Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or sonothrombolysis, has been shown to improve recanalization in patients with acute ischemic stroke. Effective methods of enhancing thrombolysis have been examined in an attempt to reduce the dosage of the thrombolytic agent and reduce the risk of hemorrhagic events. We have investigated the underlying mechanism of ultrasound-assisted thrombolysis to optimize the ultrasound parameters to achieve faster lysis.
We have also shown encapsulation of rt-PA in a contrast agent specifically targeted to clot. We enlist agents specifically targeted to the thrombus which are echogenic and can be activated by US to improve thrombolysis, allow direct targeting, allow for the reduction of the rt-PA dose, and decrease complications associated with giving this agent systemically. In vitro, and in vivo studies are being performed to test the rt-PA-loaded echogenic liposomes and optimize the ultrasonic technique to maximize US-enhanced thrombolysis. Our long-term objective is to develop a transcranial, ultrasound-enhanced thrombolysis system that minimizes the risk of intracranial hemorrhage, increases the number of stroke survivors, improves long-term prognosis, and reduces health care costs. The development of the agents and techniques in the Image-guided ultrasound therapeutics Laboratory have far reaching implications in improving directed therapeutic treatment to stroke.
Singing bubbles presentation at ASA Seattle 2011:Members from IgUTL explain the prevalence of stroke and the need for more efficacious treatment startegies. The likely mechanism for ultrasound enhanced thrombolysis is discussed along with techniques to optimize ultrasound parameters for treatment.
Echogenic liposomes (ELIP) are being developed at UTHSC-Houston for use as targeted ultrasound contrast agents and drug carriers for ultrasound-triggered drug delivery. Physical and acoustical characterization of ELIP is under way in the Image-guided ultrasound therapeutics Laboratory to determine the optimum acoustic parameters for diagnostic and therapeutic applications. The utility of ELIP for contrast depends on their stability in an acoustic field and under physiological conditions, whereas the use of ELIP for drug delivery requires the liberation of encapsulated gas and drug payload at the desired treatment site. Our long-term goals are to determine, quantitate, and characterize the stage, extent, and pathophysiologic development of atherosclerosis, allowing directed therapy to improve physiologic flow following clinical intervention.
Our long-term goal is to develop therapeutic-loaded echogenic liposomes (ELIP) which, when exposed to pulsed ultrasound, trigger drug or gene intravascular release and enhance uptake in targeted vascular beds. Therapeutic agents of interest include anti-inflammatory drugs (rosiglitazone),thrombolytics (recombinant tissue plasminogen activator), anti-angiogenesis (bevacizumab), vasoactive gases (nitric oxide and xenon), and anti-inflammatory genes (eNOS). Experiments at the Image-guided ultrasound therapeutics labs are focused on the development of optimal ultrasound parameters for therapeutic delivery and determination of the efficacy of therapeutic release to arrest atheroma progression.
Screen capture of ELIP circulating in a flow phantom exposed to color Doppler ultrasound:ELIP rapidly lose echogenicity as they pass through the ultrasound field from right to left. This demonstrates how gas and therapeutic agents may be released from circulating ELIP exposed to ultrasound from a clinical diagnostic scanner.
As demonstrated at IgUTL, and other laboratories around the world, microbubble cavitation activity has been tied to a variety of bioeffects, including sonothrombolysis, HIFU thermal ablation, sonoporation, drug and gene delivery, and hemostasis. The microbubble cavitation activities that induces these bioeffects also produces characteristic cavitation emissions. The experiments that have shown these correlations have almost exclusively used single-element transducers. These single-element transducers typically provide good spatial sensitivity or specificity for cavitation activity, but not both. Passive cavitation imaging is an array-based approach to processing cavitation emissions that can provide excellent spatial sensitivity and specificity. Recent work within IgUTL has implemented passive cavitation imaging on a clinical scanner. Using this platform, we have used in vitro experiments to investigate the properties of passive cavitation imaging. We have demonstrated that passive cavitation imaging can accurately map cavitation activity. Furthermore, we have shown that different types of cavitation activity can be mapped based on the frequency content of cavitation emissions. The array-based approach can provide superior signal-to-noise as compared to single-element transducers by reducing the incoherent noise that occurs across the individual elements in an array. Experiments were also performed to determine whether the pulse shape of the emissions affect passive cavitation imaging resolution. It was found that longer pulses result in larger amplitudes in the passive cavitation images, but they do not affect the image resolution. This is in opposition standard b-mode imaging. These results show that passive cavitation imaging has the potential to be a powerful tool for monitoring and controlling cavitation-based therapies.
PCI overlaid (hot colormap) on a B-mode (grayscale)
Echogenic liposomes were flowing (left to right) through a vessel phantom. Cavitation of the echogenic liposomes is induced with a clinical scanner in spectral Doppler mode (MI = 0.8). Loss of echogenicity in the B-mode images occurs at the same spatial location as subharmonic emissions in the passive cavitation images.
Recent studies have demonstrated that simultaneous exposure of blood clots to ultrasound and rt-PA results in an increased thrombolytic effect. The Image guided Ultrasound Therapeutics Labs at the University of Cincinnati are 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.
Simulation of acoustic wave propagation through the skull
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, investigation of the thresholds of damage in rat lungs exposed to diagnostic ultrasound were carried out.