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Medical Imaging in ThickTissues Using Diffuse Optics
Laser Microbeam and Medical Program (LAMMP)Beckman Laser Institute
Department of Biomedical Engineering
University of California, Irvinewww.bli.uci.edu
Bruce J. Tromberg
BLI
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Australian “National” Team
International rugby sevens tournament: 1982
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Beckman Laser Institute and Medical Clinic
http://www.bli.uci.edu/Five Beckman Institutes in U.S.
Univ. of Illinois
UC Irvine
(1982)
Caltech
Stanford
City of Hope
Nat. Med. Ctr.
BLI: Co-founders Michael Berns and Arnold Beckman
BLI
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Optical Imaging in Thick Tissues
800 nm NIR light
Optical Imaging in Thick Tissues
• What is the biologic origin of contrast?
• Can contrast be quantified?
• Can light be localized?
Key Questions
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Optical Imaging in Thick Tissues
• What is the biologic origin of contrast?
• Can contrast be localized?
• Can contrast be quantified?
Key Questions
Intrinsic Optical Contrast0.1 µm
1.0 µm
10 µm
1 cm
5 cm
500 µm
5mm
1mm
{Sub-cellular Structures:
Size/Shape/Density
Scattering
(lsc ~20 �m)
Scattering
&
Absorption
(labs ~10 cm)
Scattering and absorption: across
spatial scales
{Cell Proliferation
Hypoxia
Fibrosis
Edema
Necrosis
Angiogenesis{
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Tissue Spectroscopy
Scattering
600-1000 nm
NIR Optical Spectrosocpy
600 650 700 750 800 850 900 950 10000.0
0.2
0.4
0.6
0.8
1.0
AB
SO
RP
TIO
N(m
m-1
mM
-1
)
WAVELENGTH (nm)
HHb
O2Hb
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NIR Optical Spectroscopy
600 650 700 750 800 850 900 950 10000.0
0.2
0.4
0.6
0.8
1.0
AB
SO
RP
TIO
N(m
m-1
mM
-1
)
WAVELENGTH (nm)
HHb
O2Hb
Lipid
H2O
Optical Imaging in Thick Tissues
• What is the biologic origin of contrast?
• Can contrast be localized?
• Can contrast be quantified?
Key Questions
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Multiple Light Scattering
Light Propagation in TissueOptical Imaging in Thick Tissues
• What is the biologic origin of contrast?
• Can contrast be localized?
• Can contrast be quantified?
Key Questions
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Technology for Tissue Spectroscopy
and Imaging
• Based on broadband modulation of semiconductor diode
lasers, “photon diffusion” models
• Quantitatively separates absorption from scattering
• Tomography of biochemical composition and structure
Time and Frequency-Domain Photon Migration
Tromberg et al. Neoplasia 2, (2000).
Diffuse Optical Imaging/Spectroscopy
Quantitative Measurements, Biochemical Composition
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Quantitative Measurements, Biochemical Composition
• Hemoglobin– Oxy-, Deoxy-, Met-, Total, Tissue oxygen saturation
• % Water– Protein bound, deep tissue temperature
• % Lipid
• Cytochrome oxidase– Oxidized, reduced forms
• Tissue Scatter Power– Density of cells, collagen, lipid
• Exogenous probes– ICG, Methylene Blue, Evans Blue…NIR fluorescent probes,
etc.
Diffuse Optical Imaging/Spectroscopy Diffuse Optics Technologies
Diffuse Optical Imaging (DOI)
Diffuse Optical Spectroscopy (DOS)
• Humans– Breast, Brain, Bone, Muscle
• Small animal models– Whole body
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• Cancer– Detection, image-guided therapy
• Functional Activation– Brain, muscle
• Wound Healing– Tissue viability, perfusion
• Therapeutic drug monitoring
Diffuse Optics Applications
Mammography: Poor Performance inDense Breast (~60% sensitivity)
Breast Cancer Motivation
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Consequences of Age Related
Changesx-ray mammograms (normal breasts)
DENSEMILDY
DENSE FATTY
AGE
http://homearts.com/depts/health/a8bhty51.htm
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1) Detection
• Pre- Peri-menopausal, high risk subjects
2) Guiding Therapies• Intraoperative (nodes, margins)
• Neoadjuvant Chemotherapy
locally advanced disease
Breast Cancer Role
(>600 subjects NTROI-wide)
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Broadband Frequency Domain Photon MigrationPham, Tromberg, et al., Rev. Sci. Instr., 71, 2500, (2000)
�
light scattering tissuesµ µa s’,
Frequency-DomainInstrument
I
time (ns)
sourcelight
detectedlight
�(�,�)
�(�,�) NonlinearLeast
Square Fits
Experimental Response
�(�,�)
�(�,�)
�
�
NIR TissueSpectroscopy
SpectroscopicAnalysis
Bulk TissueFunction &Structure
Theoretical Response
|�(�,µ ,µ )|a s’
�{ �,µ ,µa s’�( )}
�
�
::
White
light
Laser
diodes
�
Spectro-
graph
APDFDPM
SS
z
Measurement
time: ~15 sec
Bevilacqua, et al., Applied Optics, 39, 2000.
Combined FDPM and Steady State Spectroscopy
Broadband Diffuse Optical Spectroscopy
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The Laser Breast Scanner
-50-500 MHz (FDPM)
-Full NIR (600-1000nm) ~ 30 s
-Point-point scan measurement
The LBS handheld probe
Pham, TH., et al. Review of Scientific Instruments, 71 , 1 – 14, (2000).Bevilacqua, F., et al. Applied Optics, 39, 6498-6507, (2000).
The Laser Breast Scanner
-50-500 MHz (FDPM)
-Full NIR (600-1000nm) ~ 30 s
-Point-point scan measurement
The LBS handheld probe
Pham, TH., et al. Review of Scientific Instruments, 71 , 1 – 14, (2000).Bevilacqua, F., et al. Applied Optics, 39, 6498-6507, (2000).
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Hand-held Scanner
10 mm
+30
-30
-10
0
-20
+10
+20
SCAN
DIRECTION
-Y
+Y x y
Linescan Geometry
10 mm
+30
-30
-10
0
-20
+10
+20
600 650 700 750 800 850 900 950 1000 10500.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
0.020
AB
SO
RP
TIO
N (
mm
-1
)
WAVELENGTH (nm)
600 650 700 750 800 850 900 950 1000 10500.66
0.68
0.70
0.72
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
RE
DU
CE
D S
CA
TT
ER
ING
(m
m-1
)
WAVELENGTH (nm)
600 650 700 750 800 850 900 950 1000 10500.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
0.020
AB
SO
RP
TIO
N (
mm
-1
)
WAVELENGTH (nm)
600 650 700 750 800 850 900 950 1000 10500.66
0.68
0.70
0.72
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
RE
DU
CE
D S
CA
TT
ER
ING
(m
m-1
)
WAVELENGTH (nm)
600 650 700 750 800 850 900 950 1000 10500.66
0.68
0.70
0.72
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
RE
DU
CE
D S
CA
TT
ER
ING
(m
m-1
)
WAVELENGTH (nm)
600 650 700 750 800 850 900 950 1000 10500.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
0.020
AB
SO
RP
TIO
N (
mm
-1
)
WAVELENGTH (nm)
Y= +20 mm
Y= 0 mm
Y= -30 mm
SCAN
DIRECTION
-Y
+Y
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Linescan Geometry
Parameters:�Hb-R
�Hb-O2
�Lipid
�H2O
�SP
�PRE
Indices:�THC
�Hb-Sat
�…-5 -4 -3 -2 -1 0 1 2 3 4 5
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PA
RA
ME
TE
R
POSITION
TMAX
TBASE
TPEAK
TAVG
– What Do Tumors “Look” Like?
– Can Optical Signatures Be Used for Diagnosis?
– Can Optics Monitor Therapy?
– Validate Optical Signatures by Conventional Imaging?
– Can Optics Predict Individual Therapeutic Response?
Major Questions
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– What Do Tumors “Look” Like?
– Can Optical Signatures Be Used for Diagnosis?
– Can Optics Monitor Therapy?
– Validate Optical Signatures by Conventional Imaging?
– Can Optics Predict Individual Therapeutic Response?
Major Questions Population Statistics
27±21Avg. Tumor Size (mm)
27.5±7.1BMI (m2/kg)
23.5Median Tumor Size (mm)
50.5± 13.8Age (years)
58Lesions (#)
57Subjects (#)
ValueItem
Invasive Ductal Carcinoma Study
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Averages (N=58)
650 700 750 800 850 900 950 1000
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
0.020
0.022
0.024
TBASE
AB
SO
RP
TIO
N(m
m-1
)
WAVELENGTH(nm)
TMAX
HHb & O2Hb
H2O & Lipid
Max Contrast (N=58)
0.026#37.5146PRE
0.0038*0.634±0.2780.830± 0.412SP
<0.0001*20.0±10.533.8±21.0WATER
<0.0001*63.2±12.349.7±18.0LIPID
<0.0001*14.6±7.521.5±11.3Hb-O2
<0.0001*5.93±2.429.98±5.02Hb-R
pNormalTumor
Invasive Ductal Carcinoma Study, <d>=2.7±2.1 cm
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Tumor Stratification by Age
650 700 750 800 850 900 950 10000.000
0.005
0.010
0.015
0.020
0.025
0.030
E
C
D
A
AB
SO
RP
TIO
N(m
m-1
)
WAVELENGTH ( nm)
B
AGE(< 30)
(30-39)
(40-49)
(50-59)
(>60)
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Summary: Tumor Detection
Encouraging Findings:
– Optical contrast of tumors: more than Hb
– Functional baselines are age dependent
– Evidence of success in women < 50
• Not prospective study
– What Do Tumors “Look” Like?
– Can Optical Signatures Be Used for Diagnosis?
– Can Optics Monitor Therapy?
– Validate Optical Signatures by Conventional Imaging?
– Can Optics Predict Individual Therapeutic Response?
Major Questions
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Monitoring of NAC
– Individualize treatment to optimize survivaland quality of life
– Complete pathological response increasedsurvival (NSABP trial, Fisher et al J Clin Onc, 1998)
– Need imaging to predict pathologicalresponse (pR)
Conventional Methods
• Recent 31 patient study correlationwith pathology:
– Palpation: 19%
– Mammography: 26%
– Ultrasound: 35%
– MRI: 71%
Yeh, E., et al., AJR Am J Roentgenol, 184, 868-77 (2005)
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Kinetic MRI and DOS
+33.0-17.1-43.7-69.0-39.7-36.4Difference
(%)
Lipid
avg, %
Water
avg, %
ctTHb
avg, �M
% tumor
volume
SER �1.30
Peak
Enhancement
Tumor
Volume
(cc)
Shah, N., et al. J. Biomed Opt, (2005)
Post 1 Post 4
Jakubowski, D. et al. J Biomed Opt, (2004)
Long-term tracking: ~12 weeks
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Why Optics and not MRI?
• Do methods probe different regions?
• Differential sensitivity?
– DCE-MRI: vessel resolution limit ~mm
– Optics: Sensitivity to <1 �M changes,
microvessels
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MRI-Optics Co-Registration Possible Mechanisms
• Early optical sensitivity to cell death
– Drop in Hb: reduced O2 consumption,
– Drop in H2O: loss of cellular water (MRI:increase ADC)
• Changes prior to MRI
– Similar to MRS choline signal
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– What Do Tumors “Look” Like?
– Can Optical Signatures Be Used for Diagnosis?
– Can Optics Monitor Therapy?
– Validate Optical Signatures by Conventional Imaging?
– Can Optics Predict Individual Therapeutic Response?
Major Questions Complete Responder
0 20 40 60 80 100 1200.04
0.05
0.06
0.07
0.08
0.09
0.10
0.11
0.12
TO
IA
VE
RA
GE
DAY
TUMOR AVERAGENORMAL AVERAGE
2306-13
Tumor approaches contra-lateral normal baseline
pathologic Response (pR)
Predict pR after 1 week?
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Pathology Response Predictions
757510050100SPECIFICITY (%)
4343715786SENSITIVITY (%)
SPLIPIDH2OO2HbHbITEM
100
100
Hb
& H2O
Based on Optical Measurements at day 6
11 patients, AC Therapy
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