High Resolution Photoacoustic Tomography

1
High Resolution Photoacoustic Tomography

• Lihong V. Wang, PhD
• Gene K. Beare Distinguished Professor
• Optical Imaging Laboratory
• Department of Biomedical Engineering
• Department of Radiology (secondary appt.)
• Washington University, St. Louis
• LHWang_at_biomed.wustl.edu

2
Credits to Lab Members

• CURRENT MEMBERS
• H. Fang
• A. Garcia-Uribe
• S. Hu
• X. Jin
• R. Kothapalli
• C. Kim
• G. Ku
• C. Li
• L. Li
• Y. Li
• K. Maslov
• M. Pramanik
• K. Song
• L. Song
• E. Stein
• M. Todorovic
• X. Xu
• X. Yang

• FORMER MEMBERS
• X. Xie, MS
• M. Xu, PhD
• Y. Xu, PhD
• G. Yao, PhD
• W. Yu, MS
• X. Zhao, MS

• FORMER MEMBERS
• J. Ai, PhD
• D. Feng, MS
• J. Hollmann
• S. Jiao, PhD
• J. Li, PhD
• M. Li, PhD
• G. Marquez, PhD
• M. Mehrubeoglu, PhD
• J. Oh, PhD
• Y. Pang, MS
• S. Sakadzic, PhD
• M. Sivaramakrishnan, MS
• E. Smith, MS
• H. Sun, PhD
• X. Wang, PhD
• Y. Wang, MS

3
Credits to Collaborators

• Texas AM University (Animal study)
• G. Stoica, DVM
• UT MD Anderson Cancer Center (Clinical study
  contrast agents)
• M. Duvic, MD
• B. Fornage, MD
• K. Hunt, MD
• C. Li, PhD
• V. Prieto, MD
• Nanospectra (Nanoshells)
• P. ONeal, PhD
• J. Schwartz, PhD
• D. Payne
• USC (high-frequency ultrasound array)
• K. Shung, PhD (R. Bitton, PhD candidate)

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Outline

• Motivation and challenges
• Reconstruction-based photoacoustic tomography
• Confocal photoacoustic microscopy
• Deeply penetrating RF-based thermoacoustic
  tomography
• Summary

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Motivation for Optical Imaging

• Safety Non-ionizing radiation photon energy is
  2 eV.
• Physics Related to the molecular conformation
  of tissue.
• Optics High intrinsic contrast
• Optical absorption oxyhemoglobin,
  deoxyhemoglobin, melanin, and exogenous contrast
  agents.
• Optical scattering Size of cell nuclei.
• Optical polarization Collagen and muscle fibers.
• Physiology Functional imaging of physiological
  parameters
• Oxygen saturation of hemoglobin (related to
  hyper-metabolism)
• Total hemoglobin concentration (related to
  angiogenesis)
• Enlargement of cell nuclei
• Orientation of collagen
• Denaturation of collagen
• Blood flow (Doppler)
• Physiology Molecular imaging
• Integrin, VEGF, etc
• Reporter genes
• .

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Challenges in Optical Imaging
OM, SNOM
1 mm
CFM, 2PM, SHM, etc.
Soft limit lt
OCT
DOT, UOT, PAT
Hard limit 10 d 5 cm

• OM Optical microscopy
• SNOM Scanning near-field optical microscopy
• CFM Confocal microscopy
• 2PM Two-photon microscopy
• SHM Second harmonic microscopy
• OCT Optical coherence tomography
• DOT Diffuse optical tomography
• UOT Ultrasound-modulated optical tomography
• PAT Photoacoustic tomography

Simulation software MCML available
from http//oilab.seas.wustl.edu
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High Relative ResolutionDepth-to-Resolution
Ratio gt 100
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Outline

• Motivation and challenges
• Reconstruction-based photoacoustic tomography
• Confocal photoacoustic microscopy
• Deeply penetrating RF-based thermoacoustic
  tomography
• Summary

