Method and device for detecting substances in body fluids by raman spectroscopy

• US 20030176777A1
• Filed: 05/12/2003
• Published: 09/18/2003
• Est. Priority Date: 05/31/2000
• Status: Active Grant

• Current Assignee: Klaus Muller- Dethlefs
• Original Assignee: Klaus Muller- Dethlefs
• Inventors: Muller- Dethlefs, Klaus
• Granted Patent: US 6,868,285 B2
• Time in Patent Office: Days
• US Class Current: 600/322
• 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 21/65 Raman scattering

Abstract

The invention relates to a method and to a device for the non-invasive detection or determination, by Raman spectroscopy, of the concentration of substances in body fluids. The aim of the invention is to facilitate a non-invasive in vivo detection of substances in body fluids that allows for very accurate, reproducible results of analysis while requiring only little time for measuring which is acceptable for the patient. To this end, the inventive method and device for carrying out a Raman spectroscopy of a body fluid in a body tissue (1) records at least two Raman spectrums under different physical conditions and compares them with each other. The result of comparison allows detection of the substance one is looking for and measurement of the concentration of said substance.

Claims

1. A method for the non-invasive determination of a concentration of a substance in a body fluid in a body tissue by Raman spectroscopy comprising the following steps:

a) irradiating monochromatic primary light of a first wavelength into the body tissue,

b) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a first memory according to its wavelength as a first Raman spectral signal for the first primary wavelength,

c) irradiating monochromatic primary light of a second wavelength into the body tissue,

d) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a second memory according to its wavelength as a second Raman spectral signal for the second primary wavelength,

e) comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and generating a compare signal in which spectral structures caused by the body tissue are substantially eliminated,

f) determining an intensity of the compare signal at at least one sample wavelength for which the intensity corresponds to the concentration of the substance in the body fluid.

4. The method according to claim 1 or 3, wherein the primary light of the first and/or second wavelength is irradiated with a preset irradiation frequency and the first and second Raman spectral signals are recorded with the irradiation frequency.

5. The method according to claim 4, wherein the irradiation frequency is in the range of some kHz.

8. The method according to any of the preceding claims, wherein the primary light of the first and/or second wavelength is pulsed with a pulse length in the order of a picosecond.

9. The method according to claim 8, wherein the primary light is generated by a laser.

10. The method according to any of the preceding claims, wherein the secondary light is recorded in the Stokes- and/or in the anti-Stokes region of the Raman-spectrum.

11. The method according to any of the preceding claims, wherein the wavelength of the primary light is in the range between 750 nm and 850 nm.

12. The method according to any of the preceding claims, wherein the modulus of the difference of the primary light wavelength and the sample wavelength is less than 2000 cm⁻

1.

13. The method according to any of the preceding claims, wherein the modulus of the difference of the primary light wavelength and the sample wavelength is greater than 20 cm⁻

1.

14. The method according to any of the preceding claims, wherein at least one notch-filter is used for eliminating Rayleigh scattering.

15. The method according to claim 1 or 2, wherein an excitation light wavelength is irradiated into the body tissue substantially at the same time as the primary light that is absorbed by the sought after substance.

16. The method according to any of the preceding claims, wherein the excitation wavelength is in the range between 1.2 μ

m and 3 μ

m.

17. The method according to any of the preceding claims, wherein for calibrating the concentration analysis of the sought after substance the intensity of the first compare signal at the at least one sample wavelength is compared to an intensity of the first and/or second Raman spectral signal at another sample wavelength.

2. A method for non-invasive determination of a concentration of a substance in a body tissue by Raman spectroscopy comprising the following steps:

a) irradiating monochromatic primary light of a given wavelength into the body tissue at a first temperature of the body tissue,

b) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a first memory according to its wavelength as a first Raman spectral signal for the first temperature,

c) irradiating monochromatic primary light of a given wavelength into the body tissue at a second temperature of the body tissue,

d) recording secondary light that is back scattered from the body tissue and storing the intensity of the secondary light in a second memory according to its wavelength as a second Raman spectral signal for the second temperature,

e) comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

f) determining an intensity of the compare signal at at least one sample wavelength for which the intensity corresponds to the concentration of the substance in the body fluid.

6. The method according to claim 2 or 3, wherein the first and the second temperature of the body tissue is adjusted with a preset temperature variation frequency.

7. The method according to claim 6, wherein the temperature variation frequency is the heart rate.

3. A method for non-invasive determination of a concentration of a substance in a body tissue by Raman spectroscopy comprising the following steps:

a) irradiating monochromatic primary light of a first wavelength into the body tissue at a first temperature of the body tissue,

b) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a first memory according to its wavelength as a first Raman spectral signal for the first wavelength and for the first temperature,

c) irradiating monochromatic primary light of a second wavelength into the body tissue at a first temperature of the body tissue,

d) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a second memory according to its wavelength as a second Raman spectral signal for the second wavelength and for the first temperature,

e) comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

f) determining an intensity of the compare signal at at least one sample wavelength,

g) repeating steps a) to f) for a second temperature and generating a second compare signal at at least one sample wavelength for which the intensity of the secondary light for the first and second wavelength are stored in a third and a fourth memory, respectively, and a second compare signal is generated,

h) comparing the first and the second compare signal and, depending of the result of this comparison, generating an identification signal at at least one sample wavelength.

