U.S. patent application number 14/207516 was filed with the patent office on 2014-07-10 for methods and devices for thermally induced hepatic neuromodulation.
This patent application is currently assigned to Kona Medical, Inc.. The applicant listed for this patent is Kona Medical, Inc.. Invention is credited to Michael Gertner.
Application Number | 20140194785 14/207516 |
Document ID | / |
Family ID | 45807355 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140194785 |
Kind Code |
A1 |
Gertner; Michael |
July 10, 2014 |
METHODS AND DEVICES FOR THERMALLY INDUCED HEPATIC
NEUROMODULATION
Abstract
A system for treatment includes a focused ultrasound energy
source for placement outside a patient, wherein the focused
ultrasound energy source is configured to deliver ultrasound energy
towards a blood vessel with a surrounding nerve that is a part of
an autonomic nervous system inside the patient, and wherein the
focused ultrasound energy source is configured to deliver the
ultrasound energy from outside the patient to the nerve located
inside the patient to treat the nerve.
Inventors: |
Gertner; Michael; (Menlo
Park, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kona Medical, Inc. |
Palo Alto |
CA |
US |
|
|
Assignee: |
Kona Medical, Inc.
Palo Alto
CA
|
Family ID: |
45807355 |
Appl. No.: |
14/207516 |
Filed: |
March 12, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13896252 |
May 16, 2013 |
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14207516 |
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13048830 |
Mar 15, 2011 |
8517962 |
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13896252 |
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12902133 |
Oct 11, 2010 |
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13048830 |
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12725450 |
Mar 16, 2010 |
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12902133 |
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12685655 |
Jan 11, 2010 |
8295912 |
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12725450 |
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61377908 |
Aug 27, 2010 |
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61347375 |
May 21, 2010 |
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61256983 |
Oct 31, 2009 |
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61250857 |
Oct 12, 2009 |
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61261741 |
Nov 16, 2009 |
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61291359 |
Dec 30, 2009 |
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61303307 |
Feb 10, 2010 |
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61256983 |
Oct 31, 2009 |
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61250857 |
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61261741 |
Nov 16, 2009 |
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61291359 |
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Current U.S.
Class: |
601/2 |
Current CPC
Class: |
A61B 90/37 20160201;
A61N 5/062 20130101; A61B 5/0263 20130101; A61B 8/06 20130101; A61B
2018/00434 20130101; A61B 5/4839 20130101; A61B 5/201 20130101;
A61N 2007/0052 20130101; A61B 6/506 20130101; A61B 8/488 20130101;
A61B 8/0891 20130101; A61N 2007/0078 20130101; A61B 5/061 20130101;
A61B 8/00 20130101; A61B 8/485 20130101; A61B 5/0225 20130101; A61N
5/0622 20130101; A61N 2007/003 20130101; A61B 6/487 20130101; A61B
2018/00404 20130101; A61N 2005/063 20130101; A61B 2090/3762
20160201; A61B 2090/378 20160201; A61B 6/504 20130101; A61B 8/0841
20130101; A61B 8/14 20130101; A61B 5/055 20130101; A61B 6/03
20130101; A61B 6/032 20130101; A61B 8/08 20130101; A61N 7/00
20130101; A61N 2007/0026 20130101; A61B 6/037 20130101; A61B 5/489
20130101; A61B 2018/00511 20130101; A61B 5/4528 20130101; A61B
5/4893 20130101; A61B 5/412 20130101; A61B 8/4245 20130101; A61B
2090/374 20160201; A61N 5/0601 20130101; A61N 7/02 20130101 |
Class at
Publication: |
601/2 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1-32. (canceled)
33. A method of modulating a nerve associated with a pulmonary
blood vessel comprising: directing a therapeutic ultrasound energy
applicator towards a target region comprising a nerve associated
with a pulmonary blood vessel; determining a position of the target
region with respect to the energy applicator; determining an
ultrasound energy delivery pattern; and delivering ultrasound
energy with the energy applicator to the target region based on the
determined ultrasound energy delivery pattern.
34. The method of claim 33, wherein the delivery of ultrasound
energy generates heat around the pulmonary blood vessel, but not
inside a wall of the pulmonary blood vessel.
35. The method of claim 33, wherein the delivery of ultrasound
energy generates a temperature around the pulmonary blood vessel
between 40 and 60 degrees Fahrenheit.
36. The method of claim 33, wherein the delivery of ultrasound
energy generates a temperature around the pulmonary blood vessel
between 60 and 90 degrees Fahrenheit.
37. The method of claim 33, wherein the method further comprises
cooling a region that is being heated by the delivered ultrasound
energy.
38. The method of claim 33, wherein an intensity of the delivered
ultrasound energy is between 50 mW/cm.sup.2 and 1 W/cm.sup.2.
39. The method of claim 33, wherein a frequency of the delivered
ultrasound energy is between 0.5 Mhz and 10 Mhz.
40. The method of claim 33, wherein the delivered ultrasound energy
comprises unfocused ultrasound energy.
41. The method of claim 33, wherein the delivered ultrasound energy
at least partially modulates the nerve.
42. The method of claim 33, wherein the ultrasound energy is
delivered to form a heated region having an approximately
ellipsoidal shape.
43. The method of claim 33, wherein the ultrasound energy is
delivered to form a heated region having an approximately spherical
shape.
44. The method of claim 33, wherein the act of directing the energy
applicator comprises directing the energy applicator from outside
the patient towards the target region inside the patient.
45. The method of claim 33, wherein the act of directing the energy
applicator comprises directing the energy applicator from inside
the patient towards the target region.
46. The method of claim 33, wherein the act of delivering
ultrasound energy to the target region comprises delivering the
ultrasound energy to the target region around a reference position
associated with a pulmonary vein.
47. The method of claim 33, wherein the act of delivering
ultrasound energy to the target region comprises delivering the
ultrasound energy to the target region around a reference position
associated with a pulmonary artery.
48. The method of claim 33, further comprising utilizing ultrasound
imaging to identify the target region.
49. The method of claim 33, further comprising utilizing Doppler
flow based imaging to identify the target region.
50. The method of claim 33, further comprising determining a
position of an ultrasound imaging with respect to the energy
applicator.
Description
RELATED APPLICATION DATA
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 12/902,133 filed Oct. 11, 2010, which claims
priority to and the benefit of U.S. Provisional patent application
61/377,908 filed Aug. 27, 2010, now pending, and U.S. Provisional
patent application 61/347,375 filed May 21, 2010, now pending, and
is a continuation-in-part of U.S. patent application Ser. No.
12/725,450 filed Mar. 16, 2010, now pending, which is a
continuation-in-part of U.S. patent application Ser. No.
12/685,655, filed on Jan. 11, 2010, now pending, which claims
priority to and the benefit of U.S. Provisional Patent Application
No. 61/256,983 filed Oct. 31, 2009, now lapsed, U.S. Provisional
Patent Application No. 61/250,857 filed Oct. 12, 2009, now lapsed,
U.S. Provisional Patent Application No. 61/261,741 filed Nov. 16,
2009, now lapsed, and U.S. Provisional Patent Application No.
61/291,359 filed Dec. 30, 2009, now lapsed.
[0002] U.S. patent application Ser. No. 12/725,450 also claims
priority to, and the benefit of U.S. Provisional Patent Application
No. 61/303,307 filed Feb. 10, 2010, now lapsed, U.S. Provisional
Patent Application No. 61/256,983 filed Oct. 31, 2009, now lapsed,
U.S. Provisional Patent Application No. 61/250,857 filed Oct. 12,
2009, now lapsed, U.S. Provisional Patent Application No.
61/261,741 filed Nov. 16, 2009, now lapsed, and U.S. Provisional
Patent Application No. 61/291,359 filed Dec. 30, 2009, now
lapsed.
[0003] The disclosures of all of the above referenced applications
are expressly incorporated by reference herein.
[0004] This application is related to U.S. patent application Ser.
Nos. ______, ______, and ______, all entitled "Energetic modulation
of nerves", and having respective attorney docket Nos.
KM-003-US-CIP2, KM-003-US-CIP3, and KM-003-US-CIP4, filed
concurrently with this application.
[0005] The following patent applications are also expressly
incorporated by reference herein.
[0006] U.S. patent application Ser. Nos. 11/583,569, 12/762,938,
11/583,656, 12/247,969, 10/633,726, 09/721,526, 10/780,405,
09/747,310, 12/202,195, 11/619,996, 09/696,076, 11/016,701,
12/887,178, 12/390,975, 12/887,178, 12/887,211, 12/887,232,
11/583,656.
[0007] It should be noted that the subject matters of the above
applications and any other applications referenced herein are
expressly incorporated into this application as if they are
expressly recited in this application. Thus, in the instance where
the references are not specifically labeled as "incorporated by
reference" in this application, they are in fact deemed described
in this application.
BACKGROUND
[0008] Energy delivery from a distance involves transmission of
energy waves to affect a target at a distance. It allows for more
efficient delivery of energy to targets and a greater cost
efficiency and technologic flexibility on the generating side. For
example, cellular phones receive targets from towers close to the
user and the towers communicate with one another over a long range;
this way, the cell phones can be low powered and communicate over a
relatively small range yet the network can quickly communicate
across the world. Similarly, electricity distribution from large
generation stations to the users is more efficient than the users
themselves looking for solutions.
[0009] In terms of treating a patient, delivering energy over a
distance affords great advantages as far as targeting accuracy,
technologic flexibility, and importantly, limited invasiveness into
the patient. In a simple form, laparoscopic surgery has replaced
much of the previous open surgical procedures and lead to creation
of new procedures and devices as well as a more efficient
procedural flow for disease treatment. Laparoscopic tools deliver
the surgeon's energy to the tissues of the patient from a distance
and results in improved imaging of the region being treated as well
as the ability for many surgeons to visualize the region at the
same time.
[0010] Perhaps the most important aspect is the fact that patients
have much less pain, fewer complications, and the overall costs of
the procedures are lower. Visualization is improved as is the
ability to perform tasks relative to the visualization.
[0011] Continued advances in computing, miniaturization and
economization of energy delivery technologies, and improved imaging
will lead to still greater opportunities to apply energy from a
distance into the patient and treat disease.
SUMMARY
[0012] In some embodiments, procedures and devices are provided,
which advance the art of medical procedures involving transmitted
energy to treat disease. The procedures and devices follow along
the lines of: 1) transmitting energy to produce an effect in a
patient from a distance; 2) allowing for improved imaging or
targeting at the site of treatment; 3) creating efficiencies
through utilization of larger and more powerful devices from a
position of distance from or within the patient as opposed to
attempting to be directly in contact with the target as a surgeon,
interventional cardiologist or radiologist might do. In many cases,
advanced visualization and localization tools are utilized as
well.
[0013] In accordance with some embodiments, a system for treatment
includes a focused ultrasound energy source for placement outside a
patient, wherein the focused ultrasound energy source is configured
to deliver ultrasound energy towards a blood vessel with a
surrounding nerve that is a part of an autonomic nervous system
inside the patient, and wherein the focused ultrasound energy
source is configured to deliver the ultrasound energy from outside
the patient to the nerve located inside the patient to treat the
nerve.
[0014] In any of the embodiments described herein, the focused
ultrasound energy source comprises a transducer, and a angle of the
focused ultrasound source is anywhere between 30 degrees to 80
degrees with respect to a line traveling down a center of the
transducer relative to a line connecting the transducer to the
blood vessel.
[0015] In any of the embodiments described herein, the focused
ultrasound energy source is configured to provide the ultrasound
energy to achieve partial ablation of the nerve.
[0016] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy to the nerve from multiple directions outside the patient
while the focused ultrasound energy source is stationary relative
to the patient.
[0017] In any of the embodiments described herein, the system
further includes an imaging processor for determining a position of
the blood vessel.
[0018] In any of the embodiments described herein, the imaging
processor comprises a CT device, a MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography
device, a photoacoustic imaging device, a PET imaging device, a
SPECT imaging device, or an ultrasound device.
[0019] In any of the embodiments described herein, the processor is
configured to operate the focused ultrasound energy source to
target the nerve that surrounds the blood vessel during the
ultrasound energy delivery based on the determined position.
[0020] In any of the embodiments described herein, the processor is
configured to determine the position using a Doppler triangulation
technique.
[0021] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy having an energy level sufficient to decrease a sympathetic
stimulus to the kidney, decrease an afferent signal from the kidney
to an autonomic nervous system, or both.
[0022] In any of the embodiments described herein, the focused
ultrasound energy source has an orientation so that the focused
ultrasound energy source aims at a direction that aligns with the
vessel that is next to the nerve.
[0023] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track a movement of the
nerve.
[0024] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track the movement of the
nerve by tracking a movement of the blood vessel next to the
nerve.
[0025] In any of the embodiments described herein, the focused
ultrasound energy source is configured to aim towards the nerve by
aiming towards the blood vessel that is surrounded by the
nerve.
[0026] In any of the embodiments described herein, the system
further includes a device for placement inside the patient, and a
processor for determining a position using the device, wherein the
focused ultrasound energy source is configured to deliver the
ultrasound energy based at least in part on the determined
position.
[0027] In any of the embodiments described herein, the device is
sized for insertion into the blood vessel that is surrounded by the
nerve.
[0028] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy towards the blood vessel at an angle anywhere between -10
degrees and -48 degrees relative to a horizontal line connecting
transverse processes of a spinal column, the angle directed from a
lower torso to an upper torso of the patient.
[0029] In accordance with some embodiments, a system for treatment
of a nerve surrounding a blood vessel traveling to a kidney
includes an ultrasound energy source for placement outside a
patient wherein the ultrasound energy source comprises an array of
ultrasound transducers, and a programmable interface, configured to
control the ultrasound energy source to deliver focused ultrasound
to a region surrounding a blood vessel leading to the kidney
through energizing one or more elements of the array in one or more
phases, at an angle and offset to a central axis of the array to a
tissue depth anywhere from 6 cm to 15 cm.
[0030] In any of the embodiments described herein, the focused
ultrasound energy source comprises a transducer, and an angle of
the focused ultrasound source is anywhere between 30 degrees to 80
degrees with respect to a line traveling down a center of the
transducer relative to a line connecting from the transducer to the
blood vessel.
[0031] In any of the embodiments described herein, the focused
ultrasound energy source is configured to provide the ultrasound
energy to achieve partial ablation of the nerve.
[0032] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy to the nerve from multiple directions outside the patient
while the focused ultrasound energy source is stationary relative
to the patient.
[0033] In any of the embodiments described herein, the system
further includes an imaging processor for determining a position of
the blood vessel.
[0034] In any of the embodiments described herein, the imaging
processor comprises a CT device, a MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography
device, a photoacoustic imaging device, a PET imaging device, a
SPECT imaging device, or an ultrasound device.
[0035] In any of the embodiments described herein, the processor is
configured to operate the focused ultrasound energy source to
target the nerve that surrounds the blood vessel during the
ultrasound energy delivery based on the determined position.
[0036] In any of the embodiments described herein, the processor is
configured to determine the position using a Doppler triangulation
technique.
[0037] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy having an energy level sufficient to decrease a sympathetic
stimulus to the kidney, decrease an afferent signal from the kidney
to an autonomic nervous system, or both.
[0038] In any of the embodiments described herein, the focused
ultrasound energy source has an orientation so that the focused
ultrasound energy source aims at a direction that aligns with the
vessel that is next to the nerve.
[0039] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track a movement of the
nerve.
[0040] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track the movement of the
nerve by tracking a movement of the blood vessel next to the
nerve.
[0041] In any of the embodiments described herein, the focused
ultrasound energy source is configured to aim towards the nerve by
aiming towards the blood vessel that is surrounded by the
nerve.
[0042] In any of the embodiments described herein, the system
further includes a device for placement inside the patient, and a
processor for determining a position using the device, wherein the
focused ultrasound energy source is configured to deliver the
ultrasound energy based at least in part on the determined
position.
[0043] In any of the embodiments described herein, the device is
sized for insertion into the blood vessel that is surrounded by the
nerve.
[0044] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy towards the blood vessel at an angle anywhere between -10
degrees and -48 degrees relative to a horizontal line connecting
transverse processes of a spinal column, the angle directed from a
lower torso to an upper torso of the patient.
[0045] In accordance with some embodiments, a system for treatment
of an autonomic nervous system of a patient includes a focused
ultrasound energy source for placement outside the patient, wherein
the focused ultrasound energy source is configured to deliver
ultrasound energy towards a blood vessel with a surrounding nerve
that is a part of the autonomic nervous system inside the patient,
and wherein the focused ultrasound energy source is configured to
deliver the ultrasound energy based on a position of an indwelling
vascular catheter.
[0046] In any of the embodiments described herein, the focused
ultrasound energy source comprises a transducer, and a angle of the
focused ultrasound source is anywhere between 30 degrees to 80
degrees with respect to a line traveling down a center of the
transducer relative to a line connecting from the transducer to the
blood vessel.
[0047] In any of the embodiments described herein, the focused
ultrasound energy source is configured to provide the ultrasound
energy to achieve partial ablation of the nerve.
[0048] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy to the nerve from multiple directions outside the patient
while the focused ultrasound energy source is stationary relative
to the patient.
[0049] In any of the embodiments described herein, the system
further includes an imaging processor for determining a position of
the blood vessel.
[0050] In any of the embodiments described herein, the imaging
processor comprises a CT device, a MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography
device, a photoacoustic imaging device, a PET imaging device, a
SPECT imaging device, or an ultrasound device.
[0051] In any of the embodiments described herein, the processor is
configured to operate the focused ultrasound energy source to
target the nerve that surrounds the blood vessel during the
ultrasound energy delivery based on the determined position.
[0052] In any of the embodiments described herein, the processor is
configured to determine the position using a Doppler triangulation
technique.
[0053] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy having an energy level sufficient to decrease a sympathetic
stimulus to the kidney, decrease an afferent signal from the kidney
to an autonomic nervous system, or both.
[0054] In any of the embodiments described herein, the focused
ultrasound energy source has an orientation so that the focused
ultrasound energy source aims at a direction that aligns with the
vessel that is next to the nerve.
[0055] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track a movement of the
nerve.
[0056] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track the movement of the
nerve by tracking a movement of the blood vessel next to the
nerve.
[0057] In any of the embodiments described herein, the focused
ultrasound energy source is configured to aim towards the nerve by
aiming towards the blood vessel that is surrounded by the
nerve.
[0058] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy towards the blood vessel at an angle anywhere between -10
degrees and -48 degrees relative to a horizontal line connecting
transverse processes of a spinal column, the angle directed from a
lower torso to an upper torso of the patient.
[0059] In accordance with some embodiments, a system for treatment
includes a focused ultrasound energy source for placement outside a
patient, wherein the focused ultrasound energy source is configured
to deliver ultrasound energy towards a blood vessel with a
surrounding nerve that is a part of an autonomic nervous system
inside the patient, and wherein the focused ultrasound energy
source is configured to deliver the ultrasound energy towards the
blood vessel at an angle anywhere between -10 degrees and -48
degrees relative to a horizontal line connecting transverse
processes of a spinal column, the angle directed from a lower torso
to an upper torso of the patient.
[0060] In any of the embodiments described herein, the focused
ultrasound energy source comprises a transducer, and a angle of the
focused ultrasound source is anywhere between 30 degrees to 80
degrees with respect to a line traveling down a center of the
transducer relative to a line connecting from the transducer to the
blood vessel.
[0061] In any of the embodiments described herein, the focused
ultrasound energy source is configured to provide the ultrasound
energy to achieve partial ablation of the nerve.
[0062] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy to the nerve from multiple directions outside the patient
while the focused ultrasound energy source is stationary relative
to the patient.
[0063] In any of the embodiments described herein, the system
further includes an imaging processor for determining a position of
the blood vessel.
[0064] In any of the embodiments described herein, the imaging
processor comprises a CT device, a MRI device, a thermography
device, an infrared imaging device, an optical coherence tomography
device, a photoacoustic imaging device, a PET imaging device, a
SPECT imaging device, or an ultrasound device.
[0065] In any of the embodiments described herein, the processor is
configured to operate the focused ultrasound energy source to
target the nerve that surrounds the blood vessel during the
ultrasound energy delivery based on the determined position.
[0066] In any of the embodiments described herein, the processor is
configured to determine the position using a Doppler triangulation
technique.
[0067] In any of the embodiments described herein, the focused
ultrasound energy source is configured to deliver the ultrasound
energy having an energy level sufficient to decrease a sympathetic
stimulus to the kidney, decrease an afferent signal from the kidney
to an autonomic nervous system, or both.
[0068] In any of the embodiments described herein, the focused
ultrasound energy source has an orientation so that the focused
ultrasound energy source aims at a direction that aligns with the
vessel that is next to the nerve.
[0069] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track a movement of the
nerve.
[0070] In any of the embodiments described herein, the focused
ultrasound energy source is configured to track the movement of the
nerve by tracking a movement of the blood vessel next to the
nerve.
[0071] In any of the embodiments described herein, the focused
ultrasound energy source is configured to aim towards the nerve by
aiming towards the blood vessel that is surrounded by the
nerve.
[0072] In any of the embodiments described herein, the system
further includes a device for placement inside the patient, and a
processor for determining a position using the device, wherein the
focused ultrasound energy source is configured to deliver the
ultrasound energy based at least in part on the determined
position.
[0073] In any of the embodiments described herein, the device is
sized for insertion into the blood vessel that is surrounded by the
nerve.
[0074] In accordance with some embodiments, a method to apply a
nerve inhibiting cloud surrounding a blood vessel includes creating
a treatment plan, wherein the treatment plan prescribes application
of the nerve inhibiting cloud towards at least a majority portion
of a circumference of a blood vessel wall, and applying the nerve
inhibiting cloud towards the majority portion of the circumference
of the blood vessel wall for a time sufficient to inhibit a
function of a nerve that surrounds the blood vessel wall.
[0075] In any of the embodiments described herein, the nerve
inhibiting cloud comprises a cloud of light.
[0076] In any of the embodiments described herein, the nerve
inhibiting cloud comprises a gaseous cloud.
[0077] In any of the embodiments described herein, the nerve
inhibiting cloud comprises a heat cloud.
[0078] In any of the embodiments described herein, the nerve
inhibiting cloud is applied using a transcutaneous energy
source.
[0079] In any of the embodiments described herein, the nerve
inhibiting cloud is applied using a transcutaneous energy source
that is configured to deliver a focused ultrasound.
[0080] In any of the embodiments described herein, the nerve
inhibiting cloud is applied using ionizing radiation.
[0081] In any of the embodiments described herein, the nerve
inhibiting cloud is applied by delivering focused ultrasound, and
the imaging device comprises an MRI device.
[0082] In any of the embodiments described herein, the method
further includes obtaining an image of the blood vessel using an
imaging device, wherein the treatment plan is created using the
image.
[0083] In accordance with some embodiments, a system to deliver a
nerve inhibiting cloud to a region surrounding a blood vessel
includes a catheter comprising a plurality of electrodes configured
to apply a cloud of heat, a processor storing a treatment plan that
prescribes an application of the cloud of heat towards at least a
majority of a circumference of a blood vessel wall surrounded by
nerve, and an external detector configured for measuring
temperature associated with the application of the cloud of
heat.
[0084] In any of the embodiments described herein, the external
detector comprises an ultrasound device.
[0085] In any of the embodiments described herein, the external
detector comprises an MRI device.
[0086] In any of the embodiments described herein, the catheter is
configured to be placed in a vein.
[0087] In any of the embodiments described herein, the catheter is
configured to be placed into a visceral artery.
[0088] In accordance with some embodiments, a system to deliver a
nerve inhibiting treatment to a nerve region surrounding a blood
vessel includes a catheter comprising a component which is
configured to be heated in response to an externally applied
electromagnetic field, and a device configured for applying the
electromagnetic field through a skin of a patient to heat the
component of the catheter, wherein the heated component provides a
heat cloud to the nerve region surrounding the blood vessel.
[0089] In any of the embodiments described herein, the catheter
comprises an expandable member for pressing up against a wall of
the blood vessel when the expandable member is expanded.
[0090] In any of the embodiments described herein, the device is
further configured for measuring a temperature using the
electromagnetic field.
