U.S. patent application number 13/257657 was filed with the patent office on 2012-05-24 for ultrasound-mediated inducement, detection, and enhancement of stable cavitation.
This patent application is currently assigned to University of Cincinnati. Invention is credited to Saurabh Datta, Kevin Haworth, Kathryn Elizabeth Hitchcock, Christy K. Holland, Nikolas Ivancevich, T. Douglas Mast.
Application Number | 20120130288 13/257657 |
Document ID | / |
Family ID | 42740017 |
Filed Date | 2012-05-24 |
United States Patent
Application |
20120130288 |
Kind Code |
A1 |
Holland; Christy K. ; et
al. |
May 24, 2012 |
ULTRASOUND-MEDIATED INDUCEMENT, DETECTION, AND ENHANCEMENT OF
STABLE CAVITATION
Abstract
Methods and systems for passively detecting stable cavitation
and enhancing stable cavitation during sonothrombolysis are
provided. The method of passively detecting stable cavitation
includes providing a determined level of ultrasonic energy and
detecting a scattered level of ultrasonic energy. The system for
inducing and passively detecting stable cavitation includes a
dual-element annular transducer array configured to provide a
fundamental ultrasonic frequency and to detect an ultrasonic
frequency that is a derivative of the fundamental frequency. The
method of enhancing stable cavitation includes administering a
nucleating agent and a thrombolytic agent to a treatment zone,
providing a determined level of ultrasonic energy, and detecting a
scattered level of ultrasonic energy.
Inventors: |
Holland; Christy K.;
(Cincinnati, OH) ; Datta; Saurabh; (Pleasanton,
CA) ; Mast; T. Douglas; (Cincinnati, OH) ;
Ivancevich; Nikolas; (Seattle, WA) ; Hitchcock;
Kathryn Elizabeth; (Cincinnati, OH) ; Haworth;
Kevin; (Cincinnati, OH) |
Assignee: |
University of Cincinnati
Cincinnati
OH
|
Family ID: |
42740017 |
Appl. No.: |
13/257657 |
Filed: |
March 19, 2010 |
PCT Filed: |
March 19, 2010 |
PCT NO: |
PCT/US10/27992 |
371 Date: |
February 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61162061 |
Mar 20, 2009 |
|
|
|
Current U.S.
Class: |
601/2 |
Current CPC
Class: |
A61N 7/00 20130101; A61B
2017/00172 20130101; A61B 8/0808 20130101; A61N 2007/0039 20130101;
G01S 7/52038 20130101; A61B 17/2202 20130101; A61B 8/06 20130101;
A61M 37/0092 20130101; A61B 2017/00194 20130101; A61B 8/481
20130101; A61B 2017/0019 20130101; A61B 2017/22008 20130101; A61B
2017/22088 20130101 |
Class at
Publication: |
601/2 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1. A method for inducing and passively detecting stable cavitation
during sonothrombolysis, comprising: providing a determined level
of ultrasonic energy substantially throughout a treatment zone of a
patient, wherein the determined level of ultrasonic energy is
produced by a source transducer and comprises a fundamental
ultrasonic frequency; and detecting a scattered level of ultrasonic
energy, wherein the scattered level of ultrasonic energy is
received by a detector transducer and comprises a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof, wherein detection of the
derivative frequency is indicative of stable cavitation during
sonothrombolysis.
2. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the source transducer and the
detector transducer comprise an annular transducer array.
3. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the source transducer has a circular
cross-section having a diameter of about 3 centimeters.
4. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the detector transducer has an
annular cross-section having an inner diameter of about 3
centimeters and an outer diameter of about 4 centimeters.
5. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the ultrasonic energy is emitted
from the source transducer with a Rayleigh distance from about 0.1
cm to about 30 cm.
6. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the source transducer produces a
fundamental ultrasonic frequency of from about 100 kHz to about 10
MHz.
7. The method for inducing and passively detecting stable
cavitation of claim 6, wherein the source transducer produces a
fundamental ultrasonic frequency of from about 100 kHz to about 2
MHz.
8. The method for inducing and passively detecting stable
cavitation of claim 7, wherein the source transducer produces a
fundamental ultrasonic frequency of about 120 kHz.
9. The method for inducing and passively detecting stable
cavitation of claim 1, wherein the derivative frequency is a
subharmonic frequency of about 60 kHz.
10. The method for inducing and passively detecting stable
cavitation of claim 1, further comprising detecting the scattered
level of ultrasonic energy with a hydrophone.
11. A system for inducing and passively detecting stable cavitation
comprising: a dual-element annular transducer array having a source
transducer and a detector transducer; and an ultrasonic driver
adapted to generate energy that can be converted at the source
transducer to ultrasonic energy suitable for penetrating a
treatment zone of a patient; wherein, the system is adapted to
provide a determined level of ultrasonic energy and to receive a
scattered level of ultrasonic energy substantially throughout the
treatment zone of the patient, in which: the source transducer
provides an ultrasonic frequency that is a fundamental ultrasonic
frequency, and the detector transducer receives an ultrasonic
frequency that is a derivative frequency of the fundamental
ultrasonic frequency selected from the group consisting of a
subharmonic frequency, an ultraharmonic frequency, and combinations
thereof.
12. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the derivative frequency received
by the detector transducer comprises a signal.
13. The system for inducing and passively detecting stable
cavitation of claim 12, wherein the signal received by the detector
transducer is gated.
14. The system for inducing and passively detecting stable
cavitation of claim 13, further comprising a pre-amplifier for
amplifying the signal received by the detector transducer.
15. The system for inducing and passively detecting stable
cavitation of claim 14, further comprising a digital oscilloscope
for storing the signal amplified by the pre-amplifier.
16. The system for inducing and passively detecting stable
cavitation of claim 15, further comprising a computer for acquiring
the signal stored in the digital oscilloscope.
17. The system for inducing and passively detecting stable
cavitation of claim 16, further comprising a hydrophone for
detecting the scattered level of ultrasonic energy.
18. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the source transducer has a
circular cross-section having a diameter of about 3 centimeters
19. The system for inducing and passively detecting stable
cavitation of claim 18, wherein the detector transducer has an
annular cross-section having an inner diameter of about 3
centimeters and an outer diameter of about 4 centimeters.
20. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the source transducer has an
annular cross-section having an inner diameter of about 3
centimeters and an outer diameter of about 4 centimeters.
21. The system for inducing and passively detecting stable
cavitation of claim 20, wherein the detector transducer has a
circular cross-section having a diameter of about 3
centimeters.
22. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the source transducer is adjustable
to vary the duty cycle of the ultrasonic energy.
23. The system for inducing and passively detecting stable
cavitation of claim 22, wherein the source transducer is adjustable
to vary the duty cycle from about 0.01% to about 100%.
24. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the source transducer produces a
fundamental ultrasonic frequency of from about 100 kHz to about 10
MHz.
25. The system for inducing and passively detecting stable
cavitation of claim 24, wherein the source transducer produces a
fundamental ultrasonic frequency of from about 100 kHz to about 2
MHz.
26. The system for inducing and passively detecting stable
cavitation of claim 25, wherein the source transducer produces a
fundamental ultrasonic frequency of about 120 kHz.
27. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the detector transducer has a
bandwidth centered at a subharmonic or ultraharmonic frequency of
the fundamental frequency.
28. The system for inducing and passively detecting stable
cavitation of claim 27, wherein the subharmonic frequency is about
60 kHz.
29. The system for inducing and passively detecting stable
cavitation of claim 11, wherein the source transducer is adjustable
to select an ultrasonic pressure amplitude.
30. The system for inducing and passively detecting stable
cavitation of claim 29, wherein the source transducer is adjusted
to produce an ultrasonic pressure amplitude of from about 0.1 MPa
to about 10.0 MPa.
31. A method for enhancing stable cavitation during
sonothrombolysis, comprising: administering a nucleating agent and
a thrombolytic agent to a treatment zone of a patient; providing a
determined level of ultrasonic energy substantially throughout the
treatment zone of the patient, wherein the determined level of
ultrasonic energy is produced by a source transducer and comprises
a fundamental ultrasonic frequency, wherein the determined level of
ultrasonic energy is provided in intervals separated by rest
periods, wherein substantially no ultrasonic energy is provided
during the rest periods, such that the intervals of the determined
level of ultrasonic energy enhance stable cavitation during
sonothrombolysis.
32. The method of enhancing stable cavitation of claim 31, wherein
the method further comprises detecting a scattered level of
ultrasonic energy, wherein the scattered level of ultrasonic energy
is received by a detector transducer and comprises a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof.
33. The method of enhancing stable cavitation of claim 32, wherein
the source transducer is a single element transducer, a linear
array transducer, or a two-dimensional array transducer.
34. The method of enhancing stable cavitation of claim 32, wherein
the source transducer has a circular cross-section having a
diameter of about 3 centimeters.
