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From the Cardiovascular Division (D.M.S., A.Z.L., S.K.) and the
Department of Biomedical Engineering (R.J.P., T.C.S., S.K.), University of
Virginia School of Medicine, Charlottesville.
Correspondence to Sanjiv Kaul, MD, Cardiovascular Division, Box 158, Medical Center, University of Virginia, Charlottesville, VA 22908. E-mail sk{at}virginia.edu
Abstract
Background—Our aim was to observe
ultrasound-induced intravascular microbubble destruction in vivo and to
characterize any resultant bioeffects.
Methods and Results—Intravital microscopy was used to visualize
the spinotrapezius muscle in 15 rats during ultrasound delivery.
Microbubble destruction during ultrasound exposure caused rupture of
Conclusions—Microbubbles can be destroyed by ultrasound,
resulting in a bioeffect that could be used for local drug delivery,
angiogenesis, and vascular remodeling, or for tumor destruction.
Microbubbles used as
ultrasound contrast agents can be destroyed by ultrasound. Although
this phenomenon has been described in vitro,1 2
it has not been directly visualized in vivo. The purpose of this study
was to demonstrate intravascular microbubble destruction in vivo and to
study any potential bioeffects of this phenomenon.
Methods
The study was approved by the Animal Research Committee at the
University of Virginia and conformed to the American Heart Association
Guidelines for Use of Animals in Research. Fifteen female
Sprague-Dawley rats (Hilltop) were anesthetized by an injection
(0.6 mL · kg-1 body wt IM) of a 1%
The muscle was visualized by means of a x20 water immersion objective
attached to a microscope (ACM, Zeiss). Data were recorded on
1.25-cm videotape by means of a video recorder (model AG-1730,
Matsushita) connected to a video camera (model CCD-72, Dage-MTI), which
was mounted on the microscope. An image intensifier (GenIIsys,
Dage-MTI) was used to improve the quality of the images, which were
displayed on a high-resolution monochrome monitor (model PVM-137,
Sony).
To facilitate their identification, microbubbles were labeled with
5-([4,6-dichlorotriazin-2-yl]amino)fluorescein
hydrochloride (DTAF) (Sigma).3 In the first 2
rats, we used several types of microbubbles: Optison (Molecular
Biosystems), Imagent (Alliance Pharmaceuticals), DMP-115 (ImaRx
Pharmaceutical), and BR1 (Bracco Imaging). Optison was selected for the
remaining 13 rats because it provided the best DTAF labeling. It
consists of microbubbles containing a mixture of perfluoropropane and
air,1 with a mean diameter of 3.7
µm and a mean concentration of 0.8x109
· mL-1.
A phased-array system (HDI 3000cv, Advanced Technologies Laboratories)
was used to deliver ultrasound and to image the exteriorized rat
spinotrapezius muscle. Harmonic imaging was performed with a mean
transmit frequency of 2.3 MHz and a mean receive frequency of 4.6 MHz.
The tip of the ultrasound transducer was lowered into the chamber
containing the muscle, the distal edge of which was positioned at the
single focal point (5.1 cm) of the transducer. The thinness of the
muscle (
Before microbubble infusion was started, 5 ultrasound frames were
acquired as precontrast baseline images at a specified mechanical index
(MI). Each frame consisted of 128 lines delivered over a period of 12.8
ms, forming a 90° sector. Each line was fired as a single burst of
ultrasound with 4 cycles over 0.1 ms. The muscle was scanned to ensure
that no microvessel ruptures were present, thereby demonstrating a
control state. DTAF-labeled microbubbles (0.24 mL) were then infused
into the femoral vein over 1 minute, followed by a single ultrasound
frame applied at a specified MI. The different MIs used and their
corresponding acoustic intensities and peak negative acoustic pressures
are depicted in Table 1
After 10 minutes was allowed for PI binding to nonviable cells, the
muscle was optically scanned. Each field of view was examined under
transillumination for microvessel rupture sites, which were identified
by localized bleeding into the adjacent interstitium. These fields were
then reexamined under epi-illumination with a dual red-green
fluorescence filter. The total numbers of PI-positive nuclei
(red fluorescence) and microbubble fragments (green
fluorescence) were determined. To calculate the total numbers
of microvessel ruptures and PI-positive nuclei at the higher MI, values
from the previous lower MI were subtracted from the new total. After
termination of each experiment, the wet weight of the muscle was
determined.
