Shai Ashkenazi Biomedical Ultrasound Lab Dept. Biomedical Engineering University of Michigan

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

2. Imaging devices Imaging methods Photoacoustic Ultrasound Imaging agents Outline

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 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 Etalon PD Array (camera) CW laser

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

10. Piezo vs. EtalonComparison of sensitivity Pulse-Echo Etalon Amplitude 0 0 2.7 2.9 5.3 5.5 5.7 Time (s) Time (s) PIEZO TRANS 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 128 nm 20 nm 220 nm Glass Substrate

13. Acoustic Signal

14. Spectrum

15. 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 Acoustic Pressure

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

20. Ultrasound Transducer US Pulser Transmission c a b  (nm) 1558 1563 0 16.5 18 Time (s) Experimental verification Tunable Laser Photodetector

21. 0 Trans. Modulation Transmission c 0 a b  (nm) 1558 1563 0 16.5 18 Time (s) Wavelength dependence 10 MHz Transducer

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

23. 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) Why Micro-Optics for Ultrasound Devices?

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

25. 500 mm Photoacoustic Imaging

26. PA imaging • 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 PD Array (camera) CW laser Etalon for Photoacoustic imaging

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

29. 500 mm Nerve cord imaging 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: 128x128 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 0 -10 Conjugated Nanorods -20 -30 1 mm -40 0 -10 Unconjugated Nanorods -20 -30 -40

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

39. Animal Imaging

40. Prostate Imaging

41. PEBBLES – Molecular Contrast

42. 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 Conclusions

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

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

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

46. 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 Sensor dyes for functional PAI Combine versatility of molecular probes with PAI

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

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