1. Combining Light & Sound Can ultrasound become the preferred modality for functional and molecular imaging?
Shai Ashkenazi
Biomedical Ultrasound Lab
Dept. Biomedical Engineering
University of Michigan

2. Outline Imaging devices Imaging methods Imaging agents Photoacoustic
Ultrasound
Photoacoustic
Imaging agents

3. Ultrasound Imaging Array of Tx/Rx elements
Beam steering and focusing – time delayed channel excitation
Receive – delay & sum
Reflections – different density, speed of sound

4. Ultrasound Imaging Penetration depth (mm) Low MHz 10 – 20 MHz
100
Penetration depth (mm)
Low MHz
10 – 20 MHz 10
> 20 MHz (UBM)
Abnormal Thyroid Gland 1
0.01
0.1 1
Resolution (mm)

5. Opto-Acoustic Ultrasound Transducers

6. Optoacoustic US Transducers
Receive /
Transmit
Hi Q

7. Bell’s Photophone
February 1880

8. Etalon detector – principle of operation
PD Array (camera)
CW laser

9. Etalon detector – principle of operation
Ultrasound – Space/time load
2Kg
Etalon
PD Array (camera)
CW laser

10. Piezo vs. Etalon Comparison of sensitivity
TRANS
2.7
2.9
Time (s)
Amplitude
Etalon
5.3
5.5
5.7
Time (s)
Pulse-Echo
ETALON

11. Optical Generation of Ultrasound
Water
Black PDMS
Clear PDMS
Laser pulse
High thermal expansion
Optically absorbing

12. 2D Gold Nanostructure 4.5 um PDMS layer 220 nm Glass Substrate 128 nm

13. Acoustic Signal

14. Spectrum

15. Acoustic Pressure
Acoustic pressure increases linearly with optical input energy
Thermal damage threshold: 25 uJ delivered to a spot size of 25 um
Acoustic pressure at thermal damage threshold: 500 kPa at 10 mm

16. Integrated Device SU-8 protection layer PDMS layer Etalon 6 um 200 nm
Ultrasound Generation Beam
Ultrasound Detection Beam

17. Pulse-echo Results

18. Optical Microring detectors

19. Resonance optics l Output = T + S T = - S (critical coupling)
S = 0 (off-resonance phase cancelation)

20. Experimental verification
16.5 18
Time (s)
Ultrasound
Transducer US
Pulser a b c
1558
1563
 (nm)
Transmission
Tunable
Laser
Photodetector

21. Wavelength dependence
Trans. Modulation a b c
1558
1563
 (nm)
Transmission
16.5 18
Time (s)
10 MHz Transducer

22. Array configurations 80 elements sharing 1 waveguide 2D Arrays
Demultiplexer and Photodetector array In
Out λ1 λm
λm+1 …
λ2m
λ3 … λ2
Fiber coupled optical circulator
Demux and Photodetector array
Tunable laser
Miniaturization of high-Freq arrays for intravascular and “in-vivo” microscope application

23. Why Micro-Optics for Ultrasound Devices?
Micron size elements
High frequency arrays > 30 MHz
High SNR (size independent noise)
Wide Bandwidth > 50 MHz
Selectable sensitivity
“Shiftable” dynamic range
High BW signal comm. (80 Ch. on SMF using 100 GHz standard grid)

24. Applications – Smart Needle
High resolution ultrasound microscopy at the tip of a needle
Guiding biopsy
Reducing bleeding complications (e.g. in kidney biopsy)
200 µm
Receive
r array
Transmitter
2 mm
Side viewing
G23
0.64 mm

25. Photoacoustic Imaging
500 mm

26. PA imaging Receiver Laser pulse (~5 ns) Heat absorption
Temp. rise (~ 0.01 °C)
Thermal expansion (strain ~ 10-5)
Acoustic propogation
Detection and Source reconstruction
Receiver

27. Etalon for Photoacoustic imaging
PD Array (camera)
CW laser
Etalon

28. 2D phantom imaging
Photoacoustic image
100 mm
0.11mm
Optical image

29. 532 nm pulsed illumination
Nerve cord imaging
500 mm
Nerve Cord In Lobster Tail
532 nm pulsed illumination
Probe laser scan lines
(4mm x 0.36mm aperture)

