Title of Invention

"A METHOD OF ENHANCING THE CAVITATIONAL EFFECT PRODUCED BY ULTRA SOUND SIGNALS FOCUSED AT A SPECIFIC LOCATION IN A MEDIUM AND AN UNLTRASOUND IMAGING OR NON-IMAGING SYSTEM USED TO VIEW AND MONITOR THE REGION BEING TARGETED"

Abstract The present invention relates to a method of enhancing the cavitational effect produced by ultrasound signals focused at a specific location in a medium, said method comprising the following steps: (a) using one or more transducers(206) to apply said ultrasound signals to create a waveform that causes formation of bubbles at said location; and (b) modulating the amplitude of said ultrasound signals at a frequency between 5 KHz and 25 KHz immediately following or coincident with the formation of said bubbles such that the waveform causing the production of bubbles is a waveform comprising negative peaks and positive peaks, wherein the negative peaks are greater in absolute value than the positive peaks.
Full Text

Field of the Invention
The present invention relates to the field of ultrasound technology. Specifically the invention relates to a system for creating ultrasound waves
and focusing them at a location in a medium and to methods for enhancing
the resultant cavitational effects that take place in the focal region.
Background of the Invention
The use of ultrasound for medical diagnostics and therapy is well known.
Diagnostic techniques are based on the production and transmission of
ultrasound waves into the body, and detection of the scattered echoes from
the scanned region. Therapeutic methods are generally based on the use of
focused beams of ultrasonic energy to produce high-powered mechanical
energy for disintegration of medical targets by heat and ablation or
cavitation caused by pressure waves. In body fluids such as blood or in the
intercellular fluids in living tissue, the application of ultrasonic energy often
leads to the creation of bubbles which grow in volume by a process known as
rectified diffusion and eventually implode releasing large amounts of energy
and generating sites of locally high temperature and pressure for very short
periods of time.

In industry cavitational effects are used for a wide variety of applications
from cleaning of objects to initiating chemical reactions.
Conventional ultrasound signals are generated by transducers powered by a
sinusoidal waveform such as that shown in Fig. 1. The horizontal axis
represents time measured in µsec and the vertical axis the voltage applied
to the transducer. When the applied electrical signal is in the frequency
range of the transducer's frequency bandwidth and the signal is at least a
few cycles long, the pressure wave generated by the transducer is of similar
shape. The waves that are emitted from the transducer travel through the
media as longitudinal waves (the transverse waves usually attenuate very
rapidly in tissue and thus are ignored herein) having alternating
compression and de-compression regions corresponding to the positive and
negative portions of the waveform shown in Fig. 1. When the wave passes
through a fluid, gases trapped inside dust motes or other particles in the
fluid, or on the walls of the region containing the fluid will be drawn out
from the fluid forming a small bubble. If the acoustic power density is small,
then the bubble will oscillate around a relatively constant radius. This
process is known as stable cavitation. If the power density is high, then gas
diffuses into the bubble during the de-compression half-cycle of the sound
waves and diffuses out from the bubble during the compression half-cycle.
The rate of diffusion is proportional to the radius of the bubble and therefore

the rate of diffusion into the bubble (which occurs when the bubble has
expanded during the de-compression phase) exceeds that of the rate of
diffusion out of the bubble (which occurs when the bubble has been
compressed). The net result is that the radius of the bubble increases as the
bubble oscillates. This process is known as rectified diffusion. Once the
bubble's radius reaches a critical value, which depends on the power and
frequency of the ultrasonic energy, it can no longer remain stable and the
pressure caused by the next compression half-cycle will cause the bubble to
implode, i.e. the fluids in the vicinity of the bubble oscillate with such an amplitude that the bubble breaks into small fractions.
In medical applications the energy released by the implosion of the bubbles
in the rectified diffusion process is used to destroy near by cells. Various
methods are known to produce cavitation at the desired location. For
example, US 5,219,401 teaches the use of relatively low power ultrasound
energy to produce stable cavitation resulting in a population of bubbles at a
site and then applying a second signal at another frequency and higher
power to cause the bubbles to implode. US 6,413,216 teaches the use of an
unfocused transducer operating at a low frequency to create bubbles in a
treatment area of a patient followed by the use of a focused ultrasound beam
at a different frequency aimed at a specific region within the treatment area
in order to cause cavitation and thereby create a lesion at a desired location.
US 5,827,204 teaches a method reported to produce large vaporous