Regions of interest encompassing
Comparisons between different MIs were made by 1-way repeated-measures
ANOVA, and differences were considered significant at
P<0.05 (2-sided). Correlations between MI and other
measured variables were performed by use of the function
f(x)=axlog10(x)+b.
Results
Before infusion of microbubbles, no microvessel ruptures were seen
after ultrasound exposure. Similarly, no ruptures were seen when
microbubbles were infused in the absence of ultrasound. When
microbubble infusion and ultrasound exposure were performed
simultaneously, destruction of microbubbles was seen in
microvessels
Figure 1A
The number of both capillary rupture sites and PI-stained nonviable
cells increased with an increase in the MI, and a close correlation was
noted between the 2 (Figure 2
Discussion
This is the first report of direct visualization of
ultrasound-induced intravascular microbubble destruction in vivo. When
microbubbles are destroyed by ultrasound, they cause immediate rupture
of the microvessel in which they are located, with RBC extravasation
into the nearby interstitial space. Nonviable cells are
also noted at the microvessel rupture sites. The number of microbubble
destruction events and the magnitude of bioeffects is proportional to
the MI applied.
The process by which ultrasound destroys shell-free microbubbles has
been modeled previously.5 6 7 Microbubbles, being
compressible, alternately contract and expand in a ultrasound field. At
low acoustic pressure, this expansion and contraction are equal. At
higher acoustic pressure, however, the expansion and contraction of the
bubbles become unequal and also greatly exaggerated, leading to their
destruction. Direct in vitro optical observations suggest that
microbubbles with shells may have a similar fate on exposure to
ultrasound.2 It is likely that
oscillations produce defects within the shells, causing the
gas to escape as soon as 5 ms after ultrasound exposure. The resultant
microbubble fragments and escaped gas may further disintegrate and may
not be detectable on imaging. The slow video frame rate precluded the
in vivo confirmation of these events in our study.
Because liquid media have air entrapped in them, ultrasound exposure
can result in the production of microbubbles, which can
cavitate at high energy.5 6 7 Thus, the
introduction of preformed bubbles is not even essential for the
occurrence of ultrasound bioeffects. In vitro experiments have
demonstrated the ability of ultrasound to cause cell lysis through the
process of cavitation.8 In vivo experiments on
organs that contain air, such as the lungs, have shown that ultrasound
can cause tissue hemorrhage.9
Introduction of microbubbles has also been shown to result in hemolysis
of blood within the cardiac chambers.10 Ours is
the first study to report direct in vivo observation of bioeffects when
tissue is exposed to ultrasound in the presence of preformed
microbubbles. Ultrasound exposure before microbubble infusion did not
result in microvessel rupture.
Several factors have to be considered before our findings can be
extrapolated to the clinical setting. On the basis of our calculations,
the maximal number of microvessels ruptured on each ultrasound exposure
(formation of a single image frame) was 0.015% of all the
The concentration of microbubbles in tissue will also determine the
magnitude of bioeffects. We infused 0.24 mL of the contrast agent in a
0.2-kg rat over a period of 1 minute. In clinical practice, we would
give the same dose to a 70-kg adult, which would significantly reduce
the concentration of microbubbles in the blood pool and could result in
a several hundred–fold reduction in microbubble destruction. The type
of microbubble could also influence its destruction by ultrasound.
Although our quantitative data are derived from Optison, the
qualitative data were similar for the other agents tested. Agents with
thick shells or very-high-molecular-weight gases may not be destroyed
as easily by ultrasound.
The duration of ultrasound exposure could also determine the
bioeffects. The bioeffects noted in our study occurred from 1
ultrasound sweep encompassing a single frame. If imaging were performed
continuously (
Finally, the interspecies differences in terms of tissue vulnerability
are very important. For instance, although lung hemorrhage has
been observed with ultrasound in rodents,9 no
such effect has been observed in humans exposed to similar ultrasound
energies.12 Studies performed so far in thousands
of patients with ultrasound contrast agents used in our study have
failed to document any clinically detectable adverse effects.
A novel use of microvessel rupture by ultrasound could be in local drug
delivery. Microbubble destruction could result in both microvessel
rupture and release of the drug, which could enter the
interstitial space through the rupture site. In this
manner, effective drug concentrations could be achieved locally while
its accumulation elsewhere in the body was limited, thus decreasing any
side effects. This method may also offer a particularly efficient means
of delivering genetic material directly into tissue, allowing its
successful incorporation into cells.