30. 3D phantom imaging
50 µm
Array size: 128x Element spacing: 30 um

31. Pig Coronary Artery
700 nm
Axial Position (mm)
Lateral Position (mm)

32. Photoacoustics agents for functional and molecular imaging

33. Gold Nanorods – Molecular probe for PAI

34. Au Nanorod – Spectrum

35. Bioconjugation
Gold Nanorod
Surfactant (CTAB)
Antibody
PAA

36. Cell Culture Setup AM OS UT SC CC BX
Laser
OPO

37. Photoacoustic Image – LNCaP Cells
-10
Conjugated
Nanorods
-20
-30
1 mm
-40
-10
Unconjugated
Nanorods
-20
-30
-40

38. UltraSound-PhotoAcoustic (USPA) Imaging Combined Modality
Laser
OPO US UA PH
SYNC BX

39. Animal Imaging

40. Prostate Imaging

41. PEBBLES – Molecular Contrast

42. Conclusions
Photoacoustics provides an exciting vehicle for molecular imaging
PEBBLES can be detected at only 10 particles per cell with 100 nm particle diameter
Nanorods can be detected at only 50 particles per cell with volume 50 times less than PEBBLE
Both agents can be made much more efficient

43. Future research projects
Optical resonators for ultrasound sensing
PA contrast for cancer detection
Sensor dyes for functional PAI
PA sensor for protease activity

44. Optical resonators for ultrasound sensing
Waveguide Bragg Grating
Ultimate sensitivity for PAI applications – Acoustic noise limited
Explore structures for optimal acousto-optic interaction
Membrane interface
Air-water interface

45. PA contrast for cancer detection
Real-time PA imager
Small animals
Clinical trials
Stability-dynamics of nanoparticles in-vivo
Cell targeting
- Prostate Cancer
- Thyroid cancer

46. Sensor dyes for functional PAI
Combine versatility of molecular probes with PAI
Develop PA imaging of pH, Ca, O2, and other
Study PA sensing mechanisms
Absorption (change, spectral shift)
Fluorescence quenching  PA increase
Life time of non-radiative decay  change in PA shape
Delivery agents - Dye embedded nanoparticles

47. Example - pH dye
SNAFR-5F

48. PA sensor for protease activity
Abs

49. T H AN K S EECS Jay Guo ChungYen Chao Tao ling JingSung Chemistry
Raoul Kopelman
Gwangseong Kim
Tom Horvath
Rodney Agayan
Chemical Eng.
Nick Kotov
Ashish Agarwal
Cancer Center
Mark Day
Kathleen Day

50. More slides

51. Fabrication Process I SiO2 polymer Si Laser Interference Lithography
glass
Nanoimprint Lithography

52. Fabrication Process II

53. Experimental Setup Pulsed Laser Input Collimator ND filters Lens
Transducer
Data
Collection
Amplifier

54. Pulse-echo Experiment
Reflector
Ultrasound Generation Beam
Data Capture
Integrated Device
Ultrasound Detection Beam
Photodiode
Amplifier
PBS

55. Optical Absorption

56. 50 MHz Test Signals
Pulse-echo
Optic modulation
Spectra

57. Acoustic modulation
Reflection x
Wavelength y z

58. Stained live lobster nerve cordPE
Depth PA
2 mm
Lateral
DR = 32 dB

59. Phantom Image dB Detection sensitivity = 5 x 1010 particles/cc
-35
-25
-15 -5
5 mm dB
Detection sensitivity = 5 x 1010 particles/cc
= 50 particles/cell

60. PEBBLE with ICG

61. PEBBLE with ICG - Stability

62. PEBBLE with ICG - Spectrum

63. Photoacoustic Image – PEBBLES
Position (mm) 10 20 30 15 25
1010
1012
1011
Detection sensitivity = 1010 particles/cc
= 10 particles/cell

64. Photoacoustic Image – LNCaP Cells
Position (mm) 1
-40
-30
-20
-10
Conjugated
PEBBLES
Unconjugated
PEBBLES