[0091] In any of the embodiments described herein, the device
comprises a magnetic resonance imaging device.
[0092] In any of the embodiments described herein, the device
comprises an ultrasound detection device.
[0093] In accordance with some embodiments, a method to deliver
focused ultrasound energy from a position outside a skin of a
patient to a nerve surrounding a blood vessel includes placing the
patient on a table in a substantially flat position, moving a
transducer into a position inferior to ribs, superior to an iliac
crest, and lateral to a spine of the patient, maintaining the
transducer at the position relative to the patient, and delivering
focused ultrasound energy through the skin of the patient without
traversing bone, wherein the direction of the focused ultrasound is
directed from a lower torso to an upper torso of the patient.
[0094] In any of the embodiments described herein, the method
further includes detecting signals emanating from within the
patient.
[0095] In any of the embodiments described herein, the method
further includes detecting signals emanating from an intravascular
device inside the patient.
[0096] In any of the embodiments described herein, the focused
ultrasound energy is delivered to treat nerves inside the
patient.
[0097] In any of the embodiments described herein, the nerves
surrounds a vessel, and the focused ultrasound energy is delivered
to the nerves by targeting the vessel.
[0098] In accordance with some embodiments, a system to deliver a
nerve inhibiting treatment to a nerve region surrounding a blood
vessel includes a catheter comprising a component which is
configured to be heated in response to an externally applied
electromagnetic field, and a magnetic resonance device configured
for applying the electromagnetic field through a skin of a patient
to heat the component of the catheter to a level that is sufficient
to treat the nerve region surrounding the blood vessel, and a
temperature detection system configured to limit a temperature of
the nerve region surrounding the blood vessel.
[0099] In any of the embodiments described herein, the magnetic
resonance device includes the temperature detection system.
[0100] In any of the embodiments described herein, the temperature
detection system is inside the catheter.
[0101] In any of the embodiments described herein, the catheter is
configured to be steered based at least in part on a signal
provided by the magnetic resonance system.
[0102] In any of the embodiments described herein, the magnetic
resonance system is configured to move the catheter towards a wall
of the blood vessel.
[0103] In accordance with some embodiments, a system for treatment
of a nerve surrounding a blood vessel traveling to a kidney
includes an ultrasound energy source for placement outside a
patient, wherein the ultrasound energy source comprises an array of
ultrasound transducers, a programmable interface, configured to
control the ultrasound energy source to deliver focused ultrasound
to a region surrounding the blood vessel leading to the kidney
through energizing one or more elements of the array in one or more
phases, and a magnetic resonance imaging system comprising a
permanent magnet, wherein the magnetic resonance imaging system is
operatively coupled to the programmable interface.
[0104] In any of the embodiments described herein, the system
further includes an intravascular catheter device for placement
into the vessel.
[0105] In any of the embodiments described herein, the system
further includes a radiofrequency coil for placement around an
abdomen of the patient.
[0106] In any of the embodiments described herein, the system
further includes a positioning device for delivering focused
ultrasound energy to the region surrounding the blood vessel
leading to the kidney.
[0107] In any of the embodiments described herein, the ultrasound
energy source is configured to deliver the focused ultrasound at an
angle and offset to a central axis of the array to a tissue depth
anywhere from 6 cm to 15 cm.
[0108] In accordance with some embodiments, a system for treatment
of a nerve surrounding a blood vessel traveling to a kidney
includes an ultrasound energy source for placement outside a
patient wherein the ultrasound energy source comprises an array of
ultrasound transducers, a programmable interface, configured to
control the ultrasound energy source to deliver focused ultrasound
to a region surrounding the blood vessel leading to the kidney
through energizing one or more elements of the array in one or more
phases, and a processor configured to determine a quality factor
based at least on an amount of time the focused ultrasound is
within a pre-determined distance from a target.
[0109] In any of the embodiments described herein, the
pre-determined distance is 500 microns.
[0110] In any of the embodiments described herein, the
pre-determined distance is 2 mm.
[0111] In any of the embodiments described herein, the processor is
further configured to operate the ultrasound energy source based at
least in part on the quality factor.
[0112] In any of the embodiments described herein, the system
further includes an intravascular catheter for placement into the
vessel.
[0113] In any of the embodiments described herein, the
intravascular catheter is configured to provide a signal related to
movement of the region being treated, and the processor is
configured to operate the ultrasound energy source based at least
in part on the signal.
[0114] In any of the embodiments described herein, the system
further includes a motion tracking system coupled to the
processor.
[0115] In any of the embodiments described herein, the ultrasound
energy source is configured to deliver the focused ultrasound at an
angle and offset to a central axis of the array to a tissue depth
anywhere from 6 cm to 15 cm.
[0116] In accordance with some embodiments, a device to apply
focused ultrasound to a patient includes a transducer configured to
deliver focused ultrasound to a blood vessel leading to a kidney,
wherein the transducer comprises a plurality of individually
phaseable elements, and a membrane for coupling the ultrasound to
the patient, a first mechanical mover for positioning the
transducer, wherein the first mechanical mover is configured to
operate with the phaseable elements simultaneously to change a
position of a focus of the transducer, and a second mechanical
mover for maintaining a pressure between the membrane of the
transducer and a skin of the patient.
[0117] In any of the embodiments described herein, the membrane
contains fluid, and pressure and temperature of the fluid is
maintained at a constant level.
[0118] In any of the embodiments described herein, the device
further includes an imaging system operatively coupled to the first
mechanical mover.
[0119] In any of the embodiments described herein, the imaging
system is an MRI system.
[0120] In any of the embodiments described herein, the imaging
system is an ultrasound system.
[0121] In any of the embodiments described herein, the imaging
system is configured to detect an intravascular catheter.
[0122] In any of the embodiments described herein, the imaging
system is configured to determine a three dimensional coordinate,
and the transducer is configured to deliver the ultrasound based at
least in part on the determined three dimensional coordinate.
[0123] Other and further aspects and features will be evident from
reading the following detailed description of the embodiments.
DESCRIPTION OF FIGURES
[0124] FIGS. 1A-1B depict the focusing of energy sources on nerves
of the autonomic nervous system.
[0125] FIG. 1C depicts an imaging system to help direct the energy
sources.
[0126] FIG. 1D depicts a system integration schematic.
[0127] FIG. 1E depicts a box diagram of an integrated system
schematic.
[0128] FIG. 2 depicts targeting and/or therapeutic ultrasound
delivered through the stomach to the autonomic nervous system
posterior to the stomach.
[0129] FIG. 3A depicts focusing of energy waves on the renal
nerves.
[0130] FIG. 3B depicts a coordinate reference frame for the
treatment.
[0131] FIG. 3C depicts targeting catheters or energy delivery
catheters placed in any of the renal vessels.
[0132] FIG. 3D depicts an image detection system of a blood vessel
with a temporary fiducial placed inside the blood vessel, wherein
the fiducial provides positional information with respect to a
reference frame.
[0133] FIG. 3E depicts a therapy paradigm for the treatment and
assessment of hypertension.
[0134] FIG. 4A depicts the application of energy to the autonomic
nervous system surrounding the carotid arteries.
[0135] FIG. 4B depicts the application of energy to through the
vessels of the renal hilum.
[0136] FIGS. 5A-5B depict the application of focused energy to the
autonomic nervous system of the eye.
[0137] FIG. 5C depicts the application of energy to other autonomic
nervous system structures.
[0138] FIG. 6 depicts the application of constricting lesions to
the kidney deep inside the calyces of the kidney.
[0139] FIG. 7A depicts a patient in an imaging system receiving
treatment with focused energy waves.
[0140] FIG. 7B depicts visualization of a kidney being treated.
[0141] FIG. 7C depicts a close up view of the renal nerve region of
the kidney being treated.
[0142] FIG. 7D depicts an algorithmic method to treat the autonomic
nervous system using MRI and energy transducers.
[0143] FIG. 7E depicts a geometric model obtained from
cross-sectional images of the area of the aorta and kidneys along
with angles of approach to the blood vessels and the kidney.
[0144] FIG. 7F depicts a close up image of the region of
treatment.
[0145] FIG. 7G depicts the results of measurements from a series of
cross sectional image reconstructions.
[0146] FIG. 7H depicts the results of measurements from a series of
cross-sectional images from a patient in a more optimized
position.
[0147] FIG. 7I depicts an algorithmic methodology to apply
treatment to the hilum of the kidney and apply energy to the renal
blood vessels.
[0148] FIG. 7J depicts a clinical algorithm to apply energy to the
blood vessel leading to the kidney.
[0149] FIG. 7K depicts a device to diagnose proper directionality
to apply energy to the region of the kidney.
[0150] FIG. 7L depicts a methodology to ablate a nerve around an
artery by applying a cloud of heat or neurolytic substance.
[0151] FIG. 7M depicts a clinical algorithm to apply energy along a
renal blood vessel.
[0152] FIG. 7N depicts a cloud of heat to affect the nerves leading
to the kidney.
[0153] FIG. 7O depicts a close up of a heat cloud as well as nerves
leading to the kidney.
[0154] FIG. 8A depicts a percutaneous approach to treating the
autonomic nervous system surrounding the kidneys.
[0155] FIG. 8B depicts an intravascular approach to treating or
targeting the autonomic nervous system.
[0156] FIG. 8C depicts a percutaneous approach to the renal hila
using a CT scan and a probe to reach the renal blood vessels.
[0157] FIG. 8D depicts an intravascular detection technique to
characterize the interpath between the blood vessel and the
skin.
[0158] FIGS. 8E-8F depict cross sectional images with focused
energy traveling from a posterior direction.
[0159] FIGS. 9A-9C depicts the application of energy from inside
the aorta to regions outside the aorta to treat the autonomic
nervous system.
[0160] FIG. 10 depicts steps to treat a disease using HIFU while
monitoring progress of the treatment as well as motion.
[0161] FIG. 11A depicts treatment of brain pathology using cross
sectional imaging.
[0162] FIG. 11B depicts an image on a viewer showing therapy of the
region of the brain being treated.
[0163] FIG. 11C depicts another view of a brain lesion as might be
seen on an imaging device which assists in the treatment of the
lesion.
[0164] FIG. 12 depicts treatment of the renal nerve region using a
laparoscopic approach.
[0165] FIG. 13 depicts a methodology for destroying a region of
tissue using imaging markers to monitor treatment progress.
[0166] FIG. 14 depicts the partial treatment of portions of a nerve
bundle using converging imaging and therapy wave.
[0167] FIGS. 15A-15C depict the application of focused energy to
the vertebral column to treat various spinal pathologies including
therapy of the spinal or intravertebral nerves.
[0168] FIG. 16A depicts the types of lesions which are created
around the renal arteries to affect a response.
[0169] FIG. 16B depicts a simulation of ultrasound around a blood
vessel I support of FIG. 16A.
[0170] FIG. 16C depicts data from ultrasound energy applied to the
renal blood vessels and the resultant change in norepinephrine
levels.
[0171] FIGS. 16D-16H depict a simulation of multiple treatment
spots along a blood vessel.
[0172] FIGS. 16I-16K depict various treatment plans of focused
energy around a blood vessel.
[0173] FIGS. 16L-16M depict data indicating that focused energy
applied from the outside can affect sympathetic nerve supply to
organs.
[0174] FIG. 17A depicts the application of multiple transducers to
treat regions of the autonomic nervous system at the renal
hilum.
[0175] FIGS. 17B-17C depict methods for using imaging to direct
treatment of a specific region surrounding an artery as well as
display the predicted lesion morphology.
[0176] FIG. 17D depicts a method for localizing HIFU transducers
relative to Doppler ultrasound signals.
[0177] FIG. 17E depicts an arrangement of transducers relative to a
target.
[0178] FIG. 17F depicts ablation zones in a multi-focal region in
cross-section.
[0179] FIG. 18 depicts the application of energy internally within
the kidney to affect specific functional changes at the regional
level within the kidney.
[0180] FIG. 19A depicts the direction of energy wave propagation to
treat regions of the autonomic nervous system around the region of
the kidney hilum.
[0181] FIG. 19B depicts a schematic of a B mode ultrasound from a
direction determined through experimentation to provide access to
the renal hilum with HIFU.
[0182] FIGS. 19C-19D depict a setup for the treatment of the renal
blood vessels along with actual treatment of the renal blood
vessels.
[0183] FIG. 19E is a schematic algorithm of the treatment plan for
treatment shown in FIG. 19C-D.
[0184] FIG. 20 depicts the application of ultrasound waves through
the wall of the aorta to apply a therapy to the autonomic nervous
system.
[0185] FIG. 21A depicts application of focused energy to the
ciliary muscles and processes of the anterior region of the
eye.
[0186] FIG. 21B depicts the application of focused non-ablative
energy to the back of the eye to enhance drug or gene delivery or
another therapy such as ionizing radiation.
[0187] FIG. 22 depicts the application of focused energy to nerves
surrounding the knee joint to affect nerve function in the
joint.
[0188] FIGS. 23A-23B depict the application of energy to the
fallopian tube to sterilize a patient.
[0189] FIG. 24 depicts an algorithm to assess the effect of the
neural modulation procedure on the autonomic nervous system. After
a procedure is performed on the renal nerves, assessment of the
autonomic response is performed by, for example, simulating the
autonomic nervous system in one or more places.
[0190] FIG. 25 depicts an optimized position of a device to apply
therapy to internal nerves.
[0191] FIG. 26A depicts positioning of a patient to obtain
parameters for system design.
[0192] FIG. 26B depicts a device design based on the information
learned from feasibility studies.
[0193] FIG. 27 depicts a clinical paradigm for treating the renal
nerves of the autonomic nervous system based on feasibility
studies.
[0194] FIGS. 28A-28C depict a treatment positioning system for a
patient incorporating a focused ultrasound system.
[0195] FIGS. 28D-28I illustrate system configurations for a system
to treat nerves inside a patient using focused energy.
[0196] FIG. 28J is a depiction of an underlining for the patient
with partial or fully inflated elements.
[0197] FIG. 28K is a configuration of a system built into a table
for a patient.
[0198] FIGS. 29A-D depict results of studies applying focused
energy to nerves surrounding arteries and of ultrasound studies to
visualize the blood vessels around which the nerves travel.
[0199] FIG. 29E depicts the results of design processes in which
the angle, length, and surface area from CT scans is
quantified.
[0200] FIGS. 30A-30I depict results of simulations to apply focused
ultrasound to the region of a renal artery with a prototype device
design based on simulations.
[0201] FIG. 30J depicts an annular array customized to treat the
anatomy shown for the kidney and renal blood vessels above.
[0202] FIG. 30K highlights the annular array and depicts the
imaging component at the apex.
[0203] FIGS. 30L-N depict various cutouts for ultrasound imaging
probes.
[0204] FIGS. 30O-P depict projection from the proposed transducer
designs.
[0205] FIG. 30Q is a depiction of a focal zone created by the
therapeutic transducer(s) to focus a single region.
[0206] FIGS. 30R-30S depict a multi-element array in a pizza slice
shape yet with many square elements.
[0207] FIGS. 30T-30U depict simulations of the annular array
specific for the anatomy to be treated around a kidney of a
patient.
[0208] FIG. 30V depicts a housing for the custom array.
[0209] FIG. 30W depicts focusing of energy from the custom array
along a blood vessel.
[0210] FIG. 31A depicts an off center focus from an alternative
arrangement of the annular array transducer.
[0211] FIG. 31B depicts focusing of energy from an alternative
embodiment of the customized transducer array in the clinical
embodiment in which a catheter is placed within the patient.
[0212] FIG. 31C is a depiction of a movement mechanism within a
patient table.
[0213] FIG. 31D is an overall block diagram of the system
subsystems.
DETAILED DESCRIPTION
[0214] Hypertension is a disease of extreme national and
international importance. There are 80 million patients in the US
alone who have hypertension and over 200 million in developed
countries worldwide. In the United States, there are 60 million
patients who have uncontrolled hypertension, meaning that they are
either non-compliant or cannot take the medications because of the
side effect profile. Up to 10 million people might have completely
resistant hypertension in which they do not reach target levels no
matter what the medication regimen. The morbidities associated with
uncontrolled hypertension are profound, including stroke, heart
attack, kidney failure, peripheral arterial disease, etc. A
convenient and straightforward minimally invasive procedure to
treat hypertension would be a very welcome advance in the treatment
of this disease.
[0215] Congestive Heart Failure ("CHF") is a condition which occurs
when the heart becomes damaged and blood flow is reduced to the
organs of the body. If blood flow decreases sufficiently, kidney
function becomes altered, which results in fluid retention,
abnormal hormone secretions and increased constriction of blood
vessels. These results increase the workload of the heart and
further decrease the capacity of the heart to pump blood through
the kidneys and circulatory system.
[0216] It is believed that progressively decreasing perfusion of
the kidneys is a principal non-cardiac cause perpetuating the
downward spiral of CHF. For example, as the heart struggles to pump
blood, the cardiac output is maintained or decreased and the
kidneys conserve fluid and electrolytes to maintain the stroke
volume of the heart. The resulting increase in pressure further
overloads the cardiac muscle such that the cardiac muscle has to
work harder to pump against a higher pressure. The already damaged
cardiac muscle is then further stressed and damaged by the
increased pressure. Moreover, the fluid overload and associated
clinical symptoms resulting from these physiologic changes result
in additional hospital admissions, poor quality of life, and
additional costs to the health care system. In addition to
exacerbating heart failure, kidney failure can lead to a downward
spiral and further worsening kidney function. For example, in the
forward flow heart failure described above, (systolic heart
failure) the kidney becomes ischemic. In backward heart failure
(diastolic heart failure), the kidneys become congested vis-a-vis
renal vein hypertension. Therefore, the kidney can contribute to
its own worsening failure.
[0217] The functions of the kidneys can be summarized under three
broad categories: filtering blood and excreting waste products
generated by the body's metabolism; regulating salt, water,
electrolyte and acid-base balance; and secreting hormones to
maintain vital organ blood flow. Without properly functioning
kidneys, a patient will suffer water retention, reduced urine flow
and an accumulation of waste toxins in the blood and body. These
conditions result from reduced renal function or renal failure
(kidney failure) and are believed to increase the workload of the
heart. In a CHF patient, renal failure will cause the heart to
further deteriorate as fluids are retained and blood toxins
accumulate due to the poorly functioning kidneys. The resulting
hypertension also has dramatic influence on the progression of
cerebrovascular disease and stroke.
[0218] The autonomic nervous system is a network of nerves which
affect almost every organ and physiologic system to a variable
degree. Generally, the system is composed of sympathetic and
parasympathetic nerves. For example, the sympathetic nerves to the
kidney traverse the sympathetic chain along the spine and synapse
within the ganglia of the chain or within the celiac ganglia, then
proceeding to innervate the kidney via post-ganglionic fibers
inside the "renal nerves." Within the renal nerves, which travel
along the renal hila (artery and to some extent the vein), are the
post-ganglionic sympathetic nerves and the afferent nerves from the
kidney. The afferent nerves from the kidney travel within the
dorsal root (if they are pain fibers) and into the anterior root if
they are sensory fibers, then into the spinal cord and ultimately
to specialized regions of the brain. The afferent nerves,
baroreceptors and chemoreceptors, deliver information from the
kidneys back to the sympathetic nervous system via the brain; their
ablation or inhibition is at least partially responsible for the
improvement seen in blood pressure after renal nerve ablation, or
dennervation, or partial disruption. It has also been suggested and
partially proven experimentally that the baroreceptor response at
the level of the carotid sinus is mediated by the renal artery
afferent nerves such that loss of the renal artery afferent nerve
response blunts the response of the carotid baroreceptors to
changes in arterial blood pressure (American J. Physioogy and Renal
Physiology 279:F491-F501, 2000).
[0219] It has been established in animal models that the heart
failure condition results in abnormally high sympathetic activation
of the kidneys. An increase in renal sympathetic nerve activity
leads to decreased removal of water and sodium from the body, as
well as increased renin secretion which stimulates aldosterone
secretion from the adrenal gland. Increased renin secretion can
lead to an increase in angiotensin II levels which leads to
vasoconstriction of blood vessels supplying the kidneys as well as
systemic vasoconstriction, all of which lead to a decrease in renal
blood flow and hypertension. Reduction in sympathetic renal nerve
activity, e.g., via de-innervation, may reverse these processes and
in fact has been shown to in the clinic. Similarly, in obese
patients, the sympathetic drive is intrinsically very high and is
felt to be one of the causes of hypertension in obese patients.
[0220] Recent clinical work has shown that de-innervation of the
renal sympathetic chain and other nerves which enter the kidney
through the hilum can lead to profound systemic effects in patients
(rats, dogs, pig, sheep, humans) with hypertension, heart failure,
and other organ system diseases. Such treatment can lead to long
term reduction in the need for blood pressure medications and
improvements in blood pressure (O'Brien Lancet 2009 373; 9681). The
devices used in this trial were highly localized radiofrequency
(RF) ablation to ablate the renal artery adventitia with the
presumption that the nerves surrounding the renal artery are being
inhibited in the heating zone as well. The procedure is performed
in essentially a blind fashion in that the exact location of the
nerve plexus is not known prior to, during, or after the procedure.
In addition, the wall of the renal artery is invariably damaged by
the RF probe and patients whose vessels have a great deal of
atherosclerosis cannot be treated safely. In addition, depending on
the distance of the nerves from the vessel wall, the energy may not
consistently lead to ablation or interruption. Finally, the use of
internal catheters may not allow for treatment inside the kidney or
inside the aorta if more selective. In many cases, it is required
to create a spiral along the length and inside the blood vessel to
avoid circumferential damage to the vessel.
[0221] Cross-sectional imaging can be utilized to visualize the
internal anatomy of patients via radiation (CT) or magnetic fields
(MRI). Ultrasound can also be utilized to obtain cross-sections of
specific regions but only at high frequencies; therefore,
ultrasound is typically limited to imaging superficial body
regions. CT and MRI are often more amenable to cross sectional
imaging because the radiation penetrates well into tissues. In
addition, the scale of the body regions is maintained such that the
anatomy within the coordinate references remains intact relative to
one another; that is, distances between structures can be
measured.
[0222] With ultrasound, scaling can be more difficult because of
unequal penetration as the waves propagate deeper through the
tissue. CT scans and MRIs and even ultrasound devices can be
utilized to create three dimensional representations and
reconstructed cross-sectional images of patients; anatomy can be
placed in a coordinate reference frame using a three dimensional
representation. Once in the reference frame, energy devices
(transducers) can be placed in position and energy emitting devices
directed such that specific regions of the body are targeted. Once
knowledge of the transducer position is known relative to the
position of the target in the patient body, energy can be delivered
to the target.
[0223] Ultrasound is a cyclically generated sound pressure wave
with a frequency greater than the upper limit of human hearing . .
. 20 kilohertz (kHz). In medicine, ultrasound is widely utilized
because of its ability to penetrate tissues. Reflection of the
sound waves reveals a signature of the underlying tissues and as
such, ultrasound can be used extensively for diagnostics and
potentially therapeutics as well in the medical field. As a
therapy, ultrasound has the ability to both penetrate tissues and
can be focused to create ablation zones. Because of its
simultaneous ability to image, ultrasound can be utilized for
precise targeting of lesions inside the body. Ultrasound intensity
is measured by the power per cm.sup.2 (for example, W/cm.sup.2 at
the therapeutic target region). Generally, high intensity refers to
intensities over 0.1-5 kW/cm.sup.2. Low intensity ultrasound
encompasses the range up to 0.01-0.10 kW/cm.sup.2 from about 1 or
10 Watts per cm.sup.2.
[0224] Ultrasound can be utilized for its forward propagating waves
and resulting reflected waves or where energy deposition in the
tissue and either heating or slight disruption of the tissues is
desired. For example, rather than relying on reflections for
imaging, lower frequency ultrasonic beams (e.g. <1 MHz) can be
focused at a depth within tissue, creating a heating zone or a
defined region of cavitation in which micro-bubbles are created,
cell membranes are opened to admit bioactive molecules, or damage
is otherwise created in the tissue. These features of ultrasound
generally utilize frequencies in the 0.25 Megahertz (MHz) to 10 MHz
range depending on the depth required for effect. Focusing is, or
may be, required so that the surface of the tissue is not
excessively injured or heated by single beams. In other words, many
single beams can be propagated through the tissue at different
angles to decrease the energy deposition along any single path yet
allow the beams to converge at a focal spot deep within the tissue.
