From the Vascular Medicine Unit, Department of Medicine, and Department
of Electrical Engineering (E.L.C., D.D., S.C.), University of Rochester and
the Rochester Center for Biomedical Ultrasound, Rochester, NY.
Correspondence to Charles W. Francis, MD, Vascular Medicine Unit, PO Box 610, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. E-mail charles_francis{at}medicine.rochester.edu
Methods and Results—125I-fibrin–radiolabeled plasma
clots in thin-walled tubes were overlaid with plasma containing tissue
plasminogen activator (tPA) and exposed to
ultrasound. Enzymatic fibrinolysis was measured as
solubilization of radiolabel. Tissue attenuation and heating were
examined in samples of porcine rib cage. Fibrinolysis
was increased significantly in the presence of 40-kHz ultrasound at
0.25 W/cm2, reaching 39±7% and 93±11% at 60 minutes and
120 minutes, compared with 13±8% and 37±4% in the absence of
ultrasound (P<0.0001). The acceleration of
fibrinolysis increased at higher intensities.
Attenuation of the ultrasound field was only 1.7±0.5 dB/cm through the
intercostal space and 3.4±0.9 dB/cm through rib. Temperature
increments in rib were <1°C/(W/cm2).
Conclusions—These findings indicate that 40-kHz ultrasound
significantly accelerates enzymatic fibrinolysis at
intensities of
Ultrasonic radiation at megahertz frequencies enhances enzymatic
fibrinolysis in vitro1 2 3 4 5 6 7 8 and in
animal models of arterial9 10 11 12 and
small-vessel13 thrombosis with noninvasive
transdermal application. The rate of fibrinolytic enhancement is
directly related to the temporal average intensity of the
field,4 which also determines the
production of heat in the tissues by absorption of the
ultrasound. At frequencies of
Fibrinolysis
Ultrasound Treatment
The source of ultrasound was a 2.5-cm-diameter, 40-kHz piezoelectric
transducer (provided by Eastman Kodak Co), driven in continuous mode.
The acoustic pressures were measured before and after each experiment
with a hydrophone (type 8103, Brüel and Kjaer). The face of the
hydrophone was placed at the site of closest approach of the samples.
Intensities reported here are converted from measured pressures by the
relationship I=p2/2
Attenuation of Rib Cage
Heating
Statistics
The acceleration of fibrinolysis with 40-kHz ultrasound
was dependent on intensity (Figure 2
Enhancement of fibrinolysis with 40-kHz ultrasound was
also examined at various concentrations of tPA (Figure 3
Figure 4
Increased fibrinolysis with ultrasound was achieved
with minimal mechanical disruption of the clot, consistent with
prior observations at higher frequencies3 4
indicating that enhancement of clot dissolution is due primarily to
accelerated enzymatic action. At 1 W/cm2, the
maximum mechanical disruption observed in any experiment in the absence
of tPA was 0.8%. Greater mechanical disruption occurred in experiments
with tPA present, reaching a maximum of 3.8% at 1 µg/mL and
1.5 W/cm2. This is consistent with the
hypothesis that tPA and ultrasound act together, and the mechanical
effects of low-intensity ultrasound are observed only after the fibrin
network has been proteolytically weakened. Generation of large amounts
of clot fragments may be undesirable therapeutically, because they
could obstruct distal small arteries.