There are other potentially beneficial uses of this bioeffect.
Microvessel rupture could initiate angiogenesis and vascular
remodeling. In addition, destruction of microvessels supplying a tumor
could also result in its regression. Finally, destroying microbubbles
containing thrombogenic material in tumors could result in vascular
thrombosis and "choking" of tumors, with subsequent cell death and
tumor eradication. Such applications will require specially designed
transducers and will need to be tested in future studies.
Acknowledgments
This study was supported in part by grants from the National
Institutes of Health, Bethesda, Md (R01-HL-48890 and R01-HL-52309) and
from Molecular Biosystems, Inc, San Diego, Calif, and an equipment
grant from Advanced Technologies Laboratories, Bothell, Wash. Dr Skyba
is the recipient of a postdoctoral fellowship grant from the National
Institutes of Health (F32-HL-09540), and Dr Price is supported by a
Scientist Development Grant (9730025N) from the American Heart
Association, Dallas, Tex. Dr Linka was supported by the CIBA-Geigy
Jubiläums-Stiftung, Basel, Switzerland, and the Theodor und Ida
Herzog-Egli Stiftung, Zurich, Switzerland. We would like to thank Jeff
Powers, PhD, and Michalakis Averkiou, PhD, of Advanced Technologies
Laboratories for the technical information they provided and for their
valuable comments, and Katherine Ferrara, PhD, for a helpful critique
of the manuscript.
Footnotes
Presented at the Young Investigator Award Competition of the 7th American Society of Echocardiography Annual Scientific Meeting, June 10, 1998, San Francisco, Calif.
Received December 2, 1997;
revision received February 23, 1998;
accepted February 25, 1998.
References
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Carstensen EL. Age-dependence of ultrasonically-induced lung
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Dalecki D, Raeman CH, Child SZ, Cox C, Meltzer RS,
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Ultrasound Med Biol. 1997;23:307–313.[Medline]
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Hsiung HH, Skalak TC. Three-dimensional reconstruction
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Meltzer RS, Adsumelli R, Risher WH, Hicks GL, Stern DH,
Shah PM, Wojtczak JA, Lustik SJ, Gayeski TE, Shapiro JR, Carstensen EL.
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© 1998 American Heart Association, Inc.
Brief Rapid Communication
Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and its Local Effects on Tissue
7-µm microvessels (mostly capillaries) and the production
of nonviable cells in adjacent tissue. The number of microvessels
ruptured and cells damaged correlated linearly
(P<0.001) with the amount of ultrasound energy
delivered.
Key Words: ultrasonics • microspheres • tissue
-chloralose and 13.3% urethane solution (Sigma Chemical Co). The
left femoral vein was cannulated to allow microbubble infusion. The
right spinotrapezius muscle was exteriorized3 and
positioned in a custom-built chamber filled with Ringer's solution (pH
7.4) presaturated with a mixture of 5% CO2 and
95% N2 and kept at a constant temperature of
37°C. To minimize the effects of differences in tissue flow between
animals, maximal arteriolar vasodilation was achieved by addition of
10-4 mol · L-1
adenosine (Sigma) to the Ringer's solution. Propidium iodide
(PI) (Sigma), which exhibits red fluorescence when bound to
DNA,4 was also added to the Ringer's solution to
visualize nonviable cells (final concentration,
2x10-6 mol ·
L-1). 
0.25 mm) allowed it to be contained within the
elevation of the ultrasound beam (5.0 mm). 
.
The MIs are the values displayed on the ultrasound system. The MIs
actually delivered to the tissue were not measured. Each animal was
subjected to 2 MIs varying from 0.4 to 1.0.
View this table:
[in a new window]
Table 1. Displayed MI, Acoustic Intensity, and Peak Negative
Acoustic Pressure 80% of the muscle (>2000 pixels)
were placed over the digitally stored ultrasound images, and mean video
intensity (VI) in these regions was measured in the precontrast and
contrast-enhanced images obtained at various
MIs.3 VI from averaged contrast-enhanced images
was subtracted from that of the corresponding averaged precontrast
images. 7 µm in diameter (mostly capillaries). Often,
bubbles could be pulsed by ultrasound while in flux through the field
of view, where their immediate destruction could be directly observed.
