U.S. patent application number 16/771771 was filed with the patent office on 2021-06-24 for controlling delivery of therapeutic agent in microbubble-enhanced ultrasound procedures.
The applicant listed for this patent is INSIGHTEC, LTD.. Invention is credited to Yoav LEVY, Eyal ZADICARIO.
Application Number | 20210187331 16/771771 |
Document ID | / |
Family ID | 1000005449972 |
Filed Date | 2021-06-24 |
United States Patent
Application |
20210187331 |
Kind Code |
A1 |
ZADICARIO; Eyal ; et
al. |
June 24, 2021 |
CONTROLLING DELIVERY OF THERAPEUTIC AGENT IN MICROBUBBLE-ENHANCED
ULTRASOUND PROCEDURES
Abstract
Various approaches for microbubble-enhanced ultrasound treatment
of target tissue include receiving a desired characteristic of the
microbubbles for treating the target tissue; causing the
microbubbles to be dispensed from the administration device; and
comparing a characteristic of the dispensed microbubbles to the
desired characteristic so as to validate a match therebetween.
Inventors: |
ZADICARIO; Eyal; (Tel
Aviv-Yafo, IL) ; LEVY; Yoav; (Hinanit, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INSIGHTEC, LTD. |
Tirat Carmel |
|
IL |
|
|
Family ID: |
1000005449972 |
Appl. No.: |
16/771771 |
Filed: |
December 5, 2018 |
PCT Filed: |
December 5, 2018 |
PCT NO: |
PCT/IB2018/001537 |
371 Date: |
June 11, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62597071 |
Dec 11, 2017 |
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62597076 |
Dec 11, 2017 |
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62597073 |
Dec 11, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 2007/0004 20130101;
A61N 7/02 20130101; A61N 2007/0073 20130101; A61N 2007/0052
20130101; A61N 2007/0039 20130101 |
International
Class: |
A61N 7/02 20060101
A61N007/02 |
Claims
1. A system for microbubble-enhanced treatment of target tissue,
the system comprising: an administration device comprising a first
storage container for storing microbubbles; and a controller
configured to: (a) receive a desired characteristic of the
microbubbles for treating the target tissue; (b) cause the
microbubbles to be dispensed from the administration device; and
(c) compare a characteristic of the dispensed microbubbles to the
desired characteristic so as to validate a match therebetween.
2. The system of claim 1, wherein the controller is further
configured to cause the dispensed microbubbles to be introduced to
the target tissue upon validation of the match.
3. The system of claim 1, wherein the controller is further
configured to cause a precautionary action upon detecting a
clinically significant deviation between the characteristic of the
dispensed microbubbles from the desired characteristic.
4. The system of claim 1, further comprising a measurement system
for measuring the characteristic of the dispensed microbubbles.
5. The system of claim 4, wherein the measurement system comprises
an acoustic system.
6. The system of claim 5, wherein the acoustic system is configured
to apply a plurality of frequencies to the microbubbles for
measuring the characteristic thereof
7. The system of claim 5, wherein the acoustic system is configured
to measure at least one of attenuation, scattering, backscattering,
harmonic generation, or sub-harmonic generation from the
microbubbles.
8. The system of claim 4, wherein the measurement system is
configured to perform measurements of at least one of a laser light
obscuration and scattering, electrozone sensing, optical microscopy
or flow cytometry.
9. The system of claim 4, wherein the measurement system comprises
at least one sensor for measuring an administration rate of the
microbubbles.
10. The system of claim 4, further comprising an ultrasound
transducer for transmitting ultrasound waves to the microbubbles,
wherein the measurement system is configured to monitor a response
of the microbubbles to the ultrasound waves.
11. The system of claim 10, wherein the controller is further
configured to adjust at least one of an ultrasound parameter or the
characteristic of the dispensed microbubbles based at least in part
on the monitored response thereof.
12. The system of claim 11, wherein the ultrasound parameter
comprises at least one of a frequency, a phase, or an amplitude of
a signal driving the ultrasound transducer.
13. The system of claim 1, further comprising an ultrasound
transducer, wherein the administration device further comprises a
second storage container for storing a therapeutic agent and the
controller is further configured to: cause the ultrasound
transducer to transmit treatment ultrasound waves to the target
tissue and generate an acoustic field therein; and cause
administration of the therapeutic agent so as to produce an optimal
treatment effect in the target tissue.
14. The system of claim 13, further comprising a measurement system
for detecting signals indicating a condition of a treatment
procedure.
15. The system of claim 14, wherein the condition of the treatment
procedure comprises at least one of a condition of the target
tissue, a condition of the therapeutic agent, or a condition of the
microbubbles.
16. The system of claim 15, wherein the condition of the
microbubbles is a cavitation state thereof.
17. The system of claim 15, wherein the condition of the target
tissue comprises at least one of a temperature, a size, a shape or
a location of the target tissue.
18. The system of claim 14, wherein the measurement system
comprises at least one of an imager or an acoustic-signal
detector.
19. The system of claim 14, wherein the controller is further
configured to adjust the characteristic of at least one of the
administered microbubbles or the administered therapeutic agent
based at least in part on the detected signals.
20. The system of claim 19, wherein the characteristic is at least
one of an agent type, a size, a concentration, an administering
rate, an administering dose, an administering pattern, an
administering time or an administering pressure of the administered
microbubbles and/or therapeutic agent.
21. The system of claim 13, wherein the controller is further
configured to cause the ultrasound transducer to transmit
ultrasound waves to the target tissue in the presence of the
administered microbubbles.
22. The system of claim 13, wherein the administration device
further comprises a third storage container for storing a contrast
agent.
23. The system of claim 22, wherein the administration device
further comprises: an actuation mechanism; an introducing device
for delivering at least one of the microbubbles, therapeutic agent,
or contrast agent to the target tissue; and at least one channel
for delivering at least one of the microbubbles, contrast agent or
therapeutic agent from the corresponding storage container to the
introducing device.
24. The system of claim 13, wherein the therapeutic agent comprises
at least one of Busulfan, Thiotepa, CCNU (lomustine), BCNU
(carmustine), ACNU (nimustine), Temozolomide, Methotrexate,
Topotecan, Cisplatin, Etoposide, Irinotecan/SN-38, Carboplatin,
Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel,
Fotemustine, Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide,
Bevacizumab, 5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, or
Cytarabine (cytosine arabinoside, ara-C)/ara-U.
25. The system of claim 1, wherein the first storage container is
connected to a plurality of channels, each having a manipulation
means for changing the microbubble characteristic.
26. The system of claim 25, wherein the manipulation means
comprises a plurality of filters having different exclusion sizes,
the controller being configured to: select a channel having one of
the filters corresponding to the desired microbubble
characteristic; and cause the microbubbles to be administered only
through the selected channel.
27. The system of claim 25, wherein the manipulation means
comprises applying an acoustic field to the microbubbles.
28. The system of claim 27, wherein the controller is further
configured to tune a frequency band of the acoustic field so as to
destroy the microbubbles having a size outside a desired size
range.
29. The system of claim 1, further comprising a plurality of
storage containers, each containing microbubbles having a different
size characteristic, the controller being configured to: select one
of the storage containers having therein microbubbles corresponding
to the desired microbubble characteristic; and cause the
microbubbles to be administered only from the selected storage
container.
30. The system of claim 1, further comprising a radiation device
for transmitting a radiation dose to the target tissue.
31. The system of claim 1, wherein the controller is further
configured to dispense the microbubbles from the administration
device based at least in part on a predetermined administration
profile.
32. The system of claim 31, wherein the administration profile is
determined based at least in part on the characteristic of the
dispensed microbubbles.
33. The system of claim 32, wherein the characteristic of the
dispensed microbubbles comprises at least one of a diameter, a size
distribution, a shell composition, a gas composition or a liquid
core composition.
34. The system of claim 31, wherein the administration profile
comprises at least one of a dose, a concentration, an administering
rate, an administering timing or an administering pressure of the
microbubbles.
35. The system of claim 1, further comprising a preparation device
for preparing the microbubbles based at least in part on the
desired characteristic.
36. The system of claim 1, wherein the controller is further
configured to acquire a characteristic of the target tissue and
determine the desired characteristic of the microbubbles based at
least in part on the characteristic of the target tissue.
37-90. (canceled)
Description
RELATED APPLICATION
[0001] This application claims the benefit of and priority to U.S.
