Photoacoustic assay and imaging system

• US 6,846,288 B2
• Filed: 08/09/2001
• Issued: 01/25/2005
• Est. Priority Date: 08/24/2000
• Status: Expired due to Term

• Current Assignee: PHC Holdings Corporation
• Original Assignee: IntelliDx, Inc.
• Inventors: Ben-Ami, Udi, Pesach, Benny, Nagar, Ron
• Primary Examiner(s): Jaworski, Francis J.
• Application Number:
  US10/312,300
• Publication Number:
  US 20030167002A1
• Time in Patent Office: 1,265 Days
• Field of Search: 600310-344, 600/437, 600/443, 600/447, 600473-479
• US Class Current: 600/437
• CPC Class Codes: A61B 5/0095 by applying light and detecting acoustic waves, i.e. photoacoustic measurements
• 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 8/00 Diagnosis using ultrasonic, sonic or infrasonic waves imaging of objects using sonar G01S15/00
• CPC Class Codes: A61B 8/085 for locating body or organic structures, e.g. tumours, calculi, blood vessels, nodules

Abstract

A method for assaying a component of a localized region of interest in a body comprising: illuminating the region with at least one pulse of radiation having a wavelength at which the radiation is absorbed by the component to generate a change in an acoustic property of the region; transmitting ultrasound so that it is incident on the region; measuring at least one effect of the change on the incident ultrasound; using the measured at least one effect to determine an absorption coefficient for the radiation in the region; and using the determined absorption coefficient to determine concentration of the component in the region.

Claims

1. A method for assaying a component of a localized region of interest in a body comprising:

a) illuminating the region with at least one pulse of radiation having a wavelength at which the radiation is absorbed by the component to generate a change in acoustic property of the region;

b) transmitting ultrasound so that it is incident on the region;

c) measuring at least one effect of the change on the incident ultrasound

d) using the measured at least one effect to determine an absorption coefficient for the radiation in the region; and

e) using the determined absorption coefficient to determine concentration of the component in the region.

2. A method according to claim 1 and further comprising illuminating the region with at least one pulse of radiation-at at least one other wavelength, repeating b-d and using the determined absorption coefficient for the at least one other wavelength to determine concentration of the component in the region.

3. A method according to claim 1 wherein an effect of the at least one effect of the change on the incident ultrasound comprises a change acoustic energy reflectance of the region.

4. A method according to claim 3 wherein measuring the change in reflectance comprises:

reflecting at least one first pulse of ultrasound from the region before illumination of the region with the at least one radiation pulse;

determining a first acoustic energy reflectance from the region using the amplitude of the at least one reflected pulse;

reflecting at least one second pulse of ultrasound from the region after illumination of the region with the at least one radiation pulse;

determining a second acoustic energy reflectance from the region using the amplitude of the second at least one reflected pulse;

determining a difference between the first and second acoustic energy reflectances.

5. A method according to claim 3 wherein measuring the change in reflectance comprises:

measuring acoustic energy reflectance from the region before illumination with the at least one radiation pulse;

measuring amplitude of Doppler shifted ultrasound waves reflected from the incident ultrasound during illumination of the region with the at least one light pulse;

using the amplitude of the Doppler shifted ultrasound waves to determine acoustic energy reflectance that characterizes the region during illumination with the at least one radiation pulse; and

determining a difference between the reflectance before illumination and during illumination.

6. A method according to claim 1 wherein an effect of the at least one effect of the change on the incident ultrasound comprises a change in speed of sound in the region.

7. A method according to claim 6 wherein measuring the change in speed of sound comprises:

transmitting an ultrasound wave from a first transducer towards a second transducer so that the ultrasound wave traverses the region;

illuminating the region while the ultrasound wave is present in the region;

determining a first transit time from the first to the second transducer of a first portion of the ultrasound wave, which first portion is present at a first location in region while the region is illuminated;

determining a second transit time from the first to the second transducer of a second portion of the ultrasound wave which second portion is present at a second location in the region at a time at which the first portion is located at the first location; and

using the difference in the transit times to determine a change in a speed of sound through the region at a location in the region between the first and second locations.

8. A method according to claim 6 wherein the region is sandwiched between a first and a second acoustic interface at which ultrasound is partially reflected and wherein measuring the change in the speed of sound comprises:

measuring before illumination a difference between a transit time of ultrasound between a first and second location that is reflected from the first interface and a transit time of ultrasound energy between the first and second locations that is reflected from the second interface;

determining a speed of sound before illumination for the region from the transit time difference;

measuring after illumination a difference between a transit time of ultrasound between a first and second location that is reflected from the first interface a transit time of ultrasound energy between the first and second locations that is reflected from the second interface;

determining a speed of sound after illumination for the region from the transit time difference; and

determining the change in the speed of sound from the determine speeds of sound before and after illumination.