35. The method of enhancing stable cavitation of claim 32, wherein
the ultrasonic energy is emitted from the source transducer with a
Rayleigh distance of from about 0.1 cm to about 30 cm.
36. The method of enhancing stable cavitation of claim 32, wherein
the determined level of ultrasonic energy comprises pulsed wave or
continuous wave ultrasound.
37. The method of enhancing stable cavitation of claim 32, wherein
the determined level of ultrasonic energy is provided for an
interval duration of from about 10 milliseconds to about 5
minutes.
38. The method of enhancing stable cavitation of claim 37, wherein
the determined level of ultrasonic energy is provided for an
interval duration of about 8.5 seconds.
39. The method of enhancing stable cavitation of claim 32, wherein
the rest period duration is from about 1 second to about 5
minutes.
40. The method of enhancing stable cavitation of claim 39, wherein
the rest period duration is about 19 seconds.
41. The method of enhancing stable cavitation of claim 32, wherein
the source transducer produces a fundamental ultrasonic frequency
of from about 100 kHz to about 10 MHz.
42. The method of enhancing stable cavitation of claim 41, wherein
the source transducer produces a fundamental ultrasonic frequency
of from about 100 kHz to about 2 MHz.
43. The method of enhancing stable cavitation of claim 32, wherein
the treatment zone comprises a clot and the source transducer
produces a fundamental ultrasonic frequency of about 120 kHz.
44. The method of enhancing stable cavitation of claim 32, wherein
the scattered level of ultrasonic energy is received by a passive
cavitation detector.
45. The method of enhancing stable cavitation of claim 44, wherein
the passive cavitation detector is selected from the group
consisting of a hydrophone, a detector transducer, and a transducer
array.
46. The method of enhancing stable cavitation of claim 32, further
comprising monitoring the detected scattered level of ultrasonic
energy received by a passive cavitation detector and adjusting the
determined level of ultrasonic energy produced by the source
transducer in order to optimize stable cavitation.
47. The method of enhancing stable cavitation of claim 32, wherein
the nucleating agent is selected from the group consisting of
nanobubbles, microbubbles, and ultrasound contrast agents.
48. The method of enhancing stable cavitation of claim 47, wherein
the ultrasound contrast agent is perflutren-lipid micro
spheres.
49. The method of enhancing stable cavitation of claim 48, wherein
the nucleating agent is a gas releasably contained by a protective
material that allows the nucleating agent to be released when
exposed to a determined level of ultrasonic energy.
50. The method of enhancing stable cavitation of claim 49, wherein
the protective material is a liposome.
51. The method of enhancing stable cavitation of claim 50, wherein
the liposome is an echogenic liposome.
52. The method of enhancing stable cavitation of claim 32, wherein
the treatment zone comprises a blood clot and thrombolysis is
enhanced substantially throughout the treatment zone.
Description
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/162,061, filed Mar. 20, 2009, the contents
of which are hereby incorporated by reference in their
entirety.
[0002] The present invention relates to methods and systems of
inducing, detecting, and enhancing stable cavitation using
ultrasound. More specifically, the present invention relates to
methods and systems of inducing, passively detecting, and enhancing
stable cavitation during sonothrombolysis.
[0003] Due to the prevalence of thrombo-occlusive disease worldwide
and the need for improved clinical treatments, ultrasound has been
investigated, either alone or in combination with thrombolytic
drugs, to improve recanalization in patients with this disease. A
common thrombo-occlusive disease is ischemic stroke, whereby a clot
within a vessel in the brain interrupts blood supply to the brain
tissue. The occurrence of ischemic strokes is widespread, with
greater than seven hundred thousand occurrences within the United
States each year. Ischemic strokes occur as a result of a loss of
blood supply to a portion of the brain which may be caused by
thrombosis, embolism, or hypoperfusion. Ischemic strokes can lead
to a variety of physical complications including permanent
neurological damage and death. When brain tissue is deprived of
oxygen for more than 60-90 seconds, the brain tissue loses its
function; when brain tissue is deprived of oxygen for greater than
three hours, irreversible injury results, leading to infarction.
Thus, the ability to promptly treat a stroke is critical to the
survival of a patient suffering from ischemic stroke.
[0004] Currently, treatment of ischemic stroke is generally limited
to thrombolytic therapies, whereby a blood clot is broken up or
dissolved. The American Heart Association recommends the
administration of the thrombolytic agent tissue plasminogen
activator ("t-PA") for the treatment of ischemic strokes. However,
this therapy possesses a number of drawbacks. For example, the
administration of recombinant tissue plasminogen activator
("rt-PA") is only moderately efficacious, resulting in a 30%
greater chance of little or no disability in rt-PA treated patients
as compared to a control at 3 months. Further, there is a 6.4%
incidence of intracerebral hemorrhage in patients receiving this
thrombolytic therapy. Thus, there is a substantial need for
improved therapies to treat ischemic strokes.
[0005] The addition of ultrasound with clinically relevant
intensities and frequencies has been shown to enhance the rate of
some thrombolytic therapies in vitro. Moreover, a correlation has
recently been observed between stable cavitation and
ultrasound-enhanced thrombolysis. Cavitation is the formation,
oscillation, and/or collapse of gaseous and/or vapor bubbles in a
liquid due to an acoustic pressure field. In particular, stable
cavitation results in emissions at subharmonic and ultraharmonic
frequencies of the main excitation frequency.
[0006] Currently, methods of detecting cavitation include a variety
of techniques, including acoustic cavitation detection and optical
cavitation detection. However, these detection methods are also
limited. Further, detection methods have yet to be employed to
enhance stable cavitation during sonothrombolysis. Thus, additional
methods and systems for ultrasound-mediated inducement, detection,
and enhancement of stable cavitation are needed.
[0007] In one embodiment, a system for inducing and passively
detecting stable cavitation is provided, the system comprising a
dual-element annular transducer array having a source transducer
and a detector transducer, and an ultrasonic driver adapted to
generate energy that can be converted at the source transducer to
ultrasonic energy suitable for penetrating a treatment zone of a
patient. The system is adapted to provide a determined level of
ultrasonic energy and to receive a scattered level of ultrasonic
energy substantially throughout the treatment zone of the patient,
in which the source transducer provides an ultrasonic frequency
that is a fundamental ultrasonic frequency, and the detector
transducer receives an ultrasonic frequency that is a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof.
[0008] In another embodiment, the present invention relates to a
method for inducing and passively detecting stable cavitation
during sonothrombolysis. The method comprises providing a
determined level of ultrasonic energy substantially throughout a
treatment zone of a patient and detecting a scattered level of
ultrasonic energy. The determined level of ultrasonic energy is
produced by a source transducer and comprises a fundamental
ultrasonic frequency. The scattered level of ultrasonic energy is
received by a detector transducer and comprises a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof, wherein detection of the
derivative frequency is indicative of stable cavitation during
sonothrombolysis.
[0009] In still another embodiment, a method for enhancing stable
cavitation during sonothrombolysis is provided, the method
comprising administering a nucleating agent and a thrombolytic
agent to a treatment zone of a patient and providing a determined
level of ultrasonic energy substantially throughout the treatment
zone of the patient. The determined level of ultrasonic energy is
produced by a source transducer and comprises a fundamental
ultrasonic frequency, wherein the determined level of ultrasonic
energy is provided in intervals separated by rest periods, wherein
substantially no ultrasonic energy is provided during rest periods,
such that the intervals of the determined level of ultrasonic
energy enhance stable cavitation during sonothrombolysis.
[0010] These and other features and advantages of these and other
various embodiments according to the present invention will become
more apparent in view of the drawings, detailed description, and
claims provided herein.
[0011] The following detailed description of the embodiments of the
present invention can be better understood when read in conjunction
with the following drawings, where like structure is indicated with
like reference numerals, and in which:
[0012] FIG. 1 is a schematic of an apparatus for inducing and
passively detecting stable cavitation during ultrasound-enhanced
thrombolysis experiments with video microscopy data
acquisition.
[0013] FIG. 2 is a schematic of a dual-element annular array for
120-kHz sonothrombolysis and 60 kHz passive cavitation
detection.
[0014] FIG. 3 is a schematic of the determined level of ultrasonic
energy being provided in intervals separated by rest periods,
wherein substantially no ultrasonic energy is provided during the
rest periods. The interval includes either continuous wave or
pulsed wave ultrasound activity of the source transducer; the rest
period is a quiescent period. The interval duration is determined
by assessing the duration of stable cavitation and the rest period
duration is selected to allow the in-flow of a nucleating agent or
an ultrasound contrast agent.
[0015] FIG. 4 is a block diagram of a passive stable cavitation
detection and control system for ultrasound-enhanced
thrombolysis.
