Research Areas

Transcranial Ultrasound Thrombolysis System (TUTS)

Transmission of Ultrasound Through the Skull

Ultrasound Bioeffects

Characterization and Optomization of Contrast Agents

Assessment of Severity of Arterial Stenosis by Doppler Ultrasound

DESIGN OF A TRANSCRANIAL ULTRASOUND THROMBOLYSIS SYSTEM

Currently, the only therapy for ischemic stroke (other than aspirin and surgery) that is FDA approved is the thrombolytic agent recombinant tissue Plasminogen Activator (rt-PA).   Studies have shown that rt-PA is effective in lysing blood clots in ischemic stroke patients if given within 3 hours after the onset of stroke symptoms.  Unfortunately, only about 2 to 7% of ischemic stroke patients actually receive rt-PA due to various factors.  One factor is the lack of recognizing and diagnosing strokes in a timely manner.  Physicians are also reluctant to administer rt-PA because of the resulting increased risk of intracranial hemorrhage (ICH).  Administering rt-PA to a misdiagnosed hemorrhagic stroke patient could be serious and life threatening.

Any adjuvant therapy that lowers the dose of rt-PA or increases its efficacy would represent a significant breakthrough.  Improved effectiveness or greater safety would provide a powerful impetus for physicians to administer rt-Pa to a larger portion of the patients with ischemic stroke.  

Experimental setup for assessing the combined thrombolytic action of ultrasound and r-tPA: The custom-designed transducerto the right of the picture exposes a whole blood clot bathing in plasma and rt-PA within the central holder to ultrasound in a temperature-controlled water tank. The clot is then removed and weighed so as to assess percent mass loss relative to its initial mass. The two sound absorvers to the left of the picture are used to prevent the generation of reflections and standing waves during ultrasound exposure.

Recent studies have demonstrated that simultaneous exposure of blood clots to ultrasound and rt-PA results in an increased thrombolytic effect. The Ultrasound Laboratory at the University of Cincinnati is currently developing a novel transcranial ultrasound thrombolysis system (TUTS). With TUTS, an ultrasonic transducer is held against the temporal bone; energy radiates from the transducer, through the bone, and into the brain.  It is hoped that application of ultrasound via TUTS will permit the usage of lower dosages of rt-PA than are currently used clinically, yet resulting in increased thrombolysis with reduced risks of hemorrhage. The benefits of the TUTS system potentially include an increased number of stroke survivors, improved long-term prognosis and reduced health care costs.

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TRANSMISSION OF ULTRASOUND THROUGH THE SKULL

A significant part of developing TUTS is understanding and optimizing the transmission of ultrasound through the human skull. The strong impedance mismatch between the bone and the surrounding tissue causes substantial attenuation of the incident waveform, making intracranial ultrasound delivery especially challenging. At high frequencies in particular, a large proportion of the incident intensity is absorbed by the skull and converted into heat, resulting in a localized temperature increase that could prove damaging to the brain.  An experimental setup was devised in the Ultrasound Laboratory that makes it possible to assess the effect of ultrasound parameters (frequency, pulse duration and pulse repetition frequency) and transducer positioning on the resulting intracranial sound field.

Optimization of the intracranial transmission of ultrasound: The large custom-designed transducer to the right of the picture produces an ultrasound beam that penetrates the skull through the temporal bone inside a large water tank. The needle hydrophone (top-left) is used to obtain pressure measurements of the intracranial sound field, which can then be compared to the ultrasound beam characteristics in the free field.

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ULTRASOUND BIOEFFECTS

Recent increases in the pressure output of diagnostic ultrasound scanners have generated concern as to the potentially damaging effects of ultrasound on various tissues. This type of damage may be mediated by the expansion and violent collapse of gas bubbles exposed to ultrasonic excitation, a phenomenon known as inertial cavitation.  This has led to an interest in establishing thresholds for bioeffects in many organs, including the lungs of mammals.  In order to explore the hypothesis of cavitation-based bioeffects, the Ultrasound Laboratory is carrying out an extensive in vivo investigation of the thresholds of damage in rat lungs exposed to diagnostic ultrasound.

Histopathology of petechial hemorrhage in rat lung exposed to 6 MHz Doppler Pulse for 1.5 minutes at an MI=1.5.  Click on the box for an enlarged view of the damage.

Histopathology of normal rat lung.

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CHARACTERIZATION AND OPTIMIZATION OF CONTRAST AGENTS

Contrast agents – gas bubbles entrapped in a protein or lipid shell – are emerging as a novel technique for ultrasound image enhancement and targeted drug delivery. Only two such agents, Optison^® and Definity^®, have currently been approved by the FDA for clinical use to enhance cardiovascular flow images. However, many more new contrast agents are currently under study for a variety of specific applications. Amongst the most promising is a new generation of conjugated liposomes developed by our colleagues David McPherson and Robert MacDonald at Northwestern University . These particles are composed of air and fluid entrapped in a lipid bi-layer, making them suitable both as contrast agents and as a vehicle for targeted drug delivery.

Experimental Setup for Contrast Agent Characterization: The transducer to the left of the picture is used in pulse-echo mode. The portion of the received signal corresponding to backscattering from the contrast agent can be used to evaluate the backscattering coefficient. The PVDF hydrophone to the far right is used to ensure correct alignment and to obtain attenuation measurements.