Post on 30-Dec-2015
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Combining Light & SoundCan ultrasound become the preferred modality for functional and molecular
imaging?
Shai AshkenaziBiomedical Ultrasound Lab
Dept. Biomedical EngineeringUniversity of Michigan
Outline
Imaging methods
Ultrasound Photoacoustic
Imaging devices
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
> 20 MHz (UBM)
10 – 20 MHz
Low MHz
Resolution (mm)
Pen
etra
tion
dep
th
(mm
)
0.01 0.1 1
10
100
1
Abnormal Thyroid Gland
Opto-Acoustic Ultrasound Transducers
Optoacoustic US Transducers
Receive Transmit
Hi Q
/
Bell’s Photophone
February 1880
Etalon detector – principle of operation
Etalon
PD Array (camera)
CW laser
Etalon detector – principle of operation
Etalon
PD Array (camera)
CW laser
Ultrasound – Space/time load
Piezo vs. EtalonComparison of
sensitivity
ETALON
2.7 2.9
0
Time (s)
Am
plit
ud
e
Etalon
5.3 5.5 5.7
0
Time (s)
Pulse-EchoPIEZO
TRANS
Optical Generation of Ultrasound
High thermal expansion
Optically absorbing
Water
Black PDMS
Clear PDMS
Laser pulse
2D Gold Nanostructure
220 nm
128 nm
20 nm
Glass
Substrate
4.5 um PDMS layer
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
Ultrasound Generation
Beam
Ultrasound Detection
Beam
Etalon
6 um
PDMS layer
SU-8 protection layer
200 nm
Pulse-echo Results
Optical Microring detectors
Resonance optics
Output = T + S
T = - S (critical coupling)
S = 0 (off-resonance phase cancelation)
TS
Experimental verification
Tunable LaserPhotodetector
Ultrasound Transducer
USPulser0
0.01
0.02
0.03
0.04
1550 1560 1570
Wavelength (nm)
Tra
ns
mis
sio
n
a
b
c
1558 1563 (nm)T
ran
smis
sio
n
0
16.5 18Time (s)
a
b
c
1558 1563 (nm)
Tra
nsm
issi
on
Wavelength dependence
0
0
16.5 18Time (s)
0
Tra
ns.
Mod
ula
tion
10 MHz Transducer
Array configurations
In
Out
λ1 λm
λm+1 … λ2
m
λ3 …λ2Fiber coupled optical circulator
Demux and Photodetector array
Tunable laser
Demultiplexer and Photodetector array
Miniaturization of high-Freq arrays for intravascular and “in-vivo” microscope application
80 elements sharing 1 waveguide 2D Arrays
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)
G23
0.64 mm
Side viewing
Transmitter
Receiver array
200 µ
m
2 mm
Photoacoustic Imaging
Position (mm)
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500 m
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
PD Array (camera)
CW laser
Etalon
Etalon for Photoacoustic imaging
2D phantom imaging
0.11mm
100 m
Photoacoustic image
Optical image
Nerve cord imaging
Probe laser scan lines
(4mm x 0.36mm aperture)
532 nm pulsed illumination
500 m
Nerve Cord In Lobster Tail
3D phantom imaging
50 µm
Array size: 128x128 Element spacing: 30 um
Pig Coronary Artery
Lateral Position (mm)A
xial
pos
ition
(m
m)
0 2
4
6
8
Lateral position (mm)
Axi
al p
ositi
on (
mm
)
-2 0 2
4
6
8
Lateral Position (mm)
Axia
l Posi
tion
(m
m)
700 nm
Photoacoustics agents for functional and molecular imaging
Gold Nanorods – Molecular probe for PAI
Au Nanorod – Spectrum
400 500 600 700 800 900 10000
0.2
0.4
0.6
0.8
1
Wavelength (nm)
Ab
sorp
tio
n e
ffic
ien
cy
Bioconjugation
PAA
Surfactant (CTAB)
Antibody
Gold Nanorod
OS AM
Laser
OPO
UTSC
BXCC
Cell Culture Setup
Photoacoustic Image – LNCaP Cells
ConjugatedNanorods
UnconjugatedNanorods