18. A device for the non-invasive determination of a concentration of a substance in a body fluid in a body tissue by Raman spectroscopy comprising:

a) a first light source for irradiating monochromatic primary light of a first wavelength into the body tissue,

b) a photo detector means for recording secondary light that is backscattered from the body tissue,

c) a first memory for storing the intensity of the secondary light according to its wavelength as a first Raman spectral signal for the first wavelength,

d) a second light source for irradiating monochromatic primary light of a second wavelength into the body tissue,

e) a second memory for storing the intensity of the secondary light according to its wavelength as a second Raman spectral signal for the second wavelength,

f) a comparator means for comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and for generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

g) a discriminator unit for determining an intensity of the compare signal at at least one sample wavelength for which the intensity corresponds to the concentration of the substance in the body fluid.

21. The device according to claim 18 or 20, wherein the first and/or second light source, the photo-detector means and the first and third, respectively, and/or second and fourth memory, respectively, is/are pulsed with a preset irradiation frequency.

22. The method according to claim 21, wherein the irradiation frequency is in the range of some kHz.

25. The device according to any of claims 18 to 24, wherein the first and/or second light source generates pulses of a pulse length in the picosecond region.

26. The device according to claim 25, wherein the first and/or the second primary light source is a laser.

27. The device according to any of claims 18 to 26, wherein the first and/or second light source generates a primary light wavelength between 750 nm and 850 nm.

28. The device according to any of claims 18 to 27, wherein at least one notch filter is positioned between the projection optics and the photo detector assembly to eliminate Rayleigh scattering.

29. The device according to any of claims 18 to 28, wherein a third light source is provided for generating an excitation light wavelength which is absorbed by the substance.

30. The device according to claim 29, wherein the third light source generates light of a wavelength between 1.2 μ

m and 3 μ

m.

31. The device according to any of claims 29 or 30, wherein the third light source is a laser for generating, picosecond pulses.

19. A device for the non-invasive determination of a concentration of a substance in a body fluid in a body tissue by Raman spectroscopy comprising:

a) a light source for irradiating monochromatic primary light of a given wavelength into the body tissue,

b) a heating means for adjusting a first temperature and a second temperature in the body tissue,

c) a photo detector means for recording secondary light that is backscattered from the body tissue,

d) a first memory for storing the intensity of the secondary light according to its wavelength as a first Raman spectral signal for the first temperature and a second memory for storing the intensity of the secondary light according to its wavelength as a second Raman spectral signal for the second temperature,

e) a comparator means for comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and for generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

f) a discriminator unit for determining an intensity of the compare signal at at least one sample wavelength for which the intensity corresponds to the concentration of the substance in the body fluid.

23. The device according to claim 19 or 20, wherein the heating means for adjusting the first and second temperature of the body tissue is triggered with a preset temperature variation frequency.

24. The device according to claim 23, wherein a receiver means is provided for recording the heart rate and the temperature variation frequency is the heart rate.

20. A device for the non-invasive determination of a concentration of a substance in a body fluid in a body tissue by Raman spectroscopy comprising:

a) a first light source for irradiating monochromatic primary light of a first wavelength into the body tissue,

b) a second light source for irradiating monochromatic primary light of a second wavelength into the body tissue,

c) a heating means for adjusting a first temperature and a second temperature in the body tissue,

d) a photo detector means for recording secondary light that is backscattered from the body tissue,

e) a first memory for storing the intensity of the secondary light according to its wavelength as a first Raman spectral signal for the first wavelength and for the first temperature, a second memory for storing the intensity of the secondary light according to its wavelength as a second Raman spectral signal for the second wavelength and for the first temperature, a third memory for storing the intensity of the secondary light according to its wavelength as a third Raman spectral signal for the first wavelength and for the second temperature and a fourth memory for storing the intensity of the secondary light according to its wavelength as a fourth Raman spectral signal for the second wavelength and for the second temperature,

f) a first comparator means for comparing the first Raman spectral signal in the first memory with the second Raman spectral signal in the second memory and for generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

g) a second comparator means for comparing the third Raman spectral signal in the third memory with the fourth Raman spectral signal in the fourth memory and for generating a compare signal for which spectral structures caused by the body tissue are substantially eliminated,

h) a third comparator means for comparing the first compare signal with the second compare signal for generating a third compare signal depending of the result of this comparison,

i) a discriminator unit for determining an intensity of the third compare signal at at least one sample wavelength,

j) an output unit for the output of an identification signal according to the intensity at at least one sample wavelength for which the intensity corresponds to the concentration of the substance in the body fluid.

32. A method for the non-invasive determination of a concentration of a substance in a body fluid in a body tissue by Raman spectroscopy comprising the following steps:

a) irradiating monochromatic primary light of a first wavelength into the body tissue at a first parameter value,

b) recording secondary light that is back scattered by the body tissue and storing the intensity of the secondary light in a first memory according to its wavelength as a first Raman spectral signal for the first primary wavelength and for the first parameter value,

c) repeating steps a) and b) for other primary wavelengths and other parameter values for which the intensity of the secondary light is stored in a further memory for each further primary wavelength and for each further parameter value,

d) multivariate statistical comparison of the Raman signals for the determining at least one sample wavelength for which the intensity changes analogously to the parameter values, and

e) determining and outputting the intensity at at least one sample wavelength in several Raman spectral signals according to the parameter values.

33. The method according to claim 32, wherein the parameter is the blood sugar level.