9. A method according to claim 6 wherein the region is sandwiched between two acoustic interfaces at which ultrasound is partially reflected and wherein measuring the change in the speed of sound comprises:

a) introducing a pulse of ultrasound into the region before illumination so that the pulse bounces back and forth between the interfaces and repeatedly traverse the region;

b) sensing energy from the pulse that exits the region through one of the interfaces for each of a plurality of back and forth traversals of the pulse through the region;

c) determining a speed of sound in the region from the times at which the energy is sensed;

d) introducing a pulse of ultrasound into the region after illumination so that the pulse bounces back and forth between the interfaces and repeatedly traverses the region and repeating b and c; and

e) determining a difference between the determined speeds of sound.

10. A method according to claim 6 wherein the region is sandwiched between two acoustic interfaces at which ultrasound is partially reflected and wherein measuring the change in speed of sound comprises:

transmitting ultrasound which is incident on the region prior to illumination of the region with the at least one radiation pulse;

determining a first frequency for which transmission of the ultrasound through the region is a maximum or a minimum;

transmitting ultrasound which is incident on the region after illumination of the region with the at least one radiation pulse;

determining a second frequency for which transmission of ultrasound through the region is a maximum or a minimum and for which the wavelength of propagation of ultrasound in the region for the first and second frequencies is substantially the same; and

using a difference between the first and second frequencies to determine the change in the speed of sound in the region.

11. A method according to claim 6 wherein the region is sandwiched between two acoustic interfaces at which ultrasound is partially reflected and wherein measuring the change in speed of sound comprises:

transmitting ultrasound which is incident on the region prior to illumination of the region with the at least one radiation pulse;

determining a first frequency for which reflection of the ultrasound through the region is a maximum or a minimum;

transmitting ultrasound which is incident on the region after illumination of the region with the at least one radiation pulse;

determining a second frequency for which reflection of ultrasound through the region is a maximum or a minimum and for which the wavelength of propagation of ultrasound in the region for the first and second frequencies is substantially the same; and

using a difference between the first and second frequencies to determine the change in the speed of sound in the region.

12. A method according to claim 1 wherein an effect of the at least one effect of the change on the incident ultrasound comprises a change in the frequency of ultrasound that traverses the region.

13. A method according to claim 12 wherein measuring the change in frequency comprises:

transmitting an ultrasound wave from a first transducer towards a second transducer so that the ultrasound wave traverses the region;

illuminating the region with the at least one light pulse while the ultrasound wave is present in the region and wherein the at least one light pulse has a pulse width substantially longer than the transit time of ultrasound through the region;

determining a first frequency shift in the frequency of a first portion of the ultrasound wave, which first portion is present at a first location in the region while the region is illuminated;

determining a second frequency shift in the frequency of a second portion of the ultrasound wave which second portion is present at a second location in the region at a time at which the first portion is located at the first location; and

using a difference in the first and second frequency shifts to determine a frequency shift that occurs in the ultrasound at a location in the region between the first and second locations.

14. A method according to claim 13 wherein an effect of the at least one effect comprises a change in absorption of ultrasound along a path length in the region.

15. A method according to claim 14 wherein the region is sandwiched between two acoustic interfaces at which ultrasound is partially reflected and wherein measuring the change in absorption over the path length comprises;

a) introducing a pulse of ultrasound into the region before illumination so that the pulse bounces back and forth between the interfaces and repeatedly traverses the region;

b) sensing an amount of energy from the pulse of ultrasound exits the region through one of the interfaces for each of a plurality of times that the pulse travels back and forth through the region;

c) determining amounts of energy absorbed from the pulse for each back and forth traversal through the region;

d) introducing a pulse of ultrasound into the region after illumination so that the pulse bounces back and forth between the interfaces and repeatedly traverses the region and repeating b and c; and

e) determining the change in absorption over the path length using the determined amounts of absorbed energy.

16. A method according to claim 1 wherein transmitting ultrasound incident on the region and measuring an effect of the change on the incident ultrasound is mediated by at least one ultrasound transducer coupled to the body and wherein the method comprises measuring acoustic properties of the coupling between the at least one transducer and the body.