Low-frequency ultrasound at high intensity has been used in a
qualitatively different manner in earlier investigations. Several
studies demonstrated the ability of wires vibrating at frequencies of
20 to 25 kHz and high power levels of up to 20 W to disrupt clots in
vitro.14 15 16 17 This approach has been used to
fragment thrombi into small particles, resulting in reperfusion in
patients with obstructed peripheral
arteries.18 19 20 A preliminary study in 20
patients undergoing coronary artery bypass graft surgery for
angina demonstrated complete recanalization in 70%
of vessels, but arterial perforation occurred in 2
cases.21 Additional difficulties with this
approach for therapy include the unknown effects of distal embolization
of fragments, damage to the vessel wall, and heating. Technical
problems include limited flexibility of the ultrasonic wire and
breakage. In addition, the need for selective
catheterization requires specialized facilities and
highly trained personnel. Ultrasound at 20 kHz applied transdermally in
combination with an echo contrast agent induced reperfusion in
thrombosed rabbit femoral arteries without administration of any
plasminogen activator, presumably by causing
mechanical fragmentation, but excessive heating was a
problem.22 Transdermal application of ultrasound
at
Our approach is different in concept and uses low-intensity ultrasound
to accelerate enzymatic fibrinolysis. A critical issue
in developing ultrasound to enhance enzymatic
thrombolysis for therapeutic application is
identification of the optimum frequency and intensity. Prior
reports1 2 3 4 5 6 have demonstrated enhancement of
thrombolysis by use of ultrasound at
Some published information indicates that enzymatic
thrombolysis may be enhanced at lower ultrasound
frequencies. Tachibana2 found acceleration of
urokinase-induced lysis of whole blood clots in a Chandler loop model
with 48-kHz ultrasound, and Olsson et al7
demonstrated increased fibrinolysis in vitro with
streptokinase using 170-kHz pulsed ultrasound at 0.5
W/cm2 and 1% duty cycle. Luo et
al26 reported that 28-kHz ultrasound at 18
W/cm2 applied transcutaneously significantly
accelerated streptokinase-induced thrombolysis in
rabbit femoral arteries in comparison with ultrasound alone or
streptokinase alone. Thermal injury to the dermis also occurred. A more
recent report27 showed a small acceleration of
whole-blood clot lysis with urokinase in combination with 170-kHz
ultrasound at 0.5 W/cm2. A catheter-mounted
transducer at 225 kHz accelerated thrombolysis with
urokinase in vitro,20 as did a 20-kHz
catheter-mounted transducer.25 The latter
demonstrated enhancement of fibrinolysis with 20-kHz
ultrasound at intensities of 1 and 1.5 W/cm2 and
reported up to 40% "fibrinolysis" that may have
represented mechanical clot disruption. The intensity of
the acoustic field was not fully characterized in the latter reports
because of the difficulty in calibration of the very small transducer,
which approximated a point source. None of these earlier studies,
however, make possible a direct comparison of the relative
effectiveness of midkilohertz and megahertz frequencies. This study,
however, used the same sample preparations and exposure conditions as
were used at megahertz frequencies in earlier experiments in this
laboratory. Figure 5
The capacity to enhance fibrinolysis at a
frequency as low as 40 kHz is important for several reasons. At 1 MHz,
the attenuation of soft tissues, such as liver and muscle, is
For clinical application, it will be necessary to balance the risk of
adverse effects of ultrasonic heating against the benefit of an
increased rate of thrombolysis. As an illustration,
contrast 40 kHz with 1 MHz in a hypothetical application in which the
site of interest is 5 cm below the skin surface, the path of the site
is soft tissue, and the goal of the treatment is to achieve 50%
thrombolysis in 60 minutes (Figure 5
At midkilohertz frequencies, even the brain may be accessible for
noninvasive treatment with ultrasound. Figure 6
Received January 28, 1998;
revision received April 6, 1998;
accepted April 14, 1998.
© 1998 American Heart Association, Inc.
Basic Science Reports
Enhancement of Fibrinolysis With 40-kHz Ultrasound
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Ultrasound at frequencies
of 0.5 to 1 MHz and intensities of 
0.5 W/cm2 accelerates
enzymatic fibrinolysis in vitro and in some animal
models, but unacceptable tissue heating can occur, and limited
penetration would restrict application to superficial vessels. Tissue
heating is less and penetration better at lower frequencies, but little
information is available regarding the effect of lower-frequency
ultrasound on enzymatic fibrinolysis. We therefore
examined the effect of 40-kHz ultrasound on
fibrinolysis, tissue penetration, and heating. 0.25 W/cm2 with excellent tissue
penetration and minimal heating. Externally applied 40-kHz ultrasound
at low intensities is a potentially useful therapeutic adjunct to
enzymatic fibrinolysis with sufficient tissue
penetration for both peripheral vascular and
coronary applications.