Provisional Patent Application Nos. 62/597,071, 62/597,076 and
62/597,073 (all filed on Dec. 11, 2017), the entire disclosures of
which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates, generally, to
microbubble-enhanced ultrasound procedures, and more particularly
to systems and methods for controlling microbubble characteristics
(e.g., an agent type, a size, a concentration, a dose, an
administration rate, pressure, or timing, and/or a location of an
injection site) and delivery of therapeutic agents prior to and/or
during procedures for increasing procedural efficiency.
BACKGROUND
[0003] Focused ultrasound (i.e., acoustic waves having a frequency
greater than about 20 kiloHertz) can be used to image or
therapeutically treat internal body tissues within a patient. For
example, ultrasound imaging systems produce images of body tissue
by transmitting ultrasound waves to the body tissue and detecting
and analyzing echoes reflected therefrom. In addition, ultrasound
waves may be used in applications involving ablation of tumors,
targeted drug delivery, disruption of the blood-brain barrier
(BBB), lysing of clots, and other surgical procedures. During
imaging and/or tumor ablation, a piezoceramic transducer is placed
externally to the patient, but in close proximity to the tissue to
be imaged and/or ablated (i.e., the target region). The transducer
converts an electronic drive signal into mechanical vibrations,
resulting in the emission of acoustic waves. The transducer may be
geometrically shaped and positioned along with other such
transducers so that the ultrasound energy they emit collectively
forms a focused beam at a "focal zone" corresponding to (or within)
the target region. Alternatively or additionally, a single
transducer may be formed of a plurality of individually driven
transducer elements whose phases can each be controlled
independently. Such a "phased-array" transducer facilitates
steering the focal zone to different locations by adjusting the
relative phases among the transducers. As used herein, the term
"element" means either an individual transducer in an array or an
independently drivable portion of a single transducer. Magnetic
resonance imaging (MM) may be used to visualize the patient and
target, and thereby to guide the ultrasound beam. MRI may also
provide information about changes in the target resulting from the
therapeutic effect and thus supports a feedback mechanism to
control the therapy.
[0004] During a focused ultrasound procedure, small gas/liquid
bubbles (or "microbubbles") may be generated and/or introduced into
the target region. Depending upon the amplitude and frequency of
the applied acoustic field, the microbubbles may oscillate or
collapse (this mechanism is called "cavitation") and thereby cause
various thermal effects in the target region and/or its surrounding
region. For example, cavitation of microbubbles may enhance energy
absorption at the ultrasound focal region such that the tissue
therein may be heated faster and be ablated more efficiently than
would occur in the absence of microbubbles. This effect and the
response of the microbubbles to the ultrasound waves are referred
to herein as the "microbubble response." If utilized in the central
nervous system, microbubble cavitation may cause disruption of
blood vessels, thereby inducing "opening" of the BBB for enhancing
targeted drug delivery. Further, microbubbles may be employed for
contrast enhanced ultrasound imaging, drug and gene delivery and/or
metabolic gas delivery.
[0005] The mechanism of the microbubble response to application of
the ultrasound waves involves a resonant property of the
microbubbles--i.e., the microbubbles may oscillate at a resonance
frequency in response to the applied acoustic field. The
microbubble resonance frequency generally depends on the sizes of
the microbubbles, the shell composition, the gas core composition,
and the properties of the ambient medium in which they are present
(e.g., a viscosity of the agent, a size of a vessel, etc.).
Accordingly, one approach to controlling the microbubble response
to the ultrasound waves is to control the sizes of the
microbubbles. Microbubble preparations with various size
distributions, shell compositions, and gas core compositions are
available commercially. Accordingly, when the microbubble size
optimal for an ultrasound procedure is determined, one of these
preparations may be selected and administered to the patient. The
microbubble size distribution may, however, be unstable--i.e., it
may change with time; as a result, the microbubble response to the
applied ultrasound may differ from what is expected, thereby
reducing the clinical effect on the target tissue. In addition,
even if the microbubble size distribution remains stable, the
condition (e.g., the size or temperature) of the target tissue
and/or non-target tissue may change during the ultrasound
procedure, similarly detracting from the clinical effects of the
microbubbles and potentially resulting in damage to non-target
tissue.
[0006] Accordingly, there is a need for improved
microbubble-enhanced ultrasound procedures that reliably control
the type, size, concentration, and administration of the
microbubbles so as to optimize the performance of the procedure
(e.g., optimize treatment effects on the target region) and avoid
damage to non-target regions.
SUMMARY
[0007] The present invention relates to microbubble-enhanced
ultrasound procedures that employ an ultrasound system and an
administration system for introducing the microbubbles into the
patient's body during the ultrasound procedure. The ultrasound
procedure may involve imaging the target region and/or non-target
region (e.g., regions surrounding the target region and/or
intervening regions located between the target region and the
ultrasound system) or treating the target region (e.g., opening the
BBB and/or ablating a target tumor). For ease of reference, the
following description only refers to an ultrasound treatment
procedure; it should be understood, however, that the same
approaches generally apply as well to an ultrasound imaging
procedure.
[0008] In various embodiments, prior to and/or during treatment,
the optimal microbubble size for enhancing treatment effects is
determined based on the characteristics of the target and/or
non-target regions. As used herein, the terms "optimal" and
"optimizing" generally involve determining and selecting the best
microbubble size, shell composition, gas core composition, and/or
size distribution practically discernible within the limitations of
the utilized technology for imaging and/or treating the target
region. The term "microbubble size" means the mean (or median or
mode) microbubble radius in a distribution (e.g., a normal
distribution) of microbubbles, a maximum microbubble radius, a
normal size distribution around a specified mean or other size
characteristic of the microbubbles.
[0009] Microbubbles having the determined optimal size may be
manufactured using any suitable approach known to one of skill in
the art or, alternatively, they may be acquired off-the-shelf. In
one embodiment, the size of the microbubbles to be administered is
verified using any suitable technique (e.g., laser light
obscuration and scattering, electrozone sensing, optical
microscopy, ultrasound or flow cytometry) prior to administration.
If the measured size differs clinically significantly from the
optimal size (e.g., by a factor of two or, in some embodiments,
ten), a precautionary action may be taken. For example, the system
may generate a warning signal to the user. Additionally or
alternatively, the microbubbles may be centrifuged or otherwise
fractionated to isolate the microbubbles having the desired size.
Alternatively, and particularly in the case of an optimal maximum
microbubble radius, the microbubbles may be filtered through a
filter having a pore size corresponding to the determined size. The
isolated/filtered microbubbles may then be verified again to ensure
that the size thereof matches the optimal value; subsequently, the
verified microbubbles may be administered to the patient to enhance
ultrasound treatment. Accordingly, this approach allows
substantially (e.g., >50%, 90%, 95% or 99%) only the
microbubbles having the desired characteristic to be administered
to the patient.
[0010] In some embodiments, the administration profile (e.g., a
dose, concentration, rate, timing or pressure) of the microbubbles
is determined based on a characteristic (e.g., the diameter, size
distribution, shell composition, or gas and/or liquid core
composition) thereof prior to treatment. During the ultrasound
procedure, the treatment effects (such as tissue-permeability
enhancement, tissue disruption or ablation) of the target and/or
non-target regions may be monitored and/or assessed using, for
example, an imager, a contrast agent (e.g., a gadolinium-based
contrast agent) and/or acoustic signals from the target and/or
non-target regions. Based on the monitored treatment effects, the
administration profile of the microbubbles and/or an ultrasound
parameter (e.g., frequency, amplitude, phase, or activation time)
may be adjusted in real time to optimize the treatment or achieve a
desired target effect.
[0011] In various embodiments, the ultrasound treatment procedure
is performed in combination with other therapeutic methods. For
example, after the desired target effect on the target tissue is
achieved, a therapeutic agent may be introduced for targeted drug
delivery. Alternatively, a radiation device may be used
therapeutically in conjunction with the ultrasound procedure.
[0012] In some embodiments, the administration system includes
three independent channels fluidly coupled to three containers
having the microbubbles, an MRI contrast agent, and a therapeutic
agent, respectively. The three channels are also fluidly coupled to
an introducing device (e.g., a catheter or a needle) for
administering the microbubbles, contrast agent and/or therapeutic
agent from their corresponding channels into the patient's body. In
some embodiments, the administration system includes an actuation
mechanism (e.g., a syringe, a peristaltic pump, etc.) for
dispensing the fluid from the container(s) to the patient.
