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 synergistic effect of rt-PA and 120-KHz ultrasound on thrombolysis using in vitro porcine and human whole blood clot models. In our ongoing studies, we have demonstrated that significant enhancement of thrombolysis correlates with the presence of stable cavitation and this type of gentle bubble activity can be sustained using an intermittent infusion of a contrast agent. In addition, we have shown that inertial cavitation, which elicits broadband acoustic emissions, is counter-productive for enhanced thrombolysis. Rather, the most effective form of bubble activity is stable cavitation, which elicits ultrasonic subharmonic generation. Importantly, we have shown encapsulation of rt-PA in a contrast agent specifically targeted to clot. These preliminary data strongly support the central hypothesis of our proposal that ultrasound enhances thrombolysis primarily via mechanical mechanisms. To test this hypothesis we propose to investigate three Specific Aims:
In Aim #1, we will develop a dual-element annular array transducer to facilitate simultaneous 120-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo.
In Aim #2, we will demonstrate the efficacy of 120-kHz ultrasound-enhanced thrombolysis through in vivo studies in a porcine intracerebral hemorrhagic stroke model using fluorescently labeled rt-PA-loaded liposomes or gas contrast agents and neuropathologic examination. As a novel approach in Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, near an intravascular clot in an ex vivo porcine carotid model. Vascular reactivity and the degree of rt-PA leakage across the vascular endothelium will be assessed to clarify the potential risks for sonothrombolysis in the presence of gas contrast agents. Successful completion of these studies will contribute significantly to our long-term goal to develop a sonothrombolysis system that delivers and enhances thrombolytic therapy in the cerebral vasculature and rapidly restores perfusion after ischemic stroke.

Public Health Relevance

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 listed in this proposal would have far reaching implications in improving directed therapeutic treatment of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047603-08
Application #
8231400
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Janis, Scott
Project Start
2004-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$554,244
Indirect Cost
$134,986
Name
University of Cincinnati
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Bader, Kenneth B; Holland, Christy K (2016) Predicting the growth of nanoscale nuclei by histotripsy pulses. Phys Med Biol 61:2947-66
Haworth, Kevin J; Raymond, Jason L; Radhakrishnan, Kirthi et al. (2016) Trans-Stent B-Mode Ultrasound and Passive Cavitation Imaging. Ultrasound Med Biol 42:518-27
Haworth, Kevin J; Raymond, Jason L; Radhakrishnan, Kirthi et al. (2016) Erratum to: "Trans-stent B-mode Ultrasound and Passive Cavitation Imaging" in Ultrasound Med Biol 2016;42(2):518-527. Ultrasound Med Biol 42:1244
Kandadai, Madhuvanthi A; Mukherjee, Prithviraj; Shekhar, Himanshu et al. (2016) Microfluidic manufacture of rt-PA -loaded echogenic liposomes. Biomed Microdevices 18:48
Bader, Kenneth B; Crowe, Michael J; Raymond, Jason L et al. (2016) Effect of Frequency-Dependent Attenuation on Predicted Histotripsy Waveforms in Tissue-Mimicking Phantoms. Ultrasound Med Biol 42:1701-5
Bader, Kenneth B; Bouchoux, Guillaume; Holland, Christy K (2016) Sonothrombolysis. Adv Exp Med Biol 880:339-62
Klegerman, Melvin E; Naji, Ali K; Haworth, Kevin J et al. (2016) Ultrasound-enhanced bevacizumab release from echogenic liposomes for inhibition of atheroma progression. J Liposome Res 26:47-56
Kandadai, Madhuvanthi A; Meunier, Jason M; Hart, Kimberley et al. (2015) Plasmin-loaded echogenic liposomes for ultrasound-mediated thrombolysis. Transl Stroke Res 6:78-87
Haworth, Kevin J; Weidner, Christopher R; Abruzzo, Todd A et al. (2015) Mechanical properties and fibrin characteristics of endovascular coil-clot complexes: relevance to endovascular cerebral aneurysm repair paradigms. J Neurointerv Surg 7:291-6
Raymond, Jason L; Luan, Ying; van Rooij, Tom et al. (2015) Impulse response method for characterization of echogenic liposomes. J Acoust Soc Am 137:1693-703

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