Key Words: fibrinolysis • ultrasonics • tissue
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Fibrinolytic therapy
is widely used to accelerate the enzymatic dissolution of thrombotic
vascular occlusions and thereby restore blood flow and limit
ischemic damage. It has application in the treatment of deep
vein thrombosis and pulmonary embolism and also in
arterial disease, including peripheral
arterial occlusion, stroke, and acute myocardial
infarction. Therapeutic success in treatment of arterial
occlusion depends on the rapidity of restoring blood flow, because
tissue necrosis increases rapidly with the duration of
ischemia. Therefore, several approaches have been used to
maximize both the rate and completeness of reperfusion, including the
use of adjunctive antiplatelet or anticoagulant therapy as well as
new fibrinolytic agents and regimens. 1 MHz, the intensities necessary to
achieve significant enhancement of thrombolysis cause
tissue heating that approaches levels that could be harmful. Although
the elevated temperature can cause minor acceleration of
thrombolysis by itself, the predominant mechanism of
action of ultrasound is nonthermal.4 The
present study shows quantitatively that midkilohertz frequencies
are more effective in enhancement of thrombolysis than
megahertz frequencies. These lower frequencies have important potential
advantages for therapy, because the lower absorption of ultrasound in
tissues causes less heating and the acoustic field can be broader and
more uniform with a greater depth of penetration than occurs at
megahertz frequencies.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clot Preparation
Fresh-frozen plasma anticoagulated with acid citrate dextrose
was obtained through the American Red Cross (Rochester Region), pooled,
divided into aliquots, and stored at -70°C until use. Clots were
prepared in thin-walled, 8-mm-diameter polyester tubes (Beckman) with
an attenuation of <0.8 dB at 1 MHz as determined by insertion loss
measurements when the water-filled tube was placed between the
ultrasound source and a PVDF needle hydrophone (type 80-0.5-4.0 Imotek
GmbH). It can be assumed that the attenuation is even less at lower
frequencies. To prepare clots, aliquots of 160 µL of plasma were
transferred into the tubes after being mixed with a trace amount of
125I-radiolabeled
fibrinogen.3 Clotting was induced by addition of
calcium chloride to a final concentration of 20 mmol/L and bovine
thrombin (Calbiochem) to a concentration of 0.5 NIH U/mL. Clots were
incubated for 1 hour at 37°C before use.
Plasma clots were overlayed with 820 µL of plasma containing 2
U/mL heparin (Riker Labs, Inc), and recombinant tPA (Activase,
Genentech) was added to the overlying solution. At desired times, tubes
were removed from the apparatus, and
fibrinolysis was stopped by the addition of 500
kallikrein inhibitory units/mL aprotinin (Trasylol, FBA
Pharmaceuticals) to inhibit plasmin. The residual clot was removed, and
the remaining fluid was centrifuged at 2300g for 5
minutes. The sediment and supernatant were counted separately, and
sedimentable radioactivity was considered to represent clot
fragments and nonsedimentable to represent soluble
derivatives.
Sample tubes were suspended on a 2.5-cm-diameter circular
test-tube rack and immersed in a tank of water at 37°C. The axis of
the rack was adjusted so that tubes approached within 1 cm from the
face of the transducer, and the rack was rotated at a frequency of 6 to
8 rpm to give equal average exposures to all of the tubes. A 3-cm-thick
block of natural rubber mounted on a 1-cm-thick sheet of acrylic was
placed behind the sample to minimize reflections. A thin sheet of
air-saturated cork-rubber material was attached to the back side of the
acrylic to prevent exposure of control samples that were placed behind
this barrier. 
c, where I is intensity, p
is the acoustic pressure amplitude, is the density, and c is the
speed of sound in water.