Operation of the actuation mechanism may be controlled by a
controller. In addition, the controller may be in communication
with the ultrasound controller to cause activation and deactivation
of the transducer in order to optimize the treatment effect and/or
destroy microbubbles that do not conform to the size criterion
(e.g., the determined optimal microbubble size).
[0013] In some embodiments, the administration system includes
multiple fluidic channels coupled to the microbubble container;
each channel may include a filter having a different pore size.
During treatment, based on the condition (e.g., size, location,
shape or temperature) of the target and/or non-target regions
and/or a desired effect on acoustic energy delivery, the optimal
microbubble size for achieving a treatment goal (e.g., maximizing
the temperature at the target region and minimizing damage to
non-target tissue) can be determined and dynamically updated. If
the optimal size changes over the course of the procedure, the
channel corresponding to the new optimal size can be activated,
i.e., microbubbles are forced therethrough for administration to
the patient. In this way, the size of the administered microbubbles
can be controlled in real time. In addition, the control or
administration system may adjust an administration profile (e.g., a
concentration, an administering dose, rate, timing or pressure) of
the microbubbles in real time during treatment based on the
condition of the target/non-target region and/or the microbubble
response.
[0014] In various embodiments, each of the microbubble channels is
coupled to one of a plurality of microbubble vials/containers each
having microbubbles of a different size. During the ultrasound
procedure, based on the condition of the target and/or non-target
regions and/or the response of the microbubbles to the ultrasound,
the channel corresponding to the updated optimal size is connected
to a microbubble administration device (e.g., a catheter or a
needle) for introducing the microbubbles into the patient's body.
Again, the administration system may adjust the administration
profile of the microbubbles, contrast agent, and/or therapeutic
agent in the channels and/or in the introducing device based on
real-time feedback of the target/non-target condition and/or
microbubble response so as to optimize the treatment effects and/or
minimize undesired damage to the non-target tissue.
[0015] Accordingly, in one aspect, the invention pertains to a
system for microbubble-enhanced treatment of target tissue. In
various embodiments, the system includes an administration device
having the first storage container for storing microbubbles; and a
controller configured to receive a desired characteristic of the
microbubbles for treating the target tissue; cause the microbubbles
to be dispensed from the administration device; and compare a
characteristic of the dispensed microbubbles to the desired
characteristic so as to validate a match therebetween. In one
implementation, the controller is further configured to cause the
dispensed microbubbles to be introduced to the target tissue upon
validation of the match. Additionally or alternatively, the
controller may be further configured to cause a precautionary
action upon detecting a clinically significant deviation between
the characteristic of the dispensed microbubbles from the desired
characteristic.
[0016] The system may further include a measurement system for
measuring the characteristic of the dispensed microbubbles. In one
embodiment, the measurement system includes an acoustic system. The
acoustic system is configured to apply multiple frequencies to the
microbubbles for measuring the characteristic thereof In addition,
the acoustic system may be further configured to measure
attenuation, scattering, backscattering, harmonic generation,
and/or sub-harmonic generation from the microbubbles. In another
embodiment, the measurement system is configured to perform
measurements of a laser light obscuration and scattering,
electrozone sensing, optical microscopy and/or flow cytometry.
Additionally or alternatively, the measurement system may include
one or more sensors for measuring an administration rate of the
microbubbles.
[0017] In various embodiments, the system further includes an
ultrasound transducer for transmitting ultrasound waves to the
microbubbles. The measurement system may then be configured to
monitor a response of the microbubbles to the ultrasound waves. In
one embodiment, the controller is further configured to adjust an
ultrasound parameter (e.g., a frequency, a phase, and/or an
amplitude) and/or the characteristic of the dispensed microbubbles
based at least in part on the monitored response thereof. In some
embodiments, the administration device further includes the second
storage container for storing a therapeutic agent. The therapeutic
agent may include Busulfan, Thiotepa, CCNU (lomustine), BCNU
(carmustine), ACNU (nimustine), Temozolomide, Methotrexate,
Topotecan, Cisplatin, Etoposide, Irinotecan/SN-38, Carboplatin,
Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel,
Fotemustine, Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide,
Bevacizumab, 5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel,
and/or Cytarabine (cytosine arabinoside, ara-C)/ara-U. The
controller is further configured to cause the ultrasound transducer
to transmit treatment ultrasound waves to the target tissue and
generate an acoustic field therein; and cause administration of the
therapeutic agent so as to produce an optimal treatment effect in
the target tissue. In addition, the system may further include a
measurement system (e.g., an imager and/or an acoustic-signal
detector) for detecting signals indicating a condition of a
treatment procedure. The condition of the treatment procedure may
include a condition (e.g., a temperature, a size, a shape and/or a
location) of the target tissue, a condition of the therapeutic
agent, and/or a condition (e.g., a cavitation state) of the
microbubbles.
[0018] The controller may be further configured to adjust the
characteristic (e.g., an agent type, a size, a concentration, an
administering rate, an administering dose, an administering
pattern, an administering time and/or an administering pressure) of
the administered microbubbles and/or the administered therapeutic
agent based at least in part on the detected signals. In addition,
the controller may be further configured to cause the ultrasound
transducer to transmit ultrasound waves to the target tissue in the
presence of the administered microbubbles. In some embodiments, the
administration device further includes the third storage container
for storing a contrast agent. In addition, the administration
device further includes an actuation mechanism; an introducing
device for delivering the microbubbles, therapeutic agent and/or
contrast agent to the target tissue; and one or more channels for
delivering the microbubbles, contrast agent and/or therapeutic
agent from the corresponding storage container to the introducing
device.
[0019] In various embodiments, the first storage container is
connected to multiple channels, each having a manipulation means
for changing the microbubble characteristic. The manipulation means
may include multiple filters having different exclusion sizes; the
controller is then configured to select a channel having one of the
filters corresponding to the desired microbubble characteristic;
and cause the microbubbles to be administered only through the
selected channel. Additionally or alternatively, the manipulation
means may include applying an acoustic field to the microbubbles.
The controller may then be further configured to tune a frequency
band of the acoustic field so as to destroy the microbubbles having
a size outside a desired size range. In addition, the system may
further include multiple storage containers, each containing
microbubbles having a different size characteristic; the controller
is then configured to select one of the storage containers having
therein microbubbles corresponding to the desired microbubble
characteristic; and cause the microbubbles to be administered only
from the selected storage container.
[0020] The system may further include a radiation device for
transmitting a radiation dose to the target tissue. In addition,
the controller may be further configured to dispense the
microbubbles from the administration device based at least in part
on a predetermined administration profile (e.g., a dose, a
concentration, an administering rate, an administering timing
and/or an administering pressure of the microbubbles). The
administration profile may be determined based at least in part on
the characteristic (e.g., a diameter, a size distribution, a shell
composition, a gas composition and/or a liquid core composition) of
the dispensed microbubbles. In some embodiments, the system further
includes a preparation device for preparing the microbubbles based
at least in part on the desired characteristic. In addition, the
controller may be further configured to acquire a characteristic of
the target tissue and determine the desired characteristic of the
microbubbles based at least in part on the characteristic of the
target tissue.
[0021] In another aspect, the invention relates to a method for
microbubble-enhanced treatment of target tissue. In various
embodiments, the method includes receiving a desired characteristic
of the microbubbles for treating the target tissue; causing the
microbubbles to be dispensed from the administration device; and
comparing a characteristic of the dispensed microbubbles to the
desired characteristic so as to validate a match therebetween. In
one implementation, the method further includes causing the
dispensed microbubbles to be introduced to the target tissue upon
validation of the match. Additionally or alternatively, the method
may further include causing a precautionary action upon detecting a
clinically significant deviation between the characteristic of the
dispensed microbubbles from the desired characteristic.
[0022] The method may further include measuring the characteristic
of the dispensed microbubbles. In one embodiment, the
characteristic of the dispensed microbubbles is measured using an
acoustic system. The method further includes applying multiple
frequencies to the microbubbles for measuring the characteristic
thereof. In addition, the method may include measuring a signal of
attenuation, scattering, backscattering, harmonic generation,
and/or sub-harmonic generation from the microbubbles. In another
embodiment, the characteristic of the dispensed microbubbles is
measured using a laser light obscuration and scattering,
electrozone sensing, optical microscopy and/or flow cytometry.
