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An Investigation of High Intensity Focused Ultrasound Thrombolysis
Cameron Wright, Kullervo Hynynen, and David Goertz
Citation: AIP Conference Proceedings 1359, 246 (2011);
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Published by the American Institute of Physics
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An Investigation of High Intensity Focused
Ultrasound Thrombolysis
Cameron Wrighta,b, Kullervo Hynynena,b and David Goertza,b
Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada, M4N 3M5
Department of Medical Biophysics, University of Toronto
Abstract. Investigations into high intensity focused ultrasound (HIFU) thrombolysis in vitro and
in vivo in a rabbit femoral artery thrombus model were performed. A 1.51 MHz focused
transducer was used to treat clots with pulse lengths of 1-10 ms, acoustic powers of 1-300 W and
exposure durations of 5-20 s. Our measurements indicate the creation of acoustic radiation force
induced clot displacements are insufficient to mechanically fractionate clots, despite reaching
displacements > 100 ȝm. Only under the presence of inertial cavitation was HIFU able to disrupt
clots. Cavitation thresholds of 160 W in vitro and 215 W in vivo were observed. In vitro, clots
insonified at powers above the cavitation threshold eroded regions up to 2.5x the transducer
beam width. Successful recanalization in vivo occurred in 5/20 cases for 1ms pulses at powers >
215 W. 10 ms pulses created high incidences of symptomatic bleeding while 1 ms pulses did
not. These results demonstrate treatment feasibility in vivo, although further work is required to
understand the influence of different acoustic parameters on treatment outcome.
Keywords: Thrombolysis, High Intensity Focused Ultrasound, Stroke, Cavitation
PACS: 43.80.Sh, 87.50.yg,
Ultrasound potentiated thrombolysis with conjunctive agents has been used for
three decades to enhance clot disruption [1]. The use of high intensity focused
ultrasound (HIFU) is an alternative approach to sonothrombolysis which may avoid
the risks and limitations of conjunctive agents. Preliminary in vitro investigations have
demonstrated its feasibility [2,3] with short duration pulses (<0.2 ms). In these studies
cavitation is thought to be the dominant mechanism based on observations made in [3]
and in previous HIFU erosion studies in tissue [4] at similar pulse lengths. We
hypothesize that by using longer pulse lengths, HIFU may increase thrombolysis rates
through additional mechanisms besides cavitation, such as the creation of clot
displacements which may induce clot rupture. The objective of this work was to
investigate the extent to which longer HIFU pulses (1-10 ms) may initiate
thrombolysis both in vitro and in vivo.
Therapeutic pulses were provided by a custom single element focused
transducer (diameter 10 cm, focus 10 cm) with a transmit frequency of 1.51 MHz,
from below the clot. All experiments were performed in a water tank filled with
10th International Symposium on Therapeutic Ultrasound (ISTU 2010)
AIP Conf. Proc. 1359, 246-250 (2011); doi: 10.1063/1.3607913
© 2011 American Institute of Physics 978-0-7354-0917-0/$30.00
degassed water and with an acoustic absorber situated distal to the focus. In vitro clot
displacements were initiated by ten 0.5 ms pulses separated by 0.05 ms spacing for a
range of acoustic powers (1-20 W). Therapy pulses were interleaved with 30 MHz
ultrasound (VisualSonics Inc.) RF imaging pulses both during and after the “pushing”
to monitor temporal dynamics of clot displacement. Access to the RF data enabled the
spatial mapping of clot displacements initiated by the therapeutic pulse through a 2D
autocorrelation technique [5]. High power clot lysis experiments were performed at 1
Hz PRF for a range of pulse lengths (1–10 ms) and acoustic powers (80–300 W). (30
MHz) ultrasound imaging was used to provide quantitative information about clot
size, erosion, and blood flow monitoring. A passive cavitation detector transducer
(0.52 MHz) was also employed.
High power in vitro experiments were conducted on recalcified rabbit blood
clots contained within polyethylene tubing (2 mm ID, 0.01 mm wall). These clots
were lodged within a 3.5 mm diameter agar channel for displacement experiments. In
vivo experiments were conducted using a modified rabbit femoral artery thrombus
model [6] for n = 55 vessels. 1 cm clots were formed by injecting thrombin directly
into a clamped arterial segment of blood.
Fig. 1a illustrates the spatial variation of clot displacements along one line of
sight as a function of time for an example pulse at 20 W. Fig. 1b illustrates the net clot
displacement along a fixed depth, in this case coinciding with a depth that reaches the
largest displacement. Fig. 1c plots the peak clot displacement over a range of pressures
(n = 8 for each pressure).
FIGURE 1. a) spatial map of clot displacements as a function of depth along one line of sight as a
function of time. b) fixing depth at value of peak displacement depth enables clear visualization of
temporal dynamics of displacements. c) peak clot displacements as a function of acoustic power.
Fig. 2 illustrates example post-treatment longitudinal cross sectional in vitro
images of a thrombus. The clot was treated with a 1 ms pulse, 185 W, 1 Hz PRF for
(left) 5 s duration and (right) 20 s duration. Regions of clot erosion are clearly
identified by sharp delineations of hypoechogenicity.
