Diffuse Optical Spectroscopy and Imaging

Laser Microbeam and Medical Program (LAMMP) Beckman Laser Institute and Medical Clinic

Departments of Biomedical Engineering and Surgery

University of California, Irvine http://www.bli.uci.edu

Bruce J. Tromberg BLI

Computational Biophotonics Workshop: August 2016

Disclosure

Co-founder: Industry Collaboration:

Medical Imaging

MR, X-ray, Nuclear, US (Optical)

Mainstream Modalities

Where Does Biophotonics Fit In?

Masimo Pronto

Medtronic-Covidien Invos

DiagnosticsImaging/spectroscopy

NOVADAQ Pinpoint

Heidelberg Engineering Spectralis

Perimed Periscan Pentax Endoscope

Syneron-Candela, Lumenis, Alma, Cutera, Cynosure, Fotona, Lutronic, etc

AMO Intralase FS

TherapeuticsMedical Lasers

Vioptix Odissey

>$60B/yr

St. Jude C7-XR

Where Does Biophotonics Fit In?

Masimo Pronto

Medtronic-Covidien Invos

DiagnosticsImaging/spectroscopy

NOVADAQ Pinpoint

Heidelberg Engineering Spectralis

Perimed Periscan Pentax Endoscope

Syneron-Candela, Lumenis, Alma, Cutera, Cynosure, Fotona, Lutronic, etc

AMO Intralase FS

TherapeuticsMedical Lasers

Vioptix Odissey

>$60B/yr

St. Jude C7-XR

Masimo Pronto

edtronic-Me Covidien Invos

Vioptix Odisseey

XR

Diffuse Optics • Multi-Spectral (NIR) • Structured Light: Space and Time• Optical Pathlength Control

Multiple Light Scattering

850 nm NIR LEDs

O'Sullivan TD, et al. J Biomed Opt.17(7):071311 (2012).

Tissue Optics Quantitative Challenge

Measuring Optical Pathlength

Molecular Absorption Loss

Absorption + Scattering Loss

A = bC; b = 1cm

A = bC; b = ??

Fixed pathlength

Unknown pathlength

Why Measure Optical Pathlength?

• Determine Perfusion and Metabolism at depth (Oxy/Deoxy Hb) • Determine concentration of other NIR absorbers/fluors (e.g. Water,

Lipid, exogenous dyes/particles )• Correct fluorescence for tissue optical property distortions

1) Separate Absorption from Scattering 2) Localize Information in 3D (Tomography)

Physics

Physiology

Controlling Pathlength Three Ways to Control Pathlength

blue

green

red

ScatterDominated

labs ~ lscat labs >> lscat

1) Wavelength:

Controlling Pathlength

1) Wavelength: blue

green

red

100% StO2

50% StO2

Sensitive to small absorption changes

Three Ways to Control Pathlength

400 labs ~ lscat labs >> lscat

Controlling Pathlength

2) Space: labs ~ 10 cm; lscat ~ 20-40 μm;

D-1 D-2

2 10 20mm

Reflectance vs D

μa = 0.01 mm-1

μs’ = 0.1 mm-1

Scatter dominated

Scatter + Absorption

Three Ways to Control Pathlength

400 labs ~ lscat labs >> lscat

f = 0 mm-1 f = 0 mm-1

400 labs ~ lscat labs >> lscat

f = 0 mm-1 f = 0.2 mm-1

Controlling Pathlength

3) Time: abs ~ 0.5 ns, scat ~ 0.20 ps Intensity vs. Time (2 cm s-d)

Laserpulse

0.2 1.00.6ns

T-1

T-2

Scatterdominated

Absorptiondominated

Three Ways to Control Pathlength

2 cm s-d

Measuring Optical Path Length

Measuring Optical Path Length FT

(t)

FT-1

()

FT(t)

FT-1

()

Measuring Optical Path Length FT

(t)

FT-1

()

FT(t)

FT-1

()

FT

FTF-1

(

~10 cm depth, ~ cm resolution ~1 cm in depth, ~mm resolution Tromberg, et al., Appl Opt., (1993) Cuccia et. al., Opt Lett, (2005)

source detector (re ection)

scattering tissue

inte

nsity

time

source light

detected light

),(r

),(rA

Temporal Frequency Domain Photon Migration (FDPM)

Controlling Pathlength

),(),(),()(),( trStrtrrDt

trcn

a =+

Light source

Loss: Light Absorption (f/ )

Build up:Light Scattering

)]'(3/[1 saD += Photon Diffusion Coefficient

In Scatter-Dominated Region: Diffusion Equation

Light Tissue Distribution

Fluence rate:Space, time

1/labs 1/ltr T. O’Sullivan et al., JBO, 2012

Diffusion equation (time dependent)

==+= ])[exp()exp(4

)exp(4

),( rktirkDr

StikrDr

Srt imgrealACAC

AC

frequency domain scalar photon density wave

)exp()()(),(ratefluencemodulated tirrrt ACDC +=

damped wavecDi

Dk a +=2

In nite medium:

Boundary Conditions: Haskell, Tromberg et al, JOSA-A (1994)