[0016] FIG. 5 is a graph illustrating clot mass loss with treatment
in an ex vivo porcine carotid artery model with physiologic flows
and pressures of 0-8 ml/min and 80-120 mmHg, respectively.
[0017] FIG. 6 illustrates the computed cross-sectional beam pattern
for a 120 kHz unfocused source transducer and surrounding annular
60 kHz passive cavitation detector.
[0018] FIG. 7 is a graph illustrating the average relative stable
cavitation dose in the ex vivo porcine carotid artery model with
physiologic flows and pressures. The stable cavitation dose was
measured over a range of peak-to-peak acoustic pressures within a
living, excised porcine carotid artery and was normalized by the
maximum stable cavitation dose within that vessel to yield a
relative dose in arbitrary units. Error bars represent the standard
deviation. This data indicates a peak-to-peak pressure amplitude of
about 0.44 MPa yields the largest stable cavitation dose on
average.
[0019] FIG. 8 illustrates stable cavitation activity and a total
cavitation dose versus ultrasound on-time (i.e. interval duration)
in an ex vivo porcine carotid artery model with physiologic flows
and pressures. Stable cavitation power decays as a function of
time. By integrating the power signal in time over multiple pulses,
the total 30 minute cavitation dose was calculated and the on-time
that yielded the maximum cavitation dose was calculated. The system
is operated with the on-time that provides the maximum cavitation
dose, or at the center of the 90% width of the cavitation dose.
[0020] FIG. 9 is a graph illustrating optimization of on-time
ultrasound in the ex vivo porcine carotid artery model with
physiologic flows and pressures. For a selected pressure (about
0.44 MPa), twelve trials are shown with the optimal on-time for
each trial shown in blue with the error bars extending to the 90%
of optimal on-time. The optimal on-time is the time for which a 30
minute trial would give the maximum cavitation dose.
[0021] Skilled artisans appreciate that elements in the figures are
illustrated for simplicity and clarity and are not necessarily
drawn to scale. For example, the dimensions of some of the elements
in the figures may be exaggerated relative to other elements, as
well as conventional parts removed, to help to improve
understanding of the various embodiments of the present
invention.
[0022] The following terms are used in the present application:
[0023] In the context of stable cavitation, the terms "inducing"
and "inducement" are used interchangeably herein to refer to the
nucleation or initiation of stable cavitation.
[0024] In the context of passively detecting stable cavitation, the
term "passively" is used herein to refer to receiving a signal with
a transducer or hydrophone which is used exclusively to receive an
emitted and/or scattered level of ultrasonic energy from
acoustically activated bubbles. In the context of a system for
inducing and passively detecting stable cavitation, the term
"passive" is used herein to refer to a transducer and/or a
hydrophone which is used exclusively to receive an emitted and/or
scattered level of ultrasonic energy from acoustically activated
bubbles.
[0025] The term "cavitation" is used herein to refer to the
formation, oscillation, and/or collapse of gaseous and/or vapor
bubbles in a liquid due to an acoustic pressure field. Cavitation
is generally classified into two types: stable cavitation and
inertial cavitation. The term "stable cavitation" is used herein to
refer to a microbubble or nanobubble oscillating in an ultrasound
field, whereby the predominant acoustic emissions occur not only at
the fundamental ultrasonic frequency and harmonic frequency but
also at the subharmonic and ultraharmonic frequencies. The origin
of these emissions is a nonlinear standing wave, i.e. a Faraday
wave, on the outer surface of the bubble, or nonlinear volumetric
oscillations of the bubble during pulsation in the sound field. The
term "inertial cavitation" is used herein to refer to cavitation
which results in broadband emissions.
[0026] The term "thrombolysis" is used herein to refer to the
dissolution or breaking up of a clot or thrombus. The term
"sonothrombolysis" is used herein to refer to ultrasound-enhanced
or ultrasound-mediated thrombolysis.
[0027] The term "determined level of ultrasonic energy" is used
herein to refer to the ultrasound peak-to-peak pressure amplitude
that is produced by a source transducer.
[0028] In the case of thrombolysis, the term "treatment zone" is
used herein to refer to the area comprising a blood clot. In one
embodiment, the treatment zone is part of a vascular model and
comprises a blood clot. In another embodiment, the treatment zone
is located within a mammalian subject and refers to the area
surrounding and comprising a blood clot. In a specific embodiment,
in the case of sonothrombolysis of a treatment zone, the term
"treatment zone" is to the area encompassed by the -6 dB focal
volume of the source transducer, which is confocally aligned with
the -6 dB focal volume of the passive cavitation detector.
[0029] The term "source transducer" is used herein to refer to a
transducer which produces a determined level of ultrasonic energy.
The term "detector transducer" is used herein to refer to a
transducer which receives a scattered level of ultrasonic
energy.
[0030] The term "fundamental ultrasonic frequency", as used herein,
refers to the frequency of ultrasonic energy generated by a source
transducer producing pressure cycles per unit time. The fundamental
ultrasonic frequency employed herein can range from about 100 kHz
to about 10 MHz, or from about 100 kHz to about 2 MHz. In a very
specific embodiment, the fundamental ultrasonic frequency is about
120 kHz.
[0031] When the fundamental ultrasonic frequency activates nano- or
microbubbles, the bubbles scatter ultrasonic energy at a derivative
frequency. Thus, the term "scattered level of ultrasonic energy" is
used herein to refer to the pressure amplitude or the intensity of
the ultrasound which is scattered from ultrasonically activated
nano- and microbubbles.
[0032] The term "derivative frequency" is used herein to refer to
any ultrasonic frequency or combination of ultrasonic frequencies
scattered by bubbles undergoing stable cavitation. The derivative
frequency is selected from a subharmonic frequency and/or an
ultraharmonic frequency of the fundamental ultrasonic frequency
applied to a treatment zone.
[0033] The term "harmonic frequency" is used herein to refer to
integer multiples of the fundamental ultrasonic frequency. The term
"subharmonic frequency" is used herein to refer to half the
fundamental ultrasonic frequency. The detection of scattered
subharmonic frequencies is indicative of stable cavitation. The
term "ultraharmonic frequency" is used herein to refer to integer
multiples of the subharmonic frequency, excluding integer multiples
of the fundamental frequency. The detection of scattered
ultraharmonic frequencies is also indicative of stable
cavitation.
[0034] The term "dual-element annular transducer array" is used
herein to refer to an array consisting of two transducer elements,
wherein an annular element surrounds a central circular element.
The term "single element transducer" is used herein to refer to a
single element transducer that produces ultrasonic pressure waves.
The term "linear array transducer" is used herein to refer to a
multi-element transducer composed of a plurality of transducer
elements. The transducer elements are electrically separate
elements arranged along a line or curve. The term "two-dimensional
array transducer" is used herein to refer to a matrix of transducer
elements which provide beam control over a cross-sectional area. If
the matrix is arranged in annuli, or concentric circles, the beam
control provides spherical focusing at different depths from the
face of the array. In the context of a transducer array, individual
elements of the array may be square, hexagonal, annular, circular,
or any other pattern which fills the emitting area of the
transducer and can be controlled by a suitable driver system.
[0035] The term "Rayleigh distance" is used herein to refer to the
natural focus of a transducer, that is, the location from the
transducer face at which all the emitted waves are in phase. The
"Rayleigh distance" employed herein can range from about 0.1
centimeters to about 30 centimeters, or from about 0.1 centimeters
to 10 centimeters. As used herein, the terms "Rayleigh distance",
"natural focus", and "focus" are interchangeable.
[0036] The term "hydrophone" is used herein to refer to a
microphone configured to record and/or to listen to ultrasound
scattered by acoustically active bubbles.
[0037] The term "ultrasonic driver" is used herein to refer to a
device having a radio frequency signal source and a power
amplifier. Impedance matching circuitry between the power amplifier
and transducer may optionally be employed to increase the
efficiency of an ultrasonic driver.
[0038] The term "signal" is used herein to refer an electronic
signal converted from a pressure wave in ultrasound. The hydrophone
or detector transducer converts a pressure wave into a voltage
signal as a function of time. The term "gated signal" is used
herein to refer to a detected signal that is truncated in time such
that only certain signals of the scattered level of ultrasonic
energy are detected, and such that certain signals of the scattered
level of ultrasonic energy are disallowed. The signals of the
scattered level of ultrasonic energy that are detected are those
that are emitted from a scattering source at a particular distance
from the detector transducer.
[0039] The term "pre-amplifier" is used herein to refer to a device
which prepares an electronic signal for recording and/or
processing. The pre-amplifier circuitry may or may not be housed as
a separate component. In the context of amplifying a signal, the
term "amplifying" is used herein to refer to increasing the
amplitude of the signal.
[0040] The term "digital oscilloscope" is used herein to refer to a
device which converts measured voltages into digital information.
