medical imaging in thick tissues using diffuse optics

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


• What is the biologic origin of contrast?

• Can contrast be quantified?

• Can light be localized?

Key Questions



• Can contrast be localized?


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





Key Questions

Multiple Light Scattering

Light Propagation in TissueOptical Imaging in Thick Tissues




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






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






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






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

medical imaging in thick tissues using diffuse optics

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