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Reconstruction-based Photoacoustic Tomography
Physical Review E 71, 016706 (2005). Phys. Rev.
Letters 92, 033902 (2004).
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Photoacoustic Forward Solutionin an Infinite
Medium Plane Wave
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Photoacoustic Forward Solutionin an Infinite
Medium Spherical Wave
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Experimental Setup of Orthogonal-mode
Photoacoustic Tomography
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Photoacoustic Inverse Solutionin an Infinite
Medium Time-domain Reconstruction
Beamforming
High-frequency contribution
Physical Review E 71, 016706 (2005). Physical
Review Letters 92, 033902 (2004).
14
Transcranial Functional Photoacoustic Imaging of
RatWhisker Stimulation In Vivo Hemodynamics
Left-whisker stimulation
Right-whisker stimulation
Nature Biotech. 21, 803 (2003).
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Photoacoustic Angiography of Rat Brains In Vivo
(B) With ICG-PEG

• Without ICG-PEG

• Speckle free
• High resolution 60 mm
• High sensitivity fmol

(D) Open-skull photo
(C) B A
Optics Letters 8, 608 (2004).
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Monitoring of Dynamic Optical Absorption of
Nanoshells
Nano Letters 4, 1689 (2004).
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Functional and Molecular Photoacoustic
ImagingNude Mouse with a U87 Glioblastoma
Xenograft in the Brain
(b) Molecular imaging Tumor over-expression of
integrin
(a) Functional imaging Tumor hypoxia
Proc. of IEEE (accepted, 2007). Contrast agent
provided by Chun Lis Group (MD Anderson)
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Photoacoustic Imaging usingHigh-frequency (30
MHz) Ultrasound Array
Transducer built by Kirk Shungs Group (USC)
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Real-time Imaging of Nude Mouse Heart Beating
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Deeply Penetrating Photoacoustic Tomographywith
NIR Excitation ICG Contrast
Optics Letters 30, 507 (2005).
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Photoacoustic Imaging of the Breast (Fairway
Medical)
Alexander Oraevskys Group
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Photoacoustic Imaging of the Breast(Fairway
Medical) Images
X-ray Mammogram
Tumors detected 29/30
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Outline

• Motivation and challenges
• Reconstruction-based photoacoustic tomography
• Confocal photoacoustic microscopy
• Deeply penetrating RF-based thermoacoustic
  tomography
• Summary

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Reflection-mode Photoacoustic Microscopy
Illustration
Sphere
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Reflection-mode Dark-field ConfocalPhotoacoustic
Microscopy System
Optics Letters 30, 625 (2005). Nature Biotech.
24, 848 (2006).
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System Parameters

• Laser
• Tunability 570-770 nm
• Repetition rate 10 Hz
• Pulse width 6.5 ns
• Optical fiber 0.6 mm diameter
• Energy per pulse 0.2 mJ
• Energy density at focus 6 mJ/cm2 lt20 mJ/cm2
  (ANSI safety limit)
• High-frequency ultrasound transducer
• Center frequency 50 MHz
• Nominal bandwidth 70 of 50 MHz
• NA 0.44

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Imaging Depth and Resolution

• Imaging depth 3 mm
• Axial resolution 15 microns
• Depth/resolution 200 pixels
• Lateral resolution 45 microns
• Acquisition time 2 ms/A-scan
• No signal averaging

3 mm
B-scan of a black double-stranded cotton thread
embedded in rat
Optics Letters 30, 625 (2005).
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Volumetric Imaging of Rat Microvasculature In Vivo
Maximum amplitude projection onto the skin
1 mm
Volume 10 mm x 8 mm x 3 mm
Optics Express 14, 9317 (2006).
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Imaging of Skin Burn in Pigs
Acute thermal (175 oC, 20 s) burn in pig skin in
vivo. Postmortem imaging at 584-nm optical
wavelength.
Photograph
Photoacoustic image
B-scan image
Histology
J Biomed Optics 11, 054033 (2006).
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Imaging of Hemoglobin Oxygen Saturation (SO2) In
Vivo
Total hemoglobin concentration
SO2 in segmented venules and arterioles
4
1
5
2
3
1 mm
Histology
Arterial microsphere perfusion
Nature Biotech. 24, 848 (2006).
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Hemodynamics In Vivo(578, 584, 590, and 596 nm)
Total hemoglobin
Oxygen saturation
Arteries and veins
Change in oxygenation
Appl. Phys. Lett. 90, 053901 (2007).
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Imaging of Melanoma In Vivo
Composite photoacoustic image acquired at 584 and
764 nm
B-scan image at 764 nm
Photograph
Histology
Movie
Surface rendering
Contrasts Vessel 13 Melanoma 69
Nature Biotech. 24, 848 (2006).
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In Vivo Genetic ImagingGene Expression in
Gliosarcoma Tumor in Rat