Waveforms are sampled with an analog to digital converter at
approximately two times the frequency of the highest frequency
component of the observed signal. The samples are stored and
accumulate until a sufficient amount are taken to describe the
waveform. The signals are then reassembled for display. In the
context of storing a signal, the term "storing" is used herein to
refer to a data set that is stored in the memory of a
microprocessor.
[0041] In the context of acquiring a signal, the term "acquiring"
is used herein to refer to the process of sampling the voltage
received by the detector transducer, hydrophone, or passive
cavitation detector and converting the resulting samples into
digital numeric values that can be manipulated by a computer. In
the context of acquiring a signal with a computer, the term "data
acquisition" is used herein to refer to the conversion of analog
waveforms into digital values for processing on a computer.
[0042] The term "duty cycle" is used herein to refer to the pulse
duration divided by the pulse repetition period. The duty cycle
employed herein can range from about 0.01% to about 100%.
[0043] The term "bandwidth" is used herein to refer to the range of
frequencies wherein the signal's Fourier transform has a power
above about a quarter of the maximum value. In a specific
embodiment, the bandwidth is about -6 dB. As used herein, the
detector transducer is configured to receive a bandwidth centered
at one or more subharmonic and/or ultraharmonic frequencies of the
fundamental frequency.
[0044] The term "ultrasonic pressure amplitude" is used herein to
refer to the peak-to-peak pressure amplitude. In one embodiment,
the ultrasonic pressure amplitude employed herein can range from
about 0.1 MPa to about 10.0 MPa, or from about 0.1 MPa to about
10.0 MPa.
[0045] In the context of stable cavitation, the term "enhanced" is
used herein to refer to an increase in the number of ultrasonically
activated bubbles or to an increase in the duration of bubble
activity. The term "ultrasonically activated bubbles" is used
herein to refer to bubbles with larger vibrational amplitude
excursions. In the context of thrombolysis, the term "enhanced" is
used herein to refer to an increase in lytic efficacy or to a
reduced period of time for lytic effect. For example, in the
context of thrombolysis, the percent clot mass lost in the presence
of a predetermined level of ultrasound was greater than about 80%
in the presence of a thrombolytic agent, a nucleating agent, and a
determined level of ultrasound; whereas, in the presence of a
thrombolytic agent and a nucleating agent (without ultrasound), the
percent clot mass lost was less than about 35%. Thus, thrombolysis
is enhanced in the presence of ultrasound, as compared with the
absence of ultrasound.
[0046] The term "nucleating agent" is used herein to refer to an
agent that initiates cavitation.
[0047] The term "thrombolytic agent" is used herein to refer to a
therapeutic agent, such as a pharmaceutical, used in medicine to
dissolve blood clots or thrombi in order to limit the damage caused
by the blockage of the blood vessel.
[0048] The term "interval" is used herein to refer to continuous
wave or pulsed wave ultrasound produced by a source transducer. The
source transducer provides a determined level of ultrasonic energy
in an interval. The term "interval duration" is used herein to
refer to the period of time for which a determined level of
ultrasonic energy is provided. In one embodiment, the interval
duration employed herein can range from about 10 milliseconds to
about 5 minutes, or from about 10 milliseconds to about 10
seconds.
[0049] The term "rest period" is used herein to refer to providing
substantially no ultrasonic energy. The term "rest period duration"
is used herein to refer to the period of time for which
substantially no ultrasonic energy is provided. In one embodiment,
the rest period duration employed herein can range from about 1
second to about 5 minutes, or from about 1 second to about 20
seconds.
[0050] The term "continuous wave ultrasound" is used herein to
refer to a technique in which a transducer continuously emits
ultrasound, wherein the ultrasound is varied sinusoidally.
[0051] The term "pulsed wave ultrasound" is used herein to refer to
a technique in which a transducer emits ultrasound in pulses or
tone bursts.
[0052] In the context of enhancing stable cavitation, the term
"adjusting the determined level of ultrasonic energy" is used
herein to refer to increasing or decreasing the peak-to-peak
pressure output of the source transducer.
[0053] The term "passive cavitation detector" is used herein to
refer to a transducer or a hydrophone which receives a scattered
level of ultrasound from acoustically active bubbles. The term
"transducer array" is used herein to refer to a transducer array
which receives a scattered level of ultrasound from acoustically
active bubbles. In one embodiment, the transducer array is a
passive transducer array.
[0054] The term "nanobubble" is used herein to refer to bubbles on
the size scale of nanometers. The term "microbubble" is used herein
to refer to bubbles on the size scale of micrometers.
[0055] The term "ultrasound contrast agent" is used herein to refer
to gas-filled vesicles (containing nanobubbles or microbubbles),
which are administered, for example, intravenously to the systemic
circulation to increase echogenicity on an ultrasound image.
[0056] The term "protective material" is used herein to refer to a
protein, lipid or surface active agent which prevents dissolution
of an entrapped bubble.
[0057] The term "liposome" is used herein to refer to microscopic
vesicle consisting of a core enclosed by one or more phospholipid
layers, wherein hydrophobic compounds and/or hydrophilic compounds
can be contained within the core. The term "echogenic liposome" is
used herein to refer to a liposome which produces an echo when
exposed to ultrasound.
[0058] The term "beamwidth" is used herein to refer to the spatial
extent of the ultrasound beam at the focus, natural focus, or
Rayleigh distance of a transducer. In one embodiment, the beamwidth
is about -6 dB, such that the pressure output is at least a quarter
of the peak value (-6 dB beamwidth). The "beamwidth" can be
controlled by changing the diameter or aperture of the transducer
while keeping the frequency fixed. The beamwidth at the Rayleigh
distance is about half of the diameter of the transducer. The
beamwidth employed herein can range, for example, from about 0.1
centimeters to about 10 centimeters.
[0059] The terms "stable cavitation dose" and "dose" are used
interchangeably herein to refer to the cumulative amount of
acoustic energy detected that is directly attributed to nonlinear
bubble activity generating at a subharmonic frequency, an
ultraharmonic frequency, and/or combinations thereof.
[0060] Embodiments of the present invention relate to
ultrasound-mediated methods and systems of detecting and enhancing
stable cavitation. In one embodiment, a system for inducing and
passively detecting stable cavitation is provided, the system
comprising a dual-element annular transducer array having a source
transducer and a detector transducer, and an ultrasonic driver
adapted to generate energy that can be converted at the source
transducer to ultrasonic energy suitable for penetrating a
treatment zone of a patient. The system is adapted to provide a
determined level of ultrasonic energy and to receive a scattered
level of ultrasonic energy substantially throughout the treatment
zone of the patient, in which the source transducer provides an
ultrasonic frequency that is a fundamental ultrasonic frequency,
and the detector transducer receives an ultrasonic frequency that
is a derivative frequency of the fundamental ultrasonic frequency
selected from the group consisting of a subharmonic frequency, an
ultraharmonic frequency, and combinations thereof.
[0061] As shown in FIGS. 1 and 2, in one aspect of this embodiment,
the system for inducing and passively detecting stable cavitation
10 is adapted to provide a determined level of ultrasonic energy
and to receive a scattered level of ultrasonic energy substantially
throughout the treatment zone of a patient. In one particular
aspect, the system for inducing and passively detecting stable
cavitation 10 comprises a dual-element annular transducer array 20.
The dual-element annular transducer array 20 has a source
transducer 22 and a detector transducer 24. The dual-element
annular transducer array 20 provides a determined level of
ultrasonic energy and receives a scattered level of ultrasonic
energy, such that sonothrombolysis and stable cavitation detection
may be achieved substantially simultaneously. The size and
configuration of the dual-element annular transducer array 20
should be selected so that ultrasound waves, or energy, may be
provided substantially throughout the treatment zone of a patient,
while avoiding potentially harmful bioeffects such as tissue
damage, petechial hemorrhage, blood brain barrier disruption,
thermal coagulation, and/or cellular damage to the patient.
[0062] The source transducer 22 is adapted to provide a determined
level of ultrasonic energy. In one particular aspect, the source
transducer 22 has a circular cross-section having a diameter of
about 3 centimeters, and the detector transducer 24 has an annular
cross-section having an inner diameter of about 3 centimeters and
an outer diameter of about 4 centimeters. In another aspect, the
detector transducer 24 has a circular cross-section having a
diameter of about 3 centimeters, and the source transducer 22 has
an annular cross-section having an inner diameter of about 3
centimeters and an outer diameter of about 4 centimeters. However,
the dual-element annular transducer array 20 should not be limited
to the particular aspects disclosed herein, but may comprise any
configuration wherein a source transducer 22 is confocally aligned
with a detector transducer 24. Moreover, the source transducer 22
may comprise the annular transducer element surrounding the central
circular transducer element, or may comprise the central circular
transducer element. Similarly, the detector transducer 24 may
comprise the annular transducer element surrounding the central
circular transducer element, or may comprise the central circular
transducer element.