Because of their rapid flux, it was practically impossible to capture
an image of a bubble before its destruction. In fields of view not
under direct observation, bubble destruction was evidenced by the
presence of microvessel rupture and nonviable cells. depicts a normal region of the
spinotrapezius muscle under transillumination after microbubble
infusion but before ultrasound exposure, where the microvessels are
normal. Figure 1B illustrates a composite image created from
transilluminated and epi-illuminated images after microbubble
destruction by ultrasound. A capillary rupture site with extravasation
of red blood cells (RBCs) into the interstitial space is
noted. Microbubble fragments (green) are evident at the center of the
rupture area (black arrow). Two PI-positive nuclei (red), indicating
nonviable cells, are also seen (white arrows). The vascular damage was
localized to short (5- to 10-µm) segments of the vessel length,
usually to one side of the vessel wall. Because RBCs and microbubbles
are anuclear, they are not labeled with PI. Therefore, their fragments
are visible only in the green spectrum.
View larger version (84K):
[in a new window]
Figure 1. Intravital images of microvessels in rat
spinotrapezius muscle. A, Normal muscle and intact capillaries under
transillumination (x20 objective) after injection of microbubbles but
before insonification with ultrasound. B, Composite image created from
transilluminated and epi-illuminated images after ultrasound exposure
in presence of microbubbles. Ruptured capillary with extravasation of
RBCs is shown. White arrows indicate PI-labeled nonviable cells; black
arrow indicates fragments of destroyed microbubble. Scale bar=20
µm. See text for details. ). Table 2 shows the mean
background-subtracted VI derived from the spinotrapezius muscle in all
rats. A linear correlation was noted between MI and VI (y=51
log10(x)+27, P<0.0001,
r=0.81, SEE=5.6).
View larger version (19K):
[in a new window]
Figure 2. Effect of microbubble insonification at varying
MIs on number of microvessel ruptures (A) and number of PI-positive
nuclei localized to microvessel ruptures (B), both normalized to unit
muscle mass. Error bars denote SEM. MIs were measured at transducer and
were slightly higher than those displayed on ultrasound system. See
text for details.
View this table:
[in a new window]
Table 2. Displayed MI vs Background-Subtracted VI Measured
From the Spinotrapezius
Muscle 7-µm
microvessels present in the rat spinotrapezius
muscle.11 In our experiments, the transducer and
tissue were separated by Ringer's solution, so ultrasound attenuation
was practically negligible. In the clinical setting, however, tissue
attenuation is responsible for a decrease of 0.3 dB ·
cm-1 · MHz-1 in
the amount of ultrasound energy that reaches the focal point of the
transducer. The MI displayed on the ultrasound system is adjusted for
this attenuation. Because the majority of the tissue in an image is not
at the focal point of the transducer, the amount of ultrasound energy
transmitted to the tissue decreases even further outside the focal
region. We placed the tissue in a chamber from whose base ultrasound
could be reflected, resulting in higher ultrasound energy delivered
than indicated on the ultrasound system. Because we did not actually
measure the MIs delivered to the muscle, the values at the site of
microvascular injury are unknown. 
30 Hz, which is the general protocol in
cardiology), the bioeffects could be greater for the
same MI because more microbubbles would be destroyed during each
additional sweep. Intermittent imaging, whereby ultrasound is
transmitted periodically rather than continuously, reduces the duration
of ultrasound exposure.1
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D. J. Sahn Arrhythmias in Rat Hearts Exposed to Pulsed Ultrasound After Intravenous Injection of a Contrast Agent J. Ultrasound Med., December 1, 2002; 21(12): 1343 - 1345. [Full Text] [PDF]
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J. F. Zachary, S. A. Hartleben, L. A. Frizzell, and W. D. O'Brien Jr Arrhythmias in Rat Hearts Exposed to Pulsed Ultrasound After Intravenous Injection of a Contrast Agent J. Ultrasound Med., December 1, 2002; 21(12): 1347 - 1356. [Abstract] [Full Text] [PDF]
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R. Beeri, J. L. Guerrero, G. Supple, S. Sullivan, R. A. Levine, and R. J. Hajjar New Efficient Catheter-Based System for Myocardial Gene Delivery Circulation, October 1, 2002; 106(14): 1756 - 1759. [Abstract] [Full Text] [PDF]
