Biomedical Engineering Reference
In-Depth Information
Pre-FUS
T1w
Post-FUS
CE-T1w
10mm
10mm
FIGURE 14.9 Pre-FUS baseline (left) and post-FUS contrast enhanced (right) T1w images of a Wistar rat brain showing enhancement at eight
locations following sonication at 1.18 MHz. The arrow lines of four sonication points drawn in each hemisphere. The direction of the ultrasound
travel is into the page. (Based on data from O'Reilly, M.A., A.C. Waspe, M. Ganguly et al., Utrasound Med Biol , 2 011).
pigs [Xie et al., 2008], but has never been tested in humans.
Promising results have been achieved in several studies deliv-
ering anticancer agents to the brain in preclinical models
[Kinoshita et al., 2006; Treat et al., 2007], with enhanced ani-
mal survival after BBBD and doxorubicin infusion of rats with
implanted 9L gliosarcoma tumors [Treat et al., 2009]. Delivery
of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) through the
BBB using FUS to treat glioblastoma in rats demonstrated
enhanced BCNU uptake and good suppression of tumor growth
over untreated controls [Liu et al., 2010]. However, there are sev-
eral safety considerations that currently prevent clinical use of
BBBD. The biggest limitation is the lack of a real-time moni-
toring technique to monitor and control the treatment, which
will continue to keep BBBD from clinical implementation until
a solution is presented.
Increased BBB permeability by mild hyperthermia has also
been suggested. Cho et al. [2002] used mild hyperthermia to
increase BBB permeability, however it has always been associ-
ated with brain tissue damage [McDannold et al., 2004b], and
thus the most promising work to date has relied on the use of
microbubbles.
14.3.5 Blood-Brain Barrier Disruption
As mentioned before, brain tissue is protected by a series of
tight junctions that prevent large molecules from passing from
the vasculature into the tissue. While the purpose of the blood-
brain barrier is to maintain the selective environment of this
vital organ, it also prevents most useful therapeutic agents from
reaching the tissue by limiting passage to molecules with good
lipid solubility that are smaller than approximately 500 Da
[Pardrige, 2005]. There exist pharmaceuticals that can disrupt
the BBB, however they produce systemic, rather than localized
disruption and expose the whole brain to both pathogens and
the delivered drugs. Ultrasound disruption of the BBB provides
a means for more localized BBBD.
Changes in the BBB under ultrasound exposure were first
documented by Bakay et al. [1956] when they demonstrated that
Trypan Blue dye leaked into the brain tissue around locations
exposed to high intensity ultrasound. While high power BBBD
can be achieved without neuronal damage [Vykhodtseva, 1995],
it was not until 2001 that low power, microbubble mediated
BBBD was demonstrated to produce consistent and repeatable
opening without neuronal damage [Hynynen et al., 2001]. The
documented disruption is localized, transient, and reversible.
BBBD can be detected in vivo using contrast-enhanced T1w MRI
as gadolidium does not permeate the intact BBB (Figure 14.9).
The exact mechanism for the BBBD is unknown. McDannold
et al. [2006a] correlated BBBD with an increase in harmonic
acoustic emissions detected during treatment (Figure 14.10) and
further established a frequency/pressure threshold relationship
[McDannold et al., 2008b].
Microbubble-mediated, low power BBBD has been dem-
onstrated in mice [Raymond et al., 2007; Choi et al., 2007],
rats [Treat et al., 2007], rabbits [Hynynen et al., 2001], and
14.4 applications and Clinical Studies
Although there have been few clinical studies using focused
ultrasound in the brain, there are an increasing number of
large animal and cadaver feasibility studies, which suggests that
clinical implementation is not too far off. The clinical study by
Guthkelch et al. [1991] using ultrasound hyperthermia as an
adjuvant to radiation therapy was the only phase I clinical trial
to use ultrasound hyperthermia for brain cancer treatment.
Current interests lie in the use of FUS for either thermal ablation
in the brain or for BBBD.
 
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