[0063] The source transducer 22 provides an ultrasonic frequency
that is a fundamental ultrasonic frequency. Suitable fundamental
frequencies produced by the source transducer 22 can range from
about 100 kHz to about 10 MHz. In one particular aspect, the source
transducer 22 can produce a fundamental ultrasonic frequency of
from about 100 kHz to about 2 MHz. In another aspect, the source
transducer 22 can produce a fundamental ultrasonic frequency of
about 120 kHz.
[0064] In one embodiment, the source transducer 22 is configured
such that it is adjustable to vary the duty cycle of the ultrasonic
energy produced. In one particular aspect, the source transducer 22
is adjustable to vary the duty cycle from about 0.01% to about
100%. Moreover, the source transducer 22 can be configured such
that it is adjustable to vary the beamwidth of the ultrasonic
energy produced. The beamwidth may be varied such that the source
transducer 22 provides a determined level of ultrasonic energy
substantially throughout the treatment zone of a patient. In one
aspect, the source transducer 22 is configured to provide a
beamwidth of about 0.1 centimeters to about 10 centimeters.
Additionally, the source transducer 22 can be configured such that
it is adjustable to select an ultrasonic pressure amplitude of the
ultrasonic energy produced. In a particular aspect, the source
transducer 22 is configured to provide an ultrasonic pressure
amplitude of from about 0.1 MPa to about 10.0 MPa. In a further
aspect, the source transducer 22 is configured to provide an
ultrasonic pressure amplitude of from about 0.1 MPa to about 1.0
MPa.
[0065] The detector transducer 24 is adapted to receive a scattered
level of ultrasonic energy substantially throughout the treatment
zone of a patient. In this particular aspect, the detector
transducer 24 receives an ultrasonic frequency that is a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof. In this aspect, the detector
transducer 24 is configured to receive a bandwidth centered at one
or more subharmonic frequency and/or ultraharmonic frequency of the
fundamental frequency. In yet another aspect, the detector
transducer 24 is configured to receive a bandwidth centered at the
subharmonic frequency of about 60 kHz.
[0066] Detection of a derivative frequency selected from the group
consisting of a subharmonic frequency, an ultraharmonic frequency,
and combinations thereof, is indicative of stable cavitation during
sonothrombolysis. The scattering of incident wave by ultrasonically
activated bubbles on the size scale of nanometers or micrometers
occurs at the center frequency and harmonics of the insonifying
pulse. However, the presence of half of the fundamental frequency
(the subharmonic) and its odd multiples (ultraharmonics) indicate
the presence of microbubbles or nanobubbles that are cavitating
stably.
[0067] As shown in FIGS. 1 and 2, the ultrasonic driver 30 is
adapted to generate electrical energy that can be converted at the
source transducer 22 to ultrasonic energy suitable for penetrating
a treatment zone of a patient. In one aspect, the ultrasonic driver
30 includes a function generator 40, an amplifier 50, and a
matching network 60. The ultrasonic driver 30 is electrically
connected to the source transducer 22 with a cord 62, such that the
system for inducing and passively detecting stable cavitation 10 is
adapted to provide a determined level of ultrasonic energy
substantially throughout the treatment zone of a patient. The
ultrasonic driver 30 may be of a conventional design with an
adjustable frequency generator and/or an adjustable power
amplifier. The ultrasonic driver 30 should be configured such that
the ultrasound waves or energy can be selected to provide a
determined level of ultrasonic energy substantially throughout the
treatment zone of a patient.
[0068] In one embodiment, the function generator 40 is electrically
connected to the amplifier 50 with a cord 42. The amplifier 50
amplifies the electrical energy generated by the function generator
40.
[0069] In another embodiment, the matching network 60 is
electrically connected to the amplifier 50 with a cord 52. The
matching network 60 increases the efficiency of the ultrasonic
driver 30 by impedance matching circuitry between the amplifier 50
and the source transducer 22. In this particular aspect, the
matching network 60 is electrically connected to the source
transducer 22 with a cord 62.
[0070] The detector transducer 24 converts the scattered level of
ultrasonic energy received into an electronic signal. In this
particular aspect, the derivative frequency received by the
detector transducer 24 comprises a signal. In a further aspect of
this particular embodiment, the signal received by the detector
transducer 24 is gated. In one embodiment, the signal is filtered
such that the detector transducer 24 receives ultrasonic
frequencies that are substantially a derivative frequency of the
fundamental ultrasonic frequency. In one particular aspect, the
derivative frequency of the fundamental frequency received by the
detector transducer 24 is selected from the group consisting of a
subharmonic frequency, an ultraharmonic frequency, and combinations
thereof.
[0071] In still another aspect of this embodiment, the system for
inducing and passively detecting stable cavitation 10 further
comprises a pre-amplifier 70. The pre-amplifier 70 is electrically
connected to the detector transducer 24 with a cord 72. The
pre-amplifier 70 amplifies the signal received by the detector
transducer 24.
[0072] In yet another aspect of this embodiment, the system for
inducing and passively detecting stable cavitation 10 further
comprises a digital oscilloscope 80. The digital oscilloscope 80 is
electrically connected to the pre-amplifier 70 with a cord 82. The
digital oscilloscope 80 stores the signal amplified by the
pre-amplifier 70.
[0073] In yet another aspect of this embodiment, the system for
inducing and passively detecting stable cavitation 10 further
comprises a computer 90. The computer 90 is electrically connected
to the digital oscilloscope 80 with a cord 92. The computer 90
acquires the signal stored in the digital oscilloscope 80. The
computer 90 provides data acquisition from the signal stored in the
digital oscilloscope 80.
[0074] In yet still another aspect of this embodiment, the system
for inducing and passively detecting stable cavitation 10 further
comprises a hydrophone (not shown). The hydrophone is adapted to
receive a scattered level of ultrasonic energy substantially
throughout the treatment zone of a patient. In a particular aspect,
the hydrophone converts the scattered level of ultrasonic energy
received into an electronic signal. In this particular aspect, the
derivative frequency received by the hydrophone comprises a signal.
In a further aspect, the signal received by the hydrophone is
gated, such that the hydrophone receives a scattered level of
ultrasonic energy that is truncated to receive only signals from a
selected distance.
[0075] In another embodiment of the present invention, a method for
inducing and passively detecting stable cavitation during
sonothrombolysis is provided, the method comprising providing a
determined level of ultrasonic energy substantially throughout a
treatment zone of a patient and detecting a scattered level of
ultrasonic energy. The determined level of ultrasonic energy is
produced by a source transducer 22 and comprises a fundamental
ultrasonic frequency. The scattered level of ultrasonic energy is
received by a detector transducer 24 and comprises a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof, wherein detection of the
derivative frequency is indicative of stable cavitation during
sonothrombolysis.
[0076] The method for passively detecting stable cavitation
comprises providing a determined level of ultrasonic energy
substantially throughout a treatment zone of a patient, wherein the
determined level of ultrasonic energy is produced by a source
transducer 22, and detecting a scattered level of ultrasonic
energy, wherein the scattered level of ultrasonic energy is
received by a detector transducer 24. In one particular aspect, the
source transducer 22 and the detector transducer 24 comprise a
dual-element annular transducer array 20. In a further aspect, the
source transducer 22 has a circular cross-section having a diameter
of about 3 centimeters, and the detector transducer 24 has an
annular cross-section having an inner diameter of about 3
centimeters and an outer diameter of about 4 centimeters. In
another aspect, the detector transducer 24 has a circular
cross-section having a diameter of about 3 centimeters, and the
source transducer 22 has an annular cross-section having an inner
diameter of about 3 centimeters and an outer diameter of about 4
centimeters. However, the dual-element annular transducer array 20
may comprise any configuration wherein the source transducer 22 is
confocally aligned with the detector transducer 24.
[0077] The method also comprises providing a determined level of
ultrasonic energy substantially throughout the treatment zone of a
patient, wherein the determined level of ultrasonic energy is
produced by a source transducer 22. The determined level of
ultrasonic energy is produced by a source transducer 22 and
comprises a fundamental ultrasonic frequency. Suitable fundamental
frequencies produced by the source transducer 22 can be, for
example, from about 100 kHz to about 10 MHz. In one particular
aspect, the source transducer 22 can produce a fundamental
ultrasonic frequency from about 100 kHz to about 2 MHz. In another
aspect, the source transducer 22 can produce a fundamental
ultrasonic frequency of about 120 kHz.
