Over 4 million U.S. men and women suffer from Alzheimer's disease;1 million from Parkinson's disease;350,000 from multiple sclerosis (MS);and 20,000 from amythrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available mainly due to the impermeability of the blood-brain barrier (BBB). Safe and localized opening of the blood-brain barrier (BBB) has been proven to present a significant challenge in brain drug delivery. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. The underlying hypothesis of this study is that, through control over the ultrasound and microbubble parameters, the extent and reversibility of the BBB opening induced by FUS can be successfully predicted and manipulated for efficient trans-BBB delivery. The primary objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS. In addition, the mechanism of the BBB opening in vivo will be monitored by the use of an MR contrast agent attached to the microbubble shell, which will allow observation of the location and accumulation of the shell material following treatment. The team assembled encompasses all important specialty areas required, such as ultrasound and microbubble engineering as well as MR and fluorescence brain imaging.
The specific aims of the study are to: 1) engineer and determine the microbubble characteristics for a reversible and localized BBB opening;2) identify the mechanism of BBB opening at distinct microbubble and ultrasound parameters in vivo; 3) perform quantitative analysis of the BBB opening using MR and fluorescence imaging; and 4) image the mechanism of BBB opening and trans-BBB delivery in vivo. By achieving the goals of the proposed study, the mechanism of the FUS procedure will be more thoroughly understood and the FUS-induced BBB opening will be optimized for selectively and precisely delivering pharmacological agents to currently untreatable brain regions. Public Health Relevance Statement (provided by applicant): Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain untreatable despite the thousands of pharmacological agents available. The objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZEB1-OSR-B (O1))
Program Officer
Lopez, Hector
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Biomedical Engineering
Schools of Engineering
New York
United States
Zip Code
Wang, Shutao; Karakatsani, Maria E; Fung, Christine et al. (2016) Direct brain infusion can be enhanced with focused ultrasound and microbubbles. J Cereb Blood Flow Metab :
Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan et al. (2016) Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor. Sci Rep 6:28599
Kamimura, Hermes A S; Wang, Shutao; Chen, Hong et al. (2016) Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz. Med Phys 43:5730
Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao et al. (2015) Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening. Phys Med Biol 60:9079-94
Downs, Matthew E; Buch, Amanda; Sierra, Carlos et al. (2015) Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task. PLoS One 10:e0125911
Downs, Matthew E; Buch, Amanda; Karakatsani, Maria Eleni et al. (2015) Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles. Sci Rep 5:15076
Samiotaki, Gesthimani; Acosta, Camilo; Wang, Shutao et al. (2015) Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound-mediated blood--brain barrier opening in vivo. J Cereb Blood Flow Metab 35:611-22
Wang, S; Olumolade, O O; Sun, T et al. (2015) Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther 22:104-10
Kamimura, H A S; Wang, S; Wu, S-Y et al. (2015) Chirp- and random-based coded ultrasonic excitation for localized blood-brain barrier opening. Phys Med Biol 60:7695-712
Wu, Shih-Ying; Chen, Cherry C; Tung, Yao-Sheng et al. (2015) Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain. J Control Release 212:30-40

Showing the most recent 10 out of 39 publications