17. A method according to claim 1 wherein the at least one pulse of radiation comprises a microwave pulse.

18. A method according to claim 1 wherein the at least one pulse of radiation comprises a pulse of RF energy.

19. A method according to claim 1 wherein the at least one pulse of radiation comprises a pulse of light.

20. A method according to claim 1 further comprising determining a location of the region.

21. A method according to claim 20 wherein determining a location for the region comprises transmitting ultrasound into the body.

37. A method of imaging internal features of a body comprising:

assaying a component of the features for a plurality of regions in the body according to claim 1 or claim 22; and

displaying a result of measurements performed in assaying the component as a function of location of the regions to provide an image of the features.

38. A method according to claim 37 and further comprising overlaying the image provided from assaying the component on another image of the body acquired by a different imaging modality.

39. A method according to claim 38 wherein the different imaging modality comprises ultrasound imaging.

40. A method according to claim 39 and further comprising using a same at least one ultrasound transmitter or ultrasound sensor to acquire bath the image provided from assaying the component and the ultrasound image.

41. A method according to claim 37 wherein the body is a living body.

42. A method according to claim 41 wherein the living body is a human body.

43. A method according to claim 37 wherein the internal feature is a plaque deposit in a blood vessel.

44. A method according to claim 37 wherein the component is LDL cholesterol or oxidized LDL cholesterol.

45. A method according to claim 37 wherein the internal feature is a tumor.

51. A method according to claim 21 or claim 50 wherein the region of interest is located within an uncertainty of less than 5 wavelengths of the ultrasound in at least one direction.

52. A method according to claim 21 or claim 50 wherein the region of interest is located to within an uncertainty of less than 3 wavelengths of the ultrasound in at least one direction.

53. A method according to claim 21 or claim 50 wherein the region of interest is located to within an uncertainty of about a wavelength of the ultrasound in at least one direction.

22. A method for assaying a component of a region of interest in a body comprising:

a) determining a location of the region;

b) illuminating the region and a larger region comprising the region with at least one pulse of light having a wavelength at which light is absorbed by the component;

c) sensing photoacoustic waves generated in the larger region responsive to the light pulse and determining locations of their origins;

d) using intensity of those photoacoustic waves having an origin in the region of interest to determine an absorption coefficient for the light in the region of interest; and

e) using the determined absorption coefficient to determine to determine concentration of the component in the region of interest.

23. A method according to claim 22 wherein the at least one light pulse comprises at least one train of light pulses radiated at a pulse repetition rate.

24. A method according to claim 23 wherein sensing and determining locations for the photoacoustic waves comprises:

focusing an acoustic reference beam on the region of interest, which reference beam has a frequency that is shifted from the pulse repetition frequency of the at least one light pulse train by an offset frequency and an intensity that causes the region of interest to respond non-linearly to acoustic stimuli; and

detecting acoustic waves at the offset frequency.

25. A method according to claim 24 further comprising illuminating the region of interest with at least one other light pulse train characterized by a different wavelength and pulse repetition rate, repeating b and c, and using the determined absorption coefficient for the at least one other light pulse train to determine concentration of the component in the region of interest.

26. A method according to claim 25 wherein the light pulse train and at least one other light pulse train illuminate the region of interest substantially simultaneously.

27. A method according to claim 22 further comprising illuminating the region of interest with at least one pulse of light at at least one other wavelength, repeating b and c and using the determined absorption coefficient for the at least one other wavelength to determine concentration of the component in the region of interest.

28. A method according to claim 22 wherein sensing photoacoustic waves is mediated by at least one ultrasound transducer coupled to the body and wherein the method comprises measuring acoustic properties of the coupling between the at least one transducer and the body.

29. A method according to claim 22 wherein the at least one light pulse comprises a pulse of IR light.

30. A method according to claim 22 wherein the at least one light pulse comprises a pulse of visible light.

31. A method according to claim 22 and further comprising measuring acoustic properties of material in the body.

32. A method according to claim 31 wherein a determined absorption coefficient is adjusted responsive to the measured acoustic properties.

33. A method according to claim 22 wherein the body is a living body.

34. A method according to claim 33 wherein the living body is a human body.

35. A method according to claim 33 wherein the region of interest is a bolus of blood in a blood vessel of the body.

36. A method according to claim 35 wherein the a component of said bolus of blood is glucose.

46. A method according to claim 22 wherein determining a location for the region of interest comprises:

illuminating to larger region with light that is strongly absorbed by a component in the region of interest;

sensing photoacoustic waves generated in the larger region responsive to the light;

using the sensed photoacoustic waves to map concentration of the analyte in the larger region as a function of position; and

using the determined concentration map to determine a location for the region of interest.