[0078] In another aspect, the source transducer 22 is configured
such that it is adjustable to vary the Rayleigh distance to assist
in concentrating or directing ultrasound waves or energy to the
treatment zone so that ultrasound waves or energy may be provided
substantially throughout the treatment zone of a patient. In one
particular aspect, the ultrasonic energy is emitted from the source
transducer 22 with a Rayleigh distance from about 0.1 centimeters
to about 30 centimeters. In a further aspect, the ultrasonic energy
is emitted from the source transducer 22 with a Rayleigh distance
from about 0.1 centimeters to about 10 centimeters. Moreover, the
source transducer 22 is configured such that it is adjustable to
vary the beamwidth of the ultrasonic energy produced. The beamwidth
may be varied such that the source transducer 22 provides a
determined level of ultrasonic energy substantially throughout the
treatment zone of a patient. In one aspect, the source transducer
22 is configured to provide a beamwidth of about 0.1 centimeter to
about 10 centimeters.
[0079] The method also comprises detecting a scattered level of
ultrasonic energy, wherein the scattered level of ultrasonic energy
is received by a detector transducer 24. The scattered level of
ultrasonic energy is received by the detector transducer 24 and
comprises a derivative frequency of the fundamental ultrasonic
frequency selected from the group consisting of a subharmonic
frequency, an ultraharmonic frequency, and combination thereof. In
one specific aspect, the detector transducer 24 detects a
subharmonic frequency of the fundamental ultrasonic frequency of
about 60 kHz. As previously discussed, detecting a derivative
frequency selected from the group consisting of a subharmonic
frequency, an ultraharmonic frequency, and combinations thereof, is
indicative of stable cavitation during sonothrombolysis as the
presence of half of the fundamental frequency (the subharmonic) and
its odd multiples (ultraharmonics) indicate the presence of
microbubbles or nanobubbles that are cavitating stably.
[0080] In yet still another aspect of this embodiment, the method
for passively detecting stable cavitation further comprises
detecting the scattered level of ultrasonic energy with a
hydrophone.
[0081] In still another embodiment, a method for enhancing stable
cavitation during sonothrombolysis is provided, the method
comprising administering a nucleating agent and a thrombolytic
agent to a treatment zone of a patient and providing a determined
level of ultrasonic energy substantially throughout the treatment
zone of the patient. The determined level of ultrasonic energy is
produced by a source transducer and comprises a fundamental
ultrasonic frequency, wherein the determined level of ultrasonic
energy is provided in intervals separated by rest periods, wherein
substantially no ultrasonic energy is provided during rest periods,
such that the intervals of the determined level of ultrasonic
energy enhance stable cavitation during sonothrombolysis.
[0082] In a further aspect, the method of enhancing stable
cavitation further comprises detecting a scattered level of
ultrasonic energy. The scattered level of ultrasonic energy is
received by a detector transducer and comprises a derivative
frequency of the fundamental ultrasonic frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof.
[0083] The method of enhancing stable cavitation comprises
administering a nucleating agent to a treatment zone of a patient.
The nucleating agent initiates cavitation, and any agent capable of
initiating cavitation may be used. In one aspect, the nucleating
agent is gas bubbles stabilized against dissolution in a fluid. In
a further aspect, the nucleating agent is a gas releasably
contained by a protective material.
[0084] The protective material is configured to allow the
nucleating agent to be released when exposed to a determined level
of ultrasonic energy; in one aspect, the protective material is
capable of being ruptured by ultrasonic energy generated by the
source transducer 22. The protective material is also configured to
allow circulation of the encapsulated nucleating agent throughout
the patient. Suitable protective materials include, but are not
limited to, lipids and/or liposomes. Liposomes can entrap
microbubbles and nanobubbles, enabling enhanced echogenicity and
cavitation nucleation. In one particular aspect, the liposome is an
echogenic liposome ("ELIP").
[0085] Echogenic liposomes can be targeted to certain tissues by
attaching specific peptides, ligands, or antibodies to the surface
of the liposome. Additionally, echogenic liposomes may be
fragmented with ultrasound near a target tissue. In one specific
aspect, echogenic liposomes can be targeted with peptides or
ligands to bind to receptors characteristic of intravascular
diseases (or blood clots). Targeting echogenic liposomes enables
selective accumulation of the nucleating agent to a specific area.
In one particular aspect, echogenic liposomes could be targeted to
a treatment area comprising a blood clot.
[0086] In another aspect, the nucleating agent may be selected from
the group consisting of nanobubbles, microbubbles, and ultrasound
contrast agents. In one embodiment, ultrasound contrast agents act
as cavitation nuclei at the site of a blood clot. Moreover,
infusions of ultrasound contrast agents may sustain the gentle
bubble activity that is indicative of stable cavitation. In one
specific aspect, the ultrasound contrast agent is perflutren-lipid
microspheres, or Definity.RTM. (Lantheus Medical Imaging, N.
Billerica, Mass.).
[0087] The method of enhancing stable cavitation also comprises
administering a thrombolytic agent to a treatment zone of a
patient. In one aspect, the thrombolytic agent may comprise tissue
plasminogen activator ("t-PA"); t-PA is a protein manufactured by
vascular endothelial cells that regulates clot breakdown in the
body. t-PA can be manufactured using recombinant biotechnology
techniques. W. F. Bennett & D. L. Higgins, Tissue Plasminogen
Activator: The Biochemistry and Pharmacology of Variants Produced
by Mutagenesis, 30 Annual Review of Pharmacology and Toxicology 91,
91-121 (1990). Additional examples of thrombolytic agents include,
but are not limited to, recombinant tissue plasminogen activator
("rt-PA"), streptokinase, urokinase, and tenecteplase.
[0088] The method of enhancing stable cavitation also comprises
providing a determined level of ultrasonic energy substantially
throughout the treatment zone of a patient. In one aspect, the
determined level of ultrasonic energy is produced by a source
transducer 22 and comprises a fundamental ultrasonic frequency. In
one particular aspect, the source transducer 22 may be a single
element transducer, a linear array transducer, or a two-dimensional
array transducer. In a further aspect, the source transducer 22 may
have a circular cross-section having a diameter of about 3
centimeters.
[0089] In yet another aspect, the source transducer 22 is
configured such that it is adjustable to vary the Rayleigh
distance, natural focus, or focus to assist in concentrating or
directing ultrasound waves or energy to the treatment zone so that
ultrasound waves or energy may be provided substantially throughout
the treatment zone of a patient. In a further aspect, the
ultrasonic energy may be emitted from the source transducer 22 with
a Rayleigh distance, natural focus, or focus of from about 0.1 cm
to about 30 cm. In still a further aspect, the ultrasonic energy
may be emitted from the source transducer 22 with a Rayleigh
distance, natural focus, or focus of from about 0.1 cm to about 10
cm. As shown in FIG. 3, the determined level of ultrasonic energy
produced by a source transducer 22 is provided in intervals
separated by rest periods, wherein substantially no ultrasonic
energy is provided during the rest periods. The interval comprises
either continuous wave or pulsed wave ultrasound produced by the
source transducer 22; the rest period comprises a quiescent period.
The interval duration is dictated by the duration of stable
cavitation and the rest period duration is dictated by the in-flow
of the nucleating agent or ultrasound contrast agent.
[0090] The determined level of ultrasonic energy is provided in
intervals to enhance stable cavitation. By providing a determined
level of ultrasonic energy in intervals separated by rest periods,
the nucleating agent is enabled to flow into the treatment zone of
the patient. The bubble activity that elicits subharmonic
frequencies, ultraharmonic frequencies, and combinations thereof,
may be sustained using an intermittent or continuous infusion of a
commercial contrast agent; thus, providing a determined level of
ultrasonic energy in intervals separated by rest periods allows the
nucleating agent to flow into the treatment zone of the patient and
enhances stable cavitation.
[0091] In one aspect of this embodiment, the determined level of
ultrasonic energy is provided for an interval duration of from
about 10 milliseconds to about 5 minutes. In a further aspect, the
determined level of ultrasonic energy is provided for an interval
duration of from about 10 milliseconds to about 10 seconds. In
still a further aspect, the determined level of ultrasonic energy
is provided for an interval duration of about 8.5 seconds. In yet
another aspect of this embodiment, the rest period duration is from
about 1 second to about 5 minutes. In a further aspect, the rest
period duration is from about 1 second to about 60 seconds. In a
more specific aspect, the rest period duration is from about 1
second to about 30 seconds. In a very specific aspect, the rest
period duration is about 19 seconds.
[0092] The source transducer 22 provides a determined level of
ultrasonic energy substantially throughout the treatment zone of a
patient, wherein the determined level of ultrasonic energy is
produced by a source transducer 22 and comprises a fundamental
ultrasonic frequency. The determined level of ultrasonic energy may
comprise pulsed wave or continuous wave ultrasound. Suitable
fundamental frequencies produced by the source transducer 22
include frequencies from about 100 kHz to about 10 MHz. In one
particular aspect, the source transducer 22 produces a fundamental
ultrasonic frequency from about 100 kHz to about 2 MHz. In another
aspect, the treatment zone comprises a clot and the source
transducer 22 produces a fundamental ultrasonic frequency of about
120 kHz.
