Biomedical Engineering Reference
In-Depth Information
1
f
0
, therapy pulse
0.5
Wideband emissions
0
0
0.5
1
Frequency (MHz)
1.5
2
FIGURE 14.8
Wideband emissions detected around the center frequency (750 kHz) of a passive cavitation detector during focused ultrasound
treatment in rat brain at 1.503 MHz.
local temperatures and can cause mechanical damage. This has
the ability to enhance heating during FUS surgery [Hynynen,
1991; Holt and Roy, 2001; Sokka, 2003]. In the brain, however,
early experiments showed that cavitation damage during high
intensity exposures was not limited to the transducer focus,
and more often occurred at boundaries between tissue and ven-
tricles [Fry et al., 1970]. The lack of spatial control of cavitation
in the brain, and the dangers associated with damage to that
organ outside of the intended treatment volume, would suggest
that bubble-enhanced thermal surgery in the brain at this stage
requires more research to be properly utilized. One patient was
treated in Boston at Brigham and Women's Hospital with a low
frequency transducer (InSightec) intended for bubble-enhanced
tumor surgery. The patient died several days after treatment due
to bleeding that may or may not have been related to the pro-
cedure [Jolesz, 2009]. Cavitation monitoring during thermal
surgery in the brain increases treatment safety by providing
feedback to terminate treatment if broadband inertial cavitation
signatures are detected (Figure 14.8).
Stable cavitation can also increase heating and energy deposi-
tion at the transducer focus, and has interesting potential appli-
cations in low intensity procedures. Power requirements for
both inertial cavitation nucleation and for stable cavitation can
be reduced through the use of preformed gas bubbles.
filled with a perfluorocarbon gas and encapsulated with either
an albumin shell (Optison, GE Healthcare) or phospholipid
shell (Definity, Lantheus Medical Imaging; Sonovue, Bracco
Diagnostics, Inc.). Microbubbles have been shown to nucleate
inertial cavitation [Miller and Thomas, 1995] and can be manip-
ulated with pressures far below the inertial cavitation threshold
in brain tissue so bioeffects are likely to be limited to areas where
the microbubbles interact with the acoustic field. However, while
effects are mostly likely to be most prominent at the transducer
focus, interactions can occur anywhere that there are bubbles
in the sound field, leading to the possibility of effects occurring
outside the focus [McDannold et al., 2006b].
Liquid nanodroplets provide what is perhaps a better way
of localizing bubble mediated effects in the brain. Kripfgans
et al. [2000] demonstrated that superheated dodecafluoropen-
tan (DDFP) droplets could be manufactured and then vapor-
ized, and later demonstrated that this could be achieved
in
vivo
[Kripfgans et al., 2002]. DDFP droplets can be used over
a wide range of sizes and frequencies where the vaporization
threshold of the droplets is less than their inertial cavitation
threshold [Schad and Hynynen, 2010]. Liquid nanodroplets
do not interact with the ultrasound in the same way as micro-
bubbles. By vaporizing the nanodroplets at the focus, bubbles
can be formed with spatial precision, and effects outside the
focus can be avoided. Both microbubbles and liquid nanodro-
plets can be loaded with drug payloads to be delivered when
they are activated [Rapoport et al., 2009; Fabiilli et al., 2010].
This provides localized drug delivery. Both liquid nanodroplets
and microbubbles have yet to be used clinically in the brain for
therapeutic purposes, but their potential uses are being demon-
strated in important preclinical research [Hynynen et al., 2001;
McDannold et al., 2006a].
14.3.4 Microbubbles and Liquid Nanodroplets
Microbubbles used in ultrasound therapy are micron-sized
encapsulated gas-filled bubbles. Used as ultrasound contrast
agents due to their excellent scattering properties, microbubbles
can enhance energy deposition at the focus. These microbubbles
are typically on the order of a few micrometers in diameter,