47. A method according to claim 46 wherein the body is a living body.

48. A method according to claim 47 wherein the region of interest is a bolus of blood in a blood vessel of the body.

49. Method according to claim 48 wherein the component is glucose.

50. A method according to claim 22 wherein determining a location for the region of interest comprises transmitting ultrasound into the body.

54. A method for detecting photoacoustic waves generated in a region of a body by light comprising:

illuminating the region with pulses of the light at a pulse repetition frequency to generate photoacoustic waves in the region;

heterodyning the generated photoacoustic waves with an acoustic reference beam having a frequency that is shifted from the pulse repetition frequency by an offset frequency; and

detecting acoustic waves at the offset frequency.

55. A method according to claim 54 wherein heterodyning comprises focusing the acoustic reference beam in the region so that acoustic energy in the region from the reference beam is sufficient to cause the region to respond non-linearly to acoustic stimuli.

56. Apparatus for assaying a component of a blood bolus in a blood vessel of a body comprising:

a light source that illuminates a region of the body comprising the blood bolus with light at a first wavelength that is relatively strongly absorbed by blood to generate first photoacoustic waves at locations in the body region occupied by blood;

a light source that illuminates the body region with light at a second wavelength that is absorbed by the component to generate second photoacoustic waves at locations at which the component is located;

at least one ultrasound transducer that generates first and second signals responsive to the first and second photoacoustic waves respectively; and

a controller that;

a) receives the first signals and uses them determine a spatial distribution of blood in the body region and therefrom a location of the blood bolus;

b) receives the second signals and uses them to determine locations of the origins of the second photoacoustic waves;

c) uses second signals corresponding to second photoacoustic wave having an origin in the bolus to determine an absorption coefficient for the bolus; and

d) uses the determined absorption coefficient to determine concentration of the component in the bolus.

57. Apparatus according to claim 56 wherein the component is glucose.

58. Apparatus for assaying a component of a region of interest in a body comprising:

a source of radiation controllable to provide pulses of radiation having a wavelength at which the radiation is absorbed by the component and generates a change in an acoustic property of the region;

at least one ultrasound transducer controllable to transmit ultrasound;

at least one transducer for sensing ultrasound that generates signals responsive to ultrasound energy incident thereon; and

a controller that;

a) controls the radiation source to illuminate the region with at least one pulse of the radiation that generates the change in region;

b) controls at least one transmitting transducer to transmit ultrasound that is incident on the region and thereafter incident on a sensing transducer that generates signals responsive thereto;

c) receives the signals and uses them to measure at least one effect of the change on the ultrasound;

d) uses the measured effect to determine an absorption coefficient for the region; and

e) determines a concentration of the component in the region from the absorption coefficient.

59. Apparatus according to claim 58 wherein the body is a living body.

60. Apparatus according to claim 59 wherein the region of interest is a bolus of blood in a blood vessel of the body.

61. Apparatus according to claim 60 wherein the component is glucose.

62. A method for assaying glucose in a region of interest in a body comprising:

a) determining a location of the region;

b) illuminating the region and a larger region comprising the region with at least one pulse of light having a wavelength at which light is absorbed by the component;

c) sensing photoacoustic waves generated in the larger region responsive to the light pulse and determining locations of their origins;

d) using intensity of those photoacoustic waves having an origin in the region of interest to determine an absorption coefficient for the light in the region of interest; and

e) using the determined absorption coefficient to determine concentration of glucose in the region of interest.

63. Apparatus for assaying glucose in a blood bolus in a blood vessel of a body comprising:

a light source that illuminates a region of the body comprising the blood bolus with light at a first wavelength that is relatively strongly absorbed by blood to generate first photoacoustic waves at locations in the body region occupied by blood;

a light source that illuminates the body region with light at a second wavelength that is absorbed by the component to generate second photoacoustic waves at locations at which the component is located;

at least one ultrasound transducer that generates first and second signals responsive to the first and second photoacoustic waves respectively; and

a controller that.

a) receives the first signals and uses them determine a spatial distribution of blood in the body region and therefrom a location of the blood bolus;

b) receives the second signals and uses them to determine locations of the origins of the second photoacoustic waves;

c) uses second signals corresponding to second photoacoustic wave having an origin in the bolus to determine an absorption coefficient for the bolus; and

d) uses the determined absorption coefficient to determine concentration of glucose in the bolus.