Near-infrared Diffuse Optical Measurement of Tissue Blood Flow, Oxygenation and Metabolism

Guoqiang Yu

Bio-photonics LabCenter for Biomedical Engineering

University of Kentucky

Research Supported by:

•NIH R01 CA149274 (Yu)•NIH R21 HL083225 (Yu) •AHA BGIA 2350015 (Yu)•AHA BGIA 0665446 (Yu)

•DOD W81XWH-04-1-0006 (Yu)•NIH R21 PA-08-162 (Peterson & Crofford)

•University of Kentucky Research Foundation (Yu) • Tissue Blood flow

• Tissue Blood oxygenation

Diffuse Correlation Spectroscopy (DCS)

Outline

• Study Motivation• Near-infrared Diffuse Optical Spectroscopies• In-vivo Applications: From Small Animals to

Adults– Brain– Cancer– Muscle

Oxygen Exchange In Tissues

Arterioles

Venules

CirculatorySystem Microvasculatures

Oxygen Exchange

Tissue Hypoxia

• Arterial oxygen too low (e.g. apnea)?• Blood flow too slow (e.g. ischemic stroke)?• Local tissue metabolism too high (e.g. cancer)?

Oxygen Supply

Oxygen Consumption

Hypoxia

Diseases Associated with Tissue Hypoxia

• Brain– Stroke– Sleep Apnea– Traumatic Injury– …

• Muscle– Peripheral Arterial Disease (PAD)– Diabetes– Pressure Ulcer– …

• Tumor

Study Motivations

• Diagnosis of Diseases • Evaluation of Therapies

– Tissue Blood Flow– Blood Oxygenation– Oxygen Metabolism

• Techniques Needed in Clinic– Non-invasive– Fast (~ms)– Portable (bed side)– Low cost– Longitudinal Monitoring– Deep Tissue Volume (brain, tumor, muscle)

Existing Techniques for Tissue Hemodynamics and Metabolism

• Doppler ultrasound• Magnetic resonance angiography (MRA)

blood flow within large vessels

• Laser Doppler flowmetry (LDF)• Laser speckle imaging• Doppler optical coherence tomography (DOCT)

microvascular flow at superficial tissues

• Positron emission tomography (PET)• Arterial-spin labeled MRI, fMRI• Computed tomography (CT)• Photon emission computed tomography (SPECT)• Xenon-enhanced computed tomography (XeCT)

large instrumentation high cost, patient transportradiation damage

• Electrode--tissue oxygen levels (PO2) invasive

• Near-infrared spectroscopy (NIRS) can monitor microvascular hemodynamics in deep tissues noninvasively, frequently, inexpensively

Outline

• Study Motivation• Near-infrared Diffuse Optical Spectroscopies• In-vivo Applications: From Small Animals to

Adults– Brain– Cancer– Muscle

NIR Light (700-2500 nm)

Light Spectrum (100 nm to 1 mm)

NIR Light Diffuses Through Thick/Deep Tissues

Why Near-infrared Light?

www.internationalcancertherapy.com

Light Diffuses In Biological Tissue

µa : Tissue absorption coefficient

µs’ : Tissue scattering coefficient

BF: Blood Flow

Absorbers: Hemoglobins, Water, Lipids (µa)

Scatterers: Organelles, Mitochondria (µs’), Moving Blood Cells (BF)

Tissue Optical Properties:

r

Light Diffuses In Biological Tissue

µa -- absorption coefficient

D ≈ v/3 µs’ -- photon diffusion coefficient

µs’– reduced scattering coefficient

ν – light velocity

S – isotropic source term

Φ (r,t) [photons/cm2/s] ~ (µs’, µa, r, S)

Semi-infinite Mediumr

Photon Diffuse Equation:

NIRS: Frequency Domain System

Yu et al, Applied Optics (2003)

Photon Fluence Rate:

Φ (r,t) [photons/cm2/s] ~ (µa, µs’, r, S)

