Time-resolved non-invasive optometric device for medical diagnostic

• US 7,904,140 B2
• Filed: 12/13/2006
• Issued: 03/08/2011
• Est. Priority Date: 06/17/2004
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Pilon, Laurent G., Katika, Kamal M.
• Primary Examiner(s): Le; Long V
• Assistant Examiner(s): Selkin; Saurel J
• Application Number:
  US11/610,430
• Publication Number:
  US 20070156037A1
• Time in Patent Office: 1,546 Days
• Field of Search: 600/476
• US Class Current: 600/476
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• 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 5/443 Evaluating skin constituents, e.g. elastin, melanin, water
• CPC Class Codes: A61B 5/444 Evaluating skin marks, e.g. mole, nevi, tumour, scar
• CPC Class Codes: A61B 5/6816 Ear lobe
• CPC Class Codes: A61B 5/6824 Arm or wrist
• CPC Class Codes: A61B 5/6825 Hand
• CPC Class Codes: A61B 5/6829 Foot or ankle
• CPC Class Codes: G01N 2021/6421 Measuring at two or more wavelengths
• CPC Class Codes: G01N 2021/6491 Measuring fluorescence and transmission; Correcting inner filter effect
• CPC Class Codes: G01N 21/4795 spatially resolved investigating of object in scattering medium in vivo A61B
• CPC Class Codes: G01N 21/6408 with measurement of decay time, time resolved fluorescence
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 21/6486 Measuring fluorescence of biological material, e.g. DNA, RNA, cells G01N21/6428 takes precedence
• CPC Class Codes: G01N 2800/04 Endocrine or metabolic disorders
• CPC Class Codes: G01N 33/6881 from skin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

A time-resolved fluorescence device is described for the detection and diagnosis of various metabolic diseases in a noninvasive or minimally invasive manner. The device uses an ultra-short excitation pulse that comprises of a repetition of nanosecond pulses. The excitation pulse is directed incident onto a strategically selected area of the patient body such as the forearm, the feet, and the palm. This light interacts with the different layers of the skin. The absorbed light excites conditions of interest in the skin, which in turn generate a fluorescence signal, which is collected by a detector. A processor is coupled to the detector to measure the transient fluorescence intensity decay of the skin in terms of lifetimes, and the contribution of individual fluorophores to the overall fluorescence signal.

Claims

1. A method for non-invasively probing the inner structure of the skin of a patient, comprising:

directing an excitation pulse at a region of the patient'"'"'s skin;

exciting a portion of the patient'"'"'s skin as a result of the excitation pulse at the region to generate a fluorescence signal indicative of the composition of the patient'"'"'s skin;

detecting the fluorescence signal generated by the excitation pulse;

measuring an intensity decay of the fluorescence signal as a function of time to detect development of a metabolic disease affecting the patient;

measuring the reflectance of the excitation pulse;

measuring the transmittance of the excitation pulse; and

wherein the transmittance, reflectance, and time-resolved fluorescence measurements are performed simultaneously;

wherein the transmittance, reflectance, and time-resolved fluorescence measurements are calculated using an inverse marching method.

2. A method as recited in claim 1, wherein directing an excitation pulse comprises repeatedly directing a plurality of excitation pulses in succession at the region of the patient'"'"'s skin.

3. A method as recited in claim 2, wherein measuring the fluorescence signal comprises applying the modified method of characteristics to calculate fluorescence transport within the patient'"'"'s skin.

4. A method as recited in claim 2, wherein the successive pulses are added to increase the signal-to noise ratio of the signal.

5. A method as recited in claim 2:

wherein the fluorescence signal comprises intensity decay values of fluorophores of one or more molecules or proteins; and

wherein the plurality of excitation pulses each have a pulse width that it is smaller than the fluorescence lifetime of the fluorophores.

6. A method as recited in claim 1, further comprising:

storing fluorescence decay values acquired from a plurality of reference patients in a database.

7. A method as recited in claim 6, further comprising:

comparing the measured fluorescence signal to the stored fluorescence decay values.

8. A method as recited in claim 7, further comprising:

using the compared fluorescence signal to monitor the long-term effect of cholesterol in the patient.

9. A method as recited in claim 7, further comprising:

using the compared fluorescence signal to monitor genetic changes in the patient.

10. A method as recited in claim 1, further comprising identifying one or more fluorophores from the measured fluorescence signal, the one or more fluorophores corresponding to one or more measured intensity decay values.

11. A method as recited in claim 10, further comprising locating one or more fluorophores within the region of skin.

12. A method as recited in claim 10, wherein the fluorescence signal is deconvoluted to isolate the contribution of individual fluorophores to a cumulative signal.

13. A method for non-invasively probing the inner structure of the skin of a patient, comprising:

directing an excitation pulse at a region of the patient'"'"'s skin;

exciting a portion of the patient'"'"'s skin as a result of the excitation pulse at the region to generate a fluorescence signal indicative of the composition of the patient'"'"'s skin;

detecting the fluorescence signal generated by the excitation pulse;

measuring an intensity decay of the fluorescence signal as a function of time to detect development of a metabolic disease affecting the patient;

measuring the reflectance of the excitation pulse;

measuring the transmittance of the excitation pulse;

wherein the transmittance, reflectance, and time-resolved fluorescence measurements are performed simultaneously; and

wherein the transmittance, reflectance, and time-resolved fluorescence measurements are calculated by approximating photon paths from the detector to the source of the photons.

14. A method as recited in claim 13, wherein directing an excitation pulse comprises repeatedly directing a plurality of excitation pulses in succession at the region of the patient'"'"'s skin.

15. A method as recited in claim 14, wherein measuring the fluorescence signal comprises applying the modified method of characteristics to calculate fluorescence transport within the patient'"'"'s skin.

16. A method as recited in claim 14, wherein the successive pulses are added to increase the signal-to noise ratio of the signal.

17. A method as recited in claim 14, further comprising identifying one or more fluorophores from the measured fluorescence signal.

18. A method as recited in claim 17, further comprising locating one or more fluorophores within the region of skin.

19. A method as recited in claim 17, wherein the fluorescence signal is deconvoluted to isolate the contribution of individual fluorophores to a cumulative signal.

20. A method as recited in claim 13, further comprising:

storing fluorescence signal values acquired from a plurality of reference patients in a database.

21. A method as recited in claim 20, further comprising:

comparing the measured fluorescence signal to the stored fluorescence signal values.

22. A method as recited in claim 21, wherein the compared fluorescence signal is used to monitor the long-term effect of cholesterol in the patient.

23. A method as recited in claim 21, wherein the compared fluorescence signal is used to monitor genetic changes in the patient.