diffuse optical spectroscopy and imaging · vioptix odissey ~$80b/yr st. jude c7-xr diffuse optics...
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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: July 2017
Where Does Biophotonics Fit In?
Masimo Pronto
Medtronic-Covidien Invos
Diagnostics
Imaging/spectroscopy
NOVADAQ Pinpoint
Heidelberg Engineering Spectralis
Perimed Periscan Pentax Endoscope
Syneron-Candela, Lumenis, Alma, Cutera, Cynosure, Fotona, Lutronic, etc
AMO Intralase FS
Therapeutics
Medical Lasers
Vioptix Odissey
~$80B/yr
St. Jude C7-XR
Where Does Biophotonics Fit In?
Masimo Pronto
Medtronic-Covidien Invos
Diagnostics
Imaging/spectroscopy
NOVADAQ Pinpoint
Heidelberg Engineering Spectralis
Perimed Periscan Pentax Endoscope
Syneron-Candela, Lumenis, Alma, Cutera, Cynosure, Fotona, Lutronic, etc
AMO Intralase FS
Therapeutics
Medical Lasers
Vioptix Odissey
~$80B/yr
St. Jude C7-XR
Where Does Biophotonics Fit In?
Masimo Pronto
Medtronic-Covidien Invos
Diagnostics
Imaging/spectroscopy
NOVADAQ Pinpoint
Heidelberg Engineering Spectralis
Perimed Periscan Pentax Endoscope
Syneron-Candela, Lumenis, Alma, Cutera, Cynosure, Fotona, Lutronic, etc
AMO Intralase FS
Therapeutics
Medical Lasers
Vioptix Odissey
~$80B/yr
St. Jude C7-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 = εbC; b = 1cm
A = εbC; 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
Scatter Dominated
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
Controlling Pathlength
2) Space: labs ~ 10 cm; lscat ~ 20-40 µm;
D-1 D-2
2 10 20 mm
Reflectance vs D
µa = 0.01 mm-1
µs’ = 0.1 mm-1
Scatter dominated
Scatter + Absorption
Three Ways to Control Pathlength
Controlling Pathlength
3) Time: τabs ~ 0.5 ns, τscat ~ 0.20 ps Intensity vs. Time (2 cm s-d)
Laser pulse
0.2 1.0 0.6 ns
T-1
T-2
Scatter dominated
Absorption dominated
Three Ways to Control Pathlength
2 cm s-d
Measuring Optical Path Length FT
(t)
FT-1
(ω)
FT(t)
FT-1
(ω)
~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 (reflection)
scattering tissue
ρ
inte
nsity
time
source light
detected light
),( ωrΘ
),( ωrA
Temporal Frequency Domain Photon Migration (FDPM)
Controlling Pathlength
),(),(),()(),( trStrtrrDt
trcn
a =+∇⋅∇−∂
∂φμφ
φ
Light source
Loss: Light Absorption (f/λ)
Build up: Light Scattering
)]'(3/[1 saD μμ += 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)
=−−=+−=Φ ])[exp()exp(4
)exp(4
),( rktirkDr
StikrDr
Srt imgrealACAC
AC ωπ
ωπ
frequency domain → scalar photon density wave
)exp()()(),( rate fluence modulated tirrrt ACDC ωΦ+Φ=Φ⇒
damped wavecDi
Dk a ωμ
+=2
Infinite 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
μa = 0.006 mm-1
μs’ = 1 mm-1
n=1.4
photon density wavelength = 2π/kimg ≅ 10 cm @ 200 MHz
(if no scattering, in air ≅ 9 m @ 200 MHz )
phase velocity Vp = ω/kimg ={ ω << cμa ⇒ Vp = 2(D/cμa )1/2 ≈16 mm/ns ω >> cμa ⇒ Vp = (2Dωc)1/2
1/τl
δDC = 1/μeff = (D/μa)1/2 = 7.4 mm
kimag
0.05 0.1 0.15 0.2 0.25 cμa= 200 MHz
δAC = 1/kreal
(independent of ω)
(dependent on ω: 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 µM Deoxyhemoglobin = 4.1 µM
Water = 21.5% Lipid = 79.6%
LcII
ε=⎟⎟⎠
⎞⎜⎜⎝
⎛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
Oxygen Metabolism
Arteriole 90 mmHg
Tissue 17 < 47 mmHg
Cell Mitochondria 2<30 mmHg
Venule 35
mmHg 10-30 mmHg
Oxygen demand
Oxygen Supply
Cell-vascular coupling
Predicting Clinical Outcome
35 M. Herringlake, et al., Anesthesiology, 114, 58 (2011)
Total Population
High Risk Group
Optical endpoint: Pre-Surgical StO2 = HbO2/Hbtot Clinical endpoint: 30 day and 1 yr survival
n = 1200, Cardiac Bypass Surgery
Covidien INVOS
Predicting Clinical Outcome
36 M. 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/Hbtot Clinical 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