Additionally or alternatively, the method may further include
measuring an administration rate of the microbubbles.
[0023] In various embodiments, the method further includes causing
an ultrasound transducer to transmit ultrasound waves to the
microbubbles; and monitoring a response of the microbubbles to the
ultrasound waves. In addition, the method may further include
adjusting an ultrasound parameter (e.g., a frequency, a phase,
and/or an amplitude) and/or the characteristic of the dispensed
microbubbles based at least in part on the monitored response
thereof. In some embodiments, the method further includes causing
an ultrasound transducer to transmit ultrasound waves to the target
tissue and generate an acoustic field therein, and causing
administration of a therapeutic agent to the target tissue; the
microbubbles, acoustic field and therapeutic agent cooperatively
cause an optimal treatment effect in the target tissue. The
therapeutic agent may include Busulfan, Thiotepa, CCNU (lomustine),
BCNU (carmustine), ACNU (nimustine), Temozolomide, Methotrexate,
Topotecan, Cisplatin, Etoposide, Irinotecan/SN-38, Carboplatin,
Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel,
Fotemustine, Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide,
Bevacizumab, 5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel,
and/or Cytarabine (cytosine arabinoside, ara-C)/ara-U. In addition,
the method may further include detecting signals indicating a
condition of a treatment procedure. The condition of the treatment
procedure may include a condition (e.g., a temperature, a size, a
shape and/or a location) of the target tissue, a condition of the
therapeutic agent, and/or a condition (e.g., a cavitation state) of
the microbubbles. In one embodiment, the signals are measured using
an imager and/or an acoustic-signal detector.
[0024] The method may further include adjusting the characteristic
(e.g., an agent type, a size, a concentration, an administering
rate, an administering dose, an administering pattern, an
administering time and/or an administering pressure) of the
microbubbles and/or the administered therapeutic agent based at
least in part on the detected signals. In addition, the method may
further include causing the ultrasound transducer to transmit
ultrasound waves to the target tissue in the presence of the
administered microbubbles. In some embodiments, the method further
includes delivering the microbubbles, the therapeutic agent, and/or
a contrast agent to the target tissue. The method may further
include selecting a channel having a filter corresponding to the
desired microbubble characteristic; and causing the microbubbles to
be administered only through the selected channel. In addition, the
method may further include applying an acoustic field to the
microbubbles. The method may also include tuning a frequency band
of the acoustic field so as to destroy the microbubbles having a
size outside a desired size range. In one embodiment, the method
further includes selecting a storage container having therein
microbubbles corresponding to the desired microbubble
characteristic; and causing the microbubbles to be administered
only from the selected storage container.
[0025] The method may further include transmitting a radiation dose
to the target tissue. In addition, the method may include
dispensing the microbubbles from the administration device based at
least in part on a predetermined administration profile (e.g., a
dose, a concentration, an administering rate, an administering
timing and/or an administering pressure of the microbubbles). The
method may further include determining the administration profile
based at least in part on the characteristic (e.g., a diameter, a
size distribution, a shell composition, a gas composition and/or a
liquid core composition) of the microbubbles. In one
implementation, the method further includes heating the
microbubbles to a predetermined temperature. In addition, the
method further includes acquiring a characteristic of the target
tissue and determine the desired characteristic of the microbubbles
based at least in part on the characteristic of the target
tissue.
[0026] Another aspect of the invention relates to a system for
microbubble-enhanced treatment of target tissue. In various
embodiments, the system includes an administration device having a
storage container for storing microbubbles; and a controller
configured to receive a desired characteristic of the microbubbles
for treating the target tissue; and cause substantially only the
microbubbles having the desired characteristic to be administered
into the target tissue. In one implementation, the controller is
further configured to acquire a characteristic of the target tissue
and determine the desired characteristic of the microbubbles based
at least in part on the characteristic of the target tissue.
[0027] The system may further include one or more fluidic channels
coupled to the first storage container for delivering the
microbubbles to the target tissue; and a manipulator associated
with the fluidic channel(s) for changing therein the microbubble
characteristic. The manipulator may include a filter having a
determined size characteristic. Additionally or alternatively, the
manipulator may include an ultrasound transducer for applying an
acoustic field to the microbubbles in the fluidic channel(s). The
transducer may be configured to apply an acoustic field having one
or more frequency bands so as to destroy the microbubbles having a
size outside a desired size range.
[0028] In some embodiments, the controller is further configured to
administer the microbubbles based on a predetermined administration
profile (e.g., a dose, a concentration, an administering rate, an
administering timing or an administering pressure). The
administration profile is determined based at least in part on the
second characteristic (e.g., a diameter, a size distribution, a
shell composition, and/or a gas and/or liquid core composition) of
the microbubbles. In one embodiment, the system further includes a
preparation device for preparing the microbubbles based at least in
part on the desired characteristic, substantially all of the
prepared microbubbles having the desired characteristic.
[0029] In yet another aspect, the invention pertains to a method
for microbubble-enhanced treatment of target tissue. In various
embodiments, the method includes receiving a desired characteristic
of the microbubbles for treating the target tissue; and causing
substantially only the microbubbles having the desired
characteristic to be administered into the target tissue.
[0030] Still another aspect of the invention relates to a system
for microbubble-enhanced treatment of target tissue. In various
embodiments, the system includes an administration device having a
storage container for storing microbubbles; and a preparation
device for preparing the microbubbles based at least in part on a
desired characteristic (e.g., a maximum diameter, a mean diameter,
a normal size distribution around a specified mean, a shell
composition, or a gas and/or liquid core composition),
substantially all of the prepared microbubbles having the desired
characteristic. The preparation device may include a heater, a
shaker and/or an ultrasound transducer.
[0031] In another aspect, the invention relates to a system for
microbubble-enhanced treatment of target tissue. In various
embodiments, the system includes an ultrasound transducer having
multiple transducer elements; an administration device having the
first storage container for storing microbubbles and the second
storage container for storing a therapeutic agent; a manipulator
associated with the administration device for changing a
characteristic of the microbubbles; a measurement system for
detecting signals indicating a condition of a treatment procedure;
and a controller. In one embodiment, the controller is configured
to cause the ultrasound transducer to transmit ultrasound waves to
the target tissue; cause the microbubbles and therapeutic agent to
be dispensed from the administration device to the target tissue;
cause the measurement system to detect the signals indicating the
condition of the treatment procedure; and based at least in part on
the detected signals, adjust (i) a parameter value (e.g., a
frequency, a phase and/or an amplitude) associated with one or more
transducer elements, (ii) the microbubble characteristic (e.g., a
maximum diameter, a mean diameter, a normal size distribution
around a specified mean, a shell composition, or a gas and/or
liquid core composition), and/or (iii) an administration profile
(e.g., a dose, a concentration, an administering rate, an
administering timing, and/or an administering pressure) of the
microbubbles and/or the therapeutic agent. In one implementation,
the manipulator includes a filter having a determined size
characteristic.
[0032] As used herein, the term "substantially" means .+-.10%, and
in some embodiments, .+-.5%. Reference throughout this
specification to "one example," "an example," "one embodiment," or
"an embodiment" means that a particular feature, structure, or
characteristic described in connection with the example is included
in at least one example of the present technology. Thus, the
occurrences of the phrases "in one example," "in an example," "one
embodiment," or "an embodiment" in various places throughout this
specification are not necessarily all referring to the same
example. Furthermore, the particular features, structures,
routines, steps, or characteristics may be combined in any suitable
manner in one or more examples of the technology. The headings
provided herein are for convenience only and are not intended to
limit or interpret the scope or meaning of the claimed
technology.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] In the drawings, like reference characters generally refer
to the same parts throughout the different views. Also, the
drawings are not necessarily to scale, with an emphasis instead
generally being placed upon illustrating the principles of the
invention. In the following description, various embodiments of the
present invention are described with reference to the following
drawings, in which:
[0034] FIG. 1 illustrates a microbubble-enhanced focused ultrasound
system in accordance with various embodiments;
[0035] FIG. 2 depicts an exemplary relationship between the
microbubble size and the microbubble resonance frequency in
accordance with various embodiments of the present invention;
[0036] FIGS. 3A and 3B illustrate a time evolution of the
microbubble size distribution in accordance with various
embodiments of the present invention;
[0037] FIG. 4 is a flow chart illustrating an approach for
selecting a desired size distribution of microbubbles and applying
the selected microbubbles to enhance performance of an ultrasound
procedure in accordance with various embodiments of the present
invention;
[0038] FIG. 5 is a flow chart illustrating an approach for treating
a target utilizing a microbubble-enhanced ultrasound procedure in
combination with other therapeutic methods in accordance with
various embodiments of the present invention; and
[0039] FIGS. 6A-6D depicts exemplary administration systems in
accordance with various embodiments of the present invention.
