Portable raman diagnostic system

• US 9,662,047 B2
• Filed: 06/23/2011
• Issued: 05/30/2017
• Est. Priority Date: 08/05/2010
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Feld, Michael, Barman, Ishan, Dasari, Ramachandra, Kong, Chae-Ryon, Kang, Jeon Woong, Dingari, Narahara Chari
• Primary Examiner(s): Winakur, Eric
• Assistant Examiner(s): Liu, Chu (JJ) Chuan
• Application Number:
  US13/167,445
• Publication Number:
  US 20120035442A1
• Time in Patent Office: 2,168 Days
• Field of Search: 600310, 600316, 600322, 600323, 600324, 600326, 600331, 600340, 600473, 600476
• CPC Class Codes: A61B 2560/0223 of calibration, e.g. protocols for calibrating sensors
• 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: A61B 5/4312 Breast evaluation or disorder diagnosis A61B5/0091 takes precedence
• CPC Class Codes: A61B 5/444 Evaluating skin marks, e.g. mole, nevi, tumour, scar
• CPC Class Codes: G01J 3/0208 using focussing or collimating elements, e.g. lenses or mirrors; performing aberration correction
• 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 3/0272 Handheld
• CPC Class Codes: G01J 3/44 Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
• CPC Class Codes: G01N 21/65 Raman scattering
• CPC Class Codes: G01N 2201/129 Using chemometrical methods
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention further relates to the selection of the specific filter combinations, which can provide sufficient information for multivariate calibration to extract accurate analyte concentrations in complex biological systems. The present invention also describes wavelength interval selection methods that give rise to the miniaturized designs. Finally, this invention presents a plurality of wavelength selection methods and miniaturized spectroscopic apparatus designs and the necessary tools to map from one domain (wavelength selection) to the other (design parameters). Such selection of informative spectral bands has a broad scope in miniaturizing any clinical diagnostic instruments which employ Raman spectroscopy in particular and other spectroscopic techniques in general.

Claims

1. A method for measuring glucose concentration in a patient comprising:

illuminating a region of tissue with light including a plurality of sequential illumination wavelengths;

detecting Raman shifted light from the tissue with a detector in response to the plurality of sequential illumination wavelengths of light;

determining, with a data processor, a subset of the sequential illumination wavelengths using error minimization to define a plurality of separated spectral illumination bands, each spectral illumination band including a plurality of different illumination wavelengths, the determining step including processing the detected Raman shifted light to determine the illumination wavelengths of the plurality of separated spectral illumination bands;

subsequently, illuminating a region of tissue in the patient, the region of tissue having a glucose concentration to be measured, with illuminating light having the plurality of different illumination wavelengths within each of the plurality of separated spectral illumination bands;

detecting light from the tissue with the detector in response to the plurality of separated spectral illumination bands of light, the detector generating Raman spectral data; and

analyzing the Raman spectral data with the data processor to determine a concentration of glucose in the region of tissue in the patient.

2. The method of claim 1 further comprising illuminating the tissue with a fiber optic probe having an optical concentrator.

3. The method of claim 2 wherein the optical concentrator comprises a compound parabolic concentrator.

4. The method of claim 2 wherein the optical concentrator comprise a compound hyperbolic concentrator.

5. The method of claim 1 further comprising illuminating the region of tissue with a fiber optic probe having a light delivery fiber and a plurality of light collection optical fibers, the light delivery fiber having a first light filter and the plurality of light collection optical fibers having a second filter.

6. The method of claim 1 further comprising using a light source that emits illuminating light that illuminates the region of tissue with the plurality of separated bands having at least 300 spectral points and less than 900 spectral points.

7. The method of claim 1 further comprising using a illumination light filter that defines the separated spectral illumination bands.

8. The method of claim 1 wherein the determining steps further comprises processing spectral data to select the plurality of illumination bands.

9. The method of claim 8 wherein the processing step comprises using a nonlinear representation of spectral data to select the plurality of Raman spectral regions.

10. The method of claim 8 wherein the nonlinear representation comprises support vector regression.

11. The method of claim 8 further comprising forming a regression vector to determine glucose concentration.

12. The method of claim 9 wherein the step of using a non-linear representation comprises a physiological lag component of a glucose concentration measurement.