The hydrophone was located on the axis at a distance of 2 cm
from the face of the 40-kHz source, and a reference pressure amplitude
was measured at this location. A section of porcine rib cage obtained
from a meat market was inserted between source and hydrophone, and a
series of pressure amplitudes was measured as the rib cage was moved
laterally so that several ribs and intercostal spaces passed between
the source and hydrophone. Attenuation was calculated from the ratio of
the pressure amplitude with the tissue in the field to the reference
level measured without the tissue in the field. Beam patterns were
measured by recording relative output levels from the
hydrophone as it was moved transaxially.
For direct temperature measurements in porcine rib, a 25-µm
copper constantin thermocouple was cemented into a shallow groove cut
into the surface of the bone. The entire sample was degassed under
vacuum, placed on a plastic film window in a cylindrical container, and
embedded by pouring warm agar into the container. These procedures were
necessary to eliminate gas bodies near the thermocouple and convection
of the coupling medium that might cause errors in the measurement.
Absorption of ultrasound in the agar was negligible. The bone sample
was placed on the axis of the calibrated field of the 40-kHz source.
Temperatures were measured as a function of time and
intensity.
All data are expressed as mean±SD. Comparison of means was
performed with t tests assuming unequal variance between
groups, and Bonferroni's correction was applied for multiple
comparisons. The rates of fibrinolysis with tPA in the
absence or presence of ultrasound (Figure 1
) were fitted by a mixed linear model,
and P values are reported as for tests of fixed effects
analyzed with the SAS system.
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Figure 1. Fibrinolysis with and without
ultrasound. Radiolabeled plasma clots were overlayed with plasma
containing 1 µg/mL tPA and incubated at 37°C in presence of 40-kHz
ultrasound at 0.25 W/cm2 (solid line) or in absence of
ultrasound (dashed line). Controls were incubated in presence of 40-kHz
ultrasound at 0.25 W/cm2 in absence of tPA (dotted line).
Amount of fibrinolysis was determined as percentage of
radiolabel that was solubilized. Data are mean±SD.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Radiolabeled plasma clots were prepared, overlayed with
heparinized plasma containing 1 µg/mL of tPA, and incubated at 37°C
in the presence of 40-kHz ultrasound at 0.25
W/cm2 or in the absence of ultrasound (Figure 1
).
Fibrinolysis was increased significantly in the
presence of ultrasound and tPA, reaching 39±7% and 93±11% at 60
minutes and 120 minutes, respectively, compared with 13±8% and
37±4% in the absence of ultrasound (P<0.0001).
Fibrinolysis was <7% at all time points with or
without ultrasound exposure in the absence of tPA. ).
The extent of fibrinolysis at 1 hour with 1 µg/mL tPA
increased progressively from 20±5% in the absence of ultrasound to
35±6% at 0.25 W/cm2, 58±6% at 0.75
W/cm2, 75±6% at 1 W/cm2,
and 77±8% at 1.5 W/cm2 (P<0.005 for
all compared with no ultrasound). Fibrinolysis was
<10% at all ultrasound intensities without tPA. To determine whether
ultrasound caused mechanical disruption of the clot, the overlying
plasma was removed at the end of the 1-hour incubation and
centrifuged. In the presence of 1 µg/mL tPA, sedimentable
radioactivity increased from 1.6±8% without ultrasound to 1.9±1.4%
at 0.25 W/cm2, 2.2±1.5% at 0.75
W/cm2, 3.0±1.6 at 1.0
W/cm2, and a maximum of 3.8±1.8% at 1.5
W/cm2. Less disruption occurred in the absence of
tPA, with a maximum of 0.8±0.6% sedimentable radioactivity after 1
hour of exposure of clot to ultrasound at 1
W/cm2.