1.71 mm
2.26 mm
FIGURE 2. Example post- treatment images at 1 ms, 185 W, 1 Hz PRF for 5 s (left) and 20 s (right).
TABLE 1. Summary of erosion volumes for 1 ms pulses at different powers and treatment
5 s Exposure
20 s Exposure
120 W
0 mm3
0 mm3
160 W
5.17 +/- 0.50 mm
7.42 +/- 0.61 mm3
185 W
5.27 +/- 0.53 mm3
7.73 +/- 0.58 mm3
Table 1 shows the relationship between clot erosion volume vs. power and
treatment duration for 1 ms pulses (n = 7). At 120 W no observable clot erosion
occurred. At 160 W erosion volumes reached 5.17 and 7.42 mm3 for 5 and 20 s
exposures, respectively. Marginal increases in erosion volumes were observed for
exposures at 185 W.
Fig. 3 shows example power spectra for a 1 ms pulse recorded with the passive
cavitation detector during in vitro (left) and in vivo (right) treatments. 14 dB increase
in signal power is observed about the fundamental frequency of the cavitation
transducer (0.52 MHz) from the 160 W exposures, compare with the 120 W
exposures. Additionally, at 160 W large amounts of energy are observed from the
fundamental (1.5 MHz) and second harmonic (3 MHz) frequencies of the therapy
transducer. Fig. 3 (right) shows a similar recording acquired during in vivo treatment
of a rabbit femoral artery. In vivo power
FIGURE 3. Power spectra for 1 ms pulse in vitro (left) and in vivo (right)
spectra reveal negligible power at 0.52 MHz at 170 W, yet at 215 W this value
increases by 21 dB. Significant amounts of energy are observed from the fundamental
(1.5 MHz), sub-harmonic (0.75 MHz) and second harmonic (3 MHz) of the therapy
Fig. 4 illustrates a successful recanalization treatment performed using a 1 ms,
215 W, 1 Hz treatment. Pulsed wave (PW) Doppler imaging prior to treatment (fig.
4a) indicates the presence of an occlusion noted by the absence of flow. PW Doppler
imaging after treatment (fig. 4b) indicates that flow has been re-established, which is
evidenced by the appearance of vessel pulsatility.
Successful recanalization attempt for 1 ms, 215 W pulse. a) pre treatment PW image with
occlusion and b) post-treatment PW indicating restoration of flow.
Recanalization attempts were performed for n = 55 vessels over a range of
pulse lengths and acoustic powers, summarized in Table 2. For 1 ms pulses, 0/8
successful recanalization attempts occurred at 170 W or below, 2/13 occurred at 215
W, and 3/7 at 300 W. For 10 ms pulses, 0/9 successful recanalizations occurred below
120 W, 1/14 at 170 W and 1/4 at 215 W.
80 W
120 W
170 W
215 W
300 W
TABLE 2. Summary of successful recanalization attempts
1 ms Pulse
10 ms Pulse
Table 3 summarizes those in vivo exposures which initiated bleeding. 10 ms
pulses yielded significant bleeding complications at powers > 170 W (6/18). In
contrast, 1 ms exposures only initiated one minor bleed at 300 W. Importantly, all
recanalization attempts with 10 ms pulses were also associated with bleeding.
80 W
120 W
170 W
215 W
300 W
TABLE 3. Summary of treatments that initiated bleeding during in vivo treatment
1 ms Pulse
10 ms Pulse
We have shown that the effectiveness of HIFU thrombolysis for longer pulses
(1-10 ms) is dependant upon the presence of cavitation. Under the conditions
investigated, clot displacements do not mechanically fractionate thrombus. Only above
a cavitation threshold was it possible to initiate clot erosion. In vitro erosion volumes
reached almost 2.5x the beamwidth of the therapy transducer. For 1 ms pulses,
recanalization occurred for 5/20 cases > 215 W. For 10 ms pulses, recanalization only
occurred for 2/18 cases at powers > 170 W but was also associated with bleeding. The
observed correlation between erosion and cavitation parallels those findings performed
with short pulses (<0.2 ms) on ex vivo tissue [4] and more recently in clots [2]. The
influence of heating and boiling may also play a role in HIFU thrombolysis with
longer pulses although we note that the onset of cavitation was not delayed relative to
the pulse arrival (data not shown). The results of this study suggest HIFU
thrombolysis with longer pulses warrants further evaluation.
This work was funded by the National Institutes of Health (R33EB000705),
Terry Fox Foundation, CRC program, and Sunnybrook Research Institute.
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U. Rosenchein et al., “Ultrasound imaging-guided noninvasive ultrasound thrombolysis:
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Xu et al., “Controlled tissue erosion,” IEEE Trans. Ultrason. Ferroelct. Freq. Contr. 51 (6),
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T. Loupas et al. “An axial velocity estimator for ultrasound blood flow imaging, based on a
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H. K. Gold et al., “Animal models for arterial thrombolysis and prevention of reocclusion.
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