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J. Song, M. Qi, S. Kaul, and R. J. Price Stimulation of Arteriogenesis in Skeletal Muscle by Microbubble Destruction With Ultrasound Circulation, September 17, 2002; 106(12): 1550 - 1555. [Abstract] [Full Text] [PDF]
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 R. J. Price and S. Kaul Contrast Ultrasound Targeted Drug and Gene Delivery: An Update on a New Therapeutic Modality Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2002; 7(3): 171 - 180. [Abstract] [PDF]
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F. Schlachetzki, T. Holscher, H. J. Koch, B. Draganski, A. May, G. Schuierer, and U. Bogdahn Observation on the Integrity of the Blood-Brain Barrier After Microbubble Destruction by Diagnostic Transcranial Color-Coded Sonography J. Ultrasound Med., April 1, 2002; 21(4): 419 - 429. [Abstract] [Full Text] [PDF]
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J. Song, J. C. Chappell, M. Qi, E. J. VanGieson, S. Kaul, and R. J. Price Influence of injection site, microvascular pressureand ultrasound variables on microbubble-mediated delivery of microspheres to muscle J. Am. Coll. Cardiol., February 20, 2002; 39(4): 726 - 731. [Abstract] [Full Text] [PDF]
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S.-J. Rim, H. Leong-Poi, J. R. Lindner, D. Couture, D. Ellegala, H. Mason, M. Durieux, N. F. Kassel, and S. Kaul Quantification of Cerebral Perfusion With "Real-Time" Contrast-Enhanced Ultrasound Circulation, November 20, 2001; 104(21): 2582 - 2587. [Abstract] [Full Text] [PDF]
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T. Ay, X. Havaux, G. Van Camp, B. Campanelli, G. Gisellu, A. Pasquet, J.-F. Denef, J. A. Melin, and J.-L. J. Vanoverschelde Destruction of Contrast Microbubbles by Ultrasound: Effects on Myocardial Function, Coronary Perfusion Pressure, and Microvascular Integrity Circulation, July 24, 2001; 104(4): 461 - 466. [Abstract] [Full Text] [PDF]
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K. Wei, M. Ragosta, J. Thorpe, M. Coggins, S. Moos, and S. Kaul Noninvasive Quantification of Coronary Blood Flow Reserve in Humans Using Myocardial Contrast Echocardiography Circulation, May 29, 2001; 103(21): 2560 - 2565. [Abstract] [Full Text] [PDF]
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 D. L. Miller and J. Quddus Diagnostic ultrasound activation of contrast agent gas bodies induces capillary rupture in mice PNAS, August 17, 2000; (2000) 180294397. [Abstract] [Full Text]
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R. V. Shohet, S. Chen, Y.-T. Zhou, Z. Wang, R. S. Meidell, R. H. Unger, and P. A. Grayburn Echocardiographic Destruction of Albumin Microbubbles Directs Gene Delivery to the Myocardium Circulation, June 6, 2000; 101(22): 2554 - 2556. [Abstract] [Full Text] [PDF]
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D. Mukherjee, J. Wong, B. Griffin, S. G. Ellis, T. Porter, S. Sen, and J. D. Thomas Ten-fold augmentation of endothelial uptake of vascular endothelial growth factor with ultrasound after systemic administration J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1678 - 1686. [Abstract] [Full Text] [PDF]
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J. R. Lindner, M. P. Coggins, S. Kaul, A. L. Klibanov, G. H. Brandenburger, and K. Ley Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes Circulation, February 15, 2000; 101(6): 668 - 675. [Abstract] [Full Text] [PDF]
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R. J. Price, D. M. Skyba, S. Kaul, and T. C. Skalak Delivery of Colloidal Particles and Red Blood Cells to Tissue Through Microvessel Ruptures Created by Targeted Microbubble Destruction With Ultrasound Circulation, September 29, 1998; 98(13): 1264 - 1267. [Abstract] [Full Text] [PDF]
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D. L. Miller and J. Quddus Diagnostic ultrasound activation of contrast agent gas bodies induces capillary rupture in mice PNAS, August 29, 2000; 97(18): 10179 - 10184. [Abstract] [Full Text] [PDF]
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C. Teupe, S. Richter, B. Fisslthaler, V. Randriamboavonjy, C. Ihling, I. Fleming, R. Busse, A. M. Zeiher, and S. Dimmeler Vascular Gene Transfer of Phosphomimetic Endothelial Nitric Oxide Synthase (S1177D) Using Ultrasound-Enhanced Destruction of Plasmid-Loaded Microbubbles Improves Vasoreactivity Circulation, March 5, 2002; 105(9): 1104 - 1109. [Abstract] [Full Text] [PDF]
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