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

Outline Imaging devices Imaging methods Imaging agents Photoacoustic Ultrasound Photoacoustic Imaging agents

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

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)

Opto-Acoustic Ultrasound Transducers

Optoacoustic US Transducers Receive / Transmit Hi Q

Bell’s Photophone February 1880

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

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

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

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

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

Acoustic Signal

Spectrum

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

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

Pulse-echo Results

Optical Microring detectors

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

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

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

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

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)

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

Photoacoustic Imaging 500 mm

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

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

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

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)

3D phantom imaging 50 µm Array size: 128x128 Element spacing: 30 um

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

Photoacoustics agents for functional and molecular imaging

Gold Nanorods – Molecular probe for PAI

Au Nanorod – Spectrum

Bioconjugation Gold Nanorod Surfactant (CTAB) Antibody PAA

Cell Culture Setup AM OS UT SC CC BX Laser OPO

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

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

Animal Imaging

Prostate Imaging

PEBBLES – Molecular Contrast

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

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

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

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

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

Example - pH dye SNAFR-5F

PA sensor for protease activity Abs

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

More slides

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

Fabrication Process II

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

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

Optical Absorption

50 MHz Test Signals Pulse-echo Optic modulation Spectra

Acoustic modulation Reflection x Wavelength y z

Stained live lobster nerve cord PE Depth PA 2 mm Lateral DR = 32 dB

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

PEBBLE with ICG

PEBBLE with ICG - Stability

PEBBLE with ICG - Spectrum

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

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