TIME-RESOLVED NON-INVASIVE OPTOMETRIC DEVICE FOR MEDICAL DIAGNOSTIC

• US 20070156037A1
• Filed: 12/13/2006
• Published: 07/05/2007
• Est. Priority Date: 06/17/2004
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Katika, Kamal, Pilon, Laurent
• Granted Patent: US 7,904,140 B2
• Time in Patent Office: Days
• US Class Current: 600/310
• 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; and

measuring the fluorescence signal as a function of time to detect development of a metabolic disease affecting the patient.

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 1, further comprising measuring the reflectance of the excitation pulse.

6. A method as recited in claim 5, further comprising measuring the transmittance of the excitation pulse.

7. A method as recited in claim 6, wherein the transmittance, reflectance, and time-resolved fluorescence measurements are performed simultaneously.

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

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

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

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

10. A method as recited in claim 7, wherein the wherein the transmittance, reflectance, and time-resolved fluorescence measurements are calculated using to the modified method of characteristics.

11. A method as recited in claim 7, wherein the transmittance, reflectance, and time-resolved fluorescence measurements are calculated by approximating photon paths from the detector to the source of the photons.

12. A method as recited in claim 9, wherein the compared fluorescence signal is used to monitor the long-term effect of cholesterol in the patient.

13. A method as recited in claim 9, wherein the compared fluorescence signal is used to monitor genetic changes in the patient.

14. A method as recited in claim 1, further comprising identifying one or more fluorophores from the measured fluorescence signal.

15. A method as recited in claim 14, further comprising locating one or more fluorophores within the region of skin.

16. A method as recited in claim 14, wherein the fluorescence signal is deconvoluted to isolate the contribution of individual fluorophores to a cumulative signal.

17. An apparatus for non-invasively probing the inner structure of the skin of a patient;

comprising;

an excitation source configured to direct excitation energy at a region of the patient'"'"'s skin;

a first detector element directed at the region of skin;

the first detector element configured to receive a fluorescence signal resulting from the excitation energy at the patient'"'"'s skin;

a second detector element configured to receive a transmittance signal resulting from the excitation energy at the patient'"'"'s skin; and

a processor configured to measure fluorescence signal of the fluorescence signal as a function of time.

18. An apparatus as recited in claim 17, further comprising one or more light guides for directing the excitation energy at the region of the patient'"'"'s skin;

wherein the first detector element is substantially adjacent to the excitation light guides.

19. An apparatus as recited in claim 18, wherein the second detector element is positioned substantially on an opposite the region of skin from the excitation light guides.

20. An apparatus as recited in claim 19, wherein the first and second detector elements comprise one or more light guides for directing the fluorescence signal resulting from the excitation energy to a detector.

21. An apparatus as recited in claim 17, wherein the first detector element is also configured to receive a transmittance signal resulting from the excitation energy at the patient'"'"'s skin.

22. An apparatus as recited in claim 21, wherein the processor is further configured to measure the transmittance of the excitation pulses.

23. An apparatus as recited in claim 21, wherein the processor is further configured to measure the reflectance of the excitation pulse.

24. An apparatus as recited in claim 21, wherein the processor is further configured to perform transmittance, reflectance, and time-resolved fluorescence measurements simultaneously.

25. An apparatus as recited in claim 21, further comprising a monochromator to separate the reflectance signal from the fluorescence signal.

26. An apparatus as recited in claim 20, wherein the first detector element comprises an array of spaced apart light guides for directing a plurality of fluorescence signals resulting from the excitation energy traveling through different paths in the patient'"'"'s skin to the detector.

27. An apparatus as recited in claim 26, wherein the spaced apart light guides are at different angles with respect to each other.

28. An apparatus as recited in claim 20, wherein the first detector element is configured to be oriented at different angles with respect to the excitation light guides.

29. An apparatus as recited in claim 20, wherein the second detector element comprises an array of spaced apart light guides for directing a plurality of fluorescence signals resulting from the excitation energy traveling through different paths in the patient'"'"'s skin to the detector.

30. An apparatus as recited in claim 29, wherein the spaced apart light guides are at different angles with respect to each other.

31. An apparatus as recited in claim 21, wherein the second detector element is configured to be oriented at different angles with respect to the excitation light guides.

32. An apparatus as recited in claim 17, wherein the excitation source is coupled with a sphygmomanometer cuff of a blood pressure monitoring device such that excitation energy may be directed while pressure is being applied to the region of the patient'"'"'s skin.

33. An apparatus as recited in claim 17, wherein the second detector element is also configured to receive a fluorescence signal resulting from the excitation energy at the patient'"'"'s skin.

34. An apparatus as recited in claim 17, wherein the second detector element comprises a CCD array.

35. A blood pressure monitoring device, comprising;

a sphygmomanometer cuff;

a manometer coupled to the cuff for indicating a patient'"'"'s blood pressure;

an excitation source coupled to the sphygmomanometer cuff;

the excitation source configured to direct excitation energy at a region of the patient'"'"'s skin;

a detector directed at the region of skin;

the detector element configured to receive a fluorescence signal resulting from the excitation energy at the patient'"'"'s skin; and

a processor configured to measure intensity decay of the fluorescence signal as a function of time.

36. A blood pressure monitoring device as recited in claim 35, wherein the device is configured to simultaneously measure the patient'"'"'s blood pressure and measure the intensity decay of the fluorescence signal as a function of time.

37. A method for performing time-resolved fluorescence measurements on 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; and

measuring a transient intensity decay of the fluorescence signal.

38. A method as recited in claim 37, wherein exciting a portion of the patient'"'"'s skin comprises exciting a plurality of components in the patient'"'"'s skin, each of the components fluorescing into photons to generate the fluorescence signal.

39. A method as recited in claim 38, wherein the transient intensity decay measurements are calculated using to the modified method of characteristics.

40. A method as recited in claim 38, further comprising measuring the reflectance of the excitation pulse.

41. A method as recited in claim 40, further comprising:

distinguishing between the plurality of components by measuring their fluorescence emission and reflectance wavelengths.

42. A method as recited in claim 41, further comprising:

distinguishing between a plurality of components having similar wavelengths by measuring their fluorescence lifetimes.

43. A method as recited in claim 41, further comprising:

identifying the location of the plurality of components by identifying their emission and reflectance wavelengths.

44. A method as recited in claim 41, wherein the fluorescence signal is deconvoluted to isolate the contribution of individual fluorophores to a cumulative signal.

45. A method as recited in claim 41, further comprising measuring the transmittance of the excitation pulse.

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

introducing an agent into a region of the patient'"'"'s skin;

the agent comprising an exogenous fluorophore configured to bond to target component in the patient'"'"'s skin;

directing an excitation pulse at the 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;

the fluorescence signal comprising both exogenous fluorophores from the introduced agent and endogenous fluorophores naturally present in the patient'"'"'s skin;

detecting the fluorescence signal generated by the excitation pulse; and

measuring a transient intensity decay of the fluorescence signal to detect development of a metabolic disease affecting the patient.

47. A method as recited in claim 46, wherein introducing an agent comprises rubbing a cream comprising the agent at the region of the patient'"'"'s skin.

48. A method as recited in claim 46, further comprising measuring the reflectance of the excitation pulse.

49. A method as recited in claim 46, further comprising measuring the transmittance of the excitation pulse.

50. A method as recited in claim 46, wherein the transmittance, reflectance, and time-resolved fluorescence measurements are performed simultaneously.