View larger version (10K):
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Figure 2. Acceleration of fibrinolysis at
various intensities of ultrasound. Radiolabeled plasma clots were
overlayed with plasma containing 1 µg/mL tPA and incubated at 37°C
in presence of 40-kHz ultrasound at various intensities (solid line) or
in absence of tPA (dashed line). Amount of fibrinolysis
at 1 hour was determined as percentage of radiolabel that was
solubilized. Data are mean±SD. ). Fibrinolysis after 1
hour in the absence of tPA was <8% at all ultrasound intensities. At
all concentrations of tPA, fibrinolysis increased at
higher intensities of 40-kHz ultrasound exposure (P<0.001
for all compared with fibrinolysis without ultrasound).
The increases in 1 hour of fibrinolysis with 1.5
W/cm2 ultrasound were 263%, 358%, and 365% at
tPA concentrations of 0.25, 0.5, and 1.0 µg/mL, respectively. In the
presence of ultrasound, greater fibrinolysis could be
achieved after 1 hour than in the absence of ultrasound even if higher
tPA concentrations were used. For example, there was lysis of 39%
after 1 hour at 0.25 µg/mL tPA at 1.5 W/cm2
(Figure 3), and this was greater than the 17% or 20% lysis observed
in the absence of ultrasound at tPA concentrations of 0.5 and 1
µg/mL, respectively.
View larger version (37K):
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Figure 3. Enhancement of fibrinolysis at
various concentrations of tPA. Radiolabeled plasma clots were overlayed
with plasma containing no tPA or with tPA at 0.25, 0.5, or 1 µg/mL.
They were then incubated at 37°C for 1 hour and exposed to 40-kHz
ultrasound (US) at various intensities up to 1.5 W/cm2.
Solubilization at 1 hour was determined by percentage of radiolabel
remaining in solution after centrifugation. Data are
mean±SD. shows the transaxial field of
the 40-kHz transducer at a distance of 2 cm from the face. Because the
wavelength (3.7 cm) is comparable to the size of the transducer, the
field near the transducer is relatively uniform in contrast to the very
complex near field of a 1-MHz transducer of comparable size. Also shown
in Figure 4 is the transaxial field transmitted through a
representative sample of porcine rib cage under 2
conditions. In 1, a rib is centered on the axis of the field, and in
the other, the intercostal space is centered on the axis. Averaged over
4 samples, the attenuation of the field through the intercostal space
was 1.7±0.5 dB/cm, and through the bone, 3.4±0.9 dB/cm. Measurements
of heating indicate that temperature increments in rib are <1°C per
W/cm2.
View larger version (14K):
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Figure 4. Relative transaxial intensity for 40-kHz
transducer. Open symbols show intensities with a porcine rib cage
section between source and hydrophone. With 1 beam pattern ( 
), a rib
is centered on axis of sound field. In the other (
), intercostal
space is on axis. Solid symbols show intensities in absence of
tissue.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results demonstrate marked enhancement of
fibrinolysis with 40-kHz ultrasound at intensities as
low as 0.25 W/cm2 and tPA concentrations between
0.25 and 1 µg/mL. At 0.25 W/cm2, the
ultrasound-induced enhancement of fibrinolysis was
greater at higher tPA concentrations, with a 27% enhancement at 0.25
µg/mL, whereas it was 80% at 1 µg/mL. The acceleration of
fibrinolysis was also greater at higher ultrasound
intensities, which reached a maximum of nearly 4-fold at 1 µg/mL tPA
and 1.5 W/cm2, increasing from 20% to 77%.
Greater fibrinolysis could be achieved with ultrasound
at a lower tPA concentration than without ultrasound at higher tPA
concentrations. 
37 kHz in combination with intravenous stabilized
microbubbles was effective in recanalizing thrombosed rabbit
iliofemoral arteries in comparison with either ultrasound alone or
microbubbles alone.23 0.5 MHz and
intensities of 0.5 W/cm2. The limited tissue
penetration of ultrasound at 1 MHz, however, would restrict potential
therapeutic application to vessels in the arms and legs, and the levels
required would make tissue heating an additional problem. Miniaturized
transducers have also been attached to catheters for endovascular
use,23 24 25 and this offers the potential to
deliver localized ultrasound at the site of thrombosis while limiting
exposure of normal tissue. For wide therapeutic application, however,
noninvasive external application of ultrasound has greater potential,
because it requires neither angiography nor selective
catheterization, it eliminates the risk of vessel wall
damage by the catheter, and it could be used for vessels too small or
inaccessible for catheterization. is a quantitative
comparison of the data at 1 MHz (Reference 33 ) with the results at 40
kHz reported here. The advantages of 40-kHz exposures are striking.