cavitation bubbles in a small confined area. The method comprises
generating a low frequency signal having amplitude less than the cavitation
threshold to produce a population of bubbles and superimposing on this
signal a high frequency signal. The amplitude of the resulting modulated
signal exceeds the cavitation threshold at the focus of the modulated beam.
The aim of the art is to increase the magnitude of the cavitational effect
while at the same time carefully controlling the region in which cavitation
takes place in order to allow more precise therapeutic treatment while .
preventing unintended damage to surrounding cells
In recent years it has been shown that sonochemically active cavitation can
be enhanced an order of magnitude by superimposing the second harmonic
onto the fundamental in insonation [S. Umemara, K. Kawabata, and K.
Saski: "Enhancement of Sonodynamic Tissue Damage Production by
Second-Harmonic Superimposition: Theoretical Analysis of its Mechanism",
IEEE Transactions on Ultrasonics, Ferroelectricss and Frequency Control,
43 (1996) 1054-1062]; and [S. Umemara, K Kawabata, and K. Saski: "In
vitro and in vivo enhancement of sonodynamically active cavitation by
second-harmonic superimposition" J. Acoust. Soc. Am. 101 (1997) 569-577.]
In another study it has been shown that combined irradiation with two or
more orthogonal beams, of different ultrasound frequencies focused at a
common location produces a significant increase in cavitation effects over
single frequency irradiation. [Ruo Feng, Yiyun Zhao, Changping Zhu, T.J.

Mason: "Enhancement of ultrasonic cavitation yield by multi-frequency
sonification", Ultrasonics Soinochemistry 9 (2002) 231-236.]
It is a purpose of the present invention to provide an apparatus and method
for providing focused ultrasonic waves having a waveform at the focal point
that is modified to cause enhanced cavitation.
Further purposes and advantages of this invention will appear as the
description proceeds.
Summary of the Invention
The invention is a method of enhancing the cavitational effect produced by-
ultrasound signals focused at a specific location in a medium. The method of
the invention comprises two steps:
(a) using one or more transducers to apply the ultrasound signals to
create a waveform that causes formation of bubbles at the location;
and
(b) modulating the amplitude of said ultrasound signals at a frequency between 5 KHz and
25 KHz immediately following or coincident with the formation of said bubbles such
that the waveform causing the production of bubbles is a waveform comprising
negative peaks and positive peaks, wherein the negative peaks are greater in absolute
value than the positive peaks.
According to the method of the invention, the —'
~ modulation can be carried out

either by combining of two or more interfering primary beams emitted from
two or more transducers having a common focus or by exciting individual
transducers by an excitation pulse composed of two excitation pulses with
closely proximate frequencies.
According to the preferred embodiment of the method of the invention, if the
number of transducers is more than one, then the different frequencies
emitted by the transducers are integral multiples of the lowest of the
frequencies. In an embodiment three transducers are used to carry out the
invention.
The radius of the microbubbles is typically in the range from a fraction of a
micron up to 100 or more microns, preferably from approximately 3 microns
to 5 microns.
In preferred embodiments of the invention, an ultrasound imaging or non
imaging system is used to view and monitor the region being targeted, to
monitor the generation of the microbubbles at the desired location, and
control the system for one or more of the following purposes:

(a) for aiming the focused beam to enable generating the microbubbles at
the targeted location;
(b) to insure that the number of microbubbles is as planned;
(c) to re-align the beam to a different location; and
(d)to monitor the formation, maintenance, or implosion of the
microbubbles for the purpose of controlling either continuously or
intermittently the application of the waveform and/or the modulation
signals that causes these processes in order to achieve the planned
result.
The response at the half harmonic or at higher harmonics of the transmitted
frequencies can be used by the ultrasound imaging or non-imaging system
to measure the number of microbubbles generated within the targeted
region and their spatial distribution.
In preferred embodiments of the invention the multiple transducers are
arranged as an array, designed so that their mechanical focus and their own
focus combine at the same point in space. In one preferred embodiment, the
array is an annular array. Preferably the ultrasonic waves transmitted by
the different transducers are designed to produce in the microbubbles at the
focal point interference that generates specific waveforms at specific
frequencies and amplitudes, which are not produced at other locations and
the focal point can be moved axially or laterally by either shifting the whole

array, by repositioning of individual transducers, or by phase shift of the
excitation pulse. In preferred embodiments of the invention, the region
within the focal zone of all the transducers in which the specific waveform
develops at significant intensities and the amplitudes of the waveforms are
less than -3 DB of the maximum amplitude, are typically at distances less
than 25mm and preferably less than 1 mm away from the point of the
maximum amplitude in the lateral directions and less than 10mm and
preferably less than 1.5 mm away in the axial directions.
The method of the invention for the localized production of bubbles at a
location and the enhancement of the cavitational and implosion effects that
take place at that location can be used for therapeutic purposes. For this use
the one or more transducers, are placed extra-corporally, in close proximity
to the organ to be treated, with a spacer made of ultrasound-transparent
material, ultrasound gel, or water surrounding the ultrasound transducer/s
and filling the space between it and the surface of the body overlying the
organ.
All the above and other characteristics and advantages of the invention will
be further understood through the following illustrative and non-limitative
description of preferred embodiments thereof, with reference to the
appended drawings.


