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Optical, Optoacoustic, and Ultrasound
Techniques for Noninvasive Diagnostics
and Therapy
Rinat O. Esenaliev, Ph.D.
Professor,
Director of Laboratory for Optical Sensing and Monitoring,
Director of High-resolution Ultrasound Imaging Core,
Center for Biomedical Engineering,
UTMB Cancer Center,
Department of Neuroscience and Cell Biology,
and Department of Anesthesiology,
University of Texas Medical Branch, Galveston, TX
E-mail: [email protected]
Our Group Has Pioneered Noninvasive
Therapeutic and Diagnostic Technologies:
• Optoacoustic Platform for Noninvasive Sensing,
Monitoring and Imaging: absorption contrast
• Noninvasive Monitoring with Optical Coherence
Tomography (OCT): scattering contrast
• Nanoparticles and Radiation (Optical, Ultrasound)
for Cancer Therapy or for Drug Delivery: Including
laser + gold nanoparticle (nanoshells, nanorods,
etc.) for cancer therapy
Publications, Patents, Grants
• 40 peer-reviewed papers
• 15 patents including 7 issued patents
• $9.3M in 23 research grants from NIH, DOD,
state and private funding agencies
Research Team
Collaborators:
Donald S. Prough, M.D., Department of Anesthesiology, UTMB
Michael Kinsky, M.D., Department of Anesthesiology, UTMB
Claudia Robertson, M.D, Baylor College of Medicine, Houston
Luciano Ponce, M.D., Baylor College of Medicine, Houston
Joan Richardson, M.D., Department of Pediatrics, UTMB
B. Mark Evers, M.D., Department of Surgery, UTMB
Donald E. Deyo, D.V.M., Department of Anesthesiology, UTMB
Douglas S. Dewitt, Ph.D., Department of Anesthesiology, UTMB
Visiting Scientists:
Valeriy G. Andreev, Ph.D., Physics Department, Moscow State University
Alexander I. Kholodnykh, Ph.D., Physics Department Moscow State University
Research Associates, Post-Doctoral Fellows,
and Graduate and Undergraduate Students:
Christian Bartels, M.S.; Saskia Beetz, B.S.; Peter Brecht, Ph.D.;
Olga Chumakova, Ph.D., Inga Cicenaite, M.D.; Olaf Hartrumpf, B.S.; Dominique Hilbert, B.S.;
Manfred Klasing, B.S.; Anton Liopo, Ph.D., Roman Kuranov, Ph.D.;
Kirill V. Larin, Ph.D.; Irina V. Larina, Ph.D.; Margaret A. Parsley, B.S.; Igor Patrikeev, Ph.D.;
Andrey Y. Petrov, B.S.; Yuriy E. Petrov, Ph.D.; Irina Y. Petrova, Ph.D.; Emanuel Sarchen, B.S.;
Veronika Sapozhnikova, Ph.D.; Alexandra A. Vassilieva, M.D.; Karon E. Wynne, B.S.
Optoacoustic Grants
NIH R01 # EB00763 “Novel Sensor for Blood Oxygenation”.
NIH R21 # NS40531 “Optoacoustic Monitoring of Cerebral Blood Oxygenation”.
NIH R01 # NS044345 “Optoacoustic Monitoring of Cerebral Blood Oxygenation”.
John Sealy Memorial Endowment Fund for Biomedical Research. Grant: “Noninvasive
Monitoring with Novel, High-resolution Optical Techniques”.
Moody Center for Traumatic Brain & Spinal Cord Injury Research.
Seed Grant: “Noninvasive Optoacoustic Hemoglobin Monitor”
– Subaward from Noninvasix, Inc.
Texas Emerging Technology Fund (TETF): “Noninvasive Platform for Blood
Diagnostics” – Subaward from Noninvasix, Inc.
NIH STTR: “Noninvasive Optoacoustic Monitoring of Circulatory Shock”.
DOD: "Noninvasive Monitoring of Cerebral Venous Saturation in Patients with
Traumatic Brain Injury“.
DOD: “Noninvasive Circulatory Shock Monitoring with Optoacoustic Technique”.
Noninvasix, Inc.
• UTMB Incubator Startup
• Exclusive, world-wide license on optoacoustic
monitoring, sensing, and imaging in humans and
animals in vivo and in vitro (non-cancerous appl.)
• Licensed key US and International patents including
patents on monitoring OxyHb, THb, ICG, etc. in
blood vessels and in tissues
• FD: UTMB and Drs. Esenaliev and Prough are coowners of Noninvasix
Optoacoustics for Biomedical Imaging,
Monitoring, and Sensing - 1
Early 1990s: First Peer-reviewed Papers on Biomedical
Optoacoustics
Institute of Spectroscopy,
Russian Academy of Sciences:
R.O. Esenaliev, A.A.Oraevsky, V.S.Letokhov
and
A.A. Karabutov (Moscow State University)
Optoacoustics for Biomedical Imaging,
Monitoring, and Sensing - 2
Since Mid 1990s we continued the biomedical
optoacoustic works in the USA:
Mid 1990s: Optoacoustic Signals from Deep Tissues
(Depth: 5 cm)
Late 1990s: First Optoacoustic Images
Mid 1990s - Present: Optoacoustic Imaging, Monitoring
and Sensing Patents: imaging, monitoring of
temperature, coagulation, freezing, oxygenation,
hemoglobin, other important physiologic parameters, etc.
Optoacoustics for Biomedical Imaging,
Monitoring, and Sensing - 3
2001: We Obtained First High-resolution Optoacoustic
Images
Photonics West/ BIOS/SPIE Statistics: At present,
Biomedical Optoacoustics is the fastest growing and
largest area in biomedical optics
MOTIVATION - 1
Cerebral Venous Oxygenation Monitoring:
for Patients with Traumatic Brain Injury (TBI)
and Cardiac Surgery Patients
• Traumatic brain and spinal cord injuries are the leading cause of death
and disability for individuals under 50 years of age (car accidents, falls, etc.)
150,000 patients/year with moderate or severe traumatic brain injury
and 2 million/year with total TBI (mild, moderate, severe).
• Clinical data indicate that low cerebral venous blood oxygenation (below
50%) results in worse outcome (death or severe disability); 55-75% is normal
(venous!)
• Continuous and accurate monitoring of cerebral venous blood
oxygenation is critically important for successful treatment of these
groups of patients
• Existing methods are invasive (catheters in jugular bulb),
and noninvasive (NIRS) cannot measure cerebral venous oxygenation
MOTIVATION - 2
Central Venous Oxygenation Monitoring:
for Patients with Circulatory Shock
• Circulatory shock is common in critically ill patients
• Clinical data indicate that low central venous blood
oxygenation (below 70%) results in worse outcome (death or
severe complications); 70% is normal
• Continuous and accurate monitoring of central venous blood
oxygenation is critically important for successful treatment of these
patients: reduction in mortality from 46.5% to 30%
• Existing methods are invasive (pulmonary artery catheters), while
noninvasive (NIRS) cannot measure central venous oxygenation
MOTIVATION - 3
THb Monitoring
Total hemoglobin concentration ([THb]) measurement/monitoring is
important clinical test during:
 Routine health assessment (reveals anemia - [THb] < 11 g/dL
or polycythemia [THb] > 18 g/dL )
2 billion people suffer from anemia worldwide
 Surgical procedures involving rapid blood loss, fluid infusion, or blood transfusion
Existing methods are invasive:


Blood sampling
Optical monitoring in an extracorporeal blood circuit
Noninvasive methods are inaccurate:
Pressing need for noninvasive methods for continuous, accurate [THb]
measurement
Pure Optical Techniques (NIRS) Cannot Detect Signals
Directly from Blood Vessels
Due to Strong Light Scattering in Tissues
Optoacoustic Technology:
Optical Contrast + Ultrasound Resolution
1. Light pulses into blood in a
vessel
2. Blood hemoglobin absorbs
light & emits ultrasound in
proportion to concentration in
the vessel (due to thermal
expansion)
3. Ultrasound wave travels
without scattering and arrives
at specific time proportional to
blood vessel depth
4. Sensor detects ultrasound
5. Software determines location,
size, and oxygenation of blood
in the vessel
Optical
Input
Acoustic
Output
Principle of Laser Optoacoustic Monitoring and Imaging
Laser Optoacoustic Monitoring and Imaging
Is Based on Generation, Detection, and Analysis
of Thermoelastic Pressure Waves
Induced by Short Laser Pulses
Thermoelastic (Optoacoustic) Pressure, P:
P ~ T  a F / cv
T– laser-induced temperature rise;
µa – absorption coefficient;
F– fluence of the laser pulse;
 – density;
cv – heat capacity at constant volume
High Resolution and Contrast Can Be Achieved
Only when Short Laser Pulses Are Used
(The Condition of Stress Confinement)
L – desirable spatial resolution
 ac– time of propagation of acoustic wave
through the distance = L
 ac = L/ cs
where cs = 1.5 m/ns – speed of sound in tissue
The Condition of Stress Confinement:
 laser   ac
where  laser– laser pulse duration
Generation of Optoacoustic Wave
in Absorbing Medium
Spatial Distribution of Optoacoustic Pressure
in an Absorbing Medium without Scattering:
P( z )  ( cs / C p ) a F  a F ( z )  a Fo exp(  a z )
2
 [1/oC] – thermal expansion coefficient;
cs [cm/s] – speed of sound;
Cp [J/goC] – heat capacity at constant pressure;
F(z) [J/cm2] – fluence of the optical pulse;
µa [cm-1] – absorption coefficient of the medium;
 – Grüneisen parameter (dimensionless)
Since:
z  cst
Temporal Profile of Optoacoustic Waves in the Medium:
P(t )  a Fo exp(  a cs t )
Generation of Optoacoustic Wave in Tissue
Spatial Distribution of Optoacoustic Pressure
in a Tissue (not close to the surface):
P( z )  ka Fo exp(  eff z )
k – coefficient depending on tissue optical properties
µeff – tissue attenuation coefficient
eff {3a [a  s (1  g )]}1/ 2
Temporal Profile of Optoacoustic Waves in the Tissue:
P(t )  ka Fo exp(  eff cs t )
Advantages of Optoacoustic Technique
1. High Contrast (as in Optical Tomography) because
It Utilizes Optical Contrast
2. High Resolution (as in Ultrasonography) due to
Ultrasound Wave Detection
(Insignificant Scattering of Ultrasonic Waves
Compared with Light Wave Scattering in Tissues)
Absorption Spectra of Oxy- and Deoxyhemoglobin
Steven L. Jacques, Scott A. Prahl
Oregon Graduate Institute
Therapeutic Window: 600 – 1400 nm
Low absorption and low scattering = Deep penetration
Steven L. Jacques, Scott A. Prahl
Oregon Graduate Institute
Our Goal Is to Develop Optoacoustic Device
for Monitoring:
 Oxygenation




Cerebral
Central Venous
Peripheral Venous
Arterial
 Total Hb Concentration
 Pathologic Hemoglobins


Carboxyhemoglobin
Methemoglobin
 Dye Concentration (ICG)



Blood Volume
Cardiac Output
Hepatic Function
 Noninvasive Venous Pressure
 Noninvasive Arterial Pressure
Optoacoustic Monitoring Systems
Used in these Studies:
OPO-Based Optoacoustic Monitoring Systems
and
Laser Diode-Based, Optoacoustic Monitoring Systems
Wavelengths: 680 – 2400 nm; Duration: 10 - 150 ns
Optoacoustic Probes Used in these Studies:
Single-element Probes,
Focused Probes,
Optoacoustic Arrays
Specially developed sensitive, wide-band ultrasound
detectors: 25kHz – 10 MHz
Ultrasound Imaging Systems
Used in these Studies:
Standard Clinical
GE Systems
and
SiteRite Systems
High-Resolution Vevo System
Novel, High-resolution Ultrasound Imaging System
(Vevo, VisualSonics)
•
•
•
•
•
•
High Resolution: 30 microns
at depth of up to 25 mm
Real-time
Longitudinal Studies
Measure Physiological
parameters
Contrast/Molecular Imaging
Translatable to man
Outcome after Head Injury Closely Correlates
with Cerebral Venous Oxygenation / OxyHb Saturation
Below 50%:
death or
severe disability
Schell RM et al., Anesth Analg 2000;90:559.
Gopinath SP, Robertson CS, Contant CF, et al.
Jugular venous desaturation and outcome after
head injury. J. Neurol. Neurosurg. Psychiatry.
57:717-23, 1994.
Noninvasive, optoacoustic monitoring
of cerebral venous blood oxygenation
Optoacoustic
Probe
SSS SO2
Superior Sagittal
Sinus (SSS)
65%
Time (min)
Noninvasive, Optoacoustic Cerebral Venous
Blood Oxygenation Monitoring in Sheep
700 nm
SSS Blood Oxygenation (%)
1.0
80
0.8
60
0.6
40
0.4
20
0.2
0
0
10
20
30
100
80
0.8
60
0.6
40
0.4
20
0
40
1.0
0
10
Time (min)
Predicted - Actual Oxygenation (%)
Predicted oxygenation (%)
80
60
2
R = 0.99
20
0
0
20
40
60
30
40
0.2
Time (min)
100
40
20
80
100
Actual SSS Blood Oxygenation (%)
30
<> = 4.8%
2SD = 5.6%
20
<> + 2SD
10
<>
0
<> - 2SD
-10
-20
-30
0
20
40
60
80
100
Actual SSS Blood Oxygenation (%)
Peak-to-peak amplitudes (arb. un.)
100
Peak-to-peak amplitudes (arb. un.)
1.2
SSS Blood Oxygenation (%)
1064 nm
Absorption Coefficient (arb. un.)
Optoacoustic Spectra from Human SSS
and Hemoglobin Absorption Spectra
5
HbO2
Hb
10%
20%
30%
40%
50%
60%
70%
80%
90%
4
3
2
1
0
700
800
900
Wavelength (nm)
1000
Ultrasound Imaging and Corresponding
Optoacoustic Signals from Central Veins
Depth (mm)
Optoacoustic Signal (mV)
6
8
10
10
5
0
-5
4
5
Time (s)
6
7
Optoacoustic Spectra from Carotid Artery
and Central Vein
Carotid Artery
Central Vein
5
Absorption Coefficient (arb. un.)
Absorption Coefficient (arb. un.)
5
HbO2
Hb
10%
20%
30%
40%
50%
60%
70%
80%
90%
4
3
2
1
0
700
800
900
Wavelength (nm)
1000
1100
HbO2
Hb
10%
20%
30%
40%
50%
60%
70%
80%
90%
4
3
2
1
0
700
800
900
Wavelength (nm)
1000
1100
Central Venous Blood Oxygenation (%)
Continuous, Real-time Measurement of Central Venous
Oxygenation Using Optoacoustic Monitoring System
(Stable Subject)
100
SO2, %
80
60
<SO2> = 75.1 +/- 1.1 %
40
20
0
0
10
20
Time (min)
30
High-Resolution Ultrasound Imaging and Corresponding
Optoacoustic Signals from Peripheral Veins
2
Optoacoustic Signal (mV)
0
Depth (mm)
6
4
40
20
0
-20
0
1
2
Time (s)
3
4
Optoacoustic Spectra from Peripheral Vein and Radial
Artery and Hemoglobin Absorption Spectra
Radial Artery
Peripheral Vein
5
HbO2
Hb
10%
20%
30%
40%
50%
60%
70%
80%
90%
4
3
2
1
0
700
800
900
Wavelength (nm)
1000
1100
Absorption Coefficient (arb. un.)
Absorption Coefficient (arb. un.)
5
HbO2
Hb
10%
20%
30%
40%
50%
60%
70%
80%
90%
4
3
2
1
0
700
800
900
Wavelength (nm)
1000
1100
Optoacoustic Signal (V)
0.2
4.7 g/dL
8.6 g/dL
11.9 g/dL
15.8 g/dL
0.1
0.0
-0.1
2
3
Time (s)
4
Amplitude of the Optoacoustic Signal (V)
Optoacoustic Signals from Blood
in Radial Artery Phantom
2
0.25
R = 0.997
0.20
0.15
0.10
0.05
0.00
0
5
10
15
20
Total Hemoglobin Concentration (g/dL)
Optoacoustic signal from sheep blood at different concentrations of THb (gradual
dilution of blood) and its amplitude
Conclusions
•
•
•
•
The optoacoustics is a platform monitoring and imaging
technology with high (optical) contrast and high (ultrasound)
resolution in tissues
The sensitive, wide-band optoacoustic probes provide
sufficient lateral and axial resolution for measurements in
large and small blood vessels
The optoacoustic monitoring systems may provide clinically
acceptable accuracy of cerebral, central, and peripheral
venous oxygenation measurements
The optoacoustic monitoring systems may provide high
accuracy of hemoglobin measurements
Nanoparticles and Radiation
for Cancer Therapy or
for Drug Delivery
Overview of Technology
Chemotherapy, surgery, radiation therapy have limitations
and are not capable of safe and efficient therapy of solid tumors.
This technology offers efficient cancer therapy with no or minimal side effects.
The technology is based on interaction of light, microwaves, radiowaves, or ultrasound
with nanoparticles.
Radiation + Nanoparticles
US-Enhanced DD
RW-Enhanced DD
MW-Enhanced DD
Drug Delivery
Light-Enhanced DD
US-Induced Therapy
RW-Induced Therapy
MW-Induced Therapy
Light-Induced Therapy
Nanoparticle-mediated Therapy
Drug Delivery Problem
Approximately 1.4 million new cases are diagnosed and more than 500,000 deaths occur
as a result of cancer every year in the United States.
Many promising therapeutic agents have been proposed for cancer therapy for the past
two decades. Their potential is proven in numerous preclinical studies.
However, limited success has been achieved in tumor therapy.
Barriers to drug delivery:
• blood vessel wall
• interstitial space
• cancer cell membrane
Penetration is especially poor
for macromolecular therapeutic agents:
• monoclonal antibodies
150 – 300 kDa
• cytokines
6 – 70 kDa
• antisense oligonucleotides
5 – 10 kDa
• gene-targeting vectors
> 1,000 kDa
Modified from R.Jain, “Barriers to drug delivery in solid tumors”, Scientific American, 1994.
INTERACTION of NANOPARTICLES with ULTRASOUND CAN
ALTER the BARRIERS to DRUG DELIVERY
The nanoparticles can be selectively accumulated in tumors by:
• “passive” delivery due to increased leakage of tumor capillaries (EPR effect)
• “active” delivery with the use of antibodies, short peptides, etc.
Interaction of particles with radiation produce cavitation and other effects
Which RESULTS IN:
• rupture or changes in tumor blood vessel wall and cancer cell membrane
• microconvection in the interstitium
Biodegradable and biocompatible polymer
Poly (D,L-lactide-co-glycolic acid) 50:50, PLGA
The nanoparticles was prepared by double water/oil/water emulsion solvent
evaporation technique followed by filtration with 220-nm Millex filters
Advantages of PLGA nanoparticles:
• can accumulate in tumors (EPR effect)
• biodegradability,
• biocompatibility,
• may provide stable cavitation,
• PLGA approved for clinical use by FDA
(surgical sutures, etc.)
PLGA Nanoparticles
SEM
Optical Microscopy
High Performance Particle Sizer
HPPS 5001 Zetasizer Nano
PLGA nanoparticles (0.5% solution)
Definity (0.2% solution)
EXPERIMENTAL SETUP FOR STUDIES IN VIVO
In Vivo Gene Delivery
Control Tumor
Irradiated Tumor
Precise Damage Induced by
Ultrasound+Nanoparticles Deeply in Tissues
Reference subtracted Contrast Images
(whole tumor)
Reference subtracted
Wash in curve
whole tumor area
(Necrotic region)
Reference subtracted
Wash in curve
Necrotic region
Wash in curve for nanoparticles circulating in tumor
Reference subtracted Contrast Image
Acknowledgement
1. John Sealy Memorial Endowment Fund
2. Texas Advanced Technology Program
(grant #004952-0088-2001)
3. Department of Defense Breast Cancer Research Program
(grant #DAMD17-01-1-0416)
4. National Institutes of Health
(grant #RO1 CA104748)
5. Department of Defense Prostate Cancer Research Program
(grant #W81XWH-04-1-0247)