µa, µs’

Amplitude Reduction

Phase Shift

Separate

r

Near-infrared Spectroscopy (NIRS)Can Probe Tissue Oxygenation

Wavelength (nm)

ε (c

m-1/µ

M)

Fantini et al, Phys. Med. Biol. (1999), Shang et al, Optics Letters (2009)

830 nm

10-8

10-6

10-4

10-2

100

0

0.2

0.4

0.6

0.8

1

1.2

(sec)g

1(

)

Pre-arteryocclusion(fast flow)

During arteryocclusion(slow flow)

NIR Diffuse Correlation Spectroscopy (DCS)Can Probe Tissue Blood Flow

Pine et al, PRL (1988); Maret et al, Z. Phys (1987); Boas et al, PRL (1995), Yu et al, JBO (2005), Shang et al, Opt Lett (2009)

Blood Flow (BF) ~ Motion of Red Blood Cells~ Decay of Correlation Function

Source Detectors

Correlation Diffuse Equation

Boas, Campbell, and Yodh, PRL, (1995)

αDB ~ Blood Flow (BF)

Mean Square Displacement of Moving Scatterers: r2() = 6DB

G – electric field temporal autocorrelation functionDB -- effective diffusion coefficientα – percentage of moving scatterers over all scatterers

= -

G1 (r, ) ~ (µa, µs’, r, αr2())

G1 : Electric field temporal autocorrelation function

)0,r(G

),r(G),r(g

1

11

Portable DCS Flowmeter: Tissue Blood Flow (rBF)

APDs

785 nm

Correlator rBFCorrelation

Curve

Tissue

DCS Flowmeter

10-8

10-6

10-4

10-2

100

0

0.2

0.4

0.6

0.8

1

1.2

(sec)

g1(

)

Pre-arteryocclusion(fast flow)

During arteryocclusion(slow flow)

A Hybrid Diffuse Optical System

Yu Shang, Youquan Zhao, Ran Cheng, Lixin Dong, Daniel Irwin, Guoqiang Yu, Optics Letters (2009)

Portable DCS Flow-oximeter:Tissue Blood Flow & Oxygenation

Shang et al, Optics Letters (2009)

APDs

785 nm

Correlator

rBFCorrelation

Curves

Light

Intensities

Δ[HbO2]

Δ[Hb]

Tissue TTL control

DCS Flow-oximeter

854 nm

Functional Parameters:

• rBF, Δ[HbO2], Δ[Hb], rMRO2

Instrumentation:•Portable, fast, inexpensive, easy to construct and operate

Portable DCS Flow-oximeter Vs. Hybrid Instrument

DCS Flow-oximeter Hybrid System

Function:

• rBF, Δ[HbO2], Δ[Hb]Instrumentation:•portable, inexpensive, easy to construct and operateProbe:•small (shared fibers)•cover the same tissue volume for both flow and oxygenation measurements

Function:• rBF, • Absolute [HbO2], [Hb], THC• Absolute StO2

Shang et al, Optics Letters (2009)

Validation Studies of DCS Flow Measurement

• Doppler Ultrasound– Menon et al, Cancer Res (2003) – Yu et al, Clin Cancer Res (2005)– Buckley et al, Opt Exp (2009) – Roche-Labarbe et al, Human Brain Mapping (2009)

• ASL Perfusion-MRI– Yu et al, Opt Exp (2007)– Durduran, Optics Lett (2004)

• Xenon-CT-- Kim et al, Neurocritical Care (2010)

• Laser Doppler– Durduran, PhD Thesis (2004)

• Fluorescent microsphere measurement -- Zhou et al, J Bio Opt (2009)

• DCS vs. Literatures– Cheung et al, Phys Med Bio (2001)– Durduran et al, Opt Letters (2004) -- Yu et al, J Bio Opt (2005)