DETAILED DESCRIPTION
[0040] FIG. 1 illustrates an exemplary ultrasound system 100 for
generating and delivering a focused acoustic energy beam to a
target region 101 within a patient's body. The applied ultrasound
waves may be reflected from the target region and/or non-target
region, and an image of the target and/or non-target regions may be
generated based on the reflected waves. In addition, microbubbles
may be introduced to the target region 101 and/or non-target region
to increase ultrasound reflections, thereby improving the contrast
of the ultrasound image. In some embodiments, the applied
ultrasound waves may ablate tissue in the target region 101 and/or
induce microbubble oscillation and/or cavitation to improve
treatment effects. The illustrated system 100 includes a phased
array 102 of transducer elements 104, a beamformer 106 driving the
phased array 102, a controller 108 in communication with the
beamformer 106, and a frequency generator 110 providing an input
electronic signal to the beamformer 106. In various embodiments,
the system further includes an imager 112, such as a magnetic
resonance imaging (MRI) device, a computer tomography (CT) device,
a positron emission tomography (PET) device, a single-photon
emission computed tomography (SPECT) device, or an ultrasonography
device, for determining anatomical characteristics (e.g., the type,
property, structure, thickness, density, etc.) of the tissue at the
target region 101 and/or the non-target region.
[0041] The array 102 may have a curved (e.g., spherical or
parabolic) shape suitable for placement on the surface of the
patient's body, or may include one or more planar or otherwise
shaped sections. Its dimensions may vary between millimeters and
tens of centimeters. The transducer elements 104 of the array 102
may be piezoelectric ceramic elements, and may be mounted in
silicone rubber or any other material suitable for damping the
mechanical coupling between the elements 104. Piezo-composite
materials, or generally any materials capable of converting
electrical energy to acoustic energy, may also be used. To assure
maximum power transfer to the transducer elements 104, the elements
104 may be configured for electrical resonance at 50 .OMEGA.,
matching input connector impedance.
[0042] The transducer array 102 is coupled to the beamformer 106,
which drives the individual transducer elements 104 so that they
collectively produce a focused ultrasonic beam or field. For n
transducer elements, the beamformer 106 may contain n driver
circuits, each including or consisting of an amplifier 118 and a
phase delay circuit 120; each drive circuit drives one of the
transducer elements 104. The beamformer 106 receives a radio
frequency (RF) input signal, typically in the range from 0.1 MHz to
10 MHz, from the frequency generator 110, which may, for example,
be a Model DS345 generator available from Stanford Research
Systems. The input signal may be split into n channels for the n
amplifiers 118 and delay circuits 120 of the beamformer 106. In
some embodiments, the frequency generator 110 is integrated with
the beamformer 106. The radio frequency generator 110 and the
beamformer 106 are configured to drive the individual transducer
elements 104 of the transducer array 102 at the same frequency, but
at different phases and/or different amplitudes.
[0043] The amplification or attenuation factors cu-an and the phase
shifts al-an imposed by the beamformer 106 serve to transmit and
focus ultrasonic energy through the intervening tissue located
between the transducer elements 104 and the target region onto the
target region 101, and account for wave distortions induced in the
intervening tissue. The amplification factors and phase shifts are
computed using the controller 108, which may provide the
computational functions through software, hardware, firmware,
hardwiring, or any combination thereof. In various embodiments, the
controller 108 utilizes a general-purpose or special-purpose
digital data processor programmed with software in a conventional
manner, and without undue experimentation, in order to determine an
optimal value of an ultrasound parameter (e.g., a frequency, a
phase shift and/or an amplification factor) associated with each
element 104 so as to generate a desired focus or any other desired
spatial field patterns. The optimal value of the ultrasound
parameter may be refined experimentally before, after, and/or at
one or more times during the ultrasound procedure based on, for
example, the focus quality, the focus location relative to the
target 101 and/or the microbubble response to the ultrasound
sonications. The quality and location of the focus may be monitored
using the imager 112, and the microbubble response may be detected
using the transducer 102 and/or an acoustic-signal detector 122
(e.g., a hydrophone).
[0044] In certain embodiments, the optimal value of the ultrasound
parameter is computationally estimated based on detailed
information about the characteristics of the intervening tissue and
their effects (e.g., reflection, refraction, and/or scattering) on
propagation of acoustic energy. Such information may be obtained
from the imager 112 and analyzed manually or computationally. Image
acquisition may be three-dimensional or, alternatively, the imager
112 may provide a set of two-dimensional images suitable for
reconstructing a three-dimensional image of the target and/or
non-target regions. Image-manipulation functionality may be
implemented in the imager 112, in the controller 108, or in a
separate device.
[0045] In certain treatment scenarios, ultrasound waves propagating
towards the target region 101 from different directions may
encounter a highly variable anatomy, such as different thicknesses
of tissue layers and different acoustic impedances; as a result,
energy deposition at the target region 101 varies significantly and
often nonmonotonically with frequency, and the optimum frequency
for a particular patient is typically unpredictable. Accordingly,
in some embodiments, the frequency of the ultrasound is optimized
by sequentially sonicating the target region 101 with waves having
different "test frequencies" within a test frequency range; for
each tested frequency, a parameter (e.g., temperature, acoustic
force, tissue displacement, etc.) indicative of energy deposition
in the target region 101 is measured. The test range may span the
entire range of frequencies suitable for ultrasound treatment
(e.g., in various embodiments, 0.1 MHz to 10 MHz), but is typically
a much smaller sub-range thereof within which the optimal frequency
is expected. Such a sub-range may be determined, e.g., based on
computational estimates of the optimal frequency, the results of
simulations, or empirical data acquired for the same target in
other patients. Further details about determining the optimal
frequency for the ultrasound application are provided, for example,
in U.S. Patent Publication No. 2016/0008633, the entire content of
which is incorporated herein by reference.
[0046] In some embodiments, optimizing the ultrasound frequency
involves iteratively setting a test frequency, sonicating the
target region 101 at the selected frequency, and quantitatively
assessing the resulting focusing properties or energy deposition at
the target region 101. This may be accomplished using, e.g., MRI
thermometry to measure the temperature increase in the target
region 101 resulting from the deposited energy, MR-ARFI to measure
the tissue displacement resulting from the acoustic pressure at the
target region 101, ultrasound detection to measure the intensity of
the ultrasound reflected from the target region 101, or generally
any experimental technique for measuring a parameter that
correlates with energy deposition at the target region 101 in a
known and predictable manner. Following frequency optimization, the
phase and/or amplitude settings of the phased-array transducer 102
may be adjusted to optimize the focus for the selected frequency.
Approaches to assessing focusing properties at the target region
101 and, based thereon, adjusting the ultrasound frequency, phase
and/or amplitude settings of the phased-array transducer 102 are
provided, for example, in an International Patent Application
entitled "Adaptive, Closed-Loop Ultrasound Therapy" filed on even
date herewith, the entire disclosure of which is hereby
incorporated by reference.
[0047] In various embodiments, microbubbles and/or other
therapeutic agents are introduced intravenously or, in some cases,
by injection proximate to the target region 101 using an
administration system 124 for enhancing the ultrasound procedure on
the target region. For example, the microbubbles may be introduced
into the patient's brain in the form of liquid droplets that
subsequently vaporize, or as gas-filled bubbles, or entrained with
another suitable substance, such as a conventional ultrasound
contrast agent. Because of their encapsulation of gas, the
microbubbles may act as reflectors of the ultrasound. Reflections
from the microbubbles are generally more intense than the
reflections from the soft tissue of the body. Therefore, by
combining the microbubbles with a contrast agent, the contrast
level of an ultrasound image may be significantly increased.