13. The method of claim 9 wherein the step of using a non-linear representation comprises a tissue turbidity component.

14. The method of claim 1 further comprising detecting the plurality of Raman spectral regions with a single photodetector.

15. The method of claim 1 wherein the plurality of sequential illumination wavelengths comprises a moving window of illumination wavelengths that sequentially illuminates the region of tissue over an infrared spectral range.

16. The method of claim 1 wherein the determining step further comprises determining an error value for each of a plurality of spectral points and selecting the plurality of separated spectral illumination bands from the error values.

17. A portable device for measuring glucose within a body comprising:

a handheld glucose measurement device including;

a light source system in the device that illuminates a region of tissue with a plurality of separated wavelength bands with at least 300 spectral points of illumination;

an optical system in the device that delivers and collects light from the region of tissue in response to the illuminating light;

a detector in the device that detects a plurality of separated spectral regions of Raman shifted a light collected by the optical system in response to each of the at least 300 spectral points of illumination, the detector generating Raman spectral data;

a data processor in the device, the data processor being connected to the detector, the data processor being configured to process the Raman spectral data using a calculated error value to select a subset of the at least 300 spectral points of illumination and process the Raman spectral data associated with the selected subset of spectral points to determine a glucose level within the region of tissue.

18. The device of claim 17 wherein the light source system comprises a tunable laser.

19. The device of claim 17 wherein the light source system further comprises an acousto optic modulator to control the wavelength of illuminating light.

20. The device of claim 17 further comprising a phase modulator.

21. The device of claim 17 wherein the detector comprises a photodetector.

22. The device of claim 17 further comprises the data processor processes Raman spectral data to determine an increase or decrease in glucose concentration.

23. The device of claim 22 wherein the processor is programmed to apply a non-linear representation to the data.

24. The device of claim 23 wherein the representation comprises support vector regression.

25. The device of claim 17 wherein the detector comprises a tunable filter.

26. The device of claim 17 further comprising a compound optical concentrator coupled to a fiber optic device.

27. The device of claim 17 further comprising a control circuit connected to the light source system to control a sequence of illuminating wavelengths of light within the separated wavelength bands.

28. The device of claim 17 further comprising an adjustable filter that filters light incident on the detector having a wavelength outside of a separated spectral region at a selected time.

29. The device of claim 17 wherein the calculated error comprises a root mean squared error value at each spectral point.

30. A handheld Raman diagnostic device comprising:

a handheld unit having a laser light source system, a data processor and a detector system, the laser light source system configured to emit light at a plurality of different illumination wavelengths wherein the detector system detects Raman scattered light from a region of interest in a portion of tissue of a patient and wherein the device operates the laser light source to emit a plurality of illumination spectral bands, each spectral band having a plurality of separated illumination wavelengths that are optically coupled to the region of interest, the detector system configured to detect Raman light from the region of interest and to generate Raman spectral data at a plurality of Raman shifted wavelengths in response to each of the plurality of separated Illumination wavelengths in the plurality of illumination spectral bands wherein the data processor is configured to select, using error minimization, the plurality of illumination spectral bands from the plurality of different illumination wavelengths and to process the Raman spectral data to determine a glucose level in the region of interest.

31. The device of claim 30 further comprising a filter device that filters light from the region of interest to transmit selected Raman spectral detection bands.

32. The device of claim 30 further comprising a fiber optical probe connected to the handheld unit.

33. The device of claim 30 further comprising a control circuit connected to the light source system to control sequential transmission of illuminating light at the plurality of separated spectral bands with at least 300 spectral points of illumination.

34. The device of claim 30 wherein the device has a weight of less than 10 pounds and the processor is programmed to control actuation of the light source system in combination with control of the detector system.

35. The device of claim 30 further comprising a compound parabolic concentrator.

36. The device of claim 30 further comprising a compound of hyperbolic concentrator.

37. The device of claim 30 further comprising an acousto-optic tunable filter.

38. The device of claim 30 wherein the processor is programmed to compute a regression vector to determine glucose concentration.

39. The device of claim 30 further comprising a filter device that filters light incident on the detector.

40. The device of claim 30 wherein the detector system comprises a photodiode.

41. The device of claim 30 wherein the light source system comprises a diode laser.

42. The device of claim 30 wherein the device comprises a body worn device.

43. The device of claim 30 wherein the each spectral band that illuminates the region of interest comprises at least a full width at half maximum of 4 cm⁻

1.