Brief Description of the Accompanying Drawings
- Fig. 1 shows an ultrasound signal having a sinusoidal waveform;
- Fig. 2 shows a waveform supplied to a transducer produced by a
combination of a 1.00MHz and a 1.01MHz signal;
- Fig. 3 schematically shows an example of a control and driving system
for carrying out the invention;
- Fig. 4A and Fig. 4B show an embodiment of an array of transducers that
is suitable for use in carrying out the invention;
- Fig. 5A to Fig. 5D show an embodiment of an annular array of
transducers that is suitable for use in carrying out the invention;
- Fig. 6 shows a waveform comprising high amplitude negative peaks and
small amplitude positive peaks that is useful for carrying out the first
step of the method of the invention;
- Fig. 7A and Fig. 7B are images which demonstrate the two-step method
of the invention;
- Fig. 8A and Fig. 8B are power spectrum of the echoes from microbubbles
produced in fat in step one of the method of the invention; and
- Fig. 9A and Fig. 9B are power spectrum of the echoes from microbubbles
produced in fat in step two of the method of the invention.
Detailed Description of Preferred Embodiments
The enhanced cavitational effects, i.e. improving microbubble generation,
oscillation, changes in bubble size, and implosion, achieved by use of the

present invention are the result of applying a relatively low frequency
waveform to the region of interest. The theoretical and practical difficulty
that must be overcome is to focus the waveform to a sufficiently small
region, for example in human veins or in tissue underlying the skin, in order
to obtain useful therapeutic results. The invention solves this problem by
using a two-step approach. In the first step, ultrasonic energy, from one or
more transducers, is focused at the region of interest and bubbles are
formed. In the second step, which follows immediately after or coincident
with the formation of the bubbles, ultrasonic signals are applied, which are
so designed so as to produce modulated amplitude at a relatively low
frequency of several Hz to several tens of kilohertz, thereby providing the
desired low frequency waveform, which is confined to the non-linear region
created by the bubbles formed in the first step. In the presently preferred .
embodiments of the invention, frequency of the modulation is between 5kHz
and 25kHz.
The low frequency waveform can be produced either by combination of two
or more interfering primary beams emitted from two or more transducers
having a common focus or alternatively from individual transducers excited
by an excitation pulse composed of two excitation pulses with closely
proximate frequencies.

The first step of the method of the invention is carried out using one or more
energy transducers, each operating at a different frequency, which is
typically in the range of several hundreds of KHz. In order to take
advantage of the enhanced effects noted in the prior art, at least two
transducers should be used and their frequencies should be related such
that they are harmonics of each other.
In the first method of producing the waveform for the second step of the
invention, at least two transducers are used where one frequency is supplied
to one transducer, e.g. 1.00MHz, and a frequency different by several Hz to
several tens of KHz is supplied to the second transducer, e.g. 1.01MHz.
This produces at the target location, i.e., where bubbles have been formed
during the first step of the method of the invention, pressure fields at
relatively low frequencies that are typically on the order of several Hz to
several tens of KHz, e.g. 10kHz.
In the second method of producing the waveform, the relatively low
frequencies are also produced only at the location of treatment, i.e. where
microbubbles have been generated during the first step. As an example of
the second method, one frequency supplied to the transducer could be 1MHz
and the second frequency 1.01MHz. This produces an ultrasonic wave
having a frequency of approximately 1MHz, with a varying phase and with
an amplitude modulation of 10 khz. This waveform is shown in Fig. 2. Due to

the highly nonlinear behavior of the bubbles generated in the first step of
the method of the invention, a "detection" phenomenon takes place in the
focal region and in the region occupied by the bubbles, which is exposed to
ultrasonic waves of 1.0MHz and 1.01MHZ, there is generated ultrasonic
waves of ~10 KHz and ~2.0lMHz. This results in non-linear enhancement of
the cavitational effect; i.e. the cavitational effect of the resultant sonication
at the relatively low frequencies is larger than the algebraic sum of the
effects of each component at the relatively high frequencies (e.g. 1.0MHz,
1.01MHz, 2.01MHz and their harmonics).
Co-pending International Patent Application PCT/IL2005/000128 by the
same inventor, the description of which, including reference cited therein, is
incorporated herein by reference in its entirety, describes a system and
method for using ultrasound waves that are focused at a specific location in
a medium to cause localized production of bubbles at that location and to
control the production, and the cavitational and heating effects that take
place there. Much of the apparatus and methods described in this
application can be usefully adapted to carry out the present invention.
To produce the waveforms in PCT/IL2005/000128, at least three
independent high-power focused ultrasound transducers are used, housed
within a structure that produces' a common focus. Each transducer is
powered by its own amplifier, which is driven by a signal generator, usually