[0048] In addition, the microbubbles may react to an applied
oscillating acoustic pressure with volume pulsations. Depending on
the amplitude of the ultrasound waves, microbubble oscillation will
be related either linearly or nonlinearly to the applied acoustic
pressure. For a relatively low acoustic pressure, the instantaneous
radius of the microbubbles may oscillate linearly in relation to
the amplitude of the applied acoustic pressure. Microbubble
oscillation is governed by parameters such as the resonance
frequency, damping coefficients, and shell properties. Thus, if the
frequency of the applied acoustic waves is equal to the microbubble
resonance frequency, the microbubbles may experience a large force
and can collapse. This may result in undesired damage to the
non-target tissue if the microbubbles are present therein.
[0049] To avoid this undesired effect, in various embodiments, the
resonance frequency of the microbubbles is selected to be
substantially different from (e.g., two times greater than) the
selected optimal ultrasound frequency. In addition, the transducer
elements 104 are activated to transmit waves having a low acoustic
power (e.g., 5 W) during treatment. In this way, because the
ultrasound waves arriving the non-target region have a low acoustic
intensity and their frequency is substantially different from the
resonance frequency of the microbubbles, the microbubbles in the
non-target region may be unresponsive (or have a limited response
without cavitation) to the applied acoustic field. This ensures
that no (or at least a very limited amount of) non-target tissue is
damaged. In contrast, at the target region 101, where the
ultrasound beams are focused, the acoustic intensity is
substantially larger than that outside the target region and may be
sufficient to cause the microbubbles to oscillate and/or collapse.
This may enhance energy absorption at the target region 101 for
tissue ablation and/or cause disruption of blood vessels for
targeted drug delivery.
[0050] Referring to FIG. 2, the relationship between the
microbubble size, R.sub.0, and microbubble resonance frequency may
be established prior to the ultrasound procedure. As depicted, in
general, the smaller the radius R.sub.0 of the microbubbles, the
larger will be their resonance frequency. Accordingly, in some
embodiments, the resonance frequency of the introduced microbubbles
is controlled via their size distribution. For example, after the
optimal frequency of the ultrasound is determined as described
above, the microbubble radius corresponding to the optimal
ultrasound frequency may be computationally interpolated or
extrapolated using the established relationship. The size
distribution of the microbubbles may then be selected such that a
significant fraction (e.g., more than 50%, 90%, 95%, or 99% or
more) of the microbubbles have a radius below that corresponding to
a resonance frequency equal to the applied ultrasound frequency. In
one embodiment, the maximum radius of the administered microbubbles
is selected to be at least 50% (or, in some embodiments, a factor
by ten) smaller than the radius corresponding to a resonance
frequency equal to the applied ultrasound frequency. Approaches for
determining and selecting a desired size distribution of
microbubbles are provided, for example, in International
Application No. PCT/IB2018/000841 (filed on Jun. 29, 2018), the
entire content of which is incorporated herein by reference.
[0051] After the desired microbubble size is determined, the
microbubbles can be manufactured, or more typically, obtained
off-the-shelf. As depicted in FIGS. 3A and 3B, however,
commercially available microbubbles are typically polydisperse in
size and may undergo ripening during storage. As a result, the
actual size of the microbubbles when used may differ from their
size when generated and performance may suffer. To solve this
problem, in various embodiments, the size of the microbubbles is
measured prior to their administration using any suitable approach
(such as laser light obscuration and scattering, electrozone
sensing, optical microscopy, ultrasound or flow cytometry, all of
which are well-known to those of skill in the art and can be
implemented without undue experimentation). For example, the
ultrasound system 100 may transmit sonications to the microbubbles
at multiple frequencies, and based on the attenuation, scattering,
backscattering, harmonic generation, or sub-harmonic generation of
the transmitted signals and signals from the microbubbles, the size
distribution of the microbubbles can be determined. If more than a
threshold amount (e.g., 50%, 90%, 95% or 99%) of the microbubbles
is no larger than the desired size, the microbubbles may be
administered. If, however, less than the threshold amount of the
microbubbles is no larger than the desired size, a precautionary
action may be taken. For example, the administration system 124 may
generate a warning signal to the user.
[0052] Additionally, the microbubbles may be centrifuged to isolate
the ones conforming to the size criterion. Alternatively, a filter
having a pore size of the desired microbubble size may be employed
to filter the microbubbles as further described below. In some
embodiments, the ultrasound system 100 may be configured to apply
an acoustic field to the microbubbles; the acoustic filed has a
frequency band and a sufficient amplitude to destroy (e.g., cause
cavitation of) the microbubbles that do not conform to the size
criterion. After the isolation/filtration/destruction process, the
microbubbles may be verified again to ensure that the size thereof
matches the desired size; subsequently, the verified microbubbles
may be introduced into the patient's body. In one implementation,
administration of the microbubbles is synchronized with activation
of the ultrasound system 100 and/or administration of complementary
materials (such as a therapeutic agent, an MR contrast agent,
etc.). For example, upon application of the microbubbles and
ultrasound waves to open a target BBB region, the therapeutic agent
may be introduced to the target tumor region via the BBB opening to
treat the target tumor. Approaches to opening a target BBB region
for treating the target tumor are provided, for example, in
International Application No. PCT/IB2018/000834 (filed on Jun. 29,
2018), the entire content of which is incorporated herein by
reference.
[0053] FIG. 4 illustrates a representative procedure 400 for
selecting the microbubble size and applying the microbubbles to
enhance performance of an ultrasound procedure (e.g., imaging or
treatment) in accordance herewith. In a first preparatory step 402,
an optimal value of an ultrasound parameter (e.g., frequency) for
the procedure is determined based on the characteristics (such as
the location, size, shape, type, property, structure, thickness,
density, etc.) of the target and/or non-target regions. In one
embodiment, the characteristics of the target/non-target regions
are acquired using the imager 112 as described above. In a second
preparatory step 404, a desired microbubble size for enhancing the
performance of the procedure is selected based on the optimal value
of the ultrasound parameter. For example, the size distribution of
the microbubbles may then be selected such that a significant
fraction (e.g., more than 50%, 90%, 95%, or 99% or more) of the
microbubbles has a radius substantially below (e.g., a factor of
ten lower than) that corresponding to a resonance frequency equal
to the applied ultrasound frequency. In a third preparatory step
406, the microbubbles are manufactured or acquired off-the-shelf.
In a fourth preparatory step 408, the size of the
manufactured/acquired microbubbles is measured using any suitable
approach. If the size of the microbubbles satisfies a requirement
(e.g., at least 50%, 90%, 95% or 99% of the acquired microbubbles
has or is no larger than the desired size), the microbubbles may be
administered to enhance the ultrasound imaging quality or treatment
effects (step 410). If, however, the microbubbles do not satisfy
the size requirement (e.g., less than 50%, 90%, 95% or 99% of the
microbubbles has or is no larger than the desired size), the
microbubbles may be centrifuged or filtered prior to being
introduced into the patient's body (step 412). The size
distribution of the centrifuged/filtered microbubbles may be
verified again prior to administration.
[0054] In some embodiments, the administration profile (e.g., dose,
rate, timing or pressure) of the microbubbles is determined based
on one or more characteristics (e.g., diameter, size distribution,
shell composition, or gas and/or liquid core composition) of the
microbubbles prior to treatment. In addition, administration of the
microbubbles is synchronized with administration of other materials
(e.g., a therapeutic agent or an MR contrast) and/or activation of
the ultrasound procedure. For example, after administration of the
microbubbles having the desired size distribution into the target
region 101, the ultrasound transducer 102 may be activated to
perform the ultrasound-mediated, microbubble-enhanced tissue
disruption at the target region 101. During the ultrasound
procedure, focusing properties (e.g., acoustic power or peak
acoustic intensity) of the ultrasound beams and/or the treatment
effects (such as tissue-permeability enhancement or ablation) at
the target and/or non-target regions may be monitored using the
imager 112. In some embodiments, an MRI contrast agent (e.g., a
gadolinium-based contrast agent) is injected into the target and/or
non-target regions for assisting assessment of the tissue
disruption therein. Because of the disrupted tissue, the
permeability of the target region may be increased. Accordingly, by
monitoring the contrast change in the MRI images, the permeability
(and thereby the disruption) of the tissue at the target and/or
non-target region can be estimated. In addition, the microbubble
response to the applied acoustic field at the target and/or
non-target regions may be monitored using the transducer 102 and/or
acoustic-signal detector 122.
[0055] Based on the monitored treatment effects and/or microbubble
response, the controller 108 may adjust the administration profile
of the microbubbles and/or ultrasound parameters (e.g.,
frequencies, amplitudes, phases, activation times) in real time to
optimize the treatment or achieve a desired effect at the target.
