Ultrasound-Induced Blood-Brain Barrier Opening
Elisa E. Konofagou, Yao-Sheng Tunga, James Choia, Thomas Deffieuxa, Babak Baseria and Fotios Vlachosa
Affiliation: Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Keywords: Blood-brain barrier, brain drug delivery, disruption, focused ultrasound, microbubble, safety.
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 amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases
account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease.
Although great progress has been made in recent years toward understanding of these diseases, few effective treatments
and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows
only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe
and localized opening of the BBB has been proven to present a significant challenge. 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. FUS may thus have a huge impact in trans-BBB brain
drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and
the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The
mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the
safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters.
It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45
MPa) and microbubble (diameter under 8 μm) conditions.
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