In addition, reflected beams from multiple angles may be utilized
in order to create a three dimensional representation of the region
to be treated in a coordinate space.
[0225] It is important when planning an ultrasound therapy that
sharp, discontinuous interfaces be avoided. For example, bowel,
lung, bone which contain air and/or bone interfaces constitute
sharp boundaries with soft tissues. These interfaces make the
planning and therapy more difficult. If however, the interfaces can
be avoided, then treatment can be greatly simplified versus what
has to be done for the brain (e.g. MR-guided HIFU) where complex
modeling is required to overcome the very high attenuation of the
cranium. Data provided below reveals a discovery through extensive
experimentation as to how to achieve this treatment simplicity for
treatment of specific structures such as nerves surrounding blood
vessels.
[0226] Time of flight measurements with ultrasound can be used to
range find, or find distances between objects in tissues. Such
measurements can be utilized to place objects such as vessels into
three dimensional coordinate reference frames so that energy can be
utilized to target the tissues. SONAR is the acronym for sound
navigation and ranging and is a method of acoustic localization.
Sound waves are transmitted through a medium and the time for the
sound to reflect back to the transmitter is indicative of the
position of the object of interest. Doppler signals are generated
by a moving object. The change in the forward and reflected wave
results in a velocity for the object.
[0227] The concept of speckle tracking is one in which the
reflections of specific tissues is defined and tracked over time
(IEEE Transactions on Ultrasonics, Ferroelectrics, AND Frequency
Control, Vol. 57, no. 4, April 2010). With defined points in space,
a three dimensional coordinate reference can be created through
which energy can be applied to specific and well-defined regions.
To track a speckle, an ultrasound image is obtained from a tissue.
Light and dark spots are defined in the image, these light and dark
spots representing inhomgeneities in the tissues. The
inhomegeneities are relatively constant, being essentially
properties of the tissue. With relatively constant markers in the
tissue, tracking can be accomplished using real time imaging of the
markers. With more than one plane of ultrasound, the markers can be
related in three dimensions relative to the ultrasound transducer
and a therapeutic energy delivered to a defined position within the
three dimensional field.
[0228] At the time one or more of these imaging modalities is
utilized to determine the position of the target in three
dimensions, then a therapy can be both planned and applied to a
specific region within the three dimensional volume.
[0229] Lithotripsy was introduced in the early part of the 1980's.
Lithotripsy utilizes shockwaves to treat stones in the kidney. The
Dornier lithotripsy system was the first system produced for this
purpose. The lithotripsy system sends ultrasonic waves through the
patient's body to the kidney to selectively heat and vibrate the
kidney stones; that is, selectively over the adjacent tissue. At
the present time, lithotripsy systems do not utilize direct
targeting and imaging of the kidney stone region. A tremendous
advance in the technology would be to image the stone region and
target the specific region in which the stone resides so as to
minimize damage to surrounding structures such as the kidney. In
the case of a kidney stone, the kidney is in fact the speckle,
allowing for three dimensional targeting and tracking off its image
with subsequent application of ultrasound waves to break up the
stone. In the embodiments which follow below, many of the
techniques and imaging results described can be applied to clinical
lithotripsy. For example, imaging of the stone region and tracking
of the stone region can lead to an improved targeting system for
breaking up kidney stones. Rather than wasting energy on regions
which don't contain stones and destroying healthy kidney, energy
can be concentrated on the portions of the kidney which contain the
stones.
[0230] Histotripsy is a term given to a technique in which tissue
is essentially vaporized using cavitation rather than heating
(transcutaneous non-thermal mechanical tissue fractionation). These
mini explosions do not require high temperature and can occur in
less than a second. The generated pressure wave is in the range of
megapascals (MPa) and even up to or exceeding 100 MPa. To treat
small regions of tissue very quickly, this technique can be very
effective. The border of the viable and non-viable tissue is
typically very sharp and the mechanism of action has been shown to
be cellular disruption.
[0231] In one embodiment, ultrasound is focused on the region of
the renal arteries and/or veins from outside the patient; the
ultrasound is delivered from multiple angles to the target, thereby
overcoming many of the deficiencies in previous methods and devices
put forward to ablate renal sympathetic nerves which surround the
renal arteries.
[0232] Specifically, one embodiment allows for precise
visualization of the ablation zone so that the operator can be
confident that the correct region is ablated and that the incorrect
region is not ablated. Because some embodiments do not require a
puncture in the skin, they are considerably less invasive, which is
more palatable and safer from the patient standpoint. Moreover,
unusual anatomies and atherosclerotic vessels can be treated using
external energy triangulated on the renal arteries to affect the
sympathetic and afferent nerves to and from the kidney
respectively.
[0233] With reference to FIG. 1A, the human renal anatomy includes
the kidneys 100 which are supplied with oxygenated blood by the
renal arteries 200 and are connected to the heart via the abdominal
aorta 300. Deoxygenated blood flows from the kidneys to the heart
via the renal veins (not shown) and thence the inferior vena cava
(not shown). The renal anatomy includes the cortex, the medulla,
and the hilum. Blood is delivered to the cortex where it filters
through the glomeruli and is then delivered to the medulla where it
is further filtered through a series of reabsorption and filtration
steps in the loops of henle and individual nephrons; the
ultrafiltrate then percolates to the ureteral collecting system and
is delivered to the ureters and bladder for ultimate excretion.
[0234] The hila is the region where the major vessels (renal artery
and renal vein) and nerves 150 (efferent sympathetic, afferent
sensory, and parasympathetic nerves) travel to and from the
kidneys. The renal nerves 150 contain post-ganglionic efferent
nerves which supply sympathetic innervation to the kidneys.
Afferent sensory nerves travel from the kidney to the central
nervous system and are postganglionic afferent nerves with nerve
bodies in the central nervous system. These nerves deliver sensory
information to the central nervous system and are thought to
regulate much of the sympathetic outflow from the central nervous
system to all organs including the skin, heart, kidneys, brain,
etc.
[0235] In one method, energy is delivered from outside a patient,
through the skin, and to the renal afferent and/or renal efferent
nerves. Microwave, light, vibratory (e.g. acoustic), ionizing
radiation might be utilized in some or many of the embodiments.
[0236] Energy transducers 500 (FIG. 1A) deliver energy
transcutaneously to the region of the sympathetic ganglia 520 or
the post-ganglionic renal nerves 150 or the nerves leading to the
adrenal gland 400. The energy is generated from outside the
patient, from multiple directions, and through the skin to the
region of the renal nerves 624 which surround the renal artery 620
or the sympathetic ganglion 622 which house the nerves. The energy
can be focused or non-focused but in one preferred embodiment, the
energy is focused with high intensity focused ultrasound (HIFU) or
low intensity focused ultrasound.
[0237] Focusing with low intensity focused ultrasound (LIFU) may
also occur intentionally as a component of the HIFU (penumbra
regions) or unintentionally. The mechanism of nerve inhibition is
variable depending on the "low" or "high" of focused ultrasound.
Low energy might include energy levels of 25 W/cm.sup.2-200
W/cm.sup.2. Higher intensity includes energy levels from 200
W/cm.sup.2 to 1 MW/cm.sup.2. Focusing occurs by delivering energy
from at least two different angles through the skin to meet at a
focal point where the highest energy intensity and density occurs.
At this spot, a therapy is delivered and the therapy can be
sub-threshold nerve interruption (partial ablation), ablation
(complete interruption) of the nerves, controlled interruption of
the nerve conduction apparatus, partial ablation, or targeted drug
delivery. The region can be heated to a temperature of less than 60
degrees Celsius for non-ablative therapy or can be heated greater
than 60 degrees Celsius for heat based destruction (ablation). To
ablate the nerves, even temperatures in the 40 degree Celsius range
can be used and if generated for a time period greater than several
minutes, will result in ablation. For temperatures at about 50
degrees Celsius, the time might be under one minute. Heating aside,
a vibratory effect for a much shorter period of time at
temperatures below 60 degrees Celsius can result in partial or
complete paralysis or destruction of the nerves. If the temperature
is increased beyond 50-60 degrees Celsius, the time required for
heating is decreased considerably to affect the nerve via the sole
mechanism of heating. In some embodiments, an imaging modality is
included as well in the system.
[0238] The imaging modality can be ultrasound based, MRI based, or
CT (X-Ray) based. The imaging modality can be utilized to target
the region of ablation and determined the distances to the
target.
[0239] The delivered energy can be ionizing or non-ionizing energy
in some embodiments. Forms of non-ionizing energy can include
electromagnetic energy such as a magnetic field, light, an electric
field, radiofrequency energy, and light based energy. Forms of
ionizing energy include x-ray, proton beam, gamma rays, electron
beams, and alpha rays. In some embodiments, the energy modalities
are combined. For example, heat ablation of the nerves is performed
and then ionizing radiation is delivered to the region to prevent
re-growth of the nerves.
[0240] Alternatively, ionizing radiation is applied first as an
ablation modality and then heat applied afterward in the case of
re-growth of the tissue as re-radiation may not be possible
(complement or multimodality energy utilization). Ionizing
radiation may prevent or inhibit the re-growth of the nervous
tissue around the vessel if there is indeed re-growth of the
nervous tissue. Therefore, another method of treating the nerves is
to first heat the nerves and then apply ionizing radiation to
prevent re-growth.
[0241] Other techniques such as photodynamic therapy including a
photosensitizer and light source to activate the photosensitizer
can be utilized as a manner to combine modalities. Most of these
photosensitizing agents are also sensitive to ultrasound energy
yielding the same photoreactive species as if it were activated by
light. A photoreactive or photosensitive agent can be introduced
into the target area prior to the apparatus being introduced into
the blood vessel; for example, through an intravenous injection, a
subcutaneous injection, etc. However, it will be understood that if
desired, the apparatus can optionally include a lumen for
delivering a photoreactive agent into the target area. The
resulting embodiments are likely to be particularly beneficial
where uptake of the photoreactive agent into the target tissues is
relatively rapid, so that the apparatus does not need to remain in
the blood vessel for an extended period of time while the
photoreactive agent is distributed into and absorbed by the target
tissue.
[0242] Light source arrays can include light sources that provide
more than one wavelength or waveband of light. Linear light source
arrays are particularly useful to treat elongate portions of
tissue. Light source arrays can also include reflective elements to
enhance the transmission of light in a preferred direction. For
example, devices can beneficially include expandable members such
as inflatable balloons to occlude blood flow (which can interfere
with the transmission of light from the light source to the
intended target tissue) and to enable the apparatus to be centered
in a blood vessel. Another preferred embodiment contemplates a
transcutaneous PDT method where the photosensitizing agent delivery
system comprises a liposome delivery system consisting essentially
of the photosensitizing agent. Light sources may be directed at a
focus from within a blood vessel to a position outside a blood
vessel. Infrared, Red, Blue, Green, and ultraviolet light may be
used from within a blood vessel to affect nervous tissue outside
the blood vessel. Light emitting diodes may be introduced via
catheter to the vein, the artery, the aorta, etc. After
introduction of the photoreactive agent (e.g. via intravenous,
subcutaneous, transarterial, transvenous injection), the light is
applied through the blood vessel wall in a cloud of energy which
activates the photoreactive agents.
[0243] Yet another embodiment is drawn to a method for
transcutaneous ultrasonic therapy of a target lesion in a mammalian
subject utilizing a sensitizer agent. In this embodiment, the
biochemical compound is activated by ultrasound through the
following method:
[0244] 1) administering to the subject a therapeutically effective
amount of an ultrasonic sensitizing agent or a ultrasonic
sensitizing agent delivery system or a prodrug, where the
ultrasonic sensitizing agent or ultrasonic sensitizing agent
delivery system or prodrug selectively binds to the thick or thin
neointimas, nerve cells, nerve sheaths, nerve nuclei, arterial
plaques, vascular smooth muscle cells and/or the abnormal
extracellular matrix of the site to be treated. Nerve components
can also be targeted, for example, the nerve sheath, myelin, S-100
protein. This step is followed by irradiating at least a portion of
the subject with ultrasonic energy at a frequency that activates
the ultrasonic sensitizing agent or if a prodrug, by a prodrug
product thereof, where the ultrasonic energy is provided by an
ultrasonic energy emitting source. This embodiment further
provides, optionally, that the ultrasonic therapy drug is cleared
from non-target tissues of the subject prior to irradiation.
[0245] A preferred embodiment contemplates a method for
transcutaneous ultrasonic therapy of a target tissue, where the
target tissue is close to a blood vessel. Other preferred
embodiments contemplate that the ultrasonic energy emitting source
is external to the patient's intact skin layer or is inserted
underneath the patient's intact skin layer, but is external to the
blood vessel to be treated. An additional preferred embodiment
provides that the ultrasonic sensitizing agent is conjugated to a
ligand and more preferably, where the ligand is selected from the
group consisting of: a target lesion specific antibody; a target
lesion specific peptide and a target lesion specific polymer. Other
preferred embodiments contemplate that the ultrasonic sensitizing
agent is selected from the group consisting of: indocyanine green
(ICG); methylene blue; toluidine blue; aminolevulinic acid (ALA);
chlorin compounds; phthalocyanines; porphyrins; purpurins;
texaphyrins; and any other agent that absorbs light in a range of
500 nm-1100 nm. A preferred embodiment contemplates that the
photosensitizing agent is indocyanine green (ICG).
[0246] Other embodiments are drawn to the presently disclosed
methods of transcutaneous PDT, where the light source is positioned
in proximity to the target tissue of the subject and is selected
from the group consisting of: an LED light source; an
electroluminesent light source; an incandescent light source; a
cold cathode fluorescent light source; organic polymer light
source; and inorganic light source. A preferred embodiment includes
the use of an LED light source.
[0247] Yet other embodiments of the presently disclosed methods are
drawn to use of light of a wavelength that is from about 500 nm to
about 1100 nm, preferably greater than about 650 nm and more
preferably greater than about 700 nm. A preferable embodiment of
the present method is drawn to the use of light that results in a
single photon absorption mode by the photosensitizing agent.
[0248] Additional embodiments include compositions of
photosensitizer targeted delivery system comprising: a
photosensitizing agent and a ligand that binds a receptor on the
target tissue with specificity. Preferably, the photosensitizing
agent of the targeted delivery system is conjugated to the ligand
that binds a receptor on the target (nerve or adventitial wall of
blood vessel) with specificity. More preferably, the ligand
comprises an antibody that binds to a receptor. Most preferably,
the receptor is an antigen on thick or thin neointimas, intimas,
adventitia of arteries, arterial plaques, vascular smooth muscle
cells and/or the extracellular matrix of the site to be
treated.
[0249] A further preferred embodiment contemplates that the
photosensitizing agent is selected from the group consisting of:
indocyanine green (ICG); methylene blue; toluidine blue;
aminolevulinic acid (ALA); chlorin compounds; phthalocyanines;
porphyrins; purpurins; texaphyrins; and any other agent that
absorbs light in a range of 500 nm-1100 nm.
[0250] Other photosensitizers that may be used with embodiments
described herein are known in the art, including, Photofrin.RTM.,
synthetic diporphyrins and dichlorins, phthalocyanines with or
without metal substituents, chloroaluminum phthalocyanine with or
without varying substituents, chloroaluminum sulfonated
phthalocyanine, O-substituted tetraphenyl porphyrins, 3,1-meso
tetrakis(o-propionamido phenyl) porphyrin, verdins, purpurins, tin
and zinc derivatives of octaethylpurpurin, etiopurpurin,
hydroporphyrins, bacteriochlorins of the
tetra(hydroxyphenyl)porphyrin series, chlorins, chlorin e6,
mono-1-aspartyl derivative of chlorin e6, di-l-aspartyl derivative
of chlorin e6, tin(IV) chlorin e6, meta-tetrahydroxphenylchlorin,
benzoporphyrin derivatives, benzoporphyrin monoacid derivatives,
tetracyanoethylene adducts of benzoporphyrin, dimethyl
acetylenedicarboxylate adducts of benzoporphyrin, Diels-Adler
adducts, monoacid ring "a" derivative of benzoporphyrin, sulfonated
aluminum PC, sulfonated AlPc, disulfonated, tetrasulfonated
derivative, sulfonated aluminum naphthalocyanines,
naphthalocyanines with or without metal substituents and with or
without varying substituents, zinc naphthalocyanine,
anthracenediones, anthrapyrazoles, aminoanthraquinone, phenoxazine
dyes, phenothiazine derivatives, chalcogenapyrylium dyes, cationic
selena and tellurapyrylium derivatives, ring-substituted cationic
PC, pheophorbide derivative, pheophorbide alpha and ether or ester
derivatives, pyropheophorbides and ether or ester derivatives,
naturally occurring porphyrins, hematoporphyrin, hematoporphyrin
derivatives, hematoporphyrin esters or ethers, protoporphyrin,
ALA-induced protoporphyrin IX, endogenous metabolic precursors,
5-aminolevulinic acid benzonaphthoporphyrazines, cationic imminium
salts, tetracyclines, lutetium texaphyrin, tin-etiopurpurin,
porphycenes, benzophenothiazinium, pentaphyrins, texaphyrins and
hexaphyrins, 5-amino levulinic acid, hypericin, pseudohypericin,
hypocrellin, terthiophenes, azaporphyrins, azachlorins, rose
bengal, phloxine B, erythrosine, iodinated or brominated
derivatives of fluorescein, merocyanines, nile blue derivatives,
pheophytin and chlorophyll derivatives, bacteriochlorin and
bacteriochlorophyll derivatives, porphocyanines, benzochlorins and
oxobenzochlorins, sapphyrins, oxasapphyrins, cercosporins and
related fungal metabolites and combinations thereof.
[0251] Several photosensitizers known in the art are FDA approved
and commercially available. In a preferred embodiment, the
photosensitizer is a benzoporphyrin derivative ("BPD"), such as
BPD-MA, also commercially known as BPD Verteporfin or "BPD"
(available from QLT). U.S. Pat. No. 4,883,790 describes BPD
compositions. BPD is a second-generation compound, which lacks the
prolonged cutaneous phototoxicity of Photofrin.RTM. (Levy (1994)
Semin Oncol 21: 4-10). BPD has been thoroughly characterized
(Richter et al., (1987) JNCI 79:1327-1331), (Aveline et al. (1994)
Photochem Photobiol 59:328-35), and it has been found to be a
highly potent photosensitizer for PDT.
[0252] In a preferred embodiment, the photosensitizer is tin ethyl
etiopurpurin, commercially known as purlytin (available from
Miravant).
[0253] In some embodiments, external neuromodulation is performed
in which low energy ultrasound is applied to the nerve region to
modulate the nerves. For example, it has been shown in the past
that low intensity (e.g. non-thermal) ultrasound can affect nerves
at powers which range from 30-500 W/Cm.sup.2 whereas HIFU (thermal
modulation), which by definition generates heat at a focus point,
requires power levels exceeding 1000 W/Cm.sup.2. The actual power
flux to the region to be ablated is dependent on the environment
including surrounding blood flow and other structures. With low
intensity ultrasound, the energy does not have to be so strictly
focused to the target because it's a non-ablative energy; that is,
the vibration or mechanical pressure may be the effector energy and
the target may have a different threshold for effect depending on
the tissue. However, even low energy ultrasound may require
focusing if excessive heat to the skin is a worry or if there are
other susceptible structures in the path and only a pinpoint region
of therapy is desired. Nonetheless, transducers 500 in FIG. 1a
provide the ability to apply a range of different energy and power
levels as well as modeling capability to target different regions
and predict the response.
[0254] In FIG. 1a, and in one embodiment, a renal artery 640 is
detected with the assistance of imaging devices 600 such as Doppler
ultrasound, infrared imaging, thermal imaging, B-mode ultrasound,
MRI, or a CT scan. With an image of the region to be treated,
measurements in multiple directions on a series of slices can be
performed so as to create a three-dimensional representation of the
area of interest. By detecting the position of the renal arteries
from more than one angle via Doppler triangulation (for example) or
another triangulation technique, a three dimensional positional map
can be created and the renal artery can be mapped into a coordinate
reference frame. In this respect, given that the renal nerves
surround the renal blood vessels in the hilum, locating the
direction and lengths of the blood vessels in three dimensional
coordinate reference is the predominant component of the procedure
to target these sympathetic nerves. Within the three dimensional
reference frame, a pattern of energy can be applied to the vicinity
of the renal artery from a device well outside the vicinity (and
outside of the patient altogether) based on knowledge of the
coordinate reference frame.
[0255] For example, once the renal artery is placed in the
coordinate reference frame with the origin of the energy delivery
device, an algorithm is utilized to localize the delivery of
focused ultrasound to heat or apply mechanical energy to the
adventitia and surrounding regions of the artery which contain
sympathetic nerves to the kidney and afferent nerves from the
kidney, thereby decreasing the sympathetic stimulus to the kidney
and decreasing its afferent signaling back to the autonomic nervous
system; affecting these targets will modulate the propensity toward
hypertension which would otherwise occur. The ultrasonic energy
delivery can be modeled mathematically by predicting the acoustic
wave dissipation using the distances and measurements taken with
the imaging modalities of the tissues and path lengths.
Furthermore, a system such as acoustic time of flight can be
utilized to quantitatively determine the distance from a position
on the therapeutic transducer to the region of the blood vessel to
the kidney. Such a system allows for detection of a distance using
an ultrasound pulse. The distance obtained as such is then utilized
for the therapeutic ultrasound treatment because the tissues and
structures which are interrogated are the same ones through which
the therapeutic ultrasound will travel, thereby allowing
essentially auto-calibration of the therapeutic ultrasound
pulse.
[0256] For example, FIG. 1D depicts a system with an integral
catheter 652 and one or more transducers 654 on the catheter.
Electrical impulses are sent from a generator 653 to the catheter
652 and to the transducers 654 which may be piezoelectric crystals.
Detectors 650 detect the distance 656 from the piezoelectric
transducers as well as the 3-dimensional orientation and exact
position of the transducers 654. With positional information in
three dimensional space, focused ultrasound transducer 662 can be
directed toward the target under the direction of motion
controllers/transducer(s) 660. In some embodiments, a single
transducer (internal) is detected. In other embodiments, multiple
transducers 654 are detected. In the embodiment in which multiple
transducers are utilized, more detail around the three dimensional
position and orientation of the vessel is available allowing for a
redundant approach to position detection. In either case, by
pulling back the catheter within the blood vessel while applying
electrical signals to the piezoelectric crystal so that they may be
detected outside the patient, the three dimensional anatomy of the
vessel can be mapped and determined quantitatively so that
treatment can be applied at an exact location along the blood
vessel. In this method, a guidewire is placed at the site of
treatment and then moved to different positions close to the
treatment site (e.g. within a blood vessel). During the movement
along the blood vessel, the detectors outside the patient are
mapping the movement and the region of treatment. The map of the
blood vessel (for example) is then used to perform the treatment in
the exact region planned with a high degree of accuracy due to the
mapping of the region. Signal generator 653 may create signals with
frequencies ranging from 0.5 MHz up to 3 MHz (or any frequency
value in this range), or even a wider range of frequencies to
ensure detection of the orientation.
