optical, optoacoustic, and ultrasound techniques for noninvasive diagnostics and therapy
DESCRIPTION
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, - PowerPoint PPT PresentationTRANSCRIPT
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]
• 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
Our Group Has Pioneered Noninvasive Therapeutic and Diagnostic Technologies:
• 40 peer-reviewed papers
• 15 patents including 7 issued patents
• $9.3M in 23 research grants from NIH, DOD, state and private funding agencies
Publications, Patents, Grants
Research Team
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.
Collaborators:Donald S. Prough, M.D., Department of Anesthesiology, UTMB
Michael Kinsky, M.D., Department of Anesthesiology, UTMBClaudia Robertson, M.D, Baylor College of Medicine, Houston
Luciano Ponce, M.D., Baylor College of Medicine, HoustonJoan Richardson, M.D., Department of Pediatrics, UTMB
B. Mark Evers, M.D., Department of Surgery, UTMBDonald E. Deyo, D.V.M., Department of Anesthesiology, UTMB
Douglas S. Dewitt, Ph.D., Department of Anesthesiology, UTMB
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 co-owners 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.Letokhovand
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
• Traumatic brain and spinal cord injuries are the leading cause of deathand 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).
• Continuous and accurate monitoring of cerebral venous blood oxygenation is critically important for successful treatment of these groups of patients
• Clinical data indicate that low cerebral venous blood oxygenation (below 50%) results in worse outcome (death or severe disability); 55-75% is normal (venous!)
MOTIVATION - 1
Cerebral Venous Oxygenation Monitoring: for Patients with Traumatic Brain Injury (TBI)
and Cardiac Surgery Patients
• Existing methods are invasive (catheters in jugular bulb), and noninvasive (NIRS) cannot measure cerebral venous oxygenation
• Circulatory shock is common in critically ill patients
• 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%
• Clinical data indicate that low central venous blood oxygenation (below 70%) results in worse outcome (death or severe complications); 70% is normal
MOTIVATION - 2Central Venous Oxygenation Monitoring:
for Patients with Circulatory Shock
• Existing methods are invasive (pulmonary artery catheters), while noninvasive (NIRS) cannot measure central venous oxygenation
MOTIVATION - 3
THb MonitoringTotal 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
– laser-induced temperature rise; µa – absorption coefficient;
F– fluence of the laser pulse; –density;
cv – heat capacity at constant volume
Thermoelastic (Optoacoustic) Pressure, P:
aclaser
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
where laser– laser pulse duration
The Condition of Stress Confinement:
[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) zcst
Spatial Distribution of Optoacoustic Pressurein an Absorbing Medium without Scattering:
Temporal Profile of Optoacoustic Waves in the Medium:Since:
Generation of Optoacoustic Wave in Absorbing Medium
2/1)]}1([3{ gsaaeff
Generation of Optoacoustic Wave in Tissue
Spatial Distribution of Optoacoustic Pressurein a Tissue (not close to the surface):
k–coefficient depending on tissue optical propertiesµeff – tissue attenuation coefficient
Temporal Profile of Optoacoustic Waves in the Tissue:
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)
1.00
10.00
100.00
1000.00
10000.00
400 600 800 1000 1200
Wavelength (nm)
Abs
orpt
ion
Coe
ffici
ent a
(1/c
m)
Oxyhemoglobin (HbO2)
Hemoglobin (Hb)
Absorption Spectra of Oxy- and Deoxyhemoglobin
Steven L. Jacques, Scott A. PrahlOregon Graduate Institute
Steven L. Jacques, Scott A. PrahlOregon Graduate Institute
Therapeutic Window: 600 – 1400 nm
Low absorption and low scattering = Deep penetration
Our Goal Is to Develop Optoacoustic Devicefor 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
andSiteRite Systems
High-Resolution Vevo System
• High Resolution: 30 microns at depth of up to 25 mm• Real-time• Longitudinal Studies• Measure Physiological parameters• Contrast/Molecular Imaging• Translatable to man
Novel, High-resolution Ultrasound Imaging System(Vevo, VisualSonics)
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.
Outcome after Head Injury Closely Correlateswith Cerebral Venous Oxygenation / OxyHb Saturation
Below 50%:death or
severe disability
Noninvasive, optoacoustic monitoring of cerebral venous blood oxygenation
Superior Sagittal Sinus (SSS)
Optoacoustic Probe
65%Time (min) SS
S SO 2
Noninvasive, Optoacoustic Cerebral Venous Blood Oxygenation Monitoring in Sheep
1064 nm 700 nm
Optoacoustic Spectra from Human SSS and Hemoglobin Absorption Spectra
Ultrasound Imaging and CorrespondingOptoacoustic Signals from Central Veins
Optoacoustic Spectra from Carotid Artery and Central Vein
Carotid Artery Central Vein
700 800 900 1000 11000
1
2
3
4
5
Abs
orpt
ion
Coe
ffici
ent (
arb.
un.
)
Wavelength (nm)
HbO2
Hb 10% 20% 30% 40% 50% 60% 70% 80% 90%
Continuous, Real-time Measurement of Central Venous Oxygenation Using Optoacoustic Monitoring System
(Stable Subject)
0 10 20 300
20
40
60
80
100
SO2, %
Cen
tral V
enou
s B
lood
Oxy
gena
tion
(%)
Time (min)
<SO2> = 75.1 +/- 1.1 %
High-Resolution Ultrasound Imaging and CorrespondingOptoacoustic Signals from Peripheral Veins
0 1 2 3 4
-20
0
20
40
0 2 4 6
Opt
oaco
ustic
Sig
nal (
mV
)
Time (s)
Depth (mm)
Optoacoustic Spectra from Peripheral Vein and Radial Artery and Hemoglobin Absorption Spectra
Peripheral Vein Radial Artery
Optoacoustic Signals from Bloodin Radial Artery Phantom
2 3 4
-0.1
0.0
0.1
0.2
Opt
oaco
ustic
Sig
nal (
V)
Time (s)
4.7 g/dL 8.6 g/dL 11.9 g/dL 15.8 g/dL
Optoacoustic signal from sheep blood at different concentrations of THb (gradual dilution of blood) and its amplitude
0 5 10 15 200.00
0.05
0.10
0.15
0.20
0.25 R2 = 0.997
Am
plitu
de o
f the
Opt
oaco
ustic
Sig
nal (
V)
Total Hemoglobin Concentration (g/dL)
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 Radiationfor Cancer Therapy or
for Drug Delivery
Overview of TechnologyChemotherapy, 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
Nanoparticle-mediated Therapy Drug Delivery
Ligh
t-Ind
uced
The
rapy
MW
-Ind
uced
The
rapy
RW
-Ind
uced
The
rapy
US-
Indu
ced
Ther
apy
Ligh
t-Enh
ance
d D
D
MW
-Enh
ance
d D
D
RW
-Enh
ance
d D
D
US-
Enha
nced
DD
Drug Delivery ProblemApproximately 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.
Modified from R.Jain, “Barriers to drug delivery in solid tumors”, Scientific American, 1994.
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
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
INTERACTION of NANOPARTICLES with ULTRASOUND CAN ALTER the BARRIERS to DRUG DELIVERY
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.)
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
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 DeliveryControl Tumor Irradiated Tumor
Precise Damage Induced by Ultrasound+Nanoparticles Deeply in Tissues
(whole tumor)
(Necrotic region)
Reference subtractedWash in curve whole tumor area
Reference subtractedWash in curve Necrotic region
Reference subtracted Contrast Images
Wash in curve for nanoparticles circulating in tumor
Reference subtracted Contrast Image
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)
Acknowledgement