-40
-30
-20
-10
0
-40
-30
-20
-10
0
1 mm
Laser OPO
US
UA
PH
SYNC
BX
UltraSound-PhotoAcoustic (USPA) Imaging
Combined Modality
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Animal Imaging
-20 -15 -10 -5 0 5 10 15
0
5
10
15
20
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
• Ultimate sensitivity for PAI applications – Acoustic noise limited
• Explore structures for optimal acousto-optic interaction
– Membrane interface
– Air-water interface
-5 -4 -3 -2 -1 0 1 2 3 4 5
x 1011
0.2
0.4
0.6
0.8
1
Frequency (Hz)
Tra
nsm
issi
on
Waveguide Bragg Grating
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
• 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
Combine versatility of molecular probes with PAI
Example - pH dye
5 6 7 8 9 100.35
0.4
0.45
0.5
0.55
0.6
0.65
0.7
pH
Phot
oaco
ustic
am
plitu
de (a
.u)
Absorption of Snarf-5F as a function of pH
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
400 500 600 700 800 900
Wavelength (nm)
Ab
sorp
tio
n
pH 5.0pH 6.0pH 7.0pH 8.0pH 9.0pH 10.0
SNAFR-5F
PA sensor for protease activity
400 450 500 550 600 650 7000
2
4
6
8
10
Wavelength (nm)A
bso
rpti
on
eff
icie
ncy
30 nm gold spheres pair (in water)
d
12 nm
6 nm
2 nm
Abs
T H AN K S
Chemistry
Raoul Kopelman
Gwangseong Kim
Tom Horvath
Rodney Agayan
Chemical Eng.
Nick Kotov
Ashish Agarwal
Cancer Center
Mark Day
Kathleen Day
EECS
Jay Guo
ChungYen Chao
Tao ling
JingSung
More slides
Fabrication Process I
Laser Interference Lithography
Si
SiO2
glass
polymer
Nanoimprint
Lithography
Fabrication Process II
Transducer
Lens
ND filters
CollimatorPulsed Laser Input
Data
Collection
Experimental Setup
Amplifier
Ultrasound Detection
Beam
Integrated Device
PBSPhotodiode
Reflector
Ultrasound Generation
Beam
Amplifier
Data Capture
Pulse-echo Experiment
Optical Absorption
50 MHz Test Signals
5.6 5.7 5.8 5.9 6 6.1-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
Time (s)
Pul
se-e
cho
Sig
nal (
V)
(a)
2.7 2.8 2.9 3 3.1 3.2
-0.2
-0.1
0
0.1
0.2
Time (s)
Det
ecte
d O
ptic
al S
igna
l (V
)
(b)
0 20 40 60 80-50
-40
-30
-20
-10
0
Frequency (MHz)
Nor
mal
ized
Mag
nitu
de (
dB)
(c)
Pulse-echo Optic modulation
Spectra
Acoustic modulation
2xk
2xk
2xk
2zk 2
yk22 / corec
x
y z
Ref
lect
ion
Wavelength
Stained live lobster nerve cord
PE
PA
Dep
th
2 mm LateralDR = 32 dB
-35
-25
-15
-5
5 mm
dB
Phantom Image
Detection sensitivity = 5 x 1010 particles/cc
= 50 particles/cell
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 5 10 15
ICG concentration (μM)
ab
so
rba
nc
e a
t 7
90
nm
Free ICG
PEBBLE
PEBBLE with ICG
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4
Time (day)
Re
lati
ve
ab
s.
at
79
0 n
m
ICG free
ICG ormosil PEBBLE
PEBBLE with ICG - Stability
0
0.4
0.8
1.2
1.6
400 600 800 1000
Wavelength (nm)
Ab
so
rba
nc
e10 μM
5 μM
2.5 μM
1 μM
0.5 μM
ICG Ormosil PEBBLE
PEBBLE with ICG - Spectrum
Photoacoustic Image – PEBBLES
Position (mm)
Po
sit
ion
(m
m)
10 20 30
15
20
25
1010 10121011
Detection sensitivity = 1010 particles/cc
= 10 particles/cell
Posi
tion (
mm
)
0 1
1
0 -40
-30
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-10
0
Position (mm)
Posi
tion (
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)
0 1
1
0 -40
-30
-20
-10
0
Photoacoustic Image – LNCaP Cells
ConjugatedPEBBLES
UnconjugatedPEBBLES