[0257] In one embodiment of an algorithm, the Doppler signal from
the artery is identified from at least two different directions and
the direction of the artery is reconstructed in three dimensional
space. In this example, acoustic time of flight may be utilized via
the Doppler ultrasound of the flow signal, or via a piezoelectric
transducer (internal) and receiver (external) 650 set up. With two
points in space, a line is created and with knowledge of the
thickness of the vessel, a tube, or cylinder, can be created to
represent the blood vessel as a virtual model. The tube is
represented in three dimensional space over time and its
coordinates are known relative to the therapeutic transducers
outside of the skin of the patient. Therapeutic energy can be
applied from more than one direction as well and can focus on the
cylinder (blood anterior vessel wall, central axis, or posterior
wall). With a third point, the position of the target can be
precisely localized in the 3D space and targeted with a HIFU
transducer 660. Position detection algorithm 666 can be utilized to
compare the baseline position of the catheter to a position after a
period of time so as to detect respiratory and patient movement. In
one embodiment, the therapeutic HIFU array 662 is also used to send
a signal out for imaging (diagnostic pulse). For example, any
number of elements can be activated from the HIFU array to deposit
energy into the tissue. Such energy deposition can be advantageous
because it is by definition focused on the region 664 that will
ultimately be treated. In this respect, the exact region of
treatment can be interrogated with the focused ultrasound pulse
from the therapeutic array 662. Parameters in addition to imagining
include Doppler flow, tissue elastography, stress strain curves,
ultrasound spectroscopy, and targeting of therapeutics to the
region. The therapeutic array 662 can be utilized as a receiver for
the diagnostic signal or a separate detector can be utilized as the
receiver. In some embodiments, the catheter may be adapted to
deliver pharmaceuticals to the region as well as to assist in beam
focusing. A Doppler targeting algorithm may complement the catheter
652 based targeting. Power supply is configured to apply the proper
power to the HIFU transducer to treat a blood vessel deep within a
patient. For example, the power input into the HIFU transducer
might be 150 W, 200 W, 500 W 750 W, or 1000 W to achieve output
suitable for deep treatment in a patient. Pulsing frequency may be
as fast as 10 Hz or even 1 KHz. The piezoelectric signal may be
detected from more than one direction outside the body of the
patient. One or more modes of ultrasound may be utilized and
detected from different directions outside the skin of the patient.
Very large impulses may be generated in the first few microseconds
of the piezoelectric impulse delivery. For example, in some
embodiments, 8 W/Cm2 may be generated for a few microseconds and
then the voltage may be quickly decreased to zero until the next
cycle (<1% duty cycle).
[0258] Focused energy (e.g. ultrasound) can be applied to the
center of the vessel (within the flow), on the posterior wall of
the vessel, in between (e.g. when there is a back to back artery
and vein next to one another) the artery vessel and a venous
vessel, etc. Mover 660 directs the ultrasound focus based on
position 666 of the catheter 652 relative to the ultrasound array
660. In some embodiments, a Doppler signal 670 is used
with/combined in the system.
[0259] Imaging 600 (FIG. 1C) of the sympathetic nerves or the
sympathetic region (the target) is also utilized so as to assess
the direction and orientation of the transducers relative to the
target 620; the target is an internal fiducial, which in one
embodiment is the kidney 610 and associated renal artery 620
because they can be localized via their blood flow, a model then
produced around it, and then they both can be used as a target for
the energy. Continuous feedback of the position of the transducers
500, 510 relative to the target 620 is provided by the imaging
system, wherein the position may be in the coordinate space of the
imaging system, for example. The imaging may be a cross-sectional
imaging technology such as CT or MRI or it may be an ultrasound
imaging technology which yields faster real time imaging. In some
embodiments, the imaging may be a combination of technologies such
as the fusion of MRI/CT and ultrasound. The imaging system can
detect the position of the target in real time at frequencies
ranging from 1 Hz to thousands and tens of thousands of images per
second.
[0260] In the example of fusion, cross-sectional imaging (e.g.
MRI/CT) is utilized to place the body of the patient in a three
dimensional coordinate frame and then ultrasound is linked to the
three dimensional reference frame and utilized to track the
patient's body in real time under the ultrasound linked to the
cross-sectional imaging. The lack of resolution provided by the
ultrasound is made up for by the cross-sectional imaging since only
a few consistent anatomic landmarks are required for an ultrasound
image to be linked to the MRI image. As the body moves under the
ultrasound, the progressively new ultrasound images are linked to
the MRI images and therefore MRI "movement" can be seen at a
frequency not otherwise available to an MRI series.
[0261] In one embodiment, ultrasound is the energy used to inhibit
nerve conduction in the sympathetic nerves. In one embodiment,
focused ultrasound (HIFU) from outside the body through the skin is
the energy used to inhibit sympathetic stimulation of the kidney by
delivering waves from a position external to the body of a patient
and focusing the waves on the sympathetic nerves on the inside of
the patient and which surround the renal artery of the patient. MRI
may be used to visualize the region of treatment either before,
during, or after application of the ultrasound. MRI may also be
used to heat a targeting catheter in the region of the sympathetic
nerves. For example, a ferromagnetic element on the tip of a
catheter will absorb energy in the presence of a magnetic field and
heat itself, thereby enabling heat to be applied to the nerves
surrounding the blood vessels leading to the kidney.
[0262] FIG. 1E depicts an overview of the software subsystems 675
to deliver a safe treatment to a patient. An executive control
system 677 contains an operating system, a recording of the system
functions, a network connection, and other diagnostic equipment.
Communication with treatment dosimetry plan 681 may be accomplished
via modeling and previously obtained empirical data. The software
within the dosimetry plan allows for further communication with the
acoustic time of flight transducer (ATOF) 679 and the motion
controller for the diagnostic and therapeutic arrays. Target
localization based on acoustic time of flight (ATOF) can provide
accurate and robust position sensing of target location relative to
the therapeutic ultrasound transducer. Direct X, Y and Z (i.e.
three-dimensional) coordinate locations of the target can be
provided without the need for image interpretation.
Three-dimensional targeting information facilitates the use of an
explicit user interface to guide operator actions. ATOF is less
sensitive to variations in patient anatomy as compared to imaging
techniques. ATOF can be accomplished with a relatively simple and
inexpensive system compared to the complex imaging systems used by
alternate techniques. In some embodiments, continuous tracking of
the target in the presence of movement between the target and the
external transducer may be provided. In some embodiments, ATOF
allows use of system architectures that utilize a larger fraction
of the patient contact area to generate therapeutic power (as
contrasted with imaging based alternatives which occupy some space
within the therapeutic transducer for diagnostic power)--thus
reducing the power density applied to the patient's skin.
[0263] As is depicted in FIG. 3a-b, transducers 900 can emit
ultrasound energy from a position outside the patient to the region
of the renal sympathetic nerves at the renal pedicle 200. As shown
in FIG. 1a, an image of the renal artery 620 using an ultrasound,
MRI, or CT scan can be utilized to determine the position of the
kidney 610 and the renal artery 620 target. Doppler ultrasound can
be used to determine the location and direction of a Doppler signal
from an artery and place the vessel into a three dimensional
reference frame 950, thereby enabling the arteries 200 and hence
the sympathetic nerves 220 (FIG. 3a) around the artery to be much
more visible so as to process the images and then utilize focused
external energy to pinpoint the location and therapy of the
sympathetic nerves. In this embodiment, ultrasound is likely the
most appropriate imaging modality. Ultrasound can refer to simple
single dimensional pulse echos, or devices which scan a region and
integrate pulse echos into an image (termed B-mode).
[0264] FIG. 1A also depicts the delivery of focused energy to the
sympathetic nerve trunks and ganglia 622 which run along the
vertebral column and aorta 300; the renal artery efferent nerves
travel in these trunks and synapse to ganglia within the trunks. In
another embodiment, ablation of the dorsal and ventral roots at the
level of the ganglia or dorsal root nerves at T9-T11 (through which
the afferent renal nerves travel) would produce the same or similar
effect to ablation at the level of the renal arteries.
[0265] In another embodiment, FIG. 1B illustrates the application
of ionizing energy to the region of the sympathetic nerves on the
renal arteries 620 and/or renal veins. In general, energy levels of
greater than 20 Gy (Gray) are required for linear accelerators or
low energy x-ray machines to ablate nervous tissue using ionizing
energy; however, lower energy is required to stun, inhibit nervous
tissue, or prevent re-growth of nervous tissue; in some embodiment,
ionizing energy levels as low as 2-5 Gy or 5-10 Gy or 10-15 Gy are
delivered in a single or fractionated doses. Ionizing energy can be
applied using an orthovoltage X-ray generator, a linear
accelerator, brachytherapy, and/or an intravascular X-ray radiator
which delivers electronic brachytherapy. X-rays such as from a
linear accelerator or from an orthovoltage x-ray generator can be
delivered through the skin from multiple directions to target
nerves surrounding a blood vessel. In one example, the blood vessel
might be a renal artery or renal vein with nerves running around
it. By targeting the blood vessel, ionizing energy can be applied
to the nerves surrounding the blood vessel. Ultrasound, Doppler
imaging, angiograms, fluoroscopy, CT scans, thermography imaging,
and MRIs can be utilized to direct the ionizing energy.
[0266] Combinations of ionizing energy and other forms of energy
can be utilized in this embodiment as well so as to prevent
re-growth of the nervous tissue. For example, a combination of heat
and/or vibration and/or cavitation and/or ionizing radiation might
be utilized to prevent re-growth of nervous tissue after the
partial or full ablation of the nervous tissue surrounding the
renal artery. Combinations of pharmaceutical agents can be combined
with one another or with device and physical means to prevent or
initially inhibit nerve tissue and/or regrowth of nerve tissue.
[0267] FIG. 2 illustrates the renal anatomy and surrounding anatomy
with greater detail in that organs such as the stomach 700 are
shown in its anatomic position overlying the abdominal aorta 705
and renal arteries 715. In this embodiment, energy is delivered
through the stomach to reach an area behind the stomach. In this
embodiment, the stomach is utilized as a conduit to access the
celiac ganglion 710, a region which would otherwise be difficult to
reach. The aorta 705 is shown underneath the stomach and the celiac
ganglion 710 is depicted surrounding the superior mesenteric artery
and aorta. A transorally placed tube 720 is placed through the
esophagus and into the stomach. The tube overlies the celiac
ganglion when placed in the stomach and can therefore be used to
deliver sympatholytic devices or pharmaceuticals which inhibit or
stimulate the autonomic celiac ganglia behind the stomach; these
therapies would be delivered via transabdominal ultrasound or
fluoroscopic guidance (for imaging) through the stomach. Similar
therapies can be delivered to the inferior mesenteric ganglion,
renal nerves, or sympathetic nerves traveling along the aorta
through the stomach or other portion of the gastrointestinal tract.
The energy delivery transducers 730 are depicted external to the
patient and can be utilized to augment the therapy being delivered
through the stomach to the celiac ganglion. Alternatively, the
energy delivery transducers can be utilized for imaging the region
of therapy. For example, an ultrasound transducer can be utilized
to image the aorta and celiac ganglion and subsequently to apply
ultrasound energy to the region to inhibit the nerves in the
region. In some cases, ablation is utilized and in other cases,
vibration is utilized to inhibit the nerves from functioning.
[0268] In one embodiment, energy is applied to the region of the
celiac ganglion from a region outside the patient. In this
embodiment, fluid is placed into the gastrointestinal system, such
as for example, in the stomach or small intestine. Ultrasound can
then be transmitted through the gastrointestinal organs to the
ganglia of interest behind the stomach.
[0269] Temporary neurostimulators can also be placed through the
tube placed into the esophagus and into the stomach, such as, for
example, in an ICU setting where temporary blockage of the
autonomic ganglia may be required. Temporary neurostimulators can
be used to over pace the celiac ganglion nerve fibers and inhibit
their function as a nerve synapse. Inhibition of the celiac
ganglion may achieve a similar function as ablation or modulation
of the sympathetic nerves around the renal arteries. That is, the
decrease in the sympathetic activity to the kidneys (now obtained
with a more proximal inhibition) leads to the lowering of blood
pressure in the patient by decreasing the degree of sympathetic
outflow from the sympathetic nerve terminals. In the celiac
ganglia, the blood pressure lowering effect is more profound given
that the celiac ganglia are pre-ganglionic and have more nerve
fibers to a greater number of regions than each renal nerve. The
effect is also likely more permanent than the effect on the
post-ganglionic nerve fibers.
[0270] FIG. 3A illustrates the renal anatomy more specifically in
that the renal nerves 220 extending longitudinally along the renal
artery 200, are located generally within, or just outside the
adventitia, of the outer portion of the artery. Arteries are
typically composed of three layers: the first is the intimal, the
second is the media, and the third is the adventitia. The outer
layer, the adventitia, is a fibrous tissue which contains blood
vessels and nerves. The renal nerves are generally postganglionic
sympathetic nerves although there are some ganglia which exist
distal to the takeoff from the aorta such that some of the nerve
fibers along the renal artery are in fact pre-ganglionic. By the
time the fibers reach the kidney, the majority of the fibers are
post-ganglionic. The afferent nerves on the other hand leave the
kidney and are post-ganglionic up to the level of the brain. These
fibers do not re-grow as quickly as the efferent fibers, if at
all.
[0271] Energy generators 900 deliver energy to the renal nerves
accompanying the renal artery, depositing energy from multiple
directions to target inhibition of the renal nerve complex. The
energy generators can deliver ultrasound energy, ionizing
radiation, light (photon) therapy, or microwave energy to the
region. The energy can be non-focused in the case where a
pharmaceutical agent is targeted to the region to be ablated or
modulated. Preferably, however, the energy is focused, being
applied from multiple angles from outside the body of the patient
to reach the region of interest (e.g. sympathetic nerves
surrounding blood vessels). The energy transducers 900 are placed
in an X-Y-Z coordinate reference frame 950, as are the organs such
as the kidneys. The x-y-z coordinate frame is a real space
coordinate frame. For example, real space means that the coordinate
reference is identifiable in the physical world; like a GPS (global
positioning system), with the physical coordinates, a physical
object can be located. Once in the x-y-z coordinate reference
frame, cross-sectional imaging using MRI, CT scan, and/or
ultrasound is utilized to couple the internal anatomy to the energy
transducers. These same transducers may be utilized for the
determination of the reference point as well as the therapy. The
transducers 900 in this embodiment are focused on the region of the
renal nerves at the level of the renal blood vessels, the arteries
and veins 200. The focus of the beams can be inside the artery,
inside the vein, on the adventitia of the artery or adventitia of
the vein.
[0272] When applying ultrasonic energy across the skin to the renal
artery region, energy densities of potentially over 1 MW/cm.sup.2
might be required at region of interest in the adventitia of the
blood vessel. Typically, however, power densities of 100 W/cm.sup.2
to 3 kW/cm.sup.2 would be expected to create the heating required
to inhibit these nerves (see Foley et. al. Image-Guided HIFU
Neurolysis of Peripheral Nerves To Treat Spasticity And Pain;
Ultrasound in Med & Biol. Vol 30 (9) p 1199-1207). The energy
may be pulsed across the skin in an unfocused manner; however, for
application of heat, the transducers must be focused otherwise the
skin and underlying tissues will receive too much heat. Under
imaging with MRI, temperature can be measured with the MRI image.
When low energy ultrasound is applied to the region, energy (power)
densities in the range of 50 mW/cm.sup.2 to 500 mW/cm.sup.2 may be
applied. Low energy ultrasound may be enough to stun or partially
inhibit the renal nerves particularly when pulsed and depending on
the desired clinical result. High intensity ultrasound applied to
the region with only a few degrees of temperature rise may have the
same effect and this energy range may be in the 0.1 kW/cm2 to the
500 kW/cm2 range. A train of pulses also might be utilized to
augment the effect on nervous tissue. For example, a train of 100
short pulses, each less than a second and applying energy densities
of 1 W/cm.sup.2 to 500 W/cm.sup.2. In some of the embodiments,
cooling may be applied to the skin if the temperature rise is
deemed too large to be acceptable. In some embodiments, infrared
thermography is utilized to determine the temperature of the skin
and subcutaneous tissues, or if detected from deeper within, from
the kidneys and even renal blood vessels themselves. Alternatively,
the ultrasound transducers can be pulsed or can be alternated with
another set of transducers to effectively spread the heat across
the surface of the skin. In some embodiments, the energy is
delivered in a pulsed fashion to further decrease the risk to the
intervening tissues between the target and the transducer. The
pulses can be as close as millisecond, as described, or as long as
hours, days or years.
[0273] In one method of altering the physiologic process of renal
sympathetic excitation, the region around the renal arteries is
imaged using CT scan, MRI, thermography, infrared imaging, optical
coherence tomography (OCT), photoacoustic imaging, pet imaging,
SPECT imaging, or ultrasound, and the images are placed into a
three dimensional coordinate reference frame 950. The coordinate
reference frame 950 refers to the knowledge of the relationship
between anatomic structures, both two dimensional and three
dimensional, the structures placed into a physical coordinate
reference. Imaging devices determine the coordinate frame. Once the
coordinate frame is established, the imaging and therapy
transducers 900 can be coupled such that the information from the
imaging system is utilized by the therapeutic transducers to
position the energy. Blood vessels may provide a useful reference
frame for deposition of energy as they have a unique imaging
signature. An ultrasound pulse echo can provide a Doppler shift
signature to identify the blood vessel from the surrounding tissue.
In an MRI, CT scan, and even an ultrasound exam, intravenous
contrast agents can be utilized to identify flow patterns useful to
determine a coordinate reference for energy deposition. Energy
transducers 900 which can deliver ultrasound, light, radiation,
ionizing radiation, or microwave energy are placed in the same
three-dimensional reference frame as the renal arteries, at which
time a processor (e.g. using an algorithm) can determine how to
direct the transducers to deliver energy to the region 220 of the
nerves 910. The algorithm consists of a targeting feature (planning
feature) which allows for prediction of the position and energy
deposition of the energy leaving the transducers 900. Once the
three dimensional coordinate reference frames 950 are linked or
coupled, the planning and prediction algorithm can be used to
precisely position the energy beams at a target in the body.
[0274] The original imaging modality can be utilized to locate the
renal sympathetic region, and/or can be used to track the motion of
the region during treatment. For example, the imaging technology
used at time zero is taken as the baseline scan and subsequent
scans at time t1 are compared to the baseline scan, t0 (start). The
frequency of updates can range from a single scan every few seconds
to many scans per second. With ultrasound as the imaging
technology, the location might be updated at a frame rate greater
than 50 Hz and up to several hundred Hz or thousand Hz. With MRI as
the imaging modality, the imaging refresh rate might be closer to
30 Hz. In other embodiments, internally placed fiducials transmit
positional information at a high frequency and this information is
utilized to fuse the target with an initial external imaging
apparatus. Internal fiducials might include one or more imageable
elements including doppler signals, regions of blood vessels, ribs,
kidneys, and blood vessels and organs other than the target (e.g.
vena cava, adrenal gland, ureter). These fiducials can be used to
track the region being treated and/or to triangulate to the region
to be treated. The fiducials can be placed externally to an
internal position or might be intrinsic fiducials such as anatomic
features and/or imageable features.
[0275] In some embodiments (FIG. 3C), a temporary fiducial 960 is
placed in the region, such as in the artery 965, renal vein 975,
aorta 945, and/or vena cava 985; such a fiducial is easily
imageable from outside the patient. In one embodiment, the
temporary fiducial may enhance imaging such as a balloon fillable
with gas or bubbles. In another embodiment, the temporary fiducial
may be a material imageable via MRI or ultrasound.
[0276] FIG. 3D depicts an imageable transducer 960 in a blood
vessel 967 within a coordinate reference 975 on a monitor system
950. Alternatively, the temporary fiducial 960 is a transducer
which further improves the ability to image and track the region to
deliver therapy. The transducer may be a piezoelectric crystal
which is stimulated to emit energy which can be detected by one or
more detectors to determine a three dimensional position. The
transducer may release radiofrequency energy which can be detected
by one or more detectors to pinpoint a three dimensional position.
The transducer may emit an audible sound or an optical signal. The
temporary fiducial might be a mechanical, optical,
electromechanical, a radiofrequency radiotransmitter, an ultrasound
generator, a global positioning tracking (GPS) device, or
ultrasound responsive technology. Similar devices that may be used
to assist in performing the treatment described herein might be
found in U.S. Pat. Nos. 6,656,131 and 7,470,241 which are
incorporated by reference herein.
[0277] Internal reflections (e.g. speckles) can be tracked as well.
These speckles are inherent characteristics of tissue as imaged
with ultrasound. They can be tracked and incorporated into
treatment planning algorithm and then linked to the therapeutic
transducers. In some embodiments, cavitation is detected, in which
vapor bubbles are detected to determine temperature or degree of
heating.
[0278] In some embodiments, a test dose of energy can be applied to
the renal sympathetic region and then a test performed to determine
if an effect was created. For example, a small amount of heat or
vibratory energy can be delivered to the region of the sympathetic
nerves and then a test of sympathetic activity such as
microneurography (detection of sympathetic nerve activity around
muscles and nerves which correlate with the beating heart) can be
performed. Past research and current clinical data have shown that
the sympathetic nerves to the peripheral muscles are affected by
interruption of the renal afferent nerves. The degree of
temperature rise with the small degree of heat can be determined
through the use of MRI thermometry or an ultrasound technique and
the temperature rise can be determined or limited to an amount
which is reversible.
[0279] In another embodiment, a stimulus is applied to a region
such as the skin and an output downstream from the skin is
detected. For example, a vibratory energy might be applied to the
skin and a sympathetic outflow such as the heart rate might be
detected. In another embodiment, heat or cold might be applied to
the skin and heart rate, blood pressure; vasoconstriction might be
detected as an output.
[0280] Alternatively, ultrasonic imaging can be utilized to
determine the approximate temperature rise of the tissue region.
The speed of ultrasonic waves is dependent on temperature and
therefore the relative speed of the ultrasound transmission from a
region being heated will depend on the temperature, therefore
providing measureable variables to monitor. In some embodiments,
microbubbles are utilized to determine the rise in temperature.
Microbubbles expand and then degrade when exposed to increasing
temperature so that they can then predict the temperature of the
region being heated. The microbubbles can be injected into the vein
or artery of a patient or the microbubbles can be injected locally
into the aorta, renal artery, renal vein, etc. A technique called
ultrasound elastography can also be utilized. In this embodiment,
the elastic properties of tissue are dependent on temperature and
therefore the elastography may be utilized to track features of
temperature change. The microbubbles can also be utilized to
augment the therapeutic effect of the region being targeted. For
example, the microbubbles can be utilized to release a
pharmaceutical when the ultrasound reaches them. Alternatively, the
microbubble structure can be utilized to enhance imaging of the
treatment region to improve targeting or tracking of the treatment
region.
[0281] In some embodiments, only the temperature determination is
utilized. That is, the temperature sensing embodiments and
algorithms described herein are utilized with any procedure in
which heating is being performed. For example, in a case where
heating of the renal nerve region is performed using radiofrequency
ablation through the renal artery, imaging of the region from a
position external to the patient can be performed while the renal
artery region is being heated via radiofrequency methods. Imaging
can be accomplished utilizing MRI, ultrasound, infrared, or OCT
methods. Imaging can be utilized to determine temperature or an
effect of temperature on the regions surrounding the blood vessel
and/or nerves. For example, a radiofrequency catheter can be
utilized to apply energy to the wall of a blood vessel and then
ultrasound imaging can be applied during or after the treatment
with the radiofrequency catheter, at which point temperature,
coagulation status, and nerve damage can be determined around the
blood vessel with the nerve. In addition or alternatively, MRI can
be utilized to determine temperature or map effect on the nerve
structures surrounding the blood vessels.
[0282] Such imaging of the treatment can assist in the directing
precise treatment to the region around the blood vessel, and allow
for safe application of heat to the blood vessel wall. For example,
in one embodiment, energy is applied to the wall of the blood
vessel and the heat is detected during the treatment. The
temperature in such an embodiment can be limited with a specified
level (e.g. 55 degrees, 60 degrees, 65 degrees) for a specific
amount of time (e.g. 30 seconds, 60 seconds, 120 seconds). MRI or
ultrasound or both can be used for this treatment. In this method
the localization of the heat about the wall of the blood vessel can
be determined.
[0283] In another embodiment, a test may be performed on the
baroreceptor complex at the region of the carotid artery
bifurcation. After the test dose of energy is applied to the renal
artery complex, pressure can be applied to the carotid artery
complex; typically, with an intact baroreceptor complex, the
systemic blood pressure would decrease after application of
pressure to the carotid artery. However, with renal afferent nerves
which have been inhibited, the baroreceptors will not be sensitive
to changes in blood pressure and therefore the efficacy of the
application of the energy to the renal nerves can be determined.