[0093] As shown in FIG. 4, in another aspect, the method of
enhancing stable cavitation further comprises detecting a scattered
level of ultrasonic energy. The scattered level of ultrasonic
energy is received by a detector transducer 24 and comprises a
derivative frequency of the fundamental frequency selected from the
group consisting of a subharmonic frequency, an ultraharmonic
frequency, and combinations thereof. In one aspect, the scattered
level of ultrasonic energy is received by a passive cavitation
detector. In a further aspect, the passive cavitation detector is
selected from the group consisting of a hydrophone, a detector
transducer, and a passive transducer array.
[0094] In a further aspect of this embodiment, the method of
enhancing stable cavitation further comprises adjusting the
determined level of ultrasonic energy produced by the source
transducer 22 in accordance with the detected scattered level of
ultrasonic energy received by a passive cavitation detector. By
monitoring the detected scattered level of ultrasonic energy
received by a passive cavitation detector, stable cavitation may
be. In response to monitoring stable cavitation, the source
transducer 22 may be adjusted to provide a modified determined
level of ultrasonic energy; additionally, in response to monitoring
stable cavitation, the interval duration and rest period duration
may also be modified to allow inflow of the nucleating agent. For
example, if the scattered level of ultrasonic energy received by
the passive cavitation detector indicates continued bubble
activity, the source transducer 22 remains on. In a further
example, if the scattered level of ultrasonic energy received by
the passive cavitation detector decreases or if cavitation is not
detected, a rest period is initiated to allow the nucleating agent
to flow into the treatment zone. In a specific embodiment, when the
scattered level of ultrasonic energy of the derivative frequency
drops below about twice the background noise level in the passive
cavitation detection system, a rest period is initiated.
[0095] In one particular aspect of this embodiment, the treatment
zone comprises a blood clot and thrombolysis is enhanced
substantially throughout the treatment zone. In one embodiment,
enhanced thrombolysis includes percent clot mass loss of about 20%
to about 500% greater than that observed without the provision of
ultrasound. See, for example, FIG. 5, wherein the percent clot mass
lost is greater than about 80%.+-.1% standard deviation wherein a
blood clot is treated with rt-PA, Definity.RTM., and ultrasound; in
contrast, the percent clot mass loss is less than about 35%.+-.1%
standard deviation wherein the blood clot is treated with rt-PA and
Definity.RTM., wherein substantially no ultrasound is provided.
[0096] It will be appreciated that the system and methods disclosed
herein are useful in sonothrombolysis. Additionally, it will be
appreciated that the system and methods disclosed herein are useful
in the treatment of thrombo-occlusive diseases including but not
limited to stroke, pulmonary emboli, myocardial infarction, deep
vein thrombosis, and/or arteriovenous fistula thrombosis. Moreover,
it will be appreciated that ultrasound-mediated enhancement of
stable cavitation increases thrombolysis substantially throughout
the treatment zone.
EXAMPLES
[0097] The following non-limiting examples illustrate the methods
and systems of the present invention.
Example 1
Passive Cavitation Detection with Dual Element Annular Array
[0098] Dual Element Annular Array for 120-kHz Sonothrombolysis and
60-kHz Passive Cavitation Detection. A dual element annular array
(FIG. 1) was designed to enable inducing and passively detecting
stable cavitation during sonothrombolysis. To test the feasibility
of this design approach, acoustic radiation from the 3 cm, 120-kHz
source was computed using an exact series solution for the field of
a baffled circular radiator in a homogeneous medium. Using the same
method, the spatial sensitivity pattern of the surrounding annular
passive cavitation detector (inner diameter 3 cm, outer diameter 4
cm) was computed at the subharmonic frequency of 60 kHz. Cross
sections of the beam patterns are shown in FIG. 6. The field of the
120-kHz source had a -6 dB depth of field of 46 mm and a -6 dB
beamwidth of 1.4 cm. The annular broadband passive cavitation
detector had a collimated beam with amplitude 0.84 (-1.5 dB
relative to surface excitation) and a beamwidth of 1.6 cm at the
Rayleigh distance of the 120 kHz source. The results demonstrated
that both uniform sonication and passive cavitation detection may
be achieved over the entire region of interest containing a blood
clot.
[0099] Assessment of Dual Element 120-kHz/60-kHz Array Beam
Distortion. Acoustic field profiles of the prototype array output
were performed. An omnidirectional hydrophone was mounted on a
computer-controlled micropositioning system to scan the interior of
human and pig skulls. The penetration of ultrasound (both 120 kHz
and 60 kHz) was through the temporal and frontal bones for the
human and the pig skulls, respectively.
[0100] Passive Cavitation Detection. A broadband passive cavitation
detector (PCD) was employed to detect cavitating micron-sized
bubbles. A dual element 120-kHz/60-kHz array transducer was used as
a passive cavitation detector with porcine blood clots in an ex
vivo porcine carotid artery model. The 60-kHz confocal annulus
(Sonic Concepts, Inc., Woodburn, Wash.) was employed to detect
cavitation activity passively in the sample volume as shown in FIG.
2. The dual element array transducer was mounted on a
micrometer-controlled 3-axis translation stage (Newport 423,
Irvine, Calif., USA) for precise alignment with the blood clots.
Moreover, as shown in FIG. 6, the detector transducer 24 enables
monitoring of stable cavitation along the entire volume of the
clot.
[0101] Detected Signal Analysis. Signals acquired by the PCD were
gated to account for travel time of the pulse from the 120-kHz
transducer to the clot and back to the 60 kHz element. The signal
received by the PCD was amplified using a pre-amplifier (Signal
Recovery 5185, Oak Ridge, Tenn., USA) and stored using a digital
oscilloscope (LeCroy Waver Surfer 424, Chestnut Ridge, N.Y., USA).
The acquired signal by the PCD was also gated to ensure that
cavitation was monitored over a region encompassing the entire clot
and surrounding fluid. The squared frequency spectra of received
pulses was processed in the frequency domain.
[0102] Acoustic Pressure Threshold Determination. Using the PCD,
the acoustic pressure threshold of stable and inertial cavitation
at 120 kHz was determined in an ex vivo porcine carotid artery flow
model with 1) plasma alone, and 2) rt-PA and Definity.RTM. in the
flowing plasma. Porcine whole blood clots were placed in excised,
living porcine carotid arteries through which porcine plasma flowed
and were maintained in a 37.degree. C. temperature-controlled water
bath. The peak rarefactional pressure amplitude was increased
slowly until initially stable and then inertial cavitation was
detected by the PCD. The lowest peak rarefactional pressure
amplitude which yielded stable and inertial cavitation was recorded
as the threshold pressure for each fluid.
Example 2
Effects of Stable Cavitation on Thrombolysis
[0103] Cavitation Nucleation with Infusion of Contrast Agent in an
In Vitro Human Clot Model. An approach for inducing cavitation
using infusion of a contrast agent, Definity.RTM., was tested
experimentally in vitro. Human whole blood clots and rt-PA (96
.mu.g/ml) were placed in human fresh frozen plasma in a thin-walled
latex sample holder which was placed in a tank of water at
37.degree. C. Percent clot mass loss was assessed as a function of
peak-to-peak acoustic pressure for the following treatments: (a) no
rt-PA, no Definity.RTM., no pulsed ultrasound (the control); (b)
rt-PA alone; (c) rt-PA, Definity.RTM. infusions, and pulsed
ultrasound (.about.0.12 MPa peak-to-peak pressure amplitude); (d)
rt-PA, Definity.RTM. infusions, and pulsed ultrasound (.about.0.21
MPa peak-to-peak pressure amplitude); (e) no rt-PA, Definity.RTM.
infusions, and pulsed ultrasound (.about.0.32 MPa peak-to-peak
pressure amplitude); (f) rt-PA, phosphate buffered saline infusions
(no Definity.RTM.) and pulsed ultrasound (.about.0.32 MPa
peak-to-peak pressure amplitude); and (g) rt-PA, Definity.RTM.
infusions, and pulsed ultrasound (.about.0.32 MPa peak-to-peak
pressure amplitude). A sample size of six was used for each
treatment. Human whole blood clots, when exposed to stable
cavitation activity in the presence of rt-PA, resulted in the
highest mass loss of 26.0.+-.4%.
[0104] Sonothrombolysis Transducer. A single-element 120-kHz source
transducer was operated in pulsed mode over a range of peak-to-peak
pressure amplitudes, with an 80% duty cycle, and 1667 Hz pulse
repetition frequency. The peak-to-peak pressure amplitudes were
selected such that no cavitation (.about.0.12 MPa and .about.0.21
MPa), or stable cavitation (.about.0.32 MPa) was induced.
[0105] Stable Cavitation Detection. Stable cavitation was detected
using a focused polyvinylidine difluoride (PVDF) hydrophone
immersed in the tank of water aligned confocally with the
sonothrombolysis transducer.
