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 Localization of brain drug deliv-
ery is extremely important because
opening the BBB across the entire
organ may expose critical brain re-
gions to a drug that may have delete-
rious effects. In addition, most of the
aforementioned brain diseases are
concentrated in specific brain struc-
tures such as the hippocampus or
striatum. FUS, in combination with
microbubbles, therefore constitutes
the only truly transient, localized,
and noninvasive technique for open-
ing the BBB. Due to these unique advantages over other ex- istent techniques, FUS may facilitate the delivery of already developed pharmacological agents and could significantly impact how devastating CNS diseases are treated.
To provide for localized delivery, FUS employs curved trans- ducers that transmit acoustic waves that converge only at the geometric focus of the transducer (Figure 2). Most of the en- ergy delivered during this sonication induces mechanical ef- fects, thermal effects, or both. When this technology is used at high intensities, it is referred to as high-intensity focused ultrasound (HIFU).
Microbubbles are gas-filled or protein- or lipid-shelled for- mations that can be formed, activated, and injected intra- venously as contrast agents to enhance ultrasound imaging and especially the vasculature. The combination of FUS with microbubbles allows the separation of the mechanical effect of cavitation to occur at low-peak negative pressures without incurring thermal effects and thus leading to reversible and safe opening of the BBB (Konofagou, 2012).
Brain-Blood Barrier Opening Using Focused Ultrasound and Microbubbles Due to the high spatial resolution of the FUS methodology, the beam can be focused in a specific region of the brain such as the hippocampus, a key short-term memory cen- ter, and thus a drug delivery target in Alzheimer’s disease or to the caudate putamen, an important region for motor control and thus relevant in Parkinson’s disease. Delivery of molecules up to 20 nm in size has also been demonstrated (Chen and Konofagou, 2014). Most important, no neuronal or cellular damage within the range of peak rarefactional pressures of 0.3 to 0.45 MPa has been reported, and the bar- rier has been shown to close within 4-48 hours under these
A) B)
  Figure 2. A: Focused ultrasound (FUS) system for opening the BBB in mice in vivo. B: Drug de- livery uptake (“brighter” regions) in the left hemisphere of a mouse brain after BBB opening with FUS. Inset: contralateral (right) hippocampus (no FUS) in the same mouse.
 conditions, thereby preventing other (unwanted) molecules from crossing the BBB at the region of opening by FUS.
The feasibility of the BBB opening through the intact skull and skin and the successful imaging of the BBB opening in the area of the hippocampus at submillimeter imaging reso- lution have been shown in both wild-type and transgenic animals including models of glioblastoma, Alzheimer’s, and Parkinson’s disease. Indeed, there have been several reports over the past decade or two of using FUS and microbubbles to disrupt the BBB. This includes studies for neuroprotection and neurorestoration in Parkinson’s disease in rodents (Sa- miotaki, 2015), amyloid reduction in Alzheimer’s disease in rodents (Jordão et al., 2013; Leinenga et al., 2016), and treat- ment of glioblastoma in patients (Carpentier et al., 2016).
Mechanism of Blood-Brain
Barrier Opening
There are two physical mechanisms for opening the BBB with FUS. The first is to use the ultrasound beam at lower pressures to induce a stable oscillation of the microbubble, also known as “stable cavitation.” The second is to use high- er pressures to increase the magnitude of oscillation of the bubble to the point that it surpasses the inertia of the fluid and collapses on itself. This is called “inertial cavitation.” Both stable and inertial cavitation can be used to induce BBB opening. Stable cavitation has the safest profile and has been successfully monitored transcranially in real time in large animals, including through the human skull (Wu et al., 2014; Karakatsani et al., 2017; Figure 3).
Molecular Delivery Through
the Opened BBB
The delivery of many large pharmacological agents across the BBB using FUS and microbubbles has been demon-
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