tuned to a different frequency. Optionally the system for producing the
waveforms may also include a control system that measures the changes in
tissue or the size of the bubbles and accordingly adjusts the waveform.
One embodiment of the control and driving system that can also be used for
carrying out the present invention is shown schematically in Fig. 3. In this
embodiment, the control and driving system 200 includes three arbitrary
waveform signal generators 202 connected to three wide-band power
amplifiers 204 and, through impedance matching, to the three transducers
206. At least one workstation 208, for example a personal computer (PC),
controls the timing of activation and amplitude of each arbitrary waveform
signal generator 202 by means of different protocols and separate cables for
each signal generator. The workstation 208 may also control a temperature
measurement system 210 that measures and records temperatures, for
example with thermocouples. Additionally or alternatively, an ultrasound
imaging or non-imaging system 212 may be used to view and monitor the
region being treated (targeted) to monitor the generation of the
microbubbles at the desired location and control the system so that the
number of microbubbles will be as planned and/or may be used for aiming
the focused beam to the targeted region and/or to re-align the beam to a
different location. The cavitation effects can be detected by many different
techniques that are known to skilled persons. For example: use of a single
transducer operating at 1/2, 1/3, 1/4, etc. of the frequency of one of the

transducers in the array as a detector; use of a single transducer operating
at 1.5, 2.5, 3.5, etc. harmonic; use of a "white noise" detector; use of a pair of
transducers working continuously as a transmitter-receiver pair; or use of a
single transducer, that both transmits and receives the reflected signal. The
ultrasound system monitoring system 212 may be controlled by the
workstation 208 to which it is connected through control box 214.
Control and driving system 200 is comprised of standard components that
are well known to persons familiar with the use of ultrasound for diagnostic
or therapeutic purposes. Typical but non-limitative examples of
commercially available components that are suitable for use in control and
driving system 200 are: arbitrary waveform signal generator 202 - Tabor
Electronics Ltd., model 8025; wide-band 10kHz-100MHz power amplifier
204 - Acoustic Research, model 150A100B; transducer 206 - Imasonic,
model no. T3035A101, T3034A101, T2336A101; workstation 208 - HP-
Compaq PC; temperature measurement system 210 - Omega
thermocouples, model no. TGC150-CPSS-150-SMP-MUK270502, National
Instruments Temperature measurement board model no. NI-4351,
Temperature I/O box model no. TC-2190, and National Labview software;
ultrasound imaging system 212 - GE Healthcare model VIVID III; and
control box 214 - HP-Compaq PC running National Instruments Labview
software, National Instruments I/O box, model no.BNC-2090, and National
Instruments DAQ board model no. PC-LPM-16.

The power transducers 206 are arranged as an array, designed so that their
mechanical focus and their own focus combine at the same point in space.
This point in space can be moved by either shifting the whole array, by
repositioning of individual transducers, or by phase shift of the excitation
pulse. The ultrasonic waves transmitted by the different transducers are
designed to produce by interference specific waveforms at the focal point,
which are not produced at other locations. The region in which the specific
waveforms develop at significant intensities, i.e. within the focal zone of all
transducers, is usually very small, where the amplitudes of —3 DB and less
of the maximum, are typically less than 1 mm away from the point of
maximum in the lateral directions and, less than 1.5 mm away in the axial
directions.
An embodiment of an array of transducers 300 that uses cylindrical power
transducers suitable for use in the invention is shown in Fig. 4A and Fig.
4B. Another embodiment, using annular transducers is described with
reference to Fig. 5A to 5D hereinbelow. Fig. 4A is a photograph showing the
array 300 from the top. Array 300 is mounted in a cylindrically shaped
holder 306 made of plexiglass or other suitable material. In the embodiment
shown, holder 306 comprises a central bore 304 coaxial with the symmetry
axis of holder 306 and six other bores 302 arranged symmetrically around
bore 304 and inclined at an angle with the symmetry axis. Array of

transducers 300 can thereby comprise up to six cylindrical power
transducers 206 which are inserted into bores 302 such that all are
physically aimed at the same focal point. The focal point of the array of
ultrasound transducers 300 depends, upon other factors on the medium
through which the ultrasound waves will be transmitted. A typical focal
distance in water for array 300 is six cm from the bottom face of transducer
holder 306. This focal distance is equivalent to five cm in gel and four cm in
liver tissue. The center bore 304 can be used for an imaging probe connected
to an imaging system 212 or for inserting thermocouples that are
components of temperature measurement system 210. Fig. 3B schematically
shows the arrangement of the bores 302 and 304 on the planar bottom face
of holder 306.
The holder 306 is designed such that array 300 can be placed extra-
corporally, in close proximity to the organ to be treated, with ultrasound-
transparent material, ultrasound gel, or water surrounding the ultrasound
transducers and filling the space between it and the organ.
As mentioned hereinabove, ultrasound system 200 may be either imaging or
non-imaging and in the preferred embodiment of the invention is used to
measure the number of microbubbles, their location in space, and their
spatial population distribution. These measurements can be made during
any phase of the process, for example when bubbles are generated during