Other tests include attaining indices of autonomic function such as
microneurography, autonomic function variability, etc.
[0284] In another embodiment, stimulation of the baroreceptor
complex is accomplished non-invasively via ultrasound pulses
applied externally to the region of the carotid body. The
ultrasound pulses are sufficient to stimulate the sinus to affect a
blood pressure change, a change which will be affected when an
afferent nerve such as the renal afferents have been altered.
[0285] More specifically, this methodology is depicted in FIG. 3E.
An ultrasound pulse 980 is utilized to stimulate the carotid sinus
which will lower blood pressure transiently 982 by activating the
baroreceptor complex; activation of the carotid sinus 980 simulates
the effect of an increase in blood pressure which leads to a
compensatory outflow of parasympathetic activity and decreased
sympathetic outflow, subsequently lowering blood pressure. In the
instance when the afferent system (e.g. from the kidney) has been
inhibited, the pressure will not be modifiable as quickly if at
all. In this case, stimulating the baroreceptor complex does not
result in a lowering of blood pressure 986, then the treatment was
successful. This diagnostic technique can therefore be utilized to
determine the effect of a therapy on a system such as the renal
nerve complex. If therapy is successful, then the modifying effect
of the ultrasound pulse on the carotid sinus and blood pressure is
less dramatic and the therapeutic (treatment of afferent nerves)
successful; therefore, therapy can be discontinued 988 temporarily
or permanently. If the blood pressure continues to decrease 982
with the baroreceptor stimulation, then the therapeutic effect has
not been reached with the therapeutic treatment and it needs to be
continued 984 and/or the dose increased. Other methods to stimulate
the baroreceptor complex are to apply pressure in the vicinity with
hands, compression balloons, electrical stimulators, and the
like.
[0286] Other regions of the autonomic nervous system can also be
affected directly by the technology described herein by applying
energy from one region and transmitted through tissue to another
region. For example, FIG. 4A illustrates a system in which energy
external to the internal carotid artery is applied to a portion of
the autonomic nervous system, the carotid body complex 1000,
through the internal jugular vein 1005, and to the carotid body
1000 and/or vagus nerve region 1022, and/or vertebral artery 1015.
Ablative energy, vibratory, or electrical stimulation energy can be
utilized to affect the transmission of signals to and from these
nerves. The transmission in this complex can be augmented,
interrupted, inhibited with over-stimulation, or a combination of
these effects via energy (e.g. ultrasound, electrical stimulation,
etc.).
[0287] In addition, or in place of, in other embodiments, energy
may be applied to peripheral nerves typically known as motor nerves
but which contain autonomic fibers. Such nerves include the
saphenous nerve, femoral nerves, lumbar nerves, median nerves,
ulnar nerves, and radial nerves. In some embodiments, energy is
applied to the nerves and specific autonomic fibers are affected
rather than the other neural fibers (e.g. motor or somatic sensory
fibers or efferent or afferent autonomic nerves). In some
embodiments, other types of autonomic fibers are affected with
energy applied internally or externally. For example, nerves
surrounding the superior mesenteric artery, the inferior mesenteric
artery, the femoral artery, the pelvic arteries, the portal vein,
hepatic artery, pulmonary arteries, pulmonary veins, aorta, vena
cava, etc. can be affected by the energy in a specific manner so as
to create changes in the autonomic responses of the blood vessels
themselves or organs related to the blood vessels, the nerves
running through and along the vessels to the organs.
[0288] In another embodiment, in FIG. 4a, a catheter 1010 is
advanced into the internal jugular vein 1005 and when in position,
stimulation or ablative energy 1020 is directed toward the
autonomic nerves, e.g. the vagus nerve and the carotid sinus/body
1000, from the catheter positioned in the venous system 1005.
[0289] In a similar type of embodiment 1100, a catheter based
therapeutic energy source 1110 can be inserted into the region of
the renal arteries or renal veins (FIG. 4B) to stimulate or inhibit
the renal nerves from the inside of the vessel, either the renal
artery 1105 or renal vein 1106. Energy is transferred through the
vessel (e.g. renal vein) to reach the nerves around another vessel
(e.g. renal artery). For example, a catheter delivering unfocused
ultrasound energy with powers in the range of 50 mW/cm.sup.2 to 50
kW/cm.sup.2 can be placed into the renal artery and the energy
transmitted radially around the artery or vein to the surrounding
nerves. As discussed below, the 500 mW-2500 W/cm.sup.2 is
appropriate to create the specific nerve dysfunction to affect the
norepinephrine levels in the kidney, a surrogate of nerve function
which has been shown to lead to decreases in blood pressure over
time. Pulsed ultrasound, for example, 100 pulse trains with each
lasting less than 1 second each, can be applied to the region.
[0290] In an exemplary embodiment, the tubular body 1105 is
elongate and flexible, and comprises an outer sheath that is
positioned over an inner core. For example, in embodiments
particularly well-suited for the renal blood vessels, the outer
sheath 108 can comprise extruded polytetrafluoroethylene ("PTFE"),
polyetheretherketone ("PEEK"), polyethylene ("PE"), polyamides,
braided polyamides and/or other similar materials. In such
embodiments, the outer sheath 108 has an outer diameter of
approximately 0.039 inch (0.039 inch.+-.0.01 inch) at its proximal
end and between approximately 0.033 inch (0.033 inch.+-.0.01 inch)
and approximately 0.039 inch (0.039 inch.+-.0.01 inch) at its
distal end. In such embodiments, the outer sheath 108 has an axial
length of approximately 150 centimeters (150 cm.+-.20 cm). In other
embodiments, the outer sheath 108 can be formed from a braided
tubing comprising high or low density polyethylenes, urethanes,
nylons, and so forth. Such configurations enhance the flexibility
of the tubular body 1105. In still other embodiments, the outer
sheath can include a stiffening member (not shown) at the tubular
body proximal end.
[0291] The inner core at least partially defines a central lumen,
or "guidewire lumen," which preferably extends through the length
of the catheter. The central lumen has a distal exit port and a
proximal access port. In some embodiments, the proximal portion of
the catheter is defined by a therapeutic compound inlet port on a
back end hub, which is attached proximally. In the exemplary
embodiment the back end hub is attached to a control box connector,
which is described in greater detail below.
[0292] In an exemplary embodiment, the central lumen is configured
to receive a guidewire (not shown) having a diameter of between
approximately 0.010 inch (0.01 inch.+-.0.005 inch) to approximately
0.012 inch (0.012 inch.+-.0.005 inch). In an exemplary embodiment,
the inner core is formed from polymide or a similar material, which
can optionally be braided to increase the flexibility of the
tubular body 1105.
[0293] Referring now to an exemplary embodiment illustrated in FIG.
4B, the distal end of the tubular body includes an ultrasound
radiating member 1110. In the illustrated embodiment, the
ultrasound radiating member 1110 comprises an ultrasonic
transducer, which converts, for example, electrical energy into
ultrasonic energy.
[0294] An inner core extends through the ultrasound radiating
member, which is positioned over the inner core. The ultrasound
radiating member can be secured to the inner core in a suitable
manner, such as with an adhesive. Extending the core through the
member advantageously provides enhanced cooling of the ultrasound
radiating member. A therapeutic compound can be injected through a
central lumen, thereby providing a heat sink for heat generated by
the ultrasound radiating member. The therapeutic compound can
enhance the effect of the ultrasound on the nerves surrounding the
blood vessel.
[0295] Suitable operating frequencies for the ultrasound radiating
member include, but are not limited to, from about 20 kHz (20
kHz.+-.2 kHz) to less than about 20 MHz (20 MHz.+-.2 MHz). In one
embodiment, the frequency is between 500 kHz and about 20 MHz (20
MHz.+-.2 MHz), and in another embodiment the frequency is between
about 1 MHz (1 MHz.+-.0.1 MHz) and about 3 MHz (3 MHz.+-.0.3 MHz).
In yet another embodiment, the ultrasonic energy has a frequency of
about 3 MHz (3 MHz.+-.0.3 MHz).
[0296] In another embodiment, light is applied through the vessel
from within the blood vessel. Infrared, red, blue, and near
infrared can all be utilized to affect the function of nerves
surrounding blood vessels. For example, a light source is
introduced into the renal artery or renal vein 1105, 1106 and the
light transmitted to the region surrounding the blood vessels. In a
preferred embodiment, a photosensitizing agent is utilized to
hasten the inhibition or destruction of the nerve bundles with this
technique. Photosensitizing agents can be applied systemically to
infiltrate the region around the blood vessels. Light is then
applied from inside the vessel to the region of the nerves outside
the vessel. For example, the light source is placed inside the
renal vein and then light is transmitted through the vein wall to
the adventitial region around the wall activating the
photosensitizer and injuring or inhibiting the nerves in the
adventitia through an apoptosis pathway. The light source may
provide light that is visible, or light that is non-visible. In
another embodiment, the light is applied to the region without
photosensitizer. The light generates heat in the region through
absorption of the light. Wavelengths such as those in the red,
near-infrared, and infrared region are absorbed by the tissues
around the artery and leads to destruction of the nerves in the
region.
[0297] In one embodiment, a string of light emitting diodes (LEDs)
is fed into the blood vessel and the vessel illuminated with light
from inside the vessel. Lights that are near infrared and infrared
have good penetration in blood and through tissues and can be
utilized to heat or activate pharmaceuticals in the region
surrounding the blood vessel leading to the kidney. These light
frequency devices and energies can be utilized to visualize the
inside and/or outside of the blood vessel. Intravascular OCT might
be utilized to visualize damage to the nerves surrounding the blood
vessels.
[0298] The therapies in FIGS. 4A-B can be delivered on an acute
basis such as for example in an ICU or critical care setting. In
such a case, the therapy would be acute and intermittent, with the
source outside the patient and the catheter within the patient as
shown in FIGS. 4a-b. The therapy can be utilized during times of
stress for the patient such that the sympathetic system is slowed
down. After the intensive care admission is nearing a close, the
catheter and unit can be removed from the patient. In one
embodiment, a method is described in which a catheter is placed
within a patient to deliver energy to a region of the body
sufficient to partially or fully inhibit an autonomic nerve complex
during a state of profound sympathetic activation such as shock,
sepsis, myocardial infarction, pancreatitis, post-surgical. After
the acute phase of implantation during which the sympathetic system
is modulated, the device is removed entirely.
[0299] FIGS. 5A-B illustrates the eye in close up detail with
sympathetic nerves surrounding the posterior of the eye. In the
eye, glaucoma is a problem of world-wide importance. The most
commonly prescribed medication to treat glaucoma is timoptic, which
is a non-selective .beta.1 and .beta.2 (adrenergic) antagonist.
Compliance with this pharmaceutical is a major problem and limits
its effectiveness in preventing the complications of glaucoma, the
major complication being progression of visual dysfunction.
[0300] Ultrasound, or other energy transducers 7000, can be applied
to focus energy from an external region (e.g. a distance from the
eye in an external location) anterior to the eye or to a region
posteriorly behind the eye 2500 on the sympathetic 2010 or
parasympathetic ganglia, all of which will affect lowering of
intra-ocular pressure. The energy transducers 7000 apply ablative
or near ablative energy to the adventitia of the blood vessels. In
some embodiments, the energy is not ablative but vibratory at
frequencies (e.g. 1-5 Mhz) and penetration depths (e.g. 0.5 mm to
0.5 cm) sufficient to inhibit the function of the nerves which are
responsible for intra-ocular pressure. Lower energy (e.g.
sub-ablative) can be applied to the eye to assist in drug delivery
or to stimulate tissue healing type of tissue responses.
[0301] FIG. 5B depicts the anatomy of the nerves which travel
behind the eye 2500. In this illustration, a catheter 2000 is
tunneled through the vasculature to the region of the sympathetic
nerves surrounding the arteries of the eye 2010 and utilized to
ablate, stun, or otherwise modulate the efferent and/or afferent
nerves through the wall of the vasculature leading to the eye.
[0302] FIG. 6 illustrates an overall schematic of the renal artery,
renal vein, the collecting system, and the more distal vessels and
collecting system within the renal parenchyma. The individual
nerves of the autonomic nervous system typically follow the body
vasculature and they are shown in close proximity 3000 to the renal
artery as the artery enters the kidney 3100 proper. The hilum of
the kidney contains pressure sensors and chemical sensors which
influence the inputs to the efferent sympathetic system via
afferent nerves traveling from the kidney to the central nervous
system and then to the efferent nervous system. Any one or multiple
of these structures can influence the function of the kidney.
Ablative or non-ablative energy can be applied to the renal vein,
the renal artery, the aorta, and/or the vena cava, the renal hilum,
the renal parenchyma, the renal medulla, the renal cortex, etc.
[0303] In another embodiment, selective lesions, constrictions or
implants 3200 are placed in the calyces of the kidney to control or
impede blood flow to specific regions of the kidney. Such lesions
or implants can be placed on the arterial 3010 or venous sides 3220
of the kidney. In some embodiments, the lesions/implants are
created so as to selectively block certain portions of the
sympathetic nerves within the kidney. The lesions also may be
positioned so as to ablate regions of the kidney which produce
hormones, such as renin, which can be detrimental to a patient in
excess. The implants or constrictions can be placed in the aorta
3210 or the renal vein 3230. The implants can be active implants,
generating stimulating energy chronically or multiple ablative or
inhibitory doses discretely over time.
[0304] In the renal vein 3230, the implants 3220, 3200 might cause
an increase in the pressure within the kidney (by allowing blood
flow to back up into the kidney and increase the pressure) which
will prevent the downward spiral of systolic heart failure
described above because the kidney will act as if it is
experiencing a high pressure head. That is, once the pressure in
the kidney is restored or artificially elevated by increased venous
pressure, the relative renal hypotension signaling to retain
electrolytes and water will not be present any longer and the
kidney will "feel" full and the renal sympathetic stimulation will
be turned off. In one embodiment, a stent which creates a stenosis
is implanted using a catheter delivery system. In another
embodiment, a stricture 3220 is created using heat delivered either
externally or internally. Externally delivered heat is delivered
via direct heating via a percutaneous procedure (through the skin
to the region of the kidney) or transmitted through the skin (e.g.
with HIFU focused through the skin). In one embodiment, an implant
is placed between girota's fascia and the cortex of the kidney. The
implant can stimulate or inhibit nerves surrounding the renal blood
vessels, or even release pharmaceuticals in a drug delivery
system.
[0305] FIG. 7A depicts at least partial ablation of the renal
sympathetic nerves 4400 to the kidney using an imaging system such
as an MRI machine or CT scanner 4000. The MRI/CT scan can be linked
to a focused ultrasound (HIFU) machine to perform the ablations of
the sympathetic nerves 4400 around the region of the renal artery
4500. The MRI/CT scan performs the imaging 4010 and transmits data
(e.g. three dimensional representations of the regions of interest)
to the ultrasound controller which then directs the ultrasound to
target the region of interest with low intensity ultrasound
(50-1000 mW/cm2), heat (>1000 mW/cm2), cavitation, or a
combination of these modalities and/or including introduction of
enhancing bioactive agent delivery locally or systemically
(sonodynamic therapy). Optionally, a doppler ultrasound or other
3D/4D ultrasound is performed and the data pushed to the MRI system
to assist with localization of the pathology; alternatively, the
ultrasound data are utilized to directly control the direction of
the energy being used to target the physiologic processes and
CT/MRI is not obtained. Using this imaging and ablation system from
a position external to a patient, many regions of the kidney can be
treated such as the internal calyces 4350, the cortex 4300, the
medulla 4320, the hilum 4330, and the region 4340 close to the
aorta. Optionally, an intravascular catheter can be introduced into
the patient to augment the procedure with intravascular energy,
temperature measurement, acoustic energy detection, ionizing
radiation detection, etc. For example, the catheter might be able
to deliver radiofrequency energy to the wall of the blood vessel,
or the catheter might be heated in response to the magnetic field
being applied across the patient. For example, a balloon or other
catheter tip with a metallic coating will be heated in the presence
of a magnetic field. This heat, typically unwanted in the presence
of an intravascular catheter, can be utilized to inhibit, or ablate
the nerves leading to the kidney (as an example). The MRI system
also has the advantage of being able to measure temperature and/or
looking at tissue changes around the blood vessels treated, as
described below. Similarly, the intravascular catheter can heat up
in response to ultrasound in the case where the catheter contains
elements
[0306] Further parameters which can be measured include temperature
via thermal spectroscopy using MRI or ultrasound
thermometry/elastography; thermal imaging is a well-known feature
of MRI scanners; the data for thermal spectroscopy exists within
the MRI scan and can be extrapolated from the recorded data in real
time by comparing regions of interest before and after or during
treatment. Temperature data overlaid on the MRI scan enables the
operator of the machine to visualize the increase in temperature
and therefore the location of the heating to insure that the
correct region has indeed been ablated and that excessive energy is
not applied to the region. Having temperature data also enables
control of the ablation field as far as applying the correct
temperature for ablation to the nerves. For example, the
temperature over time can be determined and fed back to the
operator or in an automated system, to the energy delivery device
itself. Furthermore, other spectroscopic parameters can be
determined using the MRI scan such as oxygenation, blood flow,
inflammation, or other physiologic and functional parameters. In
one embodiment, an alternating magnetic field is used to stimulate
and then over-stimulate or inhibit an autonomic nerve (e.g. to or
from the kidney).
[0307] Elastography is a technique in which the shear waves of the
ultrasound beam and reflectance are detected. The tissue
characteristics change as the tissue is heated and the tissue
properties change. An approximate temperature can be assigned to
the tissue based on elastography and the progress of the heating
can be monitored.
[0308] MRI scanners 4000 generally consist of a magnet and an RF
coil. The magnet might be an electromagnet or a permanent magnet.
The coil is typically a copper coil which generates a
radiofrequency field. Recently, permanent magnets have been
utilized to create MRI scanners which are able to be used in almost
any setting, for example a private office setting. Office based MRI
scanners enable imaging to be performed quickly in the convenience
of a physician's office as well as requiring less magnetic force
(less than 0.5 Tesla) and as a consequence, less shielding. The
lower tesla magnets also provides for special advantages as far as
diversity of imaging and resolution of certain features.
Importantly, the permanent magnet MRI scanners are open scanners
and do not encapsulate the patient during the scan.
[0309] In one embodiment, a permanent magnet MRI is utilized to
obtain an MRI image of the region of interest 4010. High intensity
focused 4100 ultrasound is used to target the region of interest
4600 identified using the MRI. In one embodiment, the MRI is
utilized to detect blood flow within one or more blood vessels such
as the renal arteries, renal veins, superior mesenteric artery,
veins, carotid arteries and veins, aortic arch coronary arteries,
veins, to name a subset.
[0310] Image 4010 is or can be monitored by a health care
professional to ensure that the region of interest is being treated
and the treatment can be stopped if the assumed region is not being
treated. Alternatively, an imaging algorithm can be initiated in
which the region of interest is automatically (e.g. through image
processing) identified and then subsequent images are compared to
the initial demarcated region of interest.
[0311] Perhaps, most importantly, with MRI, the region around the
renal arteries can be easily imaged as can any other region such as
the eye, brain, prostate, breast, liver, colon, spleen, aorta, hip,
knee, spine, venous tree, and pancreas. The imaging from the MRI
can be utilized to precisely focus the ultrasound beam to the
region of interest around the renal arteries or elsewhere in the
body. With MRI, the actual nerves to be modified or modulated can
be directly visualized and targeted with the energy delivered
through the body from the ultrasound transducers. One disadvantage
of MRI can be the frame acquisition (difficulty in tracking the
target) rate as well as the cost of introducing an MRI machine into
the treatment paradigm. In these regards, ultrasound imaging offers
a much more practical solution. In some embodiments, the advantages
of ultrasound and MRI are combined into a single system. In some
embodiments, an intravascular catheter is further combined with the
two imaging modalities to further enhance the treatment. In one
embodiment, the intravascular catheter has a ferromagnetic tip
which is moveable or heatable (or both) by the MRI scanner. The tip
can be manipulated, manually or by the magnetic field (or both) to
apply pressure to the wall of the blood vessel and subsequently
heat the wall. In some embodiments, the tip can perform the above
function(s) while measuring the temperature of the region around
the blood vessel (the nerve region). In other embodiments, another
device may be used to measure the temperature.
[0312] FIG. 7D depicts a method of treating a region with high
intensity focused ultrasound (HIFU). Imaging with an MRI 4520 or
ultrasound 4510 (or preferably both) is performed. MRI can be used
to directly or indirectly (e.g. using functional MRI or
spectroscopy) to visualize the sympathetic nerves. T1 weighted or
T2 weighted images can be obtained using the MRI scanner. In
addition to anatomic imaging, the MRI scanner can also obtain
temperature data regarding the effectiveness of the ablation zone
as well as the degree to which the zone is being heated and which
parts of the zones are being heated. Other spectroscopic parameters
can be added as well such as blood flow and even nerve activity.
Edema, inflammation, and necrosis can be detected as well with MRI.
Ultrasound 4510 can be used to add blood flow to the images using
Doppler imaging. The spectroscopic data can be augmented by imaging
moieties such as particles, imaging agents, or particles coupled to
imaging agents which are injected into the patient intravenously,
or locally, and proximal to the region of the renal arteries; these
imaging moieties may be visualized on MRI, ultrasound, or CT scan.
Ultrasound can also be utilized to determine information regarding
heating. The reflectance of the ultrasonic waves changes as the
temperature of the tissue changes. By comparing the initial images
with the subsequent images after heating, the temperature change
which occurred after the institution of heating can be determined.
Therefore, in one embodiment, information regarding heating at
baseline is determined and incorporated into the treatment modeling
during the ongoing treatment at time subsequent to t=0.
[0313] In one embodiment, the kidneys are detected by a
cross-sectional imaging modality such as MRI, ultrasound, or CT
scan. The renal arteries and veins are detected within the MRI
image utilizing contrast or not utilizing contrast. Next, the
imaging data is placed into a three dimensional coordinate system
which is linked to one or more ultrasound (e.g. HIFU) transducers
4540 which focus ultrasound onto the region of the renal arteries
in the coordinate frame 4530. The linking, or coupling, of the
imaging to the therapeutic transducers is accomplished by
determining the 3 dimensional position of the target by creating an
anatomic model. The transducers are placed in a relative three
dimensional coordinate frame as well. For example, the transducers
can be placed in the imaging field 4520 during the MRI or CT scan
such that the cross-sectional pictures include the transducers.
Optionally, the transducers contain motion sensors, such as
electromagnetic, optical, inertial, MEMS, and accelerometers, one
or more of which allow for the transducer position to be monitored
if for example the body moves relative to the transducer or the
operator moves relative to the body. With the motion sensors, the
position of the transducers can be determined with movement which
might occur during the therapy. The updated information can then be
fed back to the ultrasound therapy device so as to readjust the
position of the therapy.
[0314] In one embodiment, a system is described in which the blood
flow in the renal artery is detected by detecting the walls of the
artery or renal vein or the blood flow in the renal artery or the
renal vein. The coordinate reference of the blood vessels is then
transmitted to the therapeutic transducer, for example, ultrasound.
The therapeutic transducer is directed to the renal blood vessels
using the information obtained by imaging. A model (FIG. 16M for
example) of the vessels (including blood flow, movement, etc.)
indicates the blood flow of the vessels and the walls of the
vessels where the nerves reside. Energy is then applied to the
model of the vessels to treat the nerves around the vessels.
[0315] Alternatively, in another embodiment, ultrasound is utilized
and the ultrasound image 4510 can be directly correlated to the
origin of the imaging transducer. In some embodiments the
ultrasound is in two dimensions and in others, the ultrasound is
presented in three dimensions. In some embodiments, the ultrasound
is presented in a combination of two and three dimensions. For
example, a two dimensional transducer may be quickly rotated at a
specified speed and the integration of the pictures provides a
three dimensional approximation. The therapeutic transducer 4540 in
some embodiments is the same as the imaging transducer and
therefore the therapeutic transducer is by definition coupled in a
coordinate reference 4540 once the imaging transducer coordinates
are known. If the therapeutic transducer and the imaging transducer
are different devices, then they can be coupled by knowledge of the
relative position of the two devices. The region of interest (ROI)
is highlighted in a software algorithm; for example, the renal
arteries, the calyces, the medullary region, the cortex, the renal
hila, the celiac ganglia, the aorta, or any of the veins of the
venous system as well. In another embodiment, the adrenal gland,
the vessels traveling to the adrenal gland, or the autonomic nerves
traveling to the adrenal gland are targeted with focused ultrasound
and then either the medulla or the cortex of the adrenal gland or
the nerves and arteries leading to the gland are partially or fully
ablated with ultrasonic energy.
