Method of performing wavelength modulated differential laser photothermal radiometry with high sensitivity

• US 8,649,835 B2
• Filed: 11/17/2010
• Issued: 02/11/2014
• Est. Priority Date: 11/17/2009
• Status: Active Grant

• Current Assignee: Andreas Mandelis, Xinxin Guo
• Original Assignee: Xinxin Guo
• Inventors: Mandelis, Andreas, Guo, Xinxin
• Primary Examiner(s): WINAKUR, ERIC FRANK
• Application Number:
  US12/948,525
• Publication Number:
  US 20110118571A1
• Time in Patent Office: 1,182 Days
• Field of Search: 600/310, 600/316, 600/322, 250/252.1
• US Class Current: 600/316
• CPC Class Codes: A61B 5/0093 Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
• 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 5/7228 Signal modulation applied to the input signal sent to patient or subject; demodulation to recover the physiological signal modulation H03C
• CPC Class Codes: G01D 18/008 with calibration coefficients stored in memory
• CPC Class Codes: G01D 3/022 having an ideal characteristic, map or correction data stored in a digital memory
• CPC Class Codes: G01D 5/32 with attenuation or whole or partial obturation of beams of light G01D5/40 takes precedence ; mechanical adjustment G01D5/264
• CPC Class Codes: G01T 1/1603 with a combination of at least two different types of detector see provisionally also G01T1/16

Abstract

Methods are provided for the detection of an analyte in a sample using wavelength modulated differential photothermal radiometry with enhanced sensitivity. A wavelength modulated differential photothermal radiometry system, comprising two optical modulated beams, where each beam experiences different absorption by the analyte, is calibrated by controlling the relative phase difference between the modulated beams so that individual photothermal signals corresponding to each modulated beam are 180° out of phase, corresponding to peak sensitivity to analyte concentration. The system may be further calibrated by varying the relative intensities of the two modulated beams and measuring standards containing known analyte concentration in order to determine an optimal relative intensity for a given concentration range of interest.

Claims

1. A method of operating a wavelength modulated differential photothermal radiometry system for detecting the presence of an analyte within a substance, said method comprising the steps of:

providing a first optical beam and a second optical beam, wherein said first optical beam is characterized by a first wavelength and said second optical beam is characterized by a second wavelength, and wherein said first wavelength is selected so that analyte concentrations within a concentration range of interest will cause sufficient absorption of said first optical beam to produce detectable thermal-wave emission, and wherein an absorption coefficient of said analyte at said first wavelength exceeds that at said second wavelength;

producing a first modulated beam and a second modulated beam by modulating an intensity of said first optical beam and an intensity of said second optical beam, respectively;

wherein said first modulated beam and said second modulated beam are modulated at a substantially equal modulation frequency, and wherein a phase difference between said first modulated beam and said second modulated beam is approximately 180 degrees;

providing a reference sample substantially free of analyte;

directing and substantially overlapping said first modulated beam and said second modulated beams onto said reference sample;

measuring a first photothermal signal produced by said first modulated beam;

measuring a second photothermal signal produced by said second modulated beam;

obtaining a relative photothermal phase between said first photothermal signal and said second photothermal signal;

controlling a relative intensity of said first modulated beam and said second modulated beam such that a ratio of said first photothermal signal amplitude and said second photothermal signal amplitude is approximately unity; and

controlling a relative phase of said first modulated beam and said second modulated beam so that said relative photothermal phase is approximately 180 degrees.

2. The method according to claim 1, further comprising the steps of:

measuring a differential photothermal signal for one or more standards, each said standard comprising a known analyte concentration, while controlling a relative intensity of said first modulated beam and said second modulated beam to scan a photothermal amplitude ratio of said first photothermal signal and said second photothermal signal near unity; and

selecting said photothermal amplitude ratio corresponding to a desired sensitivity over said concentration range of interest.

3. The method according to claim 2 further comprising the step of generating calibration data for said photothermal amplitude ratio corresponding to said desired sensitivity over said concentration range of interest.

4. The method according to claim 3 further comprising measuring a sample comprising an unknown analyte concentration within said substance, and determining said unknown analyte concentration by relating a differential photothermal signal obtained when measuring said sample to said calibration data.

5. The method according to claim 2 wherein said relative intensity is controlled by varying an intensity of said second modulated beam.

6. The method according to claim 2 wherein said first optical beam is provided by a first laser, and wherein said second modulated beam is provided by a second laser.

7. The method according to claim 6 wherein said photothermal amplitude ratio is controlled by varying a voltage or current of one of more of said first and second lasers.

8. The method according to claim 6 wherein said relative phase is controlled by varying a phase difference between modulation voltages or currents of said first laser and said second laser.

9. The method according to claim 1 further comprising the steps of:

controlling a relative intensity of said first modulated beam and said second modulated beam to scan a relative photothermal amplitude of said first photothermal signal and said second photothermal signal near unity; and

measuring said first photothermal signal and said second photothermal signal; and

verifying that said relative photothermal phase is substantially 180 degrees.

10. The method according to claim 1 wherein prior to said step of controlling said relative phase, an intensity of said first modulated beam is controlled so that an amplitude of first photothermal signal is approximately half of a full-scale amplitude range corresponding to said concentration range of interest.