For example, if the treatment effect in the non-target region
exceeds a safety threshold and/or an undesired microbubble response
is detected and/or an unwanted therapeutic effect at the non-target
region is detected, the controller 108 may reduce the
administration rate or dose of the microbubbles and/or reduce the
amplitude of the sonication waves. Conversely, if the treatment
effect in the target region falls below a desired goal, the
controller 108 may increase the administration rate or
administration time of the microbubbles and/or the sonication
amplitude so as to enhance the treatment effect. In addition, the
controller 108 may adjust the administration profile of the
contrast agent until the treatment effect at the target and/or
non-target region can be evaluated. The ultrasound procedure and
tissue disruption assessment may be iteratively performed until the
volume and/or degree of disrupted tissue substantially matches a
desired target volume and/or degree. Approaches to estimating the
tissue permeability at the target/non-target regions are provided,
for example, in International Application No. PCT/IB2018/000811
(filed on Jun. 29, 2018); approaches to measuring the microbubble
response to the applied acoustic field are provided, for example,
in International Application No. PCT/IB2018/000774 (filed on May
22, 2018); and approaches to configuring the transducer array for
detecting the microbubble response are provided, for example, in
U.S. Patent Application No. 62/681,282 (filed on Jun. 6, 2018). The
entire contents of these applications are incorporated herein by
reference.
[0056] In various embodiments, the ultrasound treatment procedure
is performed in combination with other therapeutic methods, such as
radiation therapy or targeted drug delivery. For example, the
ultrasound-induced microbubble oscillation/cavitation may disrupt
vascular tissue in the target region 101; this allows a radiation
dose in the radiation therapy to be significantly reduced while
still achieving a desired treatment efficacy. In another treatment
scenario, the ultrasound-induced microbubble oscillation/cavitation
may increase the tissue permeability at the target region; this
allows a higher dose of therapeutic agent to reach the target
tissue, thereby enhancing the therapeutic effect. Generally, the
radiation therapy or targeted drug delivery is performed only after
the volume/degree of ultrasound-mediated tissue disruption is
verified to match the desired target volume/degree. In addition,
different tumors/diseases or different therapeutic agents may
require different degrees of tissue disruption mediated by the
ultrasound. Accordingly, it is important to operate the transducer
102, imager 112, acoustic-signal detector 122, administration
system 124 and/or a radiation device in a controlled manner so as
to achieve a desired treatment effect.
[0057] FIG. 5 illustrates a representative procedure 500 for a
treatment approach involving the microbubble-enhanced ultrasound
procedure in combination with other therapeutic methods (such as
radiation therapy or targeted drug delivery) in accordance with
various embodiments. In a first step 502, the microbubbles with
characteristics satisfying the predetermined requirements are
introduced via the administration system 124 into the patient's
body as described above. In a second step 504, the transducer 102
is activated to start the ultrasound-mediated tissue disruption at
the target region 101. In addition, the tissue disruption during
and/or after the ultrasound procedure may be monitored or assessed
using, for example, the imager 112, transducer 102 and/or a
contrast agent introduced by the administration system 124 (in a
third step 506). Optionally, the microbubble response to the
sonications can be monitored using the acoustic-signal detector 122
and/or transducer elements 104. Based on the monitored tissue
disruption and/or microbubble response, the transducer parameters
and/or microbubble administration profile may be dynamically
adjusted until the volume/degree of ultrasound-mediated tissue
disruption verifiably matches the desired target volume/degree (in
a fourth step 508). The target volume/degree of tissue disruption
may vary based on the type, location and/or size of the target
region and/or the type and/or size of the therapeutic agent for
targeted drug delivery. Steps 504-508 may be iteratively performed
throughout the entire ultrasound procedure. In one embodiment, the
verification is performed by introducing the contrast agent into
the target and monitoring the contrast change in the MRI images.
Following verification, the therapeutic agent for targeted drug
delivery may be introduced via the administration system 124.
Alternatively, a radiation device may be activated to start the
treatment (in a fifth step 510). Again, the conditions of the
target/non-target tissue, microbubbles and/or therapeutic agent may
be monitored in real time using, for example, the imager 112,
acoustic-signal detector 122 and/or transducer elements 104 (in a
sixth step 512); and based thereon, a characteristic (e.g., agent
type, size, concentration, administering rate, administering dose,
administering pattern, administering time and/or administering
pressure) of the microbubbles and/or therapeutic agent can be
adjusted to achieved optimal (or desired) treatment effects on the
target and/or non-target regions (in a seventh step 514).
[0058] FIG. 6A depicts an exemplary administration system 600 in
accordance with various embodiments. The system 600 may include
three independent channels 602, 604, 606. The first channel 602 may
be in fluid communication with a first container 608 that stores
the microbubbles; the second channel 604 may be in fluid
communication with a second container 610 that stores the contrast
agent; and the third channel 606 may be in fluid communication with
a third container 612 that stores the therapeutic agent for
targeted drug delivery. The three channels 602, 604, 606 may then
be fluidly coupled to an introducing device (e.g., a catheter or a
needle) 614 for administering microbubbles, contrast agent and/or
therapeutic agent from their corresponding channels into the
patient's body. In addition, the system 600 may include an
actuation mechanism (e.g., a syringe, a peristaltic pump, etc.) 616
coupled to a controller 618 for forcing the microbubbles, contrast
agent and therapeutic agent through their corresponding channels
602, 604, 606 into the introducing device 614 for administration to
the patient. Additionally, the administration system 600 may be in
communication with a microbubble-verification system 622 that can
verify the size of the microbubbles prior to their administration
as described above. For example, the microbubble-verification
system 622 may include a suitable apparatus for performing laser
light obscuration and scattering, electrozone sensing, optical
microscopy, ultrasound or flow cytometry, etc.
[0059] In some embodiments, the channels 602, 604, 606 and/or
introducing device 614 include flow detectors 620 for detecting the
flow rate or flow pressure of the fluid therein. In some
embodiments, the flow detectors 620 transmit the detected signals
to the controller 618 for analysis. In addition, the controller 618
may receive detection signals from the ultrasound transducer 102,
imager 122, acoustic-signal detector 122, and/or a radiation device
624 as described above. Based on the received signals, the
controller 618 may operate the actuation mechanism 616 for
administering the microbubbles, contrast agent and/or therapeutic
agent. In addition, the controller 618 may be in communication with
the ultrasound controller 108. For example, upon the
microbubble-verification system 622 determining that the
microbubbles in the container 608 do not conform to the desired
size distribution, the controller 618 may cause the ultrasound
system 100 to apply an acoustic field onto the microbubbles to
destroy microbubbles that do not satisfy the size criterion.
Alternatively, the controller 618 may generate a warning signal to
the user; the user may then centrifuge and/or filter the
microbubbles so as to isolate the microbubbles having the desired
size. In addition, the controller 618 may cause activation and
deactivation of the transducer 102 based on the received signals
from the imager 122, acoustic-signal detector 122, and/or radiation
device 628 so as to optimize the treatment effect or achieve a
desired treatment effect at the target. The controller 618 may be
separate from the ultrasound controller 108 or may be combined with
the ultrasound controller 108 into an integrated system control
facility.
[0060] Accordingly, various embodiments of the present invention
advantageously provide an approach that allows the controller 618
and/or the controller 108 to adjust the microbubble administration
and/or ultrasound sonication in real time during the ultrasound
procedure so as to achieve a desired tissue disruption effect. The
tissue disruption effect may be verified using the contrast agent
or other suitable approach. Finally, after the tissue disruption
effect is verified, the target treatment may be performed by
administering the therapeutic agent or activating a radiation
device.
[0061] Although the system described above has three channels, one
of ordinary skill in the art will understand that systems may have
different numbers of channels that ultimately terminate in the
introducing device 614 and are within the scope of the current
invention. For example, fewer independently controlled fluid
channels may be utilized in the current invention. Referring to
FIG. 6B, the administration system 630 may include a single channel
632; the three containers 608, 610, and 612 may be placed on a
moving tray 634. By shifting the relative locations of the
containers with respect to the channel 632, the microbubbles,
contrast agent and therapeutic agent stored in the containers 608,
610, 612, respectively, may be independently and separately
injected into the channel 632. In addition, the administration
system 630 may include a preparation device 636 for preparing the
microbubbles, contrast agent and/or therapeutic agent prior to
administration. For example, the preparation device 636 may include
a heater for heating the fluid to a predetermined temperature
(e.g., body temperature) prior to administration. In some
embodiments, the preparation device 636 includes a shaker for
shaking the container(s) so as to mix the microbubbles, contrast
agent and/or therapeutic agent prior to injection.
