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 risk of hemorrhagic events. 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 demonstrated encapsulation and ultrasound-triggered release of nitric oxide and other bioactive gases to promote vasodilation, and neuroprotection. 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 220-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo. The ability to monitor stable cavitation throughout treatment will aid in the automated control and optimization of thrombolytic enhancement.
In Aim #2, we will demonstrate the efficacy of 220-kHz ultrasound- enhanced thrombolysis using t-ELIP or rt-PA and a contrast agent through in vivo studies in a porcine hemorrhagic stroke model. As a novel approach in Aim #2, we will also evaluate the degree of neuroprotection achieved by treating the intracerebral hemorrhage with ELIP loaded with a mixture of hydrogen sulfide, a neuroprotectant, and octofluoropropane to nucleate bubble activity, and compare to ELIP loaded with a mixture of xenon, a neuroprotectant, and with a smaller amount of the bubble nucleation agent.
In Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, in a porcine arterial thrombus model. Successful completion of the proposed studies will elucidate the utility and potential risks of ultrasound-enhanced thrombolysis and ultrasound-mediated delivery of vasodilatory or cytoprotective gases and will provide important new information to assist the design of targeted agents to improve thrombolysis and neuroprotection in acute stroke treatment.

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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
Klegerman, Melvin E; Zou, Yuejiao; Golunski, Eva et al. (2014) Use of thermodynamic coupling between antibody-antigen binding and phospholipid acyl chain phase transition energetics to predict immunoliposome targeting affinity. J Liposome Res 24:216-22
Raymond, Jason L; Haworth, Kevin J; Bader, Kenneth B et al. (2014) Broadband attenuation measurements of phospholipid-shelled ultrasound contrast agents. Ultrasound Med Biol 40:410-21
Kim, Hyunggun; Britton, George L; Peng, Tao et al. (2014) Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage. Int J Nanomedicine 9:155-65
Bouchoux, Guillaume; Shivashankar, Ravishankar; Abruzzo, Todd A et al. (2014) In silico study of low-frequency transcranial ultrasound fields in acute ischemic stroke patients. Ultrasound Med Biol 40:1154-66
Gruber, Matthew J; Bader, Kenneth B; Holland, Christy K (2014) Cavitation thresholds of contrast agents in an in vitro human clot model exposed to 120-kHz ultrasound. J Acoust Soc Am 135:646-53
Bader, Kenneth B; Holland, Christy K (2013) Gauging the likelihood of stable cavitation from ultrasound contrast agents. Phys Med Biol 58:127-44
Rim, Yonghoon; McPherson, David D; Kim, Hyunggun (2013) Volumetric three-dimensional intravascular ultrasound visualization using shape-based nonlinear interpolation. Biomed Eng Online 12:39
Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail et al. (2013) Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 10:573-92
Sutton, Jonathan T; Ivancevich, Nikolas M; Perrin Jr, Stephen R et al. (2013) Clot retraction affects the extent of ultrasound-enhanced thrombolysis in an ex vivo porcine thrombosis model. Ultrasound Med Biol 39:813-24

Showing the most recent 10 out of 38 publications