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
Phenylephrine: Rapid Rise in MAP: drop in StO2
Cognitive impairment, survival risk
Pre-frontal Cortex: Paced Breathing
OxyHb and DeoxyHb phase delay
OxyHb and Khine strain sensor DeoxyHb and Khine strain sensor
2 2.5 3 2 2.5 3
minutes minutes
Peak inhale Peak inhale
Obesity and Metabolic Syndrome
Subcutaneous Adipose Tissue (AT) Promotes Insulin, Leptin Resistance and Metabolic Syndrome:
-Shrink Adipocytes and AT burden
• Does DOSI detect structural and functional changes in AT? (n=10)
• Can DOSI provide early feedback on diet and other
interventions in metabolic disease? (12 weeks)
Dr. Shaista Malik, Director, Samueli Ctr., UCI Dept. of Cardiology
Non-invasive Abdominal Fat: Weight Loss Patient
12 week Calorie Restricted Diet
0.005
0.01
0.015
0.02
0.025
650 700 750 800 850 900 950 1000
µ a (m
m-1
)
Wavelength (nm)
Absorption Coefficient – M3
Baseline Post - Weight Loss (6 weeks) 0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
1.5
650 700 750 800 850 900 950 1000
µ s' (
mm
-1)
Wavelength (nm)
Reduced Scattering Coefficient –M3 (7.5 cm right of navel)
Baseline Post - Weight Loss (6 weeks)
baseline
baseline
6 weeks
6 weeks
Absorption Spectrum Lipid
Water
DeoxyHb
Scattering Spectrum
Ultrasound 2-3 cm adipose layer
G. Ganesan et al., Int J. Obesity, (2016)
Non-invasive Abdominal Fat: Weight Loss Patient 12 week Calorie Restricted Diet
t
Baseline 3 Months “A” scattering parameter
G. Ganesan et al., Int J. Obesity, (2016)
Water
Scattering
Non-invasive Abdominal Fat: Weight Loss Patient 12 week Calorie Restricted Diet
G. Ganesan et al., Int J. Obesity, (2016)
Water
Problem: Breast Cancer Detection, Diagnosis, Therapy Monitoring
Is the Tumor Malignant or Benign? Is it Responding to Chemotherapy?
Dr. Rita Mehta
Dr. Alice Police
Dr. Freddie Combs
Diffuse Optical Spectroscopic Imaging (DOSI)
Bevilacqua, F., A. J. Berger, et al. Appl Opt 39(34): 6498-507 (2000).
Scattering Absorption : :
White light
Laser diodes
Spectro- graph
APD
SS: 650-1100 nm
Frequency-Domain: ~400 MHz
Broadband temporal Frequency Domain Photon Migration (FDPM) + CW-NIRS
Tromberg, BJ, Pogue, BW, et al., Med. Phys., 35(6), 2443-2451, (2008).
500 MHz
ACRIN trial: UCI, Penn, Dartmouth, MGH, UCSF, MD Anderson, Boston U.
DOSI Baseline 6691-08 TOI = (HbR x H2O)/lipid
US Baseline: Depth: ~0.5-1.5 cm Size: ~2cm x 1cm
DCE-MRI Baseline
Case Study: 52 yr, peri-menoapausal, BIRADS 3, 2cm, Metaplastic carcinoma, Triple negative
DOSI 1 week 6691-08 %Δ TOI ~ -30%
US 1 Week: Depth: ~0.5-1.5 cm Size: ~2cm x 1cm
%Δ ~ 0
Case Study: 52 yr, peri-menoapausal, BIRADS 3, 2cm, Metaplastic carcinoma, Triple negative
Breast Density, Risk
Does Tamoxifen Work for You?
(e.g. CYP2D6 polymorphisms)
Should You Take it For 5 Years?
12 months Tamoxifen +10% Lipid -47% Density
%Lipid
With Gopi Meenakshisundaram and Aditi Majumder, UCI
Baseline
Conclusions
Diffuse Optics: Bedside Monitoring
• Imaging drug/radiation therapy • Surgical guidance • Predicting Risk/Outcome • Multi-modality Imaging
Continuous, Frequent Monitoring, Wearable Sensors Personalized Physiology and Medicine w/genomics
Challenge: Link optical endpoints to clinical outcome
DOSI Imaging: Anais Leproux, Rob Warren, Brian Hill, Amanda Durkin, Jesse Lam, Hossain Yazdi, Drew Reilly, Goutham Ganesan, Alex Matlock Albert Cerussi (Apple), Keunsik No (LG), Darren Roblyer (BU), Tom O’Sullivan (ND) Drs. Dan Cooper, Shlomit Aizak, Pietro Gallasetti, Shaista Malik, Alice Police, Freddy Combs, Rita Mehta
NIBIB P41 Laser Microbeam and Medical Program; NCI Chao Comprehensive Cancer Center
NIH R01CA142989, R21EB014440, R21NS078634; NCI American College of Radiology Imaging Network
AFOSR Military Photomedicine Program; Arnold and Mabel Beckman Foundation
Acknowledgements