[0062] In addition, each container may be fluidly coupled to more
than one channel. Referring to FIG. 6C, in some embodiments, the
administration system 650 includes multiple channels 652, 654, 656
fluidically connected to the microbubble vial 608 having therein,
for example, microbubbles polydisperse in size; each channel has a
filter of a different pore size. For example, the channels 652,
654, 656 may have filters 658, 660, 662 with pore sizes of 0.5
.mu.m, 2 .mu.m and 5 .mu.m, respectively. By coupling the vial 608
to different channels, microbubbles having different maximum sizes
may be generated. This approach is particularly useful when the
condition (e.g., size or temperature) of the target region 101
and/or non-target region and/or microbubble response to the
ultrasound waves changes during treatment, and dynamic adjustment
of the microbubble size is desired to maintain optimal treatment
effects at the target region 101 while minimizing damage to the
non-target region. In one implementation, the fluid coupling
between the vial 608 and the channels 652-656 can be adjusted in
real time based on the monitored target/non-target condition and/or
microbubble response as described above.
[0063] In various embodiments, more than one container may be
utilized for handling each of the microbubbles, contrast agent,
and/or therapeutic agent. For example, referring to FIG. 6D, each
of the channels 672, 674, 676 may be coupled to a different
microbubble vial having microbubbles of a different size. For
example, the channels 672, 674, 676 may be coupled to vials 678,
680, 682, in which at least 50%, 80%, 90%, or 95% of the
microbubbles have a radius of 0.5 .mu.m, 2 .mu.m and 5 .mu.m,
respectively. The actuation mechanism 616 may separately force the
microbubbles in each vial through a corresponding channel to enter
the introducing device 614, via which they are administered to the
patient. Alternatively, each channel may be coupled to a separate
actuation mechanism. Again, during the ultrasound procedure, based
on the monitored condition of the target and/or non-target regions
and/or the monitored microbubble response, the controller 618 may
cause the actuation mechanism 616 to administer microbubbles having
the desired size from the vial into the patient's body so as to
optimize the imaging quality or treatment effect on the target
region. For example, when the treatment effect in the non-target
region exceeds the safety threshold and/or an undesired microbubble
response and/or therapeutic effect at the non-target region is
detected, the controller 618 may cause the actuation mechanism 616
to administer microbubbles from the vial containing microbubbles
whose size corresponds to a resonance frequency that differs
further from the ultrasound frequency. In situations where the
temperature in the target region is sufficiently below the desired
ablation temperature, the controller 618 may cause the actuation
mechanism 616 to administer microbubbles from the vial containing
microbubbles whose size corresponds to a resonance frequency that
is closer to the ultrasound frequency.
[0064] Accordingly, various embodiments of the present invention
advantageously provide an approach that allows the size and/or
administration profile of microbubbles to be verified prior to the
ultrasound procedure and adjusted in real time during the
ultrasound procedure so as to maximize the performance of the
procedure and ensure patient safety.
[0065] It should be noted although the ultrasound procedure
described herein is enhanced using microbubbles, the systems and
methods described above may also be implemented for ultrasound
procedures enhanced using other approaches. For example, emulsions
and/or droplets composed of various liquid perfluorocarbon agents
may be utilized to enhance the ultrasound procedure. Accordingly,
the administration system described herein may be used to introduce
the emulsions/droplets into the target region, and the approaches
for measuring and manipulating various characteristics of the
microbubbles may be applied to measure and manipulate the
characteristics (e.g., the size, shell composition (if any), liquid
core composition, etc.) of the emulsions/droplets as well.
[0066] The therapeutic agent may include any drug that is suitable
for treating a tumor. For example, for treating glioblastoma (GBM),
the drug may include or consist of, e.g., one or more of Busulfan,
Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine),
Temozolomide, Methotrexate, Topotecan, Cisplatin, Etoposide,
Irinotecan/SN-38, Carboplatin, Doxorubicin, Vinblastine,
Vincristine, Procarbazine, Paclitaxel, Fotemustine,
Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide, Bevacizumab,
5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, Cytarabine
(cytosine arabinoside, ara-C)/ara-U, etc.
[0067] In addition, for treating GBM, those skilled in the art can
select a drug and a BBB opening regime optimized to enhance drug
absorption across the BBB within patient safety constraints. In
this regard, it is known that the BBB is actually already disrupted
in the core of many tumors, allowing partial penetration of
antitumor drugs; but the BBB is widely intact around the "brain
adjacent to tumor" (BAT) region where invasive/escaping GBM cells
can be found, and which cause tumor recurrence. Overcoming the BBB
for better drug delivery within the tumor core and the BAT can be
accomplished using ultrasound as described herein. The drugs
employed have various degrees of toxicity and various penetration
percentages through the BBB. An ideal drug has high cytotoxicity to
the tumor and no BBB penetration (so that its absorption and
cytotoxic effects can be confined to regions where the BBB is
disrupted), low neurotoxicity (to avoid damage to the nervous
system), and tolerable systemic toxicity (e.g., below a threshold)
at the prescribed doses. The drug may be administered intravenously
or, in some cases, by injection proximate to the tumor region.
[0068] In general, functionality for utilizing microbubbles to
enhance ultrasound treatment and/or targeted drug delivery while
limiting damage to non-target tissue may be structured in one or
more modules implemented in hardware, software, or a combination of
both, whether integrated within a controller of the imager 112, an
ultrasound system 100 and/or the administration system 124, or
provided by a separate external controller or other computational
entity or entities. Such functionality may include, for example,
analyzing imaging data of the target and/or non-target regions
acquired using the imager 112, determining the optimal value(s) of
ultrasound parameter(s) empirically and/or using the imaging data,
establishing a relationship between a microbubble size distribution
and a microbubble resonance frequency, determining a microbubble
resonance frequency and its corresponding microbubble size
distribution based on the optimal ultrasound parameter value(s),
causing the size of the microbubbles to be verified using any
suitable approach, causing the microbubbles to be centrifuged,
filtered or otherwise fractionated to isolate the microbubbles
having the desired size, causing the ultrasound system 100 to apply
an acoustic field onto the microbubbles so as to destroy (e.g.,
cause cavitation thereof) the ones that do not conform to the size
criterion, causing the microbubble having the verified size
distribution to be introduced to the target region 101, causing the
ultrasound transducer to be activated using the determine optimal
parameter value(s), monitoring the therapeutic effect and/or
microbubble response at the target/non-target regions during the
ultrasound procedure, and/or adjusting the optimal ultrasound
parameter value(s) and/or microbubble resonance frequency as
described above.
[0069] In addition, the ultrasound controller 108 and/or the
administration system controller 618 may include one or more
modules implemented in hardware, software, or a combination of
both. For embodiments in which the functions are provided as one or
more software programs, the programs may be written in any of a
number of high level languages such as PYTHON, FORTRAN, PASCAL,
JAVA, C, C++, C#, BASIC, various scripting languages, and/or HTML.
Additionally, the software can be implemented in an assembly
language directed to the microprocessor resident on a target
computer; for example, the software may be implemented in Intel
80.times.86 assembly language if it is configured to run on an IBM
PC or PC clone. The software may be embodied on an article of
manufacture including, but not limited to, a floppy disk, a jump
drive, a hard disk, an optical disk, a magnetic tape, a PROM, an
EPROM, EEPROM, field-programmable gate array, or CD-ROM.
Embodiments using hardware circuitry may be implemented using, for
example, one or more FPGA, CPLD or ASIC processors.
[0070] The terms and expressions employed herein are used as terms
and expressions of description and not of limitation, and there is
no intention, in the use of such terms and expressions, of
excluding any equivalents of the features shown and described or
portions thereof. In addition, having described certain embodiments
of the invention, it will be apparent to those of ordinary skill in
the art that other embodiments incorporating the concepts disclosed
herein may be used without departing from the spirit and scope of
the invention. Accordingly, the described embodiments are to be
considered in all respects as only illustrative and not
restrictive.
* * * * *