11. The method according to claim 1 wherein said substance is tissue and said analyte is glucose.

12. The method according to claim 1 further comprising the step of:

measuring a differential photothermal signal for one or more standards, each said standard comprising a known analyte concentration, while controlling a relative intensity of said first modulated beam and said second modulated beam to scan a relative photothermal amplitude of said first photothermal signal and said second photothermal signal near unity; and

determining calibration data based on a relationship between each known analyte concentration and a relative intensity at which a phase flip-over occurs.

13. The method according to claim 12 further comprising measuring a sample comprising an unknown analyte concentration within said substance, and determining said unknown analyte concentration by relating a relative intensity at which phase flip-over occurs when measuring said sample to said calibration data.

14. A method of operating a wavelength modulated differential photothermal radiometry system for detecting the presence of an analyte within a substance, said method comprising the steps of:

providing a first optical beam and a second optical beam, wherein said first optical beam is characterized by a first wavelength and said second optical beam is characterized by a second wavelength, and wherein said first wavelength is selected so that analyte concentrations within a concentration range of interest will cause sufficient absorption of said first optical beam to produce detectable thermal-wave emission, and wherein an absorption coefficient of said analyte at said first wavelength exceeds that at said second wavelength;

producing a first modulated beam and a second modulated beam by modulating an intensity of said first optical beam and an intensity of said second optical beam, respectively;

wherein said first modulated beam and said second modulated beam are modulated at a substantially equal modulation frequency, and wherein a phase difference between said first modulated beam and said second modulated beam is approximately 180 degrees;

providing a reference sample comprising a known concentration of analyte;

directing and substantially overlapping said first modulated beam and said second modulated beams onto said reference sample;

obtaining a differential photothermal signal by detecting emission radiated by said reference sample with a phase-sensitive detection system; and

varying an intensity ratio of said first modulated beam and said second modulated beam to minimize said differential photothermal signal.

15. The method according to claim 14 wherein said known concentration of analyte is approximately zero.

16. The method according to claim 14 wherein said substance is tissue and said analyte is glucose.

17. The method according to claim 14 further comprising obtaining calibration data by relating signals obtained from standard samples with known analyte concentrations to said known analyte concentrations.

18. The method according to claim 17 further comprising measuring a sample comprising an unknown analyte concentration within said substance, and determining said unknown analyte concentration by relating a differential photothermal signal obtained when measuring said sample to said calibration data.

19. The method according to claim 14 wherein said intensity ratio is varied by controlling one or more of a spatial overlap and a relative spatial size of said first modulated beam and said second modulated beam.

20. The method according to claim 19 wherein said intensity ratio is varied by controlling a diameter of an iris placed in a path of one of said first modulated beam and said second modulated beam.

21. The method according to claim 14 wherein said step of obtaining a signal by detecting emission radiated by said reference sample with a phase-sensitive detection system comprises the steps of:

collecting said emission radiated by said reference sample;

directing said emission onto a detector, wherein said detector is adapted to produce a signal related to said emission;

providing said signal and a reference signal to a lock-in amplifier; and

obtaining a phase-sensitive differential photothermal signal.

22. The method according to claim 21 further comprising the step of spectrally filtering any collected photothermal radiation having a wavelength corresponding to said first modulated beam and said second modulated beam.

23. A method of operating a wavelength modulated differential photothermal radiometry system for detecting the presence of an analyte within a substance, said method comprising the steps of:

a) providing a first optical beam and a second optical beam, wherein said first optical beam is characterized by a first wavelength and said second optical beam is characterized by a second wavelength, and wherein said first wavelength is selected so that analyte concentrations within a concentration range of interest will cause sufficient absorption of said first optical beam to produce detectable thermal-wave emission, and wherein an absorption coefficient of said analyte at said first wavelength exceeds that at said second wavelength;

b) producing a first modulated beam and a second modulated beam by modulating an intensity of said first optical beam and an intensity of said second optical beam, respectively;

wherein said first modulated beam and said second modulated beam are modulated at a substantially equal modulation frequency, and wherein a phase difference between said first modulated beam and said second modulated beam is approximately 180 degrees;

c) selecting an intensity ratio of said first modulated beam and said second modulated beam;

d) providing a reference sample comprising a known concentration of analyte;

e) directing and substantially overlapping said first modulated beam and said second modulated beams onto said reference sample;

f) obtaining a differential photothermal signal by detecting emission radiated by said reference sample with a phase-sensitive detection system;

g) repeating steps d) to f) one or more times to measure differential photothermal signals for one or more additional standard samples, wherein each said additional standard samples comprise different known analyte concentrations;

h) obtaining a calibration curve by relating said differential photothermal signals to said known analyte concentrations;

i) repeating steps c) to h) to obtain an additional calibration curve corresponding to a different intensity ratio; and

j) selecting a preferred calibration curve having a desired sensitivity over a predetermined range of analyte concentration, and placing said system into a configuration corresponding to said preferred calibration curve.

24. The method according to claim 23 further comprising repeating step i) one or more times prior to performing step j).

25. The method according to claim 23 wherein said substance is tissue and said analyte is glucose.

26. The method according to claim 23 further comprising measuring a sample comprising an unknown analyte concentration within said substance, and determining said unknown analyte concentration by relating a signal obtained when measuring said sample to said preferred calibration curve.