the cavitation phase, during a heating phase, a phase when it is desired to
reduce or enlarge the size and/or number of microbubbles, or during
microbubble destruction usually by implosion.
The goals of the invention are achieved by selecting the range of
parameters, including frequency, phase, and amplitude, of each one of the
multiple transducers to produce the desired waveform in the region of
interest. Bubbles having a size ranging from a fraction of a micron up to 100
or more microns can be produced using the system described herein. The
presently preferred range for the bubble size for therapeutic use is between
approximately 3 to 5 microns. Similarly the size of the focal area can be
varied between spots that are typically less than 25mm radius, and
preferably less than 1 mm, radius in the lateral directions and less than
10mm, and preferably less than 1.5 mm, long in the axial directions. The
ability to achieve such a small focal zone length in the axial direction by
using the method and apparatus of the invention provides a significant
improvement in the ability to provide localized treatment for various
conditions over the prior art methods in which the focal zone length
typically ranges between 10mm and 20mm. The minimum size of the
treatment area is on the order of the minimum size of the focal area and, by
means of electrically or mechanically scanning the combined beams and/or
the array of transducers, the maximum size of the treatment area is
unlimited.

Fig. 6 shows a waveform comprising high negative peaks and small positive
peaks. This type of waveform, by increasing the ratio of the amplitudes of
the de-compression part of the acoustic wave to the compression part,
encourages the creation of a cloud of microbubbles. This type of waveform is
most effective for carrying out the first step in the method of the current
invention. In Fig. 6, the horizontal axis represents time measured in µsec
and the vertical axis the amplitude of the signal at the focus measured in
volts. The signal shown in Fig. 6 was generated, using the system shown in
Fig. 3 and the array shown in Fig. 4A comprising three transducers, by a
hydrophone that converts accurately the acoustic pressure at that point to
volts. The control and driving system operated at the frequencies, phases,
and amplitudes shown in Table 1 in order to produce the waveform shown in
Fig. 5.


Another embodiment of a transducer array that can be used to carry out the
method of the invention is shown in Figs. 5A to 5D. Fig. 5A is a side view
and Fig. 5B a perspective view showing the features of the outside of
cylindrical holder 908 of array 900. Shown in these figures are three
connectors 910 for the power cables to the three transducers and three
connectors 912 for thermocouples. The thermocouples in array 900 are
placed on the rear sides of each of the transducers to monitor their
performance during the development stage of the array. They are not
necessary features of a commercial array. Also shown on the top of holder
908 is air inlet 914 and air outlets 916, which are provided to pass air over
the backs of the transducers and remove heat from the inside of holder 908.
As opposed to the array 300 shown in Figs. 4A and 4B, which comprises
cylindrical transducers 206, the array 900 is comprised of three annular
transducers 902, 904, and 906. The three transducers are arranged such
that their front faces form a spherical shaped active area 918, which focuses
the energy from all of the transducers at the same point below the bottom of
the holder. The common focal point (f in Fig. 5C) is located on the vertical
symmetry axis of holder 908 and is the center of curvature of spherical
active area 918.
Fig. 5C is a cross-sectional view showing the arrangement of the three
transducers. Lines a, b, and c are respectively the bottom edges of

transducers 902, 904, and 906. The bottom of transducer 902 and the inner
side surfaces of transducers 904 and 906 define the spherical active surface
918. Line c also represents the bottom edge of holder 908 and therefore the
"skin plane", when the array is placed on a patient's body during a
therapeutic procedure. The distance from the skin plane to the focus f is
designated by the letter d. Fig. 5D is a view from the bottom of the array
showing the location of transducers 902, 904, and 906 on the active surface
918.
An illustrative, but nor limitative, example of the dimensions of an array
900 designed for therapeutic treatment is: height and diameter of holder
908 are 65mm and 88mm respectively; radius of curvature of the spherical
active surface 918 is 45mm; and distance d is 27mm. The frequencies of the
transducers in the array are 350KHZ, 700KHZ, and 1050KHZ. It is to be
noted that the ratio of these frequencies is 1:2:3. This is different from the
ratio 1:2:4 of array 300, which was described hereinabove. This illustrates
that the invention is not limited to any particular frequencies or for that
matter to using three transducers; however, in order to enhance the
cavitation results, it is important that if more than one transducer and/or
frequency is used then the different frequencies emitted by the transducers
should preferably be integral multiples of the lowest frequency. The main
consideration in choosing the number, frequencies, and other parameters of
the transducers and other components of the system is the waveform of the