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Figure 5. Comparison of effects of ultrasound at 1 MHz and
40 kHz on fibrinolysis. Data are taken from this report
(see Figure 2 ) at 40 kHz (dashed line) and from that reported
previously.3 Both show amount of
fibrinolysis (±SD) at 1 hour by identical systems
except for ultrasound frequency.0.5
dB/cm, and this reduces the intensity by 50% in propagation
paths on the order of 5 cm, which should be adequate for the treatment
of clots in peripheral blood vessels. The attenuation of
bone, however, is at least an order of magnitude greater, and use of
high-frequency ultrasound for noninvasive treatment of heart or brain
is essentially precluded. In contrast, the depth of penetration of
40-kHz ultrasound in soft tissues is for practical purposes infinite,
and the rib cage transmits 50% of the incident intensity into the
heart. Wavelengths of several centimeters mean that beam patterns are
broad and relatively uniform even after passing through the chest wall.
Also, there is a rather large intensity window between the minimum
values that are effective in enhancing thrombolysis
(0.25 W/cm2 in situ) and the levels that would
be thermally hazardous (1 to 2 W/cm2 at the
bone). Taken together, these factors suggest that an effective
treatment need not require critical placement of the transducer
relative to the clot or precision calibration of the acoustic fields.
In fact, a treatment procedure similar to that used for ultrasonic
diathermy in a physical therapy setting may be appropriate for cardiac
application. The transducers would be comparable in size and shape,
coupling could be via gel on the skin, and stroking of the transducer
over the target area all might be the same. Only the frequency of the
transducer would be different. ). At 1 MHz, 6
W/cm2 is required at the site or 12
W/cm2 at the surface of the body. This is an
order of magnitude greater than ordinarily would be used in physical
therapy and would produce unacceptably large heating rates. At 40 kHz,
the required intensity at the site (and at the skin surface) is only
0.5 W/cm2. Thus, the required surface intensity
is lower by more than an order of magnitude, and because the absorption
coefficient of the tissue is also much smaller at the lower frequency,
concern for heating is essentially eliminated. Two possible exceptions
may be mentioned. If a coupling gel is used to make contact between the
source transducer and the skin, highly localized heating can occur near
air bubbles that become entrapped in the gel, but this is a relatively
trivial problem. However, a more serious problem might be encountered
if the clot under treatment is located in a vessel near a bone. At 1
MHz, the excess absorption of sound in bone at levels great enough to
achieve the target rate of thrombolysis would produce
unacceptable heating. In contrast, the 40-kHz measurements of bone
heating reported above show that bone heating should not be ignored,
but the problem would be minimized by at least an order of magnitude by
the lower intensities required and the lower absorption coefficient of
bone at 40 kHz. is a summary of the published data on
the attenuation of skull bone.28 29 30 31 32 Even at 300
kHz, the intensity transmitted through the skull should be >33% of
the level incident on the scalp. Attenuation above this frequency is
roughly proportional to the frequency. This suggests that at 40 kHz,
even with the loss of intensity in passing through the skull, the
intensity reaching the brain with thermally acceptable incident levels
would be great enough to significantly enhance enzymatic
thrombolysis.
View larger version (8K):
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Figure 6. Attenuation of human skull as a function of
frequency. Data taken from literature: 
,31
,29 
,30 
.32 A compilation
of these attenuation data is found in Reference 32.
Acknowledgments
This work was supported in part by grants HL-50497, HL-30616,
and DK-39796 from the National Institutes of Health, Bethesda, Md. The
help of Carol Weed in preparing this manuscript is gratefully
acknowledged.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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