0200400600800

10001200

0 0.02 0.04 0.06 0.08 0.1

k (1/mm)

Mod

ulat

ion

Freq

uenc

y (M

hz)

Photon density wave

kreal

a = 0.006 mm-1

s’ = 1 mm-1

n=1.4

photon density wavelength = 2 /kimg 10 cm @ 200 MHz

(if no scattering, in air 9 m @ 200 MHz )

phase velocity Vp = /kimg ={ << c a Vp = 2(D/c a )1/2 16 mm/ns >> c a Vp = (2D c)1/2

1/ l

DC = 1/ eff = (D/ a)1/2 = 7.4 mm

kimag

0.05 0.1 0.15 0.2 0.25c a= 200 MHz

AC = 1/kreal

(independent of )

(dependent on : dispersion)

200 400 600 800 10000

1

2

3

4

5

x 10-4

Am

plitu

de (

a.u.

)

Frequency (MHz)

DataModel Fit

200 400 600 800 10000

50

100

150

200

250

300

Pha

se (

deg.

)Frequency (MHz)

DataModel Fit

700 800 900 10000

0.005

0.01

0.015

0.02

Abs

orpt

ion

Coe

ffic

ient

(m

m-1

)Wavelength(nm)

FDPM

700 800 900 10000.6

0.7

0.8

0.9

1

Red

uced

Sca

tter

ing

Coe

ff.

(mm

-1)

Wavelength(nm)

FDPM

700 800 900 10000

0.005

0.01

0.015

0.02

Abs

orpt

ion

Coe

ffic

ient

(m

m-1

)Wavelength(nm)

FDPM

700 800 900 10000.6

0.7

0.8

0.9

1

Red

uced

Sca

tter

ing

Coe

ff.

(mm

-1)

Wavelength(nm)

FDPMPower Law Fit

700 800 900 10000.6

0.7

0.8

0.9

1

Red

uced

Sca

tter

ing

Coe

ff.

(mm

-1)

Wavelength(nm)

FDPMPower Law Fit

700 800 900 10000

0.005

0.01

0.015

0.02

Abs

orpt

ion

Coe

ffic

ient

(m

m-1

)Wavelength(nm)

FDPM

700 800 900 10000

0.2

0.4

0.6

0.8

1

1.2R

efle

ctan

ce (

a.u.

)

Wavelength(nm)

700 800 900 10000

0.005

0.01

0.015

0.02

Abs

orpt

ion

Coe

ffic

ient

(m

m-1

)Wavelength(nm)

FDPMSSFDPM

700 800 900 10000.6

0.7

0.8

0.9

1

Red

uced

Sca

tter

ing

Coe

ff.

(mm

-1)

Wavelength(nm)

FDPMPower Law Fit

700 800 900 10000

0.005

0.01

0.015

0.02

Abs

orpt

ion

Coe

ffic

ient

(m

m-1

)Wavelength(nm)

FDPMSSFDPMChromophore Fit

Oxyhemoglobin = 12.7 μMDeoxyhemoglobin = 4.1 μM

Water = 21.5% Lipid = 79.6%

LcII

=0log

650 700 750 800 850 900 950 10000.0

0.2

0.4

0.6

0.8

1.0

Abs

orpt

ion

(mm

-1m

M-1)

Wavelength(nm)

Tissue NIR absorbers

HHb

O2Hb

BULK LIPID

H2O

OxygenMetabolism

Arteriole90 mmHg

Tissue 17 < 47 mmHg

CellMitochondria2<30 mmHg

Venule 35

mmHg10-30 mmHg

Oxygen demand

Oxygen Supply

Cell-vascularcoupling

Predicting Clinical Outcome

34M. Herringlake, et al., Anesthesiology, 114, 58 (2011)

Total Population

High Risk Group

Optical endpoint: Pre-Surgical StO2 = HbO2/HbtotClinical endpoint: 30 day and 1 yr survival

n = 1200, Cardiac Bypass Surgery

Covidien INVOS

Predicting Clinical Outcome

35M. Herringlake, et al., Anesthesiology, 114, 58 (2011)

50% StO2 = ~25% greater chance of death at 1 year 50% StO2 = 45% SURVIVAL at 1 year (high risk group)

Total Population

High Risk Group

Covidien INVOS Optical endpoint: Pre-Surgical StO2 = HbO2/HbtotClinical endpoint: 30 day and 1 yr survival

Cerebral hemodynamics during anesthesia Phenylephrine Ephedrine

Lingzhong Meng

L. Meng, et al. Brit J. Anes, 107, 209 (2011)

ISS Oxiplex (Frequency Domain)

Cerebral hemodynamics during anesthesia Phenylephrine Ephedrine

Lingzhong Meng

L. Meng, et al. Brit J. Anes, 107, 209 (2011)

ISS Oxiplex (Frequency Domain)

<65% ~3-4 minutes/bolus

Cerebral hemodynamics during anesthesia Phenylephrine Ephedrine

Lingzhong Meng

L. Meng, et al. Brit J. Anes, 107, 209 (2011)

ISS Oxiplex (Frequency Domain)

<65% ~3-4 minutes/bolus

Cardiac Output Drop