signal that is to be produced by the array in order to achieve the intended
results.
The method of the invention for enhancing cavitation effects at a specific
location in a medium is carried out using an ultrasonic energy generator
system such as 200 in Fig. 3 in the following manner:
(a) A generator of ultrasonic waves is placed on the outer surface of the
medium and directed towards the specific location. The generator can
comprise dual track transducers or an array of two or more
transducers such as those described hereinabove.
(b) Ultrasonic energy is applied to the transducer/s to produce a
waveform that generates gas bubbles at the focal point by rectified
diffusion. The process of bubble formation can be further enhanced by
using two or more frequencies that are harmonics of each other. The
size of the focal area can be more accurately controlled by using three
or more transducers to produce the waveform shown in Fig. 6 than if
the sinusoidal waveform shown in Fig. 1 is used.
(c) Immediately following, or coincident with the formation of the
bubbles, the amplitude of the elements is modulated at a relatively
low frequency (e.g. 5kHz — 25 kHz).
Step (c) can be carried out in one of the following two ways:

(i) by applying a waveform having two close frequencies to each pair of
transducers, e.g. for an array of four transducers, the transducers
could be operated at 0.5MHz, 0.51Mhz, 1.0MHz, and 1.01MHz
respectively;
(ii) by driving each transducer with a signal comprised of proximate
frequencies, e.g. for the annular array described hereinabove, the
three transducers could be operated at 350KHZ and 360KHz,
700KHZ and 710KHz, and 1050KHZ and 1060KHz respectively.
The method can be carried out with several variations. For example:
- Steps (b) and (c) can be carried out sequentially.
- Step (c) can be initiated after bubble formation however step (b) does
not cease when step (c) begins and then the two steps are carried out
simultaneously. This mode of performing the invention can be carried
out by using a different transducer or array to provide the signals
needed for each of the two steps or by using a single array in which
the signals from at least some of the transducers are alternated
between the different waveforms.
- The signals can be applied sequentially but cyclically; i.e. step (b)
(bubble formation) followed by step (c), which is carried out until a
decline in activity is observed, followed by step (b), which produces a
sufficient quantity of bubbles to make step (c) effective, followed by
step (c), etc.

An ultrasound imaging or non-imaging system can be used to view and
monitor the region being targeted, to monitor the generation of the
microbubbles at the desired location, and to control the system, either
manually or automatically, for one or more of the following purposes:
(a) for aiming the focused beam to enable generating the microbubbles at
the targeted location;
(b) to insure that the number of microbubbles is as planned;
(e) to re-align the beam to a different location; and
(d) to monitor the formation, maintenance, or implosion of the
microbubbles for the purpose of controlling either continuously or
intermittently the application of the waveform and/or the modulation
signals that causes these processes in order to achieve the planned
result.
The method of the invention is especially well suited for therapeutic
purposes. For such uses, the one or more transducers are placed extra-
corporally, in close proximity to the organ to be treated, with a spacer made
of ultrasound-transparent material, ultrasound gel, or water surrounding
the ultrasound transducer/s and filling the space between it and the surface
of the body overlying the organ.

Experiments
Experiments have been carried out in order to demonstrate the two-step
method of the invention. The following examples are provided merely to
illustrate the invention and are not intended to limit the scope of the
invention in any manner.
Experiment 1
An experiment was done in water, using a special latex tube mimicking a
vein. The energy produced by three transducers arranged in an annular
array as shown in Figs 5A to 5D and operating at 350kHz, 700kHz, and
1050kHz was focused in the water within the tube and bubbles were
produced as shown in Fig. 7A. Following the step of bubble production, the
transmission of the two higher frequency transducers was stopped and the
350kHz transducer was driven at 350kHz and 360kHz. The enhanced
cavitation effects produced in this step can be observed in Fig. 7B. The
images in Figs, 7A and 7B were acquired by a Vivid HI imaging system with
a 7L Linear array.
Experiment 2
Figs. 8A, 8B, 9A, and 9B are power spectrum of echoes obtained by
hydrophone from a sample of fat insonated by the array of transducers used
in Experiment 1. In each of these figures the vertical axis represents the