[0316] The targeting region or focus of the ultrasound is the point
of maximal intensity. In some embodiments, targeting focus is
placed in the center of the artery such that the walls on either
side receive equivalent amounts of energy or power and can be
heated more evenly than if one wall of the blood vessel is
targeted. In some embodiments in which a blood vessel is targeted,
the blood vessel being an artery and the artery having a closely
surrounding vein (e.g. the renal artery/vein pedicle), the center
of the focus might be placed at the boundary of the vein and the
artery.
[0317] Once the transducers are energized 4550 after the region is
targeted, the tissue is heated 4560 and a technique such as MRI
thermography 4570 or ultrasound thermography is utilized to
determine the tissue temperature. During the assessment of
temperature, the anatomic data from the MRI scan or the Doppler
ultrasound is then referenced to ensure the proper degree of
positioning and the degree of energy transduction is again further
assessed by the modeling algorithm 4545 to set the parameters for
the energy transducers 4550. If there is movement of the target,
the transducers may have to be turned off and the patient
repositioned. Alternatively, the transducers can be redirected to a
different position within the coordinate reference frame.
[0318] Ablation can also be augmented using agents such as magnetic
nanoparticles or liposomal nanoparticles which are responsive to a
radiofrequency field generated by a magnet. These particles can be
selectively heated by the magnetic field. The particles can also be
enhanced such that they will target specific organs and tissues
using targeting moieties such as antibodies, peptides, etc. In
addition to the delivery of heat, the particles can be activated to
deliver drugs, bioactive agents, or imaging agents at the region at
which action is desired (e.g. the renal artery). The particles can
be introduced via an intravenous route, a subcutaneous route, a
direct injection route through the blood vessel, or a percutaneous
route. As an example, magnetic nanoparticles or microparticles
respond to a magnetic field (e.g. by a MRI device) by generating
heat in a local region around them. Similarly, liposomal particles
might have a metallic particle within such that the magnetic
particle heats up the region around the liposome but the liposome
allows accurate targeting and biocompatibility.
[0319] The addition of Doppler ultrasound 4510 may be provided as
well. The renal arteries are (if renal arteries or regions
surrounding the arteries are the target) placed in a 3D coordinate
reference frame 4530 using a software algorithm with or without the
help of fiducial markers. Data is supplied to ultrasound
transducers 4540 from a heat modeling algorithm 4545 and the
transducers are energized with the appropriate phase and power to
heat the region of the renal artery to between 40.degree. C. and
90.degree. C. within a time span of several minutes. The position
within the 3D coordinate reference is also integrated into the
treatment algorithm so that the ultrasound transducers can be moved
into the appropriate position. The ultrasound transducers may have
frequencies below 1 megahertz (MHz), from 1-20 MHz, or above 30
Mhz, or around 750 kHz, 500 kHz, or 250 kHz. The transducers may be
in the form of a phased array, either annular, linear or curved, or
the transducers may be mechanically moved so as to focus ultrasound
to the target of interest. In addition, MRI thermography 4570 can
be utilized so as to obtain the actual temperature of the tissue
being heated. These data can be further fed into the system to slow
down or speed up the process of ablation 4560 via the transducers
4550. For example, in the case where the temperature is not rising
as fast as planned, the energy level can be increased. On the other
hand, where the temperature is rising faster than originally
planned, the energy density can be decreased.
[0320] Aside from focused ultrasound, ultrasonic waves can be
utilized directly to either heat an area or to activate
pharmaceuticals in the region of interest. There are several
methodologies to enhance drug delivery using focused ultrasound.
For example, particles can release pharmaceuticals when they are
heated by the magnetic field. Liposomes can release a payload when
they are activated with focused ultrasound. Ultrasound waves have a
natural focusing ability if a transducer is placed in the vicinity
of the target and the target contains an activateable moiety such
as a bioactive drug or material (e.g. a nanoparticle sensitive to
acoustic waves). Examples of sonodynamically activated moieties
include some porphyrin derivatives.
[0321] So as to test the region of interest and the potential
physiologic effect of ablation in that region, the region can be
partially heated or vibrated with the focused ultrasound to stun or
partially ablate the nerves. Next, a physiologic test such as the
testing of blood pressure or measuring norepinephrine levels in the
blood, kidney, blood vessels leading to or from the kidney, can be
performed to ensure that the correct region was indeed targeted for
ablation. Depending on the parameter, additional treatments may be
performed.
[0322] Clinically, this technique might be called fractionation of
therapy which underscores one of the major advantages of the
technique to apply external energy versus applying internal energy
to the renal arteries. An internal technique requires invasion
through the skin and entry into the renal artery lumens which is
costly and potentially damaging. Patients will likely not accept
multiple treatments, as they are highly invasive and painful. An
external technique allows for a less invasive treatment to be
applied on multiple occasions, made feasible by the low cost and
minimal invasion of the technology described herein.
[0323] In another embodiment, a fiducial is utilized to demarcate
the region of interest. A fiducial can be intrinsic (e.g. part of
the anatomy) or the fiducial can be extrinsic (e.g. placed in
position). For example, the fiducial can be an implanted fiducial,
an intrinsic fiducial, or device placed in the blood vessels, or a
device placed percutaneously through a catheterization or other
procedure. The fiducial can also be a bone, such as a rib, or
another internal organ, for example, the liver. In one embodiment,
the fiducial is a beacon or balloon or balloon with a beacon which
is detectable via ultrasound. In another embodiment, the fiducial
is a stent implanted in the renal artery, renal vein, vena cava, or
aorta. The stent can be periodically heated by the MRI or
ultrasound in the case where treatment is needed to be reapplied.
In one embodiment, the blood flow in the renal arteries, detected
via Doppler or B-mode imaging, is the fiducial and its relative
direction is determined via Doppler analysis. Next, the renal
arteries, and specifically, the region around the renal arteries
are placed into a three dimensional coordinate frame utilizing the
internal fiducials. A variant of global positioning system
technology can be utilized to track the fiducials within the artery
or around the arteries. In this embodiment, a position sensor is
placed in the artery or vein through a puncture in the groin. The
position of the sensor is monitored as the sensor is placed into
the blood vessel and its position in physical space relative to the
outside of the patient, relative to the operator and relative to
the therapeutic transducer is therefore known. The three
dimensional coordinate frame is transmitted to the therapeutic
ultrasound transducers and then the transducers and anatomy are
coupled to the same coordinate frame. At this point, the HIFU is
delivered from the transducers, calculating the position of the
transducers based on the position of the target in the reference
frame. The fiducial may be active, in which electrical current is
transmitted into the fiducial through a catheter or through
induction of energy transmitted through the skin. The energy
transmitted from the catheter back through the skin or down the
catheter and out of the patient may be utilized to indicate the
coordinates of treatment target(s) so that the externally directed
energy may be applied at the correct location(s). The internal
fiducials may be utilized to track motion of the region to which
energy is being delivered. In some embodiments, there are multiple
fiducials within the vessels being treated. For example, several
fiducials are placed inside the renal artery so that the direction
and/or shape of the vessel can be determined. Such information is
important in the case of tortuosity of the blood vessel. Such
redundancy can also be used to decrease the error and increase the
accuracy of the targeting and tracking algorithms.
[0324] In one embodiment, a virtual fiducial is created via an
imaging system. For example, in the case of a blood vessel such as
the renal artery, an image of the blood vessel using B-mode
ultrasound can be obtained which correlates to the blood vessel
being viewed in direct cross section (1705; FIG. 17F). When the
vessel is viewed in this type of view, the center of the vessel can
be aligned with the center 1700 of an ultrasound array (e.g. HIFU
array 1600) and the transducers can be focused and applied to the
vessel, applying heat lesions 1680 to regions around the vessel
1705. With different positions of the transducers 1610 along a
circumference or hemisphere 1650, varying focal points can be
created 1620, 1630, 1640. The directionality of the transducers
allows for a lesion(s) 1620, 1630, 1640 which run lengthwise along
the vessel 1700. Thus, a longitudinal lesion 1620-1640 can be
produced along the artery to insure maximal inhibition of nerve
function. In some embodiments, the center of the therapeutic
ultrasound transducer is off center relative to the center of the
vessel so that the energy is applied across the vessel wall at an
angle, oblique to the vessel. The transducer 1600 can also be
aspheric in which the focus of the transducer is off center with
respect to its central axis.
[0325] In this method of treatment, an artery such as a renal
artery is viewed in cross-section or close to a cross-section under
ultrasound guidance. In this position, the blood vessel is
substantially parallel to the axis of the spherical transducer so
as to facilitate lesion production. The setup of the ultrasound
transducers 1600 has previously been calibrated to create multiple
focal lesions 1620, 1630, 1640 along the artery if the artery is in
cross-section 1680.
[0326] In one embodiment, the fiducial is an intravascular fiducial
such as a balloon or a hermetically sealed transmitting device. The
balloon is detectable via radiotransmitter within the balloon which
is detectable by the external therapeutic transducers. The balloon
can have three transducers, each capable of relaying its position
so that the balloon can be placed in a three dimensional coordinate
reference. Once the balloon is placed into the same coordinate
frame as the external transducers using the transmitting beacon,
the energy transducing devices can deliver energy (e.g. focused
ultrasound) to the blood vessel (e.g. the renal arteries) or the
region surrounding the blood vessels (e.g. the renal nerves). The
balloon and transmitters also enable the ability to definitively
track the vasculature in the case of movement (e.g. the renal
arteries). In another embodiment, the balloon measures temperature
or is a conduit for coolant applied during the heating of the
artery or nerves. Multiple transducers might be set up outside the
patient to detect the position of the internal fiducial from
different directions (rather than three internal transducers, in
this embodiment, there are three external transducers detecting the
position of a single or multiple internal fiducials). Again, such
redundancy in targeting position is beneficial because the exact
position of the internal fiducial may be determined correctly. In
another embodiment, multiple internal fiducials are placed inside
the patient, in particular, within a blood vessel to determine the
three dimensional orientation of the blood vessel.
[0327] Delivery of therapeutic ultrasound energy to the tissue
inside the body is accomplished via the ultrasound transducers
which are directed to deliver the energy to the target in the
coordinate frame.
[0328] Once the target is placed in the coordinate frame and the
energy delivery is begun, it is important to maintain targeting of
the position, particularly when the target is a small region such
as the sympathetic nerves. To this end, the position of the region
of ablation is compared to its baseline position, both in a three
dimensional coordinate reference frame. The ongoing positional
monitoring and information is fed into an algorithm which
determines the new targeting direction of the energy waves toward
the target. In one embodiment, if the position is too far from the
original position (e.g. the patient moves), then the energy
delivery is stopped and the patient repositioned. If the position
is not too far from the original position, then the energy
transducers can be repositioned either mechanically (e.g. through
physical movement) or electrically via phased array (e.g. by
changing the relative phase of the waves emanating from the
transducers). In another embodiment, multiple transducers are
placed on the patient in different positions and each is turned on
or off to result in the necessary energy delivery. With a multitude
of transducers placed on the patient, a greater territory can be
covered with the therapeutic ultrasound. The therapeutic positions
can also serve as imaging positions for intrinsic and/or extrinsic
fiducials.
[0329] In addition to heat delivery, ultrasound can be utilized to
deliver cavitating energy which may enable drug delivery at certain
frequencies. Cavitating energy can also lead to ablation of tissue
at the area of the focus. A systemic dose of a drug can be
delivered to the region of interest and the region targeted with
the cavitating or other forms of ultrasonic energy. Other types of
therapeutic delivery modalities include ultrasound sensitive
bubbles or radiation sensitive nanoparticles, all of which enhance
the effect of the energy at the target of interest. Therefore in
one method, an ultrasonically sensitive bioactive material is
administered to a patient, and focused ultrasound is applied
through the skin of the patient to the region of the blood vessels
leading to the kidney. The effect of the ultrasound on the region
around the blood vessels is to release the bioactive material or
otherwise heat the region surrounding the blood vessel. The
ultrasonically sensitive bioactive material may be placed in a
vessel, in which cases, ultrasound can be applied through the wall
of the blood vessel to activate the material.
[0330] FIG. 7E depicts the anatomy of the region 4600, the kidneys
4620, renal arteries 4630, and bony structures 4610, 4640 as viewed
from behind a human patient. FIG. 7E depicts the real world
placement of the renal arteries into coordinate frame as outlined
in FIG. 7D. Cross sectional CT scans from actual human patients
were integrated to create a three-dimensional representation of the
renal artery, kidney, and mid-torso region. Plane 4623 is a plane
parallel to the transverse processes and angle 4607 is the angle
one has to look up (toward the head of the patient) in order to
"see" the renal artery under the rib. Such real world imaging and
modeling allows for an optimal system to be developed so as to
maximize efficacy and minimize risk of the treatment. Therefore
with these parameters to consider, a system to treat the nerves
surrounding the renal arteries is devised in which a transducer is
positionable (e.g., to adjust a line of sight) with a negative
angle with respect to a line connecting the spinal processes.
Multiple transducers may be utilized to allow variations in the
positioning associated with variations in anatomy or during
respiratory motion, wherein the anatomy may be tracked during
treatment.
[0331] FIG. 7F depicts an image of the region of the renal arteries
and kidney 4605 using ultrasound. The renal hilum containing the
arteries and vein can be visualized using this imaging modality.
This image is typical when looking at the kidney and renal artery
from the direction and angle depicted in FIG. 7E. Importantly, at
the angle 4607 in 7E, there is no rib in the ultrasound path and
there no other important structures in the path either.
[0332] An ultrasound imaging trial was then performed to detect the
available windows to deliver therapeutic ultrasound to the region
of the renal arteries 4630 from the posterior region of the
patient. It was discovered that the window depicted by arrow 4600
and depicted by arrow 4605 in the cross-sectional ultrasound image
from ultrasound (FIG. 7F) provided optimal windows to visualize the
anatomy of interest (renal pedicle).
[0333] FIG. 7G contains some of the important data from the trial
4700, the data in the "standard position 4730." These data 4720 can
be used to determine the configuration of the clinical HIFU system
to deliver ultrasound to the renal hilum. The renal artery 4635 was
determined to be 7-17 cm from the skin in the patients on average.
The flank to posterior approach was noted to be optimum to image
the renal artery, typically through the parenchyma of the kidney as
shown in FIG. 7F 4605. The hilum 4640 of the kidney is
approximately 4-8 cm from the ultrasound transducer and the angle
of approach 4637 (4607 in FIG. 7E) relative to an axis defined by
the line connecting the two spinous processes and perpendicular to
the spine . . . is approximately -10 to -48 degrees. It was also
noted that the flank approach through the kidney was the safest
approach in that it represents the smallest chances of applying
ultrasound to other organs such as bowel.
[0334] Therefore, with these data, a system algorithm for treatment
may been devised: b-mode ultrasound is utilized to visualize the
kidney in cross-section; doppler ultrasound is utilized to identify
the pedicle 4640 traveling to the kidney with the renal artery as
the identifying anatomical structure via Doppler ultrasound; the
distance to the pedical is determined via the b-mode imaging. With
the kidney inside the b-mode image, safety can be attained as the
kidney has been determined to be an excellent heat sink and
absorber (that is HIFU has little effect on the kidney) of HIFU
(see in-vivo data below); the distance is fed into the processing
algorithm and the HIFU transducer is fed the position data of the
HIFU transducer. Furthermore, small piezoelectric crystals may be
located at (e.g., along) the therapeutic ultrasound transducer, and
may be utilized to determine a safe path between a source of
ultrasound from the crystal at the ultrasound transducer and the
target blood vessel. An echo may be sent from the crystal to the
target and the time for a return signal may be determined. With the
information about the return signal (e.g. distance to target, speed
of return), the safety of the path may be determined. If bowel with
air inside (for example) were in the path, the return signal would
deviate from an expected signal, and the transducer can then be
repositioned. Similarly, if bone (e.g. rib) is in the path of the
ultrasound beam, the expected return signal will significantly
deviate from the expected return time, thereby indicating that the
path cannot be utilized.
[0335] Upon further experimentation, it was discovered that by
positioning the patient in the prone position (backside up, abdomen
down), the structures under study 4750 . . . that is, the renal
arteries 4770 and 4780, the kidney hilum were even closer to the
skin and the respiratory motion of the artery and kidney was
markedly decreased. FIG. 7H depicts these results 4750, 4760
showing the renal artery 4770 at 6-10 cm and the angle of approach
4790 relative to the spine 4607 shallower at -5 to -20 degrees.
Similar results were obtained in the case where the patient
remained flat and the legs were propped up using a wedge or bump
under them.
[0336] Therefore, with these clinical data, in one embodiment, a
method of treatment 4800 (FIG. 7I) of the renal nerves in a patient
has been devised: 1) identify the rib 4810 and iliac crest 4840 of
a patient on the left and right flank of the patient 4810; 2)
identify the left or right sided kidney with ultrasound 4820; 3)
identify the hilum of the kidney and the extent the renal hilum is
visible along surface of patient 4820 using an imaging technology;
4) identify the blood vessels leading to the kidney from one or
more angles, extracting the extent of visibility 4860 along the
surface area of the patient's back; 5) determine the distance to
the one or more of the renal artery, renal vein, kidney, and the
renal hilum 4850; 6) optionally, position patient in the prone
position with a substantive positioning device underneath the back
of the patient or overtop the abdomen of the patient 4830, to
optimize visibility; 7) optionally determine, through modeling, the
required power to obtain a therapeutic dose at the renal hilum and
region around the renal blood vessels; 8) apply therapeutic energy
to renal blood vessels; 9) optionally track the region of the blood
vessels to ensure the continued delivery of energy to the region as
planned in the modeling; 10) optionally, turning off delivery of
energy in the case the focus of the energy is outside of the
planned region; 11) optionally, adapting the system through
movement of the therapeutic and imaging ultrasound transducers so
as to orient the ultrasound applicators in relation to the vessel
target; 12) optionally placing a fiducial in one or more blood
vessels to further enhance the device's ability to localize and
track the vessel; 13) determining an algorithm for treatment based
on one or more of: the distance to the vessel, the thickness of the
skin, the thickness of the muscle, and the thickness of the kidney
through which the ultrasound traverses; 14) applying the
therapeutic ultrasound with pulses in less than 10 s to ramp up and
apply at least 100 W/cm.sup.2 for at least one second; 15)
optionally, directing the therapeutic transducer at an angle
anywhere from -5 to -25 degrees (i.e. pointing upward toward the
cephalic region) relative to a line connecting the spinous
processes.
[0337] In another embodiment, FIG. 7J, a clinical algorithm 4900 is
depicted in which a position of a blood vessel is determined 4910.
For example, the blood vessel may be adjacent a nerve region of
interest (e.g. renal artery and nerve, aorta and sympathetic
nerves, cerebral arteries and nerves, carotid artery and nerves). A
test dose of energy is applied to the threshold of patient
sensation 4920. In the case of a renal nerve, the sensation
threshold might be a renal colic type of sensation. At the point of
sensation 4920, the dose can be lowered and cooled and then an
additional dose can be applied at a level just below the sensation
threshold. Such a sequence 4900 can be repeated 4940 many times
over until the desired effect is achieved. Intermittent off time
allows for cooling 4930 of the region. In FIG. 7K, a transducer
4950 is depicted with both diagnostic and therapeutic ability. Wave
4960 is a diagnostic wave which in this example interferes with
bone (rib). In some embodiments, the therapeutic wave which would
otherwise emanate from this region of the transducer is switched
off and therapeutic waves are not generated. On the other side of
the transducer, waves 4956 do indeed allow a clear path to the
renal blood vessels 4954 and indeed a therapeutic beam is permitted
from this region. The diagnostic energy may be ultrasonic energy,
radiofrequency energy, X-ray energy, or optical energy. For
example, MRI, ultrasound, CT scan, or acoustic time of flight
technology might be utilized to determine whether or not a clear
path to the renal hilum exists.
[0338] In summary, in one technique, a diagnostic test energy is
delivered through the skin to the region of the renal blood
vessels. Next, an assessment of the visibility of the renal hilum
in terms of distance and clearance is made and therapeutic
transducers are switched on or off based on clearance to the renal
hilum from a path through the skin. Such a technique might continue
throughout treatment or prior to treatment.
[0339] Combining the above data, FIG. 7L depicts a generalized
system to inhibit nerves which surround a blood vessel 4975. In a
first step, an image of the vessel is produced 4964; next a length
of the vessel is scanned 4966; following this step, a direction of
the vessel is determined in three dimensional space and delivery of
a heat cloud is performed circumferentially around the vessel in
which the heat cloud is produced at least 5 mm from the vessel wall
in a radial direction and over a length of at least 5 mm. The cloud
is a region of diffused heat without focal hot spots. The heat
diffuses from the region and can be generated from inside the
vessel or outside the vessel. The vessel itself is protected by
convection and removal of heat from the vessel via the natural
blood flow or through the addition of an additional convective
device in or near the vessel.
[0340] The heat cloud can be generated by high intensity ultrasound
(see modeling and data below), radiofrequency energy, and/or
optical energy. For example, infrared energy can be delivered
through the blood vessel wall to heat the region surrounding the
blood vessel. The heating effect can be detected through MRI
thermometry, infrared thermometry, laser thermometry, etc. The
infrared light may be applied alone or in combination with
phototherapeutic agents.
[0341] In some embodiments, a heat cloud is not generated but a
cloud to inhibit or ablate nerves in the region may be provided.
Such cloud may be gas (e.g. carbon dioxide), liquid (hot water),
phototherapeutic agents, and other toxins such as ethanol, phenol,
and neurotoxins.
[0342] In contrast to devices which deliver highly focused heat to
the wall and rely on conduction or current fall from the vessel
wall, a heatcloud or generalized cloud presents a potentially safer
option in which the nerve ablating components are diffused around
the vessel.
[0343] FIG. 7M depicts an example of delivering a heat cloud 4974
to a blood vessel from outside the patient 4972. The vessel is
placed in a three dimensional coordinate reference. The vessel is
targeted during treatment. The cloud surrounds the vessels and the
entire hilum leading to the kidney.
[0344] FIG. 7N shows a depiction of the nerves leading to the
kidney. This picture is from an actual dissection of the vessels
from a human cadaver. As can be seen, the nerves 4982 surround the
blood vessels leading to the kidney 4984. The heat cloud 4980 is
shown surrounding the nerves 4982 leading to the kidney 4984.
Importantly, limitation of previous catheter based approaches was
that the heat cloud could not be generated around the vessels from
a location inside the vessels. This heat cloud effectively allows
for the target region to be overscanned during the treatment.
[0345] FIG. 7O depicts a cross section of the cloud 4984
surrounding the nerves 4986 and vessels 4988. It can be seen that a
focal method to heat the nerves through the vessel wall might be
difficult to affect a large portion of the nerves because the
nerves are so diffusely presented in the region in some cases.
Therefore, in this embodiment, heat is applied diffusely to the
region surrounding the blood vessel in the form of a cloud.
[0346] FIG. 8A depicts a percutaneous procedure and device 5010 in
which the region around the renal artery is directly approached
through the skin from an external position. A combination of
imaging and application of energy (e.g. ablation) may be performed
to ablate the region around the renal artery to treat hypertension,
end stage renal disease, diabetes, sleep apnea, and/or heart
failure. Probe 5010 is positioned through the skin and in proximity
to the kidney 5030. The probe may include sensors at its tip 5020
which detect heat or temperature or may enable augmentation of the
therapeutic energy delivery. One or more imaging devices (e.g., CT
device, ultrasound device, MRI device) may be utilized to ensure a
clear path for the probe to reach the region of the renal hilum.