R2 = 0.67, p < 0.001

50

100

150

200

250

300

350

0 50 100 150

MRI (ml/100mg/min)

rBF

(%

)90º

Optical Fibers (>12 meters)

MRI Room

Control Room

MRI Coil Optical Instrument (DCS)

Non-magnetic probe

Guoqiang Yu et al, Optics Express (2007)

(n = 7)

Time (sec)

Validation: DCS vs. Perfusion MRI

• Noninvasive• Fast (up to 100 Hz)• Inexpensive (vs. MRI, CT)• Portable (vs. MRI, CT)• Longitudinal (vs. MRI, CT)• Microvasculature (vs. Doppler Ultrasound)• Deep/Thick Tissue (vs. laser Doppler)

– Small and Large Animals (e.g., mouse, rat, piglet, pig)

– Children and Adults

• Limited penetration depth (~ several cm)• Low spatial resolution (mm to cm)

Advantage and Limitation of NIRS/DCS

Outline

• Study Motivation• Near-infrared Diffuse Optical Spectroscopies• In-vivo Applications: From Small Animals to

Adults– Brain– Cancer– Muscle

Brain

• Cerebral hemodynamic responses to functional activities– Finger taping– Verbal fluency– Visual stimulation

• Diagnosis of cerebral diseases– Stroke– Sleep apnea

• Monitoring of therapies– Stroke in ICU– Carotid endarterectomy

Carotid Endarterectomy

Cerebral Functional Activations in Human Cortex

Durduran et al, Optics Letters (2009)

Stroke Management in ICU

Acute Ischemic Stroke

• Early diagnosis

• Early treatment: maximize blood flow

• Bed-side continuous monitoring of progress/treatment

Stroke Management in ICU

Infarct

•Patients: Unilateral ischemic stroke in middle cerebral artery (MCA) territory

•Probe Placement: Both hemispheres (infarct vs. non-infarct)

•Protocol: Optical measurement of rCBF during head-of-bed (HOB) positioning (30, 15, 0, -5 and 0°)

• Hemisphere effect?

• HOB angle to get maximal rCBF?

• Longitudinal Monitoring of treatment effect?

Durduran et al, Optics Express (2009)

Cerebral Autoregulation

CBF vs. HOB: Healthy Controls

(n = 5)

Durduran et al, Optics Express (2009)

CBF vs. HOB: Patient 1

CBF vs. HOB: Patient 2

Group Patient Results (N = 17)

•HOB position influenced rCBF significantly (P<0.05) in both hemispheres (healthy and stroke)

•HOB was a stronger factor in the infarcted hemisphere (larger variation, p<0.02)

-- Impaired autoregulation?

•Paradoxical Response (25% of stroke group): the maximal CBF occurred at an elevated angle

-- Cardiac Disease? Others?-- Individualized management

Durduran et al, Optics Express (2009)

Stroke Flow Recovery (3 days after)

L R

• Left middle cerebral artery

• rCBF variability L > R

Cerebral Hemodynamics During Carotid Endarterectomy (CEA)

•Two fiber-optic probes were taped on both sides of frontal head

•EEG electrodes were placed all over the scalp

•ICA clamping resulted in a significant CBF decrease and cerebral deoxygenation at the surgical side

Surgical side

Cerebral Hemodynamics During Carotid Endarterectomy (CEA)

Surgical side

Control side

Comparison of CBF and EEG Responses: Individual

•The large CBF slope (S = -1.25) (a) The time duration of CBF decrease and maximal CBF change (b)

•The EEG power changes were small and slow (c), and reached its minimum in a long period of time (d)

Comparison of CBF and EEG Responses: 12 Subjects

•Faster CBF change (slope)

•Larger CBF change

•Shorter CBF time-to-minimum

•DCS measurements are more sensitive in detecting cerebral ischemia compared to EEG monitoring

Mouse Cerebral Ischemia Model: Layer Effects

Left

15:40 15:50 16:00 16:10 16:200

50

100

Time

rCB

F (

%)

Right

15:40 15:50 16:00 16:10 16:200

50

100

Time

rCBF

(%)

R ECAR CCA

L ECA

kill withisofluraneL CCA

CCA- Common carotid artery ECA- External carotid artery

ICA- internal carotid artery

• DCS is sensitive to the local CBF changes• Blood flow from the scalp are much smaller than that fro brain

S1

D1 D2

S2L R

1

2

3

4

1 23

4

Tumor

• Diagnosis of tumors– Human Breast tumor– Human Head/Neck tumor– Human Prostate tumor– Mouse radiation-induced

fibrosarcoma (RIF) tumor

• Monitoring of therapies– Chemotherapy– Chemo/Radiation therapy– Photodynamic therapy– Antivascular therapy in mice

scan tumor

Optical probe

Tumor

Diagnosis of Breast Tumors: Flow Contrast

• High blood flow contrast in tumor

T. Durduran, R. Choe, G. Yu, C. Zhou, J. C. Tchou, B. J. Czerniecki, and A. G. Yodh Optics Letters (2005)

Photodynamic Therapy (PDT) Monitoring

• Photodynamic Therapy (PDT) Dosimetry – Photosensitizer– Light– Tissue oxygen

• Blood flow

• Blood oxygenation

Photofrin-Mediated RIF mice Tumor

SO2 SO2 SO2 SO2

rBF rBF rBF

10 min 15 min

rBF

3h 6.5h

Light on Light off

30 min

• Radiation-Induced Fibrosarcoma (RIF) Mice Tumors:

Treated group = light + Photofrin (5 mg/Kg)

• Treatment Efficacy:

Days for tumor growth to a volume of 400 mm3

(starting volume ~100 mm3)Tumor

Measurement of Blood Flow During PDT

Filter > 650 nm

Tumor

630 nm

Measurement light : 785 nm

Treatment light: 630 nm

785nm

Yu et al, Clin Cancer Res (2005)

Sources (13) Detectors (4)

-0.4 -0.2 0 0.2 0.4-0.4

-0.2

0

0.2

0.4

cm

cm

1 2

3 4

5

6 7

8

9

10 11

12

13 I III

IV

II

Probe Map

Predict Treatment Efficacy (During PDT)

Slope

Slope

Time (minute)

Yu et al, Clin Cancer Res (2005)

n = 15, p = 2.02e-4

0

5

10

15

20

25

30

1 10 100D

ay o

f gro

wth

(y)

Flow Reduction Rate (Slope)

Large slope Poor treatment efficacy

Tim

e-t

o-4

00

mm

3

Hemodynamic Responses During Radiation Delivery

Optical Probe

Ultrasound Imaging of H/N Tumor

Treatment

Hemodynamic Variations During Radiation Therapy on Head/Neck Tumors

Sunar et al, J. Biomedical Optics (2006)

P = 0.0002

P = 0.007

(7 responders)

Large Hemodynamic Variations in Response to Radiation Therapy on Head/Neck Tumors

Responders (n = 7) Partial responder(n = 1)

Skeletal Muscle

• Healthy muscle physiology– Cuff Occlusion– Exercise

• Diagnosis of vascular diseases– Peripheral arterial disease (PAD)– Fibromyalgia– Diabetes– Hypercholesterolemia (mice)

• Monitoring of therapies– Arterial revascularization– Electrical stimulation (ES)– Massage therapy (MT)– Erdman (heat/cold) therapy

Muscle Hemodynamics During Arterial Cuff Occlusion: Layer Responses

0

100

200

300

400

0 50 100 150 200 250 300 350 400rela

tive

Blo

od F

low

(%)

0.5 cm

1.0 cm

2.0 cm

45

55

65

75

0 50 100 150 200 250 300 350 400

Time (sec)

Blo

od

Oxyg

en

Satu

rati

on

(%) 0.5 cm

1.5 cm

3.0 cm

4.0 cm

Cuff Occlusion

3.0 cm

Occlusion

•Light penetration depth depends on the source-detector separation.•Muscle demonstrates stronger hemodynamic responses.

Source Detectors

G. Yu, T. Durduran, G. Lech, C. Zhou, B. Chance, E. R. Mohler III, A. G. Yodh, J. Biomedical Optics (2005)

Probe

Pressure cuff

Plantar Flexion (PF) Exercise

Exercise creates both muscle fiber motion and blood flow change

Yu Shang, T. B. Symons, Turgut Durduran, A. G. Yodh, and Guoqiang Yu, Biomedical Optics Express (2010)

Toe up/down on the ground

Plantar-Flexion (PF)/Dorsi-Flexion (DF) Exercise: Muscle Fiber Motion Artifacts

•Co-registration of dynamometer recordings and DCS measurements (αDB).•Separate the true blood flow responses (PF-120º & DF-90º) from the motion artifacts (PF & DF).

PF/DF on a dynamometer

Yu Shang, T. B. Symons, Turgut Durduran, A. G. Yodh, and Guoqiang Yu, Biomedical Optics Express (2010)

• Longer recovery time• Deeper de-saturation (StO2)

Diagnosis of Peripheral Arterial Disease (PAD): Cuff Occlusion – PAD vs. Healthy

Cuff

Cuff

Therapeutic Monitoring: Aorta-Femoral Arterial Bypass Graft in PAD

• DCS for the main artery obstruction surgery operation

Graft

Optical Probe

Study Aim: Assess/predict revascularization effects in lower leg muscle.

Study Supported by:AHA (Yu)

Collaborator: Sibu P. Saha

Therapeutic Monitoring: Hemodynamic Changes During Bypass Graft

08:30 09:00 09:30 10:00 10:30 11:000

100

200

300

400

rBF

(%

)

08:30 09:00 09:30 10:00 10:30 11:00-40

-20

0

20

40

Time

M

[HbO2]

[Hb]

pre-revascularization

post-revascularization

Arterial Occlusion

• High sensitivity to physiological events (e.g., arterial clamping/releasing)• Immediate blood flow improvements in muscle microvasculature

Guoqiang Yu et al, J. Biomedical Optics, 2010 (Accepted)

Summary: Translation to Clinic

Breast (Chemotherapy)

Brain (Stroke, Trauma, Therapy Monitoring)

Head/Neck Tumor (Radiation Therapy)

Prostate (PDT)

Pleura (PDT)

Skeletal Muscle (PAD, Diabetes, Surgical Monitoring)

NIR Technologies:

• Noninvasive• Fast• Inexpensive • Portable • Longitudinal• Microvasculature• Deep/Thick Tissue–Small and Large Animals–Children and Adults

• Limited penetration• Low spatial resolution

Acknowledgements

Yu’s Bio-photonic Lab:•Dr. Yu Shang (Postdoc)• Dr. Yu Lin (Postdoc)• Dr. Youquan Zhao • Dr. Daniel Kameny

Graduate Students:• Ran Cheng• Lixin Dong• Daniel Irwin• Lian He• Katelyn Gurley Research Supported:

NIH R01 CA149274 (Yu)NIH R21 HL083225 (Yu)AHA BGIA 2350015 (Yu)AHA BGIA 0665446 (Yu)

DOD W81XWH-04-1-0006 (Yu)NIH R21 PA-08-162 (Peterson & Crofford)

University of Kentucky Research Foundation (Yu)

Collaborators:• Sibu Saha• Don Hays• Mahesh Kudrimoti• Scott Stevens• Michal Toborek• Brock Symons• Charlotte Peterson• Leslie Crofford • Leigh Callahan• Joyce Evans • Hainsworth Shin • Arjun Yodh• Turgut Durduran• Chao Zhou• Theresa Busch