power and the horizontal axis the frequency. The upper curve is the "raw"
data and the lower curve shows the results after filtering and normalization.
Figs. 8A and 8B show the results for the first step of the method. In this
step, the three transducers were operated at frequencies of 350kHz,
700kHz, and 1050kHz respectively (at different power levels). The signals
were applied in a cyclic manner for 3.2msec ON, 36msec OFF, 3.2msec ON,
etc. Fig. 8A shows the power spectrum recorded after 1sec and Fig. 8B after
2sec. The presence of microbubbles in the sample is detected by the
appearance of energy peaks corresponding to the half harmonics of the
primary frequencies. The presence of the line at 175kHz in Fig. 8B clearly
establishes that a significant population of microbubbles has been created in
the sample after 2sec.
Figs. 9A and 9B show the results for the second step of the method. In this
step, one of the transducers was operated at frequencies of 350kHz and
360kHz and the other two transducers were "shut down". The signals were
applied in a cyclic manner for 6.4msec ON, 75msec OFF, 6.4msec ON, etc.
Fig. 8A shows the power spectrum recorded after 2sec and Fig. 8B after
5sec. Observing the changes in the strength of line at 175kHz, it can be seen
that the waveform applied in this step caused enhancement of the cavitation
and implosion of the microbubbles in the fat, until the population of

microbubbles that were created in step 1, virtually disappeared after 5sec of
step 2.
Although embodiments of the invention have been described by way of
illustration, it will be understood that the invention may be carried out with
many variations, modifications, and adaptations, without departing from its
spirit or exceeding the scope of the claims.

WE CLAIM:
1. A method of enhancing the cavitational effect produced by ultrasound signals
focused at a specific location in a medium, said method comprising the
following steps: (a) using one or more transducers to apply said ultrasound
signals to create a waveform that causes formation of bubbles at said location;
and (b) modulating the amplitude of said ultrasound signals at a frequency
between 5 KHz and 25 KHz immediately following or coincident with the
formation of said bubbles such that the waveform causing the production of
bubbles is a waveform comprising negative peaks and positive peaks, wherein
the negative peaks are greater in absolute value than the positive peaks.
2. A method as claimed in claim 1, wherein the modulation is carried out in one
of the following two ways: (a) combination of two or more interfering
primary beams emitted from two or more transducers having a common focus;
and (b) exciting individual transducers by an excitation pulse composed of
two excitation pulses with closely proximate frequencies.
3. A method as claimed in claim 1, wherein, if the number of transducers is more
than one, then the different frequencies emitted by said transducers are
integral multiples of the lowest of said frequencies.
4. A method as claimed in claim 1, wherein the number of transducers is three.
5. A method as claimed in claim 1, wherein the radius of the microbubbles is in
the range from a fraction of a micron up to 100 or more microns.
6. A method as claimed in claim 1, wherein the radius of the microbubbles is in
the range from approximately 3 microns to 5 microns.

7. A method as claimed in claim 1, wherein an ultrasound imaging or non-
imaging system is used to view and monitor the region being targeted, to
monitor the generation of the microbubbles at the desired location, and control
the system for one or more of the following purposes: (a) for aiming the
focused beam to enable generating the microbubbles at the targeted location;
(b) to insure that the number of microbubbles is as planned; (c) to re-align the
beam to a different location; and (d) to monitor the formation, maintenance, or
implosion of the microbubbles for the purpose of controlling either
continuously or intermittently the application of the waveform and/or the
modulation signals that causes these processes in order to achieve the planned
result.
8. A method as claimed in claim 7, wherein the response at the half harmonic or
at higher harmonics of the transmitted frequencies is used by the ultrasound
imaging or non-imaging system to measure one or both of the following: (a)
the number of microbubbles generated within the targeted region; and (b) the
spatial distribution of said microbubbles generated within said targeted region.
9. A method as claimed in claim 1, wherein the multiple transducers are
arranged as an array, designed so that their mechanical focus and their own
focus combine at the same point in space.
10. A method as claimed in claim 9, wherein the array is an annular array.
11. A method as claimed in claim 9, wherein the point in space can be moved
axially or laterally by either shifting the whole array, by repositioning of
individual transducers, or by phase shift of the excitation pulse.

12. A method as claimed in claim 11, wherein the region within the focal zone of
all the transducers in which the specific waveform develops at significant
intensities and the amplitudes of the waveforms are less than -3 DB of the
maximum amplitude, are typically at distances less than 25 mm and
preferably less than 1 mm away from the point of said maximum amplitude in
the lateral directions and less than 10 mm and preferably less than 1.5 mm
away in the axial directions.
13. A method as claimed in claim 9, wherein the ultrasonic waves transmitted by
the different transducers are designed to produce in the microbubbles at the
focal point interference that generates specific waveforms at specific
frequencies and amplitudes, which are not produced at other locations.
14. A method as claimed in claim 1, wherein the localized production of bubbles
at the location and enhancement of the cavitational and implosion effects that
take place at said location are for therapeutic purposes.
15. A method as claimed in claim 1, wherein the one or more transducers are
placed extra-corporally, in close proximity to the organ to be treated, with a
spacer made of ultrasound-transparent material, ultrasound gel, or water
surrounding said ultrasound transducer/s and filling the space between it and
the surface of the body overlying said organ.
The present invention relates to a method of enhancing the cavitational effect
produced by ultrasound signals focused at a specific location in a medium, said
method comprising the following steps: (a) using one or more transducers(206) to
apply said ultrasound signals to create a waveform that causes formation of
bubbles at said location; and (b) modulating the amplitude of said ultrasound
signals at a frequency between 5 KHz and 25 KHz immediately following or
coincident with the formation of said bubbles such that the waveform causing the
production of bubbles is a waveform comprising negative peaks and positive
peaks, wherein the negative peaks are greater in absolute value than the positive
peaks.