Ablative, ionizing energy, heat, or light may be applied to the
region to inhibit the sympathetic nerves around the renal artery
using the probe 5010. Ultrasound, radiofrequency, microwave, direct
heating elements, and balloons with heat or energy sources may be
applied to the region of the sympathetic nerves. Imaging may be
included on the probe or performed separately while the probe is
being applied to the region of the renal blood vessels.
[0347] In one embodiment, the percutaneous procedure in FIG. 8A is
performed under MRI, CT, or ultrasound guidance to obtain
localization or information about the degree of heat being applied.
In one embodiment, ultrasound is applied but at a sub-ablative
dose. That is, the energy level is enough to damage or inhibit the
nerves but the temperature is such that the nerves are not ablated
but paralyzed or partially inhibited by the energy. A particularly
preferred embodiment would be to perform the procedure under
guidance from an MRI scanner because the region being heated can be
determined anatomically in real time as well via temperature maps.
As described above, the images after heating can be compared to
those at baseline and the signals are compared at the different
temperatures.
[0348] In one embodiment, selective regions of the kidney are
ablated through the percutaneous access route; for example, regions
which secrete hormones which are detrimental to a patient or to the
kidneys or other organs. Using energy applied externally to the
patient through the skin and from different angles affords the
ability to target any region in or on the kidney or along the renal
nerves or at the region of the adrenal gland, aorta, or sympathetic
chain. This greater breadth in the number of regions to be targeted
is enabled by the combination of external imaging and external
delivery of the energy from a multitude of angles through the skin
of the patient and to the target. The renal nerves can be targeted
at their takeoff from the aorta onto the renal artery, at their
synapses at the celiac ganglia, or at their bifurcation point along
the renal artery.
[0349] In a further embodiment, probe 5010 can be utilized to
detect temperature or motion of the region while the ultrasound
transducers are applying the energy to the region. A motion sensor,
position beacon, or accelerometer can be used to provide feedback
for the HIFU transducers. In addition, an optional temperature or
imaging modality may be placed on the probe 5010. The probe 5010
can also be used to locate the position within the laparoscopic
field for the ablations to be performed. The dose delivered by this
probe is approximately
[0350] In FIG. 8B, intravascular devices 5050, 5055 are depicted
which apply energy to the region around the renal arteries 5065
from within the renal arteries. The intravascular devices can be
utilized to apply radiofrequency, ionizing radiation, and/or
ultrasound (either focused or unfocused) energy to the renal artery
and surrounding regions. MRI or ultrasound or direct thermometry
can be further utilized to detect the region where the heat is
being applied while the intravascular catheter is in place.
[0351] In one embodiment, devices 5050, 5055 (FIG. 8B) apply
ultrasound energy which inhibits nerve function not by heating, but
by mechanisms such as periodic pressure changes, radiation
pressure, streaming or flow in viscous media, and pressures
associated with cavitation, defined as the formation of holes in
liquid media. Heat can selectively be added to these energies but
not to create a temperature which ablates the nerves, thereby
facilitating the mechanism of vibration and pressure. In this
embodiment, the ultrasound is not focused but radiates outward from
the source to essentially create a cylinder of ultrasonic waves
that intersect with the wall of the blood vessel. An interfacial
material between the ultrasound transducer and the wall of the
artery may be provided such that the ultrasound is efficiently
transduced through the arterial wall to the region of the nerves
around the artery. In another embodiment, the ultrasound directly
enters the blood and propagates through the ultrasound wall to
affect the nerves. In some embodiments, cooling is provided around
the ultrasound catheter which protects the inside of the vessel yet
allows the ultrasound to penetrate through the wall to the regions
outside the artery. A stabilization method for the ultrasound probe
is also included in such a procedure. The stabilization method
might include a stabilizing component added to the probe and may
include a range finding element component of the ultrasound so that
the operator knows where the ultrasound energy is being applied
from outside the wall of the blood vessel.
[0352] In another embodiment, an ultrasound probe is applied
directly to the wall of the blood vessel, utilizing heat and/or
vibration to inhibit the nerves surrounding the blood vessel. In
this embodiment, the temperature at the wall of the blood vessel
can be measured directly at the catheter tip through laser
thermometry or a thermistor. Alternatively, MRI or infrared
thermometry can be used as well.
[0353] Imaging can be performed externally or internally in this
embodiment in which a catheter is placed inside the renal arteries.
For example, external imaging with MRI or Ultrasound may be
utilized to visualize changes during the ultrasound modulation of
the nerve bundles. Indeed, these imaging modalities may be utilized
for the application of any type of energy within the wall of the
artery. For example, radiofrequency delivery of energy through the
wall of the renal artery may be monitored through similar
techniques. Thus the monitoring of the procedural success of the
technique is independent of the technique in most cases. In one
method, a radiofrequency catheter is applied to the wall of the
blood vessel and the temperature of the region around the blood
vessel is measured. In another embodiment, heated water vapor is
applied to the region of the blood vessel. In another embodiment,
MRI induced heating of a metallic tipped catheter is detected using
MRI thermometry. In another embodiment, focused ultrasound is
detected using MRI thermometry.
[0354] Alternatively, in another embodiment, the devices 5050, 5055
can be utilized to direct externally applied energy (e.g.
ultrasound) to the correct place around the artery as the HIFU
transducers deliver the energy to the region. For example, the
intravascular probe 5050 can be utilized as a homing beacon for the
imaging/therapeutic technology utilized for the externally
delivered HIFU.
[0355] FIG. 8C depicts a percutaneous procedure to inhibit the
renal sympathetic nerves. Probe 5010 is utilized to approach the
renal hilum 5060 region from posterior and renal artery 5065. With
the data presented below, the probe can be armed with HIFU to
denervate the region. The data presented below indicates the
feasibility of this approach as far as ultrasound enabling
denervation of the vessels quickly and easily. In another
embodiment, a cloud of heat energy is produced near or around the
blood vessel, for example, with warmed gas, with a neurotoxin, with
a gas such as carbon dioxide which is known to anesthetize nerves
at high concentrations, etc.
[0356] In FIG. 8D, a technique is shown in which ultrasound
transmitted through the wall of a blood vessel 5560 from a catheter
5140 with a piezoelectric crystal 5120 at one end. A detector 5160
is placed outside the skin 5112 of the patient to detect the signal
emitted from the piezoelectric. A number of parameters 5170 can be
determined/detected with this method including position,
temperature, acoustic power, radiation pressure, and cavitation
threshold. The detection might be done inside the catheter in some
embodiments or at the skin in other embodiments. In one embodiment,
for example, the acoustic impedance from the blood vessel to the
skin is determined through the detection of the time of flight of
the ultrasound waves from the piezoelectric transducer on the end
of the catheter. In another embodiment, structures which might
block ultrasound are detected by sending a signal to the external
detector form the internal detector.
[0357] FIGS. 8E and 8F depict cross sectional 5200 imaging of the
abdomen. Energy waves 5230 are depicted traveling from a posterior
direction through the skin to the region of the blood vessels 5210
leading to the kidney. Device 5240 can be placed outside the
patient on the skin of the patient, which transmit the waves 5230
to a nerve region surrounding a blood vessel. CT or MRI imaging can
be utilized during the procedure to help direct the waves. In
addition, or alternatively, thermal imaging (e.g. with infrared or
laser light) may be used.
[0358] In another embodiment, the physiologic process of arterial
expansion (aneurysms) is targeted. In FIG. 9a, an ultrasound
transducer is 6005 is placed near the wall of an aneurysm 6030.
Ultrasonic energy 6015 is applied to the wall 6030 of the aneurysm
to thicken the wall and prevent further expansion of the aneurysm.
In some embodiments, clot within the aneurysm is targeted as well
so that the clot is broken up or dissolved with the ultrasonic
energy. Once the wall of the aneurysm is heated with ultrasonic
energy to a temperature of between 40 and 70 degrees, the collagen,
elastin, and other extracellular matrix in the wall will harden as
it cools, thereby preventing the wall from further expansion.
[0359] In another embodiment, a material is placed in the aneurysm
sac and the focused or non-focused ultrasound utilized to harden or
otherwise induce the material in the sac to stick to the aorta or
clot in the aneurysm and thus close the aneurysm permanently. In
one embodiment therefore, an ultrasound catheter is placed in an
aorta at the region of an aneurysm wall or close to a material in
an aneurysmal wall. The material can be a man-made material placed
by an operator or it can be material such as thrombus which is in
the aneurysm naturally. Ultrasound is applied to the wall, or the
material, resulting in hardening of the wall or of the material,
strengthening the aneurysm wall and preventing expansion. The
energy can also be applied from a position external to the patient
or through a percutaneously positioned energy delivering
catheter.
[0360] FIG. 9b 6000 depicts a clot prevention device 6012 (vena
cava filter) within a blood vessel such as the aorta or vena cava
6010. The ultrasound catheter 6005 is applied to the clot
prevention device (filter) 6012 so as to remove the clot from the
device or to free the device 6012 from the wall of the blood vessel
in order to remove it from the blood vessel 6000.
[0361] FIG. 9C depicts a device and method in which the celiac
plexus 6020 close to the aorta 6000 is ablated or partially heated
using heat or vibrational energy from an ultrasonic energy source
6005 which can apply focused or unfocused sound waves 6007 at
frequencies ranging from 20 kilohertz to 5 Mhz and at powers
ranging from 1 mW to over 100 kW in a focused or unfocused manner.
Full, or partial ablation of the celiac plexus 6020 can result in a
decrease in blood pressure via a similar mechanism as applying
ultrasonic energy to the renal nerves; the ablation catheter is a
focused ultrasound catheter but can also be a direct (unfocused)
ultrasonic, a microwave transducer, or a resistive heating element.
Energy can also be delivered from an external position through the
skin to the aorta or celiac plexus region.
[0362] FIG. 10 depicts a method 6100 to treat a patient with high
intensity or low intensity focused ultrasound (HIFU or LIFU) 6260.
In a first step, a CT and/or MRI scan and/or thermography and/or
ultrasound (1D, 2D, 3D) is performed 6110. A fiducial or other
marking on or in the patient 6120 is optionally used to mark and
track 6140 the patient. The fiducial can be an implanted fiducial,
a temporary fiducial placed internally or externally in or on the
patient, or a fiducial intrinsic to the patient (e.g. bone, blood
vessel, arterial wall) which can be imaged using the
CT/MRI/Ultrasound devices 6110. The fiducial can further be a
temporary fiducial such as a catheter temporarily placed in an
artery or vein of a patient or a percutaneously placed catheter. A
planning step 6130 for the HIFU treatment is performed in which
baseline readings such as position of the organ and temperature are
determined; a HIFU treatment is then planned using a model (e.g.
finite element model) to predict heat transfer, or pressure to heat
transfer, from the ultrasound transducers 6130. The planning step
incorporates the information on the location of the tissue or
target from the imaging devices 6110 and allows placement of the
anatomy into a three dimensional coordinate reference such that
modeling 6130 can be performed.
[0363] The planning step 6130 includes determination of the
positioning of the ultrasound transducers as far as position of the
focus in the patient. X, Y, Z, and up to three angular coordinates
are used to determine the position of the ultrasonic focus in the
patient based on the cross sectional imaging 6110. The HIFU
transducers might have their own position sensors built in so that
the position relative to the target can be assessed. Alternatively,
the HIFU transducers can be rigidly fixed to the table on which the
patient rests so that the coordinates relative to the table and the
patient are easily obtainable. The flow of heat is also modeled in
the planning step 6130 so that the temperature at a specific
position with the ultrasound can be planned and predicted. For
example, the pressure wave from the transducer is modeled as it
penetrates through the tissue to the target. For the most part, the
tissue can be treated as water with a minimal loss due to
interfaces. Modeling data predicts that this is the case. The
relative power and phase of the ultrasonic wave at the target can
be determined by the positional coupling between the probe and
target. A convective heat transfer term is added to model heat
transfer due to blood flow, particularly in the region of an
artery. A conductive heat transfer term is also modeled in the
equation for heat flow and temperature.
[0364] Another variable which is considered in the planning step is
the size of the lesion and the error in its position. In the
ablation of small regions such as nerves surrounding blood vessels,
the temperature of the regions may need to be increased to a
temperature of 60-90 degrees Celsius to permanently ablate nerves
in the region. Temperatures of 40-60 degrees may temporarily
inhibit or block the nerves in these regions and these temperatures
can be used to determine that a patient will respond to a specific
treatment without permanently ablating the nerve region.
Subsequently, additional therapy can be applied at a later time so
as to complete the job or perhaps, re-inhibit the nerve regions. In
some embodiments, the temperature inside the blood vessel is
measured and held to a temperature of less than 60 degrees Celsius,
or less than 70 degrees Celsius, in which case the procedure might
be stopped (e.g., when a desired temperature is reached).
[0365] An error analysis is also performed during the treatment
contemplated in FIG. 10. Each element of temperature and position
contains an error variable which propagates through the equation of
the treatment. The errors are modeled to obtain a virtual
representation of the temperature mapped to position. This map is
correlated to the position of the ultrasound transducers in the
treatment of the region of interest.
[0366] During the delivery of the treatment 6260, the patient may
move, in which case the fiducials 6120 track the movement and the
position of the treatment zone is re-analyzed 6150 and the
treatment is restarted or the transducers are moved either
mechanically or electrically to a new focus position.
[0367] In another embodiment, a cross-sectional technique of
imaging is used in combination with a modality such as ultrasound
to create a fusion type of image. The cross-sectional imaging is
utilized to create a three dimensional data set of the anatomy. The
ultrasound, providing two dimensional images, is linked to the
three dimensional imaging provided by the cross-sectional machine
through fiducial matches between the ultrasound and the MRI. As a
body portion moves within the ultrasound field, the corresponding
data is determined (coupled to) the cross-sectional (e.g. MRI
image) and a viewing station can show the movement in the three
dimensional dataset. The ultrasound provides real time images and
the coupling to the MRI or other cross-sectional image depicts the
ultrasound determined position in the three dimensional space.
[0368] FIG. 11 depicts the treatment 7410 of another disease in the
body of a patient, this time in the head of a patient. Subdural and
epidural hematomas occur as a result of bleeding of blood vessels
in the dural or epidural spaces of the brain, spinal column, and
scalp. FIG. 11 depicts a CT or MRI scanner 7300 and a patient 7400
therein. An image is obtained of the brain 7000 using a CT or MRI
scan. The image is utilized to couple the treatment zone 7100 to
the ultrasound array utilized to heat the region. In one embodiment
7100, a subdural hematoma, either acute or chronic, is treated. In
another embodiment 7200, an epidural hematoma is treated. In both
embodiments, the region of leaking capillaries and blood vessels
are heated to stop the bleeding, or in the case of a chronic
subdural hematoma, the oozing of the inflammatory capillaries.
[0369] In an exemplary embodiment of modulating physiologic
processes, a patient 7400 with a subdural or epidural hematoma is
chosen for treatment and a CT scan or MRI 7300 is obtained of the
treatment region. Treatment planning ensues and the chronic region
of the epidural 7200 or sub-dural 7010 hematoma is targeted for
treatment with the focused ultrasound 7100 transducer technology.
Next the target of interest is placed in a coordinate reference
frame as are the ultrasound transducers. Therapy 7100 ensues once
the two are coupled together. The focused ultrasound heats the
region of the hematoma to dissolve the clot and/or stop the leakage
from the capillaries which lead to the accumulation of fluid around
the brain 7420. The technology can be used in place of or in
addition to a burr hole, which is a hole placed through the scalp
to evacuate the fluid.
[0370] FIG. 12 depicts a laparoscopic based approach 8000 to the
renal artery region in which the sympathetic nerves 8210 can be
ligated, interrupted, or otherwise modulated. In laparoscopy, the
abdomen of a patient is insufflated and laparoscopic instruments
introduced into the insufflated abdomen. The retroperitoneum is
easily accessible through a flank approach or (less so) through a
transabdominal (peritoneal) approach. A laparoscopic instrument
8200 with a distal tip 8220 can apply heat or another form of
energy or deliver a drug to the region of the sympathetic nerves
8210. The laparoscopic instrument can also be utilized to ablate or
alter the region of the celiac plexus 8300 and surrounding ganglia.
The laparoscope can have an ultrasound transducer 8220 attached, a
temperature probe attached, a microwave transducer attached, or a
radiofrequency transducer attached. The laparoscope can be utilized
to directly ablate or stun the nerves (e.g. with a lower
frequency/energy) surrounding vessels or can be used to ablate or
stun nerve ganglia which travel with the blood vessels. Similar
types of modeling and imaging can be utilized with the percutaneous
approach as with the external approach to the renal nerves. With
the discovery through animal experimentation (see below) that a
wide area of nerve inhibition can be affected with a single
ultrasound probe in a single direction (see above), the nerve
region does not have to be directly contacted with the probe, the
probe instead can be directed in the general direction of the nerve
regions and the ultrasound delivered. For example, the probe can be
placed on one side of the vessel and activated to deliver focused
or semi-focused ultrasound over a generalized region which might
not contain greater than 1 cm of longitudinal length of the artery
but its effect is enough to completely inhibit nerve function
along.
[0371] FIG. 13 depicts an algorithm 8400 for the treatment of a
region of interest using directed energy from a distance. MRI
and/or CT with or without an imaging agent 8410 can be utilized to
demarcate the region of interest (for example, the ablation zone)
and then ablation 8420 can be performed around the zone identified
by the agent using any of the modalities above. This algorithm is
applicable to any of the therapeutic modalities described above
including external HIFU, laparoscopic instruments, intravascular
catheters, percutaneous catheters and instruments, as well as any
of the treatment regions including the renal nerves, the eye, the
kidneys, the aorta, or any of the other nerves surrounding
peripheral arteries or veins. Imaging 8430 with CT, MRI,
ultrasound, or PET can be utilized in real time to visualize the
region being ablated. At such time when destruction of the lesion
is complete 8440, imaging with an imaging (for example, a molecular
imaging agent or a contrast agent such as gadolinium) agent 8410
can be performed again. The extent of ablation can also be
monitored by monitoring the temperature or the appearance of the
ablated zone under an imaging modality. Once lesion destruction is
complete 8440, the procedure is finished. In some embodiments,
ultrasonic diagnostic techniques such as elastography are utilized
to determine the progress toward heating or ablation of a
region.
[0372] FIG. 14 depicts ablation in which specific nerve fibers of a
nerve are targeted using different temperature gradients, power
gradients, or temperatures 8500. For example, if temperature is
determined by MRI thermometry or with another technique such as
ultrasound, infrared thermography, or a thermocouple, then the
temperature can be kept at a temperature in which only certain
nerve fibers are targeted for destruction or inhibition.
Alternatively, part or all of the nerve can be turned off
temporarily to then test the downstream effect of the nerve being
turned off. For example, the sympathetic nerves around the renal
artery can be turned off with a small amount of heat or other
energy (e.g. vibrational energy) and then the effect can be
determined. For example, norepinephrine levels in the systemic
blood, kidney, or renal vein can be assayed; alternatively, the
stimulation effect of the nerves can be tested after temporary
cessation of activity (e.g. skin reactivity, blood pressure
lability, cardiac activity, pulmonary activity, renal artery
constriction in response to renal nerve stimulation). For example,
in one embodiment, the sympathetic activity within a peripheral
nerve is monitored; sympathetic activity typically manifests as
spikes within a peripheral nerve electrical recording. The number
of spikes correlates with the degree of sympathetic activity or
over-activity. When the activity is decreased by (e.g. renal artery
de-inervation), the concentration of spikes in the peripheral nerve
train is decreased, indicating a successful therapy of the
sympathetic or autonomic nervous system. Varying frequencies of
vibration can be utilized to inhibit specific nerve fibers versus
others. For example, in some embodiments, the efferent nerve fibers
are inhibited and in other embodiments, the afferent nerve fibers
are inhibited. In some embodiments, both types of nerve fibers are
inhibited, temporarily or permanently. In some embodiments, the C
fibers 8520 are selectively blocked at lower heat levels than the A
nerve fibers. In other embodiment, the B fibers are selectively
treated or blocked and in some embodiments, the A fibers 8530 are
preferentially blocked. In some embodiments, all fibers are
inhibited by severing the nerve with a high dose of ultrasound
8510. Based on the experimentation described above, the power
density to achieve full blockage might be around 100-800 W/cm.sup.2
or with some nerves from about 500 to 2500 W/cm.sup.2. In some
embodiments, a pulse train of 100 or more pulses each lasting 1-2
seconds (for example) and delivering powers from about 50
w/cm.sup.2 to 500 W/cm.sup.2. Indeed, prior literature has shown
that energies at or about 100 W/Cm.sup.2 is adequate to destroy or
at least inhibit nerve function (Lele, P P. Effects of Focused
Ultrasound Radiation on Peripheral Nerve, with Observations on
Local Heating. Experimental Neurology 8, 47-83 1963). Based on data
obtained in proof of concept, the ramp up to the correct power is
desirable in some embodiments due to the nature of the region in
which there is a tremendous amount of perfusion through the large
blood vessels through the renal vein, artery, vena cava, etc.
Modeling indicates that a slow increase in power ramp up allows the
blood vessels to remove a greater amount of heat than when the rise
in temperature is performed within a few seconds.
[0373] FIG. 15a depicts treatment 8600 of a vertebral body or
intervertebral disk 8610 in which nerves within 8640 or around the
vertebral column 8630 are targeted with energy 8625 waves. In one
embodiment, nerves around the facet joints are targeted. In another
embodiment, nerves leading to the disks or vertebral endplates are
targeted. In another embodiment, nerves within the vertebral bone
8630 are targeted by heating the bone itself. Sensory nerves run
through canals 8635 in the vertebral bone 8630 and can be inhibited
or ablated by heating the bone 8630. In one method of treatment,
focused ultrasound is applied from a position external to a patient
and energy directed toward the vertebral bone; the bone is heated
by the focused ultrasound and the nerve inside the bone is injured
or paralyzed by the heat inside the bone. Such methodology can also
be utilized to harden bone in the context of treating a vertebral
body fracture to quell the pain response to the fracture.
[0374] FIG. 15B depicts a close-up of the region of the facet
joint. Focused ultrasound to this region can inhibit nerves
involved in back pain which originate at the dorsal root nerve and
travel to the facet joint 8645. Ablation or inhibition of these
nerves can limit or even cure back pain due to facet joint
arthropathy. Focused ultrasound can be applied to the region of the
facet joint from a position outside the patient to the facet joint
using powers of between 100 W/cm.sup.2 and 2500 W/cm.sup.2 at the
nerve from times ranging from 1 second to 10 minutes.
[0375] FIG. 16A depicts a set of lesion types, sizes, and anatomies
8710a-f which lead to de-innervation of the different portions of
the sympathetic nerve tree around the renal artery. For example,
the lesions can be annular, cigar shaped, linear, doughnut and/or
spherical; the lesions can be placed around the renal arteries
8705, inside the kidney 8710, and/or around the aorta 8700. For
example, the renal arterial tree comprises a portion of the aorta
8700, the renal arteries 8705, and kidneys 8715. Lesions 8714 and
8716 are different types of lesions which are created around the
aorta 8700 and vascular tree of the kidneys. Lesions 8712 and 8718
are applied to the pole branches from the renal artery leading to
the kidney and inhibit nerve functioning at branches from the main
renal artery. These lesions also can be applied from a position
external to the patient. Lesions can be placed in a spiral shape
8707 along the length of the artery as well. These lesions can be
produced using energy delivered from outside the blood vessels
using a completely non-invasive approach in which the ultrasound is
applied through the skin to the vessel region or the energy can be
delivered via percutaneous approach. Either delivery method can be
accomplished through the posterior approach to the blood vessels as
discovered and described above.
[0376] In one method therefore, ultrasound energy can be applied to
the blood vessel leading to a kidney in a pattern such that a
circular pattern of heat and ultrasound is applied to the vessel.
The energy is transmitted through the skin in one embodiment or
through the artery in another embodiment. As described below,
ultrasound is transmitted from a distance and is inherently easier
to apply in a circular pattern because it doesn't only rely on
conduction.