[0106] Tracking Emissions to Obtain Feedback. Stable cavitation was
monitored by tracking the ultraharmonic emissions during the
combined ultrasound and thrombolytic exposures in the in vitro
human blood clot model. Cavitation activity was monitored by
tracking subharmonic and ultraharmonic emissions during the
treatment. The emission's energy was integrated over time as a
metric for the amount of stable cavitation. A significant
correlation was observed between clot mass loss and ultraharmonic
signals (r=0.8549, p<0.0001, n=24).
[0107] Promotion of Stable Cavitation with Ultrasound Contrast
Agent. A dual antibody immunofluorescence technique was employed to
measure penetration depths of rt-PA and plasminogen into the clots.
The largest mean penetration depth of rt-PA (222 .mu.m) and
plasminogen (241 .mu.m) was observed in the presence of stable
cavitation activity. Thus, it was demonstrated that a contrast
agent can be used to nucleate cavitation and can result in a
desired therapeutic effect.
[0108] A contrast agent, Definity.RTM., was successfully used to
promote and sustain the nucleation of stable cavitation during
pulsed ultrasound exposure at 120 kHz for 30 minutes. The largest
percent clot mass loss of 26.2.+-.2.6% was observed in human whole
blood clots in the presence of sustained stable cavitation
activity.
[0109] Model Thresholds for Bubble Activity vs. Bubble Size to
Determine Optimal Size. The minimum inertial cavitation threshold
estimated by the microbubble response was observed at the resonance
size of the microbubble for all the frequencies studied. The
minimum inertial cavitation threshold increased with increasing
frequency. The range of bubble sizes that may cavitate stably
decreases at higher frequencies. This suggested that higher
frequencies would require the optimum sized nucleus to be present
for generating stable cavitation.
Example 3
Effects of Stable Cavitation on Thrombolysis in an Ex Vivo Porcine
Artery Model with Interval Ultrasound
[0110] Ex Vivo Porcine Carotid Artery Model with Physiologic Flows
and Pressures. Porcine whole blood clots were inserted into living,
excised porcine carotid arteries, and kept viable in a thin-walled
latex chamber filled with degassed artificial cerebrospinal fluid
while oxygenated plasma flowed through the lumen. The chamber was
placed in a tank containing degassed filtered water at 37.degree.
C. A series of experiments were performed by infusing 1 ml/min
plasma with 0.31 .mu.l Definity.RTM. per 1 ml plasma through a
porcine artery filled with a porcine whole blood clot at a
physiologic pressure of 100.+-.15 mmHg. Each clot and artery were
insonated with 120 kHz continuous wave ultrasound at peak-to-peak
pressures ranging from 0.37 MPa to 0.54 MPa for 45 seconds. The
signals were analyzed for stable and inertial cavitation power.
[0111] Ultrasound Source Transducer and Passive Cavitation
Detector. A single-element transducer operating at 120 kHz was used
to insonate the porcine clots in living, excised porcine carotid
arteries. A 2.25-MHz center frequency transducer was used as a
passive cavitation detector to receive acoustic signals scattered
from within the vessel. These signals were digitized and converted
to power spectra.
[0112] To detect stable cavitation, the power spectra at
ultraharmonic frequencies (from 300 kHz to 3.8 MHz) of the
fundamental frequency was accumulatively summed over the treatment
period to yield a total stable cavitation dose. In a similar
manner, inertial cavitation was detected by summing the power
spectra at frequencies between the harmonic frequencies and
ultraharmonic frequencies (from 300 kHz to 3.8 MHz) of the
fundamental frequency. More particularly, the power spectra was
accumulatively summed over the treatment period to yield an
inertial cavitation dose.
[0113] Pressure Determination. An "optimal" peak-to-peak pressure
output was selected based on maximizing the amount of stable
cavitation ("the dose") taking into account variable on- and
off-times (i.e. intervals and rest periods, respectively). FIG. 7
is a graph illustrating the average relative stable cavitation dose
in the ex vivo porcine carotid artery model with physiologic flows
and pressures. The stable cavitation dose was measured over a range
of peak-to-peak acoustic pressures within a living, excised porcine
carotid artery and was normalized by the maximum stable cavitation
dose within that vessel to yield a relative dose in arbitrary
units. Error bars represent the standard deviation. The data
indicate that the peak-to-peak pressure amplitude of about 0.44 MPa
gave the largest stable cavitation dose on average.
[0114] Optimization of Ultrasound Duration. The duration of
ultrasound on-time was optimized for the particular peak-to-peak
pressure amplitude yielding the largest average stable cavitation
dose. As shown in FIG. 8 (left), stable cavitation activity was
recorded passively as a function of time. As shown in FIG. 8
(right), the total stable cavitation dose during a treatment period
was calculated as a function of the ultrasound on-time. The on-time
yielding the maximum total stable cavitation dose was considered to
be optimal on-time to promote sonothrombolysis. The optimal on-time
is shown in FIG. 9 for twelve experiments in the ex vivo porcine
carotid artery model with physiologic flows and pressures. The
error bars extend over the times that yielded at least 90% of the
maximum stable cavitation dose. The mean of these optimal on-time
values was 8.5 seconds and this on-time value was used for
subsequent sonothrombolysis experiments, shown in FIG. 5.
[0115] Clot Mass Loss with Treatment. A second series of
experiments were performed to determine the thrombolytic efficacy
of ultrasound-enhanced thrombolysis using the optimized interval
ultrasound exposure in the ex vivo porcine carotid artery model
with physiologic flows and pressures. The pressure was 100.+-.15
mmHg and the mean flow velocity was 2.7.+-.1.8 ml/min. The
ultrasound insonation parameters were 120-kHz center frequency and
0.44 MPa peak-to-peak pressure amplitude for 8.5 seconds and a rest
period over a 30 minute treatment period. The rest periods were
employed within a pulsing sequence to allow the contrast agent to
entirely refill the target volume. Treatments included: 1) plasma
alone, 2) plasma and 3.15 .mu.l rt-PA /ml plasma, 3) plasma with
interval ultrasound, 4) plasma with 3.15 .mu.l/ml rt-PA and 0.31
.mu.l/ml Definity.RTM. microbubble contrast agent, 5) plasma with
3.15 .mu.l/ml rt-PA and interval ultrasound, and 6) plasma with
3.15 .mu.l/ml rt-PA, 0.31 .mu.l/ml Definity.RTM., and interval
ultrasound. Clots were weighed before and after treatment to yield
percent clot mass loss.
[0116] FIG. 5 shows the mean clot mass loss for each treatment in
the vascular model, with vertical error bars representing.+-.one
standard deviation. A two-way analysis of variance ("ANOVA") with
repeated measurements revealed that there were significant
differences in mass loss among arteries perfused with the mixture
rt-PA and Definity.RTM. and those perfused with plasma alone, with
and without ultrasound (F=60.5, p<0.0001). The ANOVA further
showed that the effects of rt-PA with Definity.RTM. interact
significantly with the effects of ultrasound.
[0117] This phenomenon was further studied with four paired t-tests
(two-tailed). To keep the overall level of significance at 0.05,
each individual t-test was performed with an alpha of 0.0125
(0.05/4) in order to be considered significant. With ultrasound,
there was a difference between groups with and without rt-PA with
Definity.RTM. (p<0.0001), and for those arteries exposed to
ultrasound and those arteries which were not (p<0.0001). In the
absence of ultrasound, rt-PA with Definity.RTM. produces a
significantly higher mass loss than plasma alone (p=0.0001). With
no rt-PA or Definity.RTM. present, however, the effect of
ultrasound was not significant (p=0.19). A follow-up student's
t-test showed no difference between rt-PA-treated arteries with or
without Definity.RTM. and without ultrasound.
[0118] It is noted that terms like "preferably," "generally,"
"commonly," and "typically" are not utilized herein to limit the
scope of the claimed invention or to imply that certain features
are critical, essential, or even important to the structure or
function of the claimed invention. Rather, these terms are merely
intended to highlight alternative or additional features that may
or may not be utilized in a particular embodiment of the present
invention.
[0119] For the purposes of describing and defining the present
invention it is noted that the term "substantially" is utilized
herein to represent the inherent degree of uncertainty that may be
attributed to any quantitative comparison, value, measurement, or
other representation. The term "substantially" is also utilized
herein to represent the degree by which a quantitative
representation may vary from a stated reference without resulting
in a change in the basic function of the subject matter at
issue.
[0120] All documents cited are incorporated herein by reference;
the citation of any document is not to be construed as an admission
that it is prior art with respect to the present invention.
[0121] While particular embodiments of the present invention have
been illustrated and described, it would be obvious to one skilled
in the art that various other changes and modifications can be made
without departing from the spirit and scope of the invention. It is
therefore intended to cover in the appended claims all such changes
and modifications that are within the scope of this invention.
* * * * *