• LacZ (gene)
• Beta-galactosidase (enzyme )
• X-gal (colorless substrate)
• Blue product

Image of blood vessels at 584-nm wavelength
Image of expression of LacZ reporter gene at
635-nm wavelength
Composite image
1 mm
J Biomed Optics 12(2), 020504 (2007).
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Imaging of Human Palm In Vivo
Photo
Maximum amplitude projection onto the skin
B-scan image

Skin surface
Stratum

corneum

4

6

3

7

2

5

1

1 mm

Optical absorption

Nature Biotech. 24, 848 (2006).
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Deep Reflection-Mode Photoacoustic Imaging
SystemSchematic
Prism
Concave lens
Spherical conical lens
Z
Optical condenser
US transducer
Y
Sample
X
(A) Schematic
(B) Light path

• Laser source
• Wavelength 804 nm
• Pulse width lt15 ns
• Repetition rate 10 Hz

• Transducer
• Frequency 5 MHz or 10 MHz
• Focal length 1
• Aperture 0.75 diameter
• f-number 1.33

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Maximum Imaging Depth in Chicken Breast Tissue

• 804 nm optical wavelength
• Exposure lt31 mJ/cm2 (ANSI)
• 5 MHz transducer
• 30 times average
• SAFT
• Axial resolution 144 µm
• Transverse resolution 560 µm
• SNR
• 37 dB (17 mm)
• 24 dB (30 mm)

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Noninvasive Photoacoustic Imaging of Rabbit In
Situ
(a) Axial view
(c) Invasive photograph
Kidney
Intestine
Vessel
5 mm
(b) Saggital view
V
I
12 mm
K
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Modern High-resolution Optical Microscopy(Depth
/ Resolution gt 100)

• Optics Letters 30, 625 (2005).
• Nature Biotech. 24, 848 (2006).
• Nature Protocols 2, 797 (2007).

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Outline

• Motivation and challenges
• Reconstruction-based photoacoustic tomography
• Confocal photoacoustic microscopy
• Deeply penetrating RF-based thermoacoustic
  tomography
• Summary

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Experimental System for Thermoacoustic Tomography
Stepper motor
Water tank
Ultrasonic transducers
Waveguide
Microwave generator
Amplifiers and scope
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Thermoacoustic Image of a Mastectomy Specimen

• 11 cm diam. X 9 cm thick
• 51 contrast
• Invasive lobular carcinoma

Tech. in Cancer Res. Treatment 4, 559 (2005).
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Hemispherical Detection Geometry
Robert Krugers Group http//optosonics.com
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Summary

• Physically combining ultrasonic and
  electromagnetic waves (light RF) provides
• improved spatial resolution compared with
  optical/RF imaging,
• new contrast mechanisms compared with ultrasound
  imaging.
• Spatial resolution is determined by the
  ultrasonic parameters.
• Spatial resolution is scalable with the
  ultrasonic parameters.
• Contrast is provided by the electromagnetic
  properties.
• Deep (cm) tissue imaging can be achieved.
• Speckle artifacts do not exist.
• Functional imaging can be accomplished with
  endogenous contrast.
• Molecular imaging can be accomplished with
  exogenous contrast agents.
• Non-ionizing radiation is used.
• Costs are comparable with those of ultrasound
  systems.

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Limitations and Future Directions

• Limitation of light penetration up to 5 cm (10
  cm thickness)
• Limitation of ultrasound penetration through
  cavities and bones
• Commercialization of photoacoustic microscopic
  and macroscopic imaging technologies
• Adaptation of commercial ultrasound technologies
• Development of reporter genes that produce
  optically absorbing gene expression products for
  molecular (genetic) imaging
• Development of RF contrast agents for molecular
  imaging

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Chapters

• Introduction to biomedical optics
• Single scattering Rayleigh theory and Mie theory
  
• Monte Carlo modeling of photon transport
• Convolution for broad-beam responses
• Radiative transfer equation and diffusion theory
• Hybrid model of Monte Carlo method and diffusion
  theory
• Sensing of optical properties and spectroscopy
• Ballistic imaging and microscopy
• Optical coherence tomography
• Mueller optical coherence tomography
• Diffuse optical tomography
• Photoacoustic tomography
• Ultrasound-modulated optical tomography

Homework solutions available to instructors.
Taped presentations available on our web.