Documents:

03704-kolnp-2006-abstract.pdf

03704-kolnp-2006-claims.pdf

03704-kolnp-2006-correspondence others.pdf

03704-kolnp-2006-description(complete).pdf

03704-kolnp-2006-drawings.pdf

03704-kolnp-2006-form-1.pdf

03704-kolnp-2006-form-3.pdf

03704-kolnp-2006-form-5.pdf

03704-kolnp-2006-international publication.pdf

3704-KOLNP-2006-(10-10-2011)-ABSTRACT.pdf

3704-KOLNP-2006-(10-10-2011)-AMANDED CLAIMS.pdf

3704-KOLNP-2006-(10-10-2011)-DESCRIPTION (COMPLETE).pdf

3704-KOLNP-2006-(10-10-2011)-DRAWINGS.pdf

3704-KOLNP-2006-(10-10-2011)-EXAMINATION REPORT REPLY RECIEVED.pdf

3704-KOLNP-2006-(10-10-2011)-FORM 1.pdf

3704-KOLNP-2006-(10-10-2011)-FORM 2.pdf

3704-KOLNP-2006-(10-10-2011)-OTHERS.pdf

3704-KOLNP-2006-(10-10-2011)-PETION UNDER RULE 137.pdf

3704-KOLNP-2006-(19-06-2012)-CORRESPONDENCE.pdf

3704-KOLNP-2006-(19-06-2012)-DRAWINGS.pdf

3704-KOLNP-2006-(19-06-2012)-FORM-1.pdf

3704-KOLNP-2006-(19-06-2012)-FORM-2.pdf

3704-KOLNP-2006-(19-06-2012)-OTHERS.pdf

3704-KOLNP-2006-(19-06-2012)-PA-CERTIFIED COPIES.pdf

3704-KOLNP-2006-(21-03-2012)-CORRESPONDENCE.pdf

3704-KOLNP-2006-(29-11-2011)-CORRESPONDENCE.pdf

3704-KOLNP-2006-ASSIGNMENT 1.1.pdf

3704-KOLNP-2006-ASSIGNMENT.pdf

3704-KOLNP-2006-CORRESPONDENCE 1.1.pdf

3704-KOLNP-2006-CORRESPONDENCE.pdf

3704-KOLNP-2006-EXAMINATION REPORT.pdf

3704-KOLNP-2006-FORM 1.pdf

3704-KOLNP-2006-FORM 18 1.1.pdf

3704-kolnp-2006-form 18.pdf

3704-KOLNP-2006-FORM 3 1.1.pdf

3704-KOLNP-2006-FORM 3.pdf

3704-KOLNP-2006-FORM 5 1.1.pdf

3704-KOLNP-2006-FORM 5.pdf

3704-KOLNP-2006-FORM 6 1.1.pdf

3704-KOLNP-2006-FORM 6.pdf

3704-KOLNP-2006-GPA.pdf

3704-KOLNP-2006-GRANTED-ABSTRACT.pdf

3704-KOLNP-2006-GRANTED-CLAIMS.pdf

3704-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

3704-KOLNP-2006-GRANTED-DRAWINGS.pdf

3704-KOLNP-2006-GRANTED-FORM 1.pdf

3704-KOLNP-2006-GRANTED-FORM 2.pdf

3704-KOLNP-2006-GRANTED-SPECIFICATION.pdf

3704-KOLNP-2006-OTHERS.pdf

3704-KOLNP-2006-PA.pdf

3704-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

abstract-03704-kolnp-2006.jpg


Patent Number 254186
Indian Patent Application Number 3704/KOLNP/2006
PG Journal Number 39/2012
Publication Date 28-Sep-2012
Grant Date 28-Sep-2012
Date of Filing 08-Dec-2006
Name of Patentee SONNETICA LTD.
Applicant Address OMER INDUSTRIAL PARK, P.O. B 3010,OMER 84965 ISRAEL
Inventors:
# Inventor's Name Inventor's Address
1 ADAM DAN 32 FINLAND STREET,34989 HAIFA ISRAEL
PCT International Classification Number A61B8/14
PCT International Application Number PCT/IL2005/000478
PCT International Filing date 2005-05-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/569,255 2004-05-10 U.S.A.