[0377] Previously, it was unknown and undiscovered whether or not
the annular shaped lesions as shown in FIG. 16a would have been
sufficient to block nerve function of the autonomic nerves around
the blood vessels. Applicant of the subject application discovered
that the annular shaped ablations 8710 not only block function but
indeed completely block nerve function around the renal artery and
kidney and with very minimal damage (FIG. 16C), if any, to the
arteries and veins themselves. In these experiments, focused
ultrasound was used to block the nerves; the ultrasound was
transmitted through and around the vessel from the top (that is,
only one side of the vessel) at levels of 200-2500 W/cm.sup.2. The
energy travels through the flowing blood to affect the opposite
side of the blood vessel. Simulations are shown in FIGS. 16B and
16D and described below. Norepinephrine levels in the kidney 8780,
which are utilized to determine the degree of nerve inhibition,
were determined before and after application of energy. The lower
the levels of norepinephrine, the more nerves which have been
inhibited or affected. In these experiments which were performed,
the norepinephrine levels approached zero 8782 versus controls
(same animal, opposite kidney) 8784 which remained high. In fact,
the levels were equal to or lower than the surgically denuded blood
vessels (surgical denudement involves directly cutting the nerves
surgically and application of phenol to the vessel wall). It is
important to note that the renal artery and vein walls remained
substantially unharmed; this is likely due to the fact that the
quick arterial blood flow removes heat from the vessel wall and the
fact that the main renal artery is extremely resilient due to its
large size, high blood flow, and thick wall; these findings are
consistent with the modeling performed as shown in FIGS. 16B and
16D. To summarize, ultrasound (focused and relatively unfocused)
was applied to one side of the renal artery and vein complex. The
marker of nerve inhibition, norepinephrine levels inside the
kidney, were determined to be approaching zero after application to
the nerves from a single direction, transmitting the energy through
the artery wall to reach nerves around the circumference of the
artery. The level of zero norepinephrine 8782 indicates essentially
complete abolition of nerve function proving that the annular
lesions were in fact created as depicted in FIG. 16A and simulated
in FIGS. 16B and 16D. Histological results also confirm the annular
nature of the lesions and limited collateral damage as predicted by
the modeling in 16B.
[0378] Therefore, in one embodiment, the ultrasound is applied from
a position external to the artery in such a manner so as to create
an annular or semi-annular rim of heat all the way around the
artery to inhibit, ablate, or partially ablate the autonomic nerves
surrounding the artery. The walls or the blood flow of the artery
can be utilized to target the ultrasound to the nerves which, if
not directly visualized, are visualized through use of a model to
approximate the position of the nerves based on the position of the
blood vessel.
[0379] FIG. 16B further supports the physics and physiology
described herein, depicting a theoretical simulation 8750 of the
physical and animal experimentation described above. That is,
focused ultrasound was targeted to a blood vessel in a computer
simulation 8750. The renal artery 8755 is depicted within the
heating zone generated within a focused ultrasound field. Depicted
in the figure is the temperature at <1 s 8760 and at
approximately 5 s 8765 and longer time >10 s 8767. Flow
direction 8770 is shown as well. The larger ovals depict higher
temperatures with the central temperature >100.degree. C. The
ultrasound field is transmitted through the artery 8755, with heat
building up around the artery as shown via the temperature maps
8765. Importantly, this theoretical simulation also reveals the
ability of the ultrasound to travel through the artery or blood
vessel 8767 and affect both walls of the blood vessel. These data
are consistent with the animal experimentation described above,
creating a unified physical and experimental dataset. In some
cases, the ultrasonic energy may be applied to the blood vessel
quickly to avoid removal of the heat by the blood flow. In the case
where the ultrasound ramp up around the vessel is not applied
quickly, a steady state is reached in which the heat applied is
equal to the heat dissipated, and it may become difficult to heat
the rim of the blood vessel.
[0380] FIG. 16C depicts the results of an experimental focused
ultrasound treatment in which one kidney was treated with the
ultrasound and the other served as a control. Norepinephrine 8780
is the marker of the effect of sympathetic nerve inhibition and its
concentration was measured in the cortex of the kidney. The
experimental result 8782 was very low compared to the control 8784
level indicating almost complete inhibition of the nerves which
travel to the kidney. A circumferential effect of the heat is
provided to obtain such a dramatic effect on norepinephrine levels
leading to the kidney.
[0381] FIG. 16D is a depiction of a simulation with multiple beams
being applied to the region of the blood vessel wall. The
ultrasound might be scanned toward the blood vessel or otherwise
located point by point within the treatment region. In one
embodiment, the power to the blood vessel is delivered such that
the temperature ramps over 60 degrees within 2 s or within 5 s or
within 10 s. Subsequently, the energy is turned off and then
reapplied after a period of 1, 2, 5, or 10 seconds. In some
embodiments, the energy may be on for a prescribed duration, such
as 1, 2, 5, 10 seconds, etc. In some embodiments, a technique such
as infrared thermography or laser Doppler thermography is used to
determine the temperature of the skin and subcutaneous tissue to
decide when it is safe to deliver an additional dose of energy to
the target zone. Such a treatment plan creates a cloud of heat
centered on the inside of the wall of the blood vessel. In other
embodiments, the energy may be on for 30, 60, or 90 seconds, but
the power is lower than that for the shorter on-time periods of 1,
2, 5, 10 seconds.
[0382] Similarly, other vessels leading to other organs which rely
on sympathetic, parasympathetic, and general autonomic innervation
can be treated as well utilizing this technique. Referring to FIG.
5C, blood vessels which lead to the eye 2105 (carotid artery), the
mouth (facial arteries) and saliva glands 2107, the heart 2109, the
bronchi 2110, the stomach 2112, the gallbladder 2114 and liver
2118, the bladder 2114, the adrenal gland 2116, the pancreas can be
stimulated or inhibited utilizing this technique of focused energy
delivery targeting a blood vessel. In one example, an underactive
pancreas is treated by denervation, which results in improved
glucose tolerance. In another embodiment, the liver is denervated
by ablated arteries surrounding portal veins or hepatic arteries
leading to the liver. Any of the above organs may be denervated
using a similar technique as that described with reference to the
blood vessels leading to the kidney.
[0383] FIGS. 16D-H depict another simulation with multiple
treatment performed over time (up to 132 s) in a pattern such as
shown in FIG. 16D. FIG. 16H is a close up of FIG. 16D and depicts a
blood vessel 8795 (with a flow rate of the renal artery and renal
vein in a human being) and vessel wall 8796. In this simulation,
the focused energy was applied in a 10 s on and 6 s off pattern to
allow heat to surround 8793 the vessel 8795. The transducer 8790,
subcutaneous tissue 8792, and muscle wall 8794 are depicted. This
simulation reveals the ability of focused energy to create a cloud
around the blood vessel particularly with high blood flow such as
to the kidney.
[0384] FIGS. 16 I,J,K depict some of the patterns which can be
applied to a blood vessel. In FIG. 16D, application of the focused
energy 8770 to the vessel is shown in a pattern created by the
transducer mover.
[0385] FIG. 16I depicts another type of pattern 8772 with a broader
brush stroke around the vessel.
[0386] FIG. 16I and FIG. 16J depict cross sectional patterns across
a blood vessel. FIG. 16K depicts a longitudinal pattern 8774 along
the vessel.
[0387] FIGS. 16L and 16M depict the results of an experiment 8787
in which nerves leading to the kidney are treated with heat from an
externally applied source, and nerves inhibited from producing
norepinephrine.
[0388] FIG. 16L depicts the results of an experiment in which the
HIFU 8644 was compared to a surgical control 8648. HIFU was applied
across the vessel so that the ultrasound passed through the blood
and the vessel to affect both walls of the vessel. As can be seen
in the FIG. 16L, the HIFU applied from outside the patient is as
good as denervation with surgery revealing that focused ultrasound
can indeed remove, inhibit, or ablate nerves surrounding blood
vessels. To the extent nerves are contained within the walls of the
blood vessel, focused ultrasound can be used to inhibit or ablate
the nerves within the media of the blood vessel wall.
[0389] FIG. 16M depicts a similar experiment in which focused
ultrasound is applied through the skin to the nerves surrounding
the blood vessels traveling to the kidney. Bar 8788 is a control
kidney and 8778 is a therapy kidney. A pattern of heat is applied
to the blood vessel over a 2-3 minute period resulting in the
observed changes in norepinephrine and indicating denervation of
the sympathetic nerves around a blood vessel leading to an
organ.
[0390] As can be seen, the control side 8788, 8644, 8646, 8648
reveal a high norepinephrine level and the therapy side 8778, 8649
reveals a low norepinephrine level, indicating treatment was
successful. This experiment was performed utilizing an externally
placed ultrasound system which focused the energy on the nerves in
one of the patterns shown above.
[0391] Therefore, based on the animal and theoretical
experimentation, there is proven feasibility of utilizing
ultrasound to quickly and efficiently inhibit the nerves around the
renal arteries from a position external to the blood vessels as
well as from a position external to the skin of the patient.
[0392] The pattern of application may be different from systems to
treat tumors and other pathologies in which it is desired that 100%
of the region be treated. The nerve region surrounding the blood
vessels is diffuse and it is not necessary to inhibit all nerves in
order to have an effect on blood pressure. Therefore, the goal is
to apply broad brush strokes of energy across the vessel to create
an annular zone, or cloud of heat around the vessel. Subsequent to
a first treatment, a second treatment may be applied in which
additional nerves are affected. The second treatment may occur
minutes, hours, days, or years after the treatment, and may depend
on physiological changes or regrowth of the nerves. In some cases,
a quality factor is calculated based on the degree of movement of
the applicator. The quality factor relates to the degree of time
the applicator actually was focused on the identified target.
Although 100% is ideal, sometimes it may not be achieved.
Therefore, in some cases, when the applicator focuses on the target
for 90% of the time, the treatment may be considered successful. In
other embodiments, the quality factor might be the amount of time
the targeted region is actually within 90% of the target, for
example, within 500 microns of the target, or within 1 mm of the
target, or within 2 mm of the target, etc. The detection of the
target is determined via imaging, internal fiducial, and/or
external fiducial.
[0393] Utilizing the experimental simulations and animal
experimentation described above, a clinical device can and has been
devised and tested in human patients. FIG. 17A depicts a
multi-transducer HIFU device 1100 which applies a finite lesion
1150 along an artery 1140 (e.g. a renal artery) leading to a kidney
1130. The lesion can be spherical in shape, cigar shaped 1150,
annular shaped 8710 (FIG. 16A), or point shaped; however, in a
preferred embodiment, the lesion runs along the length of the
artery and has a cigar shape 1150. This lesion is generated by a
spherical or semi-spherical type of ultrasound array in a preferred
embodiment. Multiple cigar shaped lesions as shown in FIG. 17C lead
to a ring type of lesion 1350.
[0394] FIG. 17B depicts an imaging apparatus display which monitors
treatment. Lesion 1150 is depicted on the imaging apparatus as is
the aorta 1160 and renal artery 1155. The image might depict heat,
tissue elastography, vibrations, temperature or might be based on a
simulation of the position of the lesion 1150. MRI, CT, infrared
thermography, ultrasound, laser thermography, or thermistors may be
used to determine temperature of the tissue region. FIG. 17C
depicts another view of the treatment monitoring, with the renal
artery in cross section 1340. Lesion 1350 is depicted in cross
section in this image as well. The lesion 1350 might be considered
to circumscribe the vessel 1340 in embodiments where multiple
lesions are applied.
[0395] FIG. 17D depicts a methodology 1500 to analyze and follow
the delivery of therapeutic focused ultrasound to an arterial
region. A key step is to first position 1510 the patient optimally
to image the treatment region; the imaging of the patient might
involve the use of Doppler imaging, M mode imaging, A scan imaging,
or even MRI, fluoroscopy, or CT scan. The imaging unit is utilized
to obtain coordinate data 1530 from the doppler shift pattern of
the artery. Next, the focused ultrasound probe is positioned 1520
relative to the imaged treatment region 1510 and treatment can be
planned or applied.
[0396] FIG. 17E depicts the pathway of the acoustic waves from a
spherical or cylindrical type of ultrasound array 1600. In some
embodiments, the transducer is aspherical such that a sharp focus
does not exist but rather the focus is more diffuse in nature or
off the central axis. Alternatively, the asphericity might allow
for different pathlengths along the axis of the focusing. For
example, one edge of the ultrasound transducer might be called upon
for 15 cm of propagation while another edge of the transducer might
be called upon to propagate only 10 cm, in which case a combination
of different frequencies or angles might be required.
[0397] Ultrasound transducers 1610 are aligned along the edge of a
cylinder 1650, aimed so that they intersect at one or more focal
spots 1620, 1630, 1640 around the vessel (e.g. renal artery). The
transducers 1610 are positioned along the cylinder or sphere or
spherical approximation (e.g. aspherical) 1650 such that several of
the transducers are closer to one focus or the other such that a
range of distances 1620, 1630, 1640 to the artery is created. The
patient and artery are positioned such that their centers 1700
co-localize with the center of the ultrasound array 1600. Once the
centers are co-localized, the HIFU energy can be activated to
create lesions along the length of the artery wall 1640, 1620, 1630
at different depths and positions around the artery. The natural
focusing of the transducers positioned along a cylinder as in FIG.
17E is a lengthwise lesion, longer than in thickness or height,
which will run along the length of an artery 1155 when the artery
1340 is placed along the center axis of the cylinder. When viewed
along a cross section (FIG. 17F), the nerve ablations are
positioned along a clock face 1680 around the blood vessel.
[0398] In another embodiment, a movement system for the transducers
is utilized so that the transducers move along the rim of the
sphere or cylinder to which they are attached. The transducers can
be moved automatically or semi-automatically, based on imaging or
based on external position markers. The transducers are
independently controlled electrically but coupled mechanically
through the rigid structure.
[0399] Importantly, during treatment, a treatment workstation 1300
(FIG. 17C) gives multiple views of the treatment zone with both
physical appearance and anatomy 1350. Physical modeling is
performed in order to predict lesion depth and the time to produce
the lesion; this information is fed back to the ultrasound
transducers 1100. The position of the lesion is also constantly
monitored in a three dimensional coordinate frame and the
transducer focus at lesions center 1150 in the context of
monitoring 1300 continually updated.
[0400] In some embodiments, motion tracking prevents the lesion or
patient from moving too far out of the treatment zone during the
ablation. If the patient does move outside the treatment zone
during the therapy, then the therapy can be stopped. Motion
tracking can be performed using the ultrasound transducers,
tracking frames and position or with transducers from multiple
angles, creating a three dimensional image with the transducers.
Alternatively, a video imaging system can be used to track patient
movements, as can a series of accelerometers positioned on the
patient which indicate movement. In some cases, this embodiment can
include a quality factor used to change the dose delivered to the
patient based on movement which tends to smear the delivered dose,
as described herein.
[0401] FIG. 18 depicts a micro-catheter 8810 which can be placed
into renal calyces 8820; this catheter allows the operator to
specifically ablate or stimulate 8830 regions of the kidney 8800.
The catheter can be used to further allow for targeting of the
region around the renal arteries and kidneys by providing
additional imaging capability or by assisting in movement tracking
or reflection of the ultrasound waves to create or position the
lesion. The catheter or device at or near the end of the catheter
may transmit signals outside the patient to direct an energy
delivery device which delivers energy through the skin. Signaling
outside the patient may comprise energies such as radiofrequency
transmission outside the patient or radiofrequency from outside to
the inside to target the region surrounding the catheter. The
following patent and patent applications describe the delivery of
ultrasound using a targeting catheter within a blood vessel, and
are expressly incorporated by reference herein: Ser. Nos.
11/583,569, 12/762,938, 11/583,656, 12/247,969, 10/633,726,
09/721,526, 10/780,405, 09/747,310, 12/202,195, 11/619,996,
09/696,076
[0402] In one system 8800, a micro catheter 8810 is delivered to
the renal arteries and into the branches of the renal arteries in
the kidney 8820. A signal is generated from the catheter into the
kidney and out of the patient to an energy delivery system. Based
on the generated signal, the position of the catheter in a three
dimensional coordinate reference is determined and the energy
source is activated to deliver energy 8830 to the region indicated
by the microcatheter 8810.
[0403] In an additional embodiment, station keeping is utilized.
Station keeping enables the operator to maintain the position of
the external energy delivery device with respect to the movement of
the operator or movement of the patient. As an example, targeting
can be achieved with the energy delivery system and tracking of
movement of the energy delivery system relative to the target. As
the energy delivery system moves from its initial state, the
station keeping allows the focus to be moved with the target as the
target moves from its original position. Such station keeping is
described herein and illustrated in FIGS. 19C-D. A quality factor
may be used by the device to increase or decrease dosing depending
on the degree of movement. For example, if the quality factor
deviation from a desired value by a certain amount, then the dose
may be increased or decreased.
[0404] The microcatheter may be also be utilized to place a flow
restrictor inside the kidney (e.g. inside a renal vein) to "trick"
the kidney into thinking its internal pressure is higher than it
might be. In this embodiment, the kidney generates signals to the
central nervous system to lower sympathetic output to target organs
in an attempt to decrease its perfusion pressure.
[0405] Alternatively, specific regions of the kidney might be
responsible for hormone excretion or other factors which lead to
hypertension or other detrimental effects to the cardiovascular
system. The microcatheter can generate ultrasound, radiofrequency,
microwave, or X-ray energy. The microcatheter can be utilized to
ablate regions in the renal vein or intra-parenchymal venous
portion as well. In some embodiments, ablation is not required but
vibratory energy emanating from the probe is utilized to affect, on
a permanent or temporary basis, the mechanoreceptors or
chemoreceptors in the location of the hilum of the kidney.
[0406] FIG. 19A depicts the application 8900 of energy to the
region of the renal artery 8910 and kidney 8920 using physically
separated transducers 8930, 8931. Although two are shown, the
transducer can be a single transducer which is connected all along
an outer frame. The transducer(s) can be spherical (sharp focus) or
aspherical (diffuse focus), they can be coupled to an imaging
transducer directly or indirectly where the imaging unit might be
separated at a distance. In contrast to the delivery method of FIG.
17, FIG. 19A depicts delivery of ultrasound transverse to the renal
arteries and not longitudinal to the artery. The direction of
energy delivery is the posterior of the patient because the renal
artery is the first vessel "seen" when traveling from the skin
toward the anterior direction facilitating delivery of the therapy.
In one embodiment, the transducers 8930, 8931 are placed under, or
inferior to the rib of the patient or between the ribs of a
patient; next, the transducers apply an ultrasound wave propagating
forward toward the anterior abdominal wall and image the region of
the renal arteries and renal veins, separating them from one
another. In some embodiments, such delivery might be advantageous,
if for example, a longitudinal view of the artery is unobtainable
or a faster treatment paradigm is desirable. The transducers 8930,
8931 communicate with one another and are connected to a computer
model of the region of interest being imaged (ROI), the ROI based
on an MRI scan performed just prior to the start of the procedure
and throughout the procedure. Importantly, the transducers are
placed posterior in the cross section of the patient, an area with
more direct access to the kidney region. The angle between the
imaging transducers can be as low as 3 degrees or as great as 180
degrees depending on the optimal position in the patient.
[0407] In another embodiment, an MRI is not performed but
ultrasound is utilized to obtain all or part of the cross-sectional
view in FIG. 19A. For example, 8930 might contain an imaging
transducer as well as a therapeutic energy source (e.g. ionizing
energy, HIFU, low energy focused ultrasound, etc.) In some
embodiments, a CT scan is utilized, which can obtain two
dimensional images and output three dimensional images. In other
embodiments, a fluoroscopy unit may be used.
[0408] FIG. 19B depicts an ultrasound image from a patient
illustrating imaging of the region with patient properly positioned
as described below. It is this cross section that can be treated
with image guided HIFU of the renal hilum region. The kidney 8935
is visualized in cross section and ultrasound then travels through
to the renal artery 8937 and vein 8941. The distance can be
accurately measure 8943 with ultrasound (in this case 8 cm 8943).
This information is useful to help model the delivery of energy to
the renal blood vessels. The blood vessels (vein and/or artery) are
utilized as fiducials for the targeting of the ultrasound, and the
kidney is used to verify that the vessels indeed are leading to the
correct organ. The kidney is further utilized to conduct the
ultrasound to the blood vessels.
[0409] FIGS. 19C-D depicts an actual treatment of the renal hilum
8945. A targeting region 8946 is shown in which movement of the
transducer and hilum is tracked and analyzed 8949 and 8948. The
accuracy of the tracking is recorded and displayed 8948 over time.
In this figure, the cool off period is shown and in FIG. 19D
treatment 8954 is shown. In some embodiments, energy is delivered
in the manner described herein through the kidney, which has been
shown to be resilient to heat. In some cases, movement of the renal
hilum and the transducer are recorded in real time, and therapy of
the blood vessels is depicted in real time during the treatment.
Success of tracking may, as well as progress of the therapy at the
time of treatment, may be presented on a screen for viewing by the
user as shown in the tracking bar below the ultrasound image.
Success may be considered when the targeting is maintained within
the target circle 8647 at least 90% of the time of each treatment.
This targeting accuracy is generally attributed to success in the
pre-clinical studies described below. A motion tracking system is
built into the system to ensure that a proper dose is delivered to
the region of the renal nerves leading to the kidney. The motion
tracking system relates the coordinates in three dimensions to the
treatment, and allows for the quality of the treatment to be
determined. Therefore, in one embodiment, focused energy is applied
to the region of the blood vessels to the kidney; hardware and
software is utilized to quantify the degree of movement between the
treatment device and the treatment region; a quality factor is
utilized to ascertain whether additional time needs to be added to
the treatment if the quality factor is too low to yield an
effective treatment.
[0410] FIGS. 19C-D depict the setup 8645 for the treatment of the
renal blood vessels along with actual treatment 8654 of the renal
blood vessels 8651. Window 8653 is the target window for the
treatment. Although renal blood vessels are depicted, any blood
vessel with a surrounding nerve can be targeted. Success factor
8648 is based on motion of the target and/or operator. If the
treatment fails to remain within the target 8647 for a set period
of time, then a failure indicator 8648 is shown on the screen 8646
rather than a success indicator.
[0411] FIG. 19E depicts a clinical method based on the treatment
shown in FIGS. 19C-D above. The first step 8972 is to consider a
delivery approach to apply ultrasound to nerves surrounding a blood
vessel. The next step is to generate an ultrasound image of the
region 8960 and the subsequent step is to determine the distance
8962 to the blood vessel and then integrate the plan with the HIFU
transducer 8964. Based on data generated above, parameters are
determined to apply pulses, generally less than 10 s of "on" time,
to ramp the temperature of the region around the blood vessel to
approximately 200 W/cm.sup.2 in at least 2 seconds 8970. The focus
is then moved along the artery or blood vessel 8968 from anterior
to posterior and/or from side to side.
[0412] FIG. 20 depicts an alternative method, system 9000 and
device to ablate the renal nerves 9015 or the nerves leading to the
renal nerves at the aorta-renal artery ostium 9010. The
intravascular device 9020 is placed into the aorta 9050 and
advanced to the region of the renal arteries 9025. Energy is
applied from the transducer 9020 and focused 9040 (in the case of
HIFU, LIFU, ionizing radiation) to the region of the takeoff of the
renal arteries 9025 from the aorta 9050. This intravascular 9030
procedure can be guided using MRI and/or MRI thermometry or it can
be guided using fluoroscopy, ultrasound, or MRI. Because the aorta
is larger than the renal arteries, the HIFU catheter can be placed
into the aorta directly and cooling catheters can be included as
well. In addition, in other embodiments, non-focused ultrasound can
be applied to the region around the renal ostium or higher in the
aorta. Non-focused ultrasound in some embodiments may require
cooling of the tissues surrounding the probe using one or more
coolants but in some embodiments, the blood of the aorta will take
the place of the coolant, by its high flow rate; HIFU, or focused
ultrasound, may not need the cooling because the waves are by
definition focused from different angles to the region around the
aorta. The vena cava and renal veins can also be used as a conduit
for the focused ultrasound transducer to deliver energy to the
region as well. In one embodiment, the vