Noninvasive Therapy and Diagnostics

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Optical, Optoacoustic, and Ultrasound Techniques for Noninvasive Diagnostics and TherapyRinat 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: riesenal@utmb.edu

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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 therapyOur Group Has Pioneered Noninvasive Therapeutic and Diagnostic Technologies:

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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

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Research TeamVisiting 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, 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

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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”.

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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

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Optoacoustics for Biomedical Imaging, Monitoring, and Sensing - 1Early 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)

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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.

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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

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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). 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

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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 normalMOTIVATION - 2 Central Venous Oxygenation Monitoring: for Patients with Circulatory Shock Existing methods are invasive (pulmonary artery catheters), while noninvasive (NIRS) cannot measure central venous oxygenation

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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

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Pure Optical Techniques (NIRS) Cannot Detect Signals Directly from Blood Vessels Due to Strong Light Scattering in Tissues

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Optoacoustic Technology: Optical Contrast + Ultrasound ResolutionLight pulses into blood in a vessel Blood hemoglobin absorbs light & emits ultrasound in proportion to concentration in the vessel (due to thermal expansion) Ultrasound wave travels without scattering and arrives at specific time proportional to blood vessel depth Sensor detects ultrasound Software determines location, size, and oxygenation of blood in the vesselOptical Input Acoustic Output

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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

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High Resolution and Contrast Can Be Achieved Only when Short Laser Pulses Are Used (The Condition of Stress Confinement) L – desirable spatial resolution t ac– time of propagation of acoustic wave through the distance = L t ac = L/ cs where cs = 1.5 mm/ns – speed of sound in tissue where t laser– laser pulse durationThe Condition of Stress Confinement:

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[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; G – Grüneisen parameter (dimensionless) Spatial Distribution of Optoacoustic Pressure in an Absorbing Medium without Scattering:Temporal Profile of Optoacoustic Waves in the Medium:Since:Generation of Optoacoustic Wave in Absorbing Medium

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Generation of Optoacoustic Wave in TissueSpatial Distribution of Optoacoustic Pressure in a Tissue (not close to the surface):k – coefficient depending on tissue optical properties µeff – tissue attenuation coefficientTemporal Profile of Optoacoustic Waves in the Tissue:

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Advantages of Optoacoustic TechniqueHigh Contrast (as in Optical Tomography) because It Utilizes Optical ContrastHigh Resolution (as in Ultrasonography) due to Ultrasound Wave Detection (Insignificant Scattering of Ultrasonic Waves Compared with Light Wave Scattering in Tissues)

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Absorption Spectra of Oxy- and DeoxyhemoglobinSteven L. Jacques, Scott A. Prahl Oregon Graduate Institute

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Steven L. Jacques, Scott A. Prahl Oregon Graduate Institute Therapeutic Window: 600 – 1400 nm Low absorption and low scattering = Deep penetration

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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

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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

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Ultrasound Imaging Systems Used in these Studies: Standard Clinical GE Systems and SiteRite Systems High-Resolution Vevo System

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High Resolution: 30 microns at depth of up to 25 mm Real-time Longitudinal Studies Measure Physiological parameters Contrast/Molecular Imaging Translatable to manNovel, High-resolution Ultrasound Imaging System (Vevo, VisualSonics)

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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 Correlates with Cerebral Venous Oxygenation / OxyHb SaturationBelow 50%: death or severe disability

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Last Updated: 8th March 2018

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