflected from the sample;a measurement module adapted to measure the intensity of the light which has passed through or reflected from the sample; anda determination module adapted to determine the concentration of the target analyte based on the intensity of the light which has passed through or reflected from the sample.

19. The apparatus of claim 18, wherein the light generation module further includes a temperature control module adapted to control the internal temperatures of at least one of the plurality of light sources using either a single heat reservoir thermal model or a multiple heat reservoir thermal model.

20. The apparatus of claim 18, wherein the light generation module adjusts input levels to each of the plurality of light sources in order to compensate for known changes in light output resulting from changes in temperature of the light sources.

21. The apparatus of claim 19, wherein the temperature control module is further adapted to at least one of (1) infer past internal temperatures over time of and (2) predict future temperatures of at least one of the plurality of light sources.

22. The apparatus of claim 21, wherein the temperature control module is further adapted to estimate the parameters of the thermal models using observations of the heating and cooling rates of the light sources as the internal temperatures are experimentally manipulated.

23. The apparatus of claim 21, wherein the temperature control module is further adapted to turn on the plurality of light sources in a manner so that each of the plurality of light sources reaches a target temperature simultaneously.

24. The apparatus of claim 23, further comprising a light stabilization module adapted to: divert a portion of the narrow beam before it passes through or is reflected from the sample;measure the strength of the diverted portion of the narrow beam; anduse the narrow beam strength measurement to stabilize light output of each of the plurality of light sources.

25. The apparatus of claim 24, wherein the light stabilization module is further adapted to stabilize the light output of each of the plurality of light sources using a thermoelectric cooler.

26. The apparatus of claim 24, wherein the light stabilization module is further adapted to stabilize the light output of each of the plurality of light sources by turning the plurality of light sources on and off for controlled periods wherein the controlled periods are calculated using a heating model of the plurality of light sources.

27. An apparatus for measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the apparatus comprising: a light generation module adapted to generate a plurality of light wavelength bands each band of a narrow wavelength;a light combination module adapted to combine the plurality of light bands into a narrow beam;a focusing module adapted to direct the narrow beam onto the sample;a light detection module adapted to detect light from the apparatus having passed through or reflected from the sample;a measurement module adapted to measure the intensity of the light which has passed through or reflected from the sample;a determination module adapted to determine the concentration of the target analyte based on the intensity of the light which has passed through or reflected from the sample;wherein the light generation module further comprises a plurality of light sources, each of the plurality of light sources adapted to generate one or more of the plurality of light bands;wherein one or more of the plurality of light sources generating a single light band are duplicated at different spatial locations within the light generation module; andwherein the determination module is further adapted to use the differences in light transmission between duplicated sources to correct measurements of the target analyte concentration.

28. The apparatus of claim 27, wherein the determination module is further adapted to: use multivariate analysis to estimate the effect of spatial distances between each of the plurality of light sources in the light generation module; andremove any resulting errors in measurement of the target analyte.

29. The apparatus of claim 28, wherein the multivariate analysis is at least one of: (1) principal component analysis; (2) multiple regression; (3) factor analysis; and (4) partial least square analysis.

30. The apparatus of claim 29, wherein: the plurality of light bands includes at least two sets of light bands such that when the narrow beam passes through the sample or is reflected from it, the difference between the average intensity of the two sets of light bands is a function of the concentration of the target analyte in the sample and is independent of the concentration of the alternate analytes in the sample;the measurement module is further adapted to determine the difference between the average intensity of the two sets of light bands; andthe determination module is further adapted to determine the concentration of the target analyte in the sample using the difference between the average intensity of the two light bands.

31. The apparatus of claim 30, wherein the sample is at least one of: (1) a living organism; (2) a material of biologic origin; and (3) an agricultural product.

32. The apparatus of claim 31, wherein the target analyte is glucose and wherein the sample is a part of a human body.

33. The apparatus of claim 4, wherein the determination module is further adapted to determine the intensity of each of the plurality of light bands emitted by the light generation module using mathematical techniques from the theory of orthogonal vectors to obtain a signal which is proportional to analyte concentration and insensitive to a plurality of alternate analytes and a plurality of other variables which cause unwanted variations; called noise signals.

34. The apparatus of claim 33, wherein the mathematical technique used by the determination module calculates the net analyte signal of Lorber.

35. The apparatus of claim 33, wherein the plurality of noise signals includes at least one of: (1) sample temperature; (2) instrument drift due to light source temperatures or aging of components (3) sample pH; (4) sample water content; (5) sample hemoglobin oxygenation; (6) sample's tissue optical properties; and (7) parameters of the optical coupling between the focusing module and the sample.

36. The apparatus of claim 35, wherein the determination module is further adapted to maximize the amplitude of difference between the light intensities of the plurality of light bands using a linear programming technique.

37. The apparatus of claim 36, wherein the determination module is further adapted to use the linear programming technique from the following: (1) a simplex technique; (2) a Karmarkar technique; (3) an ellipsoid technique; and (4) a related technique for optimizing a linear function with constraints, where 1-4 are applied after the theory of orthogonal vectors has been applied.

38. A method of measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the method comprising: generating a plurality of independently controlled light wavelength bands;switching the plurality of light bands between two or more predetermined waveband intensity distributions;combining the plurality of light bands into a narrow light beam;directing the narrow light beam onto the sample;detecting the light beam having passed through or reflected from the sample;measuring the intensity of the light beam which has passed through or reflected from the sample;determining the concentration of the target analyte based on the difference in the net intensity between two predetermined waveband intensity distributions in the light beam which has passed through or reflected from the sample; andcorrecting the analyte concentration measurement using light transmission data from one or more light sources which have been duplicated at different locations in space.

39. The method of claim 38, wherein generating a plurality of independently controlled light wavelength bands further comprises: monitoring the internal temperature of at least one of the plurality of light sources using at least one of: (1) a thermocouple; (2) a thermistor; and (3) a voltage drop measurement apparatus adapted to measure voltage drop across a semiconductor junction of the at least one of the plurality of light sources; andcalibrating output of the plurality of light sources according to their internal temperatures.

40. A method of measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the method comprising: generating a plurality of light wavelength bands;switching each of the plurality of light wavelength bands between two or more predetermined wavelength intensity distributions;combining the plurality of light bands into a narrow beam;directing the narrow beam onto the sample;detecting the narrow beam having passed through or reflected from the sample;measuring the intensity of the narrow beam which has passed through or reflected from the sample; anddetermining the concentration of the target analyte based on the intensity of the narrow beam which has passed through or reflected from the sample.

41. The method of claim 40, wherein generating a plurality of light wavelength bands further comprises generating the plurality of light wavelength bands using a plurality of light sources, each of the plurality of light sources adapted to generate one or more of the plurality of light bands.

42. The method of claim 41, further comprising controlling the average or instantaneous intensity of the plurality of light bands.

43. The method of claim 41, wherein generating the plurality of light bands further comprises generating at least two sets of light bands such that when the narrow beam passes through or is reflected from the sample, the difference between the average intensities of the two sets of light bands is a function of the concentration of the target analyte in the sample and is independent of the concentration of the alternate analytes in the sample.

44. The method of claim 41, wherein generating the plurality of light bands further comprises switching each of the plurality of light sources between the two or more predetermined wavelength intensity distributions in a synchronous manner such that at any given time each of the plurality of light sources are at a same predetermined intensity distribution.

45. The method of claim 44, wherein determining the concentration of the target analyte further comprises determining the concentration of the target analyte in a composition of analytes wherein the target analyte absorbs at least one of the plurality of light bands in a manner different than the alternate analytes.

46. The method of claim 41, wherein combining the plurality of light bands further comprises combining the plurality of light bands using a fiber optic assembly.

47. The method of claim 41, wherein detecting the narrowband light beam further comprises generating an electrical signal proportional to the light passing through or reflected from the sample.

48. The method of claim 47, wherein measuring the intensity of the narrow beam further comprises to integrating the electrical signal using a switching pattern used to switch each of the plurality of light sources between the two or more predetermined wavelength intensity distributions.

49. The method of claim 41, further comprising monitoring internal temperature of at least one of the plurality of light sources and calibrating output of the plurality of light sources according to their internal temperatures.

50. A method of measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the method comprising: generating a plurality of light wavelength bands each band of a narrow wavelength;switching each of the plurality of light wavelength bands between two or more predetermined wavelength intensity distributions;wherein generating a plurality of light wavelength bands further comprises generating a plurality of light bands using a plurality of light sources; andfurther comprising monitoring the internal temperature of at least one of the plurality of light sources using at least one of: (1) a thermocouple; (2) a thermistor; and (3) a voltage drop measurement apparatus adapted to measure voltage drop across a semiconductor junction of the at least one of the plurality of light sources; and calibrating output of the plurality of light sources according to their internal temperatures.

51. The method of claim 50, further comprising: combining the plurality of light bands into a narrow beam;directing the narrow beam onto the sample;detecting the narrow beam having passed through or reflected from the sample;measuring the intensity of the narrow beam which has passed through or reflected from the sample; anddetermining the concentration of the target analyte based on the intensity of the narrow beam which has passed through or reflected from the sample.

52. The method of claim 51, wherein generating the plurality of bands further comprises controlling the internal temperature of at least one of the plurality of light sources using either a single heat reservoir thermal model or a multiple hear reservoir thermal model.

53. The method of claim 51, wherein generating the plurality of bands further comprises adjusting the input levels to each of the plurality of light sources in order to compensate for known changes in light output resulting from changes in temperature of the light sources.

54. The method of claim 52, wherein controlling the internal temperature of at least one of the plurality of light sources further comprises estimating the parameters of the thermal models using observations of the heating and cooling rates of the light sources as the internal temperatures are experimentally manipulated.

55. The method of claim 52, wherein controlling the internal temperature of at least one of the plurality of light sources further comprises turning on the plurality of light sources in a manner so that each of the plurality of light sources reaches a target temperature simultaneously.

56. The method of claim 52, further comprising: diverting a portion of the narrow beam before it passes through or is reflected from the sample;measuring the strength of the diverted portion of the narrow beam; andusing the narrow beam strength measurement to stabilize light output of each of the plurality of light sources.

57. A method of measuring concentration of a target analyte in a sample containing a plurality of alternate analytes, the method comprising: generating a plurality of light wavelength bands;combining the plurality of light bands into a narrow beam;directing the narrow beam onto the sample;detecting the narrow beam having passed through or reflected from the sample;measuring the intensity of the narrow beam which has passed through or reflected from the sample;determining the concentration of the target analyte based on the intensity of the narrow beam which has passed through or reflected from the sample;wherein generating a plurality of light bands further comprises generating a plurality of light bands using a plurality of light sources, each of the plurality of light sources adapted to generate one or more of the plurality of light bands;wherein one or more of the plurality of light sources generating a single light band are duplicated at different spatial locations within the light generation module; andwherein determining the concentration of the target analyte further comprises using the differences in light transmission between duplicated sources to correct measurements of the target analyte concentration.

58. The method of claim 57, wherein determining the concentration of the target analyte further comprises: using multivariate analysis to estimate the effect of spatial distances between each of the plurality of light sources in the light generation module; andremoving any resulting errors in measurement of the target analyte.

59. The method of claim 57, wherein the multivariate analysis is at least one of: (1) principal component analysis; (2) multiple regression; (3) factor analysis; and (4) partial least square analysis.

60. The method of claim 59, wherein: generating the plurality of light bands further comprises generating at least two sets of light bands such that when the narrow beam passes through the sample or is reflected from it, the difference between the average intensity of the two sets of light bands is a function of the concentration of the target analyte in the sample and is independent of the concentration of the alternate analytes in the sample;measuring the intensity of the narrow beam further comprises determining the difference between the average intensity of the two sets of light bands; anddetermining the concentration of the target analyte further comprises determining the concentration of the target analyte in the sample using the difference between the average intensity of the two light bands.

61. The method of claim 60, wherein the target analyte is glucose and wherein the sample is part of a human body.

62. The method of claim 57, wherein determining the concentration of the target analyte further comprises determining the intensity of each of the plurality of light bands emitted by the light generation module using mathematical techniques from the theory of orthogonal vectors to obtain a signal which is proportional to analyte concentration and insensitive to a plurality of alternate analytes and a plurality of other variables which cause unwanted variations; called noise signals.

63. The method of claim 62, wherein determining the concentration of the target analyte further comprises maximizing the amplitude of difference between the light intensities of the plurality of light bands using a linear programming technique.