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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
Australian “National” Team
International rugby sevens tournament: 1982
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
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
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{
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
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
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
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
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
• 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
Consequences of Age Related
Changesx-ray mammograms (normal breasts)
DENSEMILDY
DENSE FATTY
AGE
http://homearts.com/depts/health/a8bhty51.htm
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)
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
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).
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
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
– 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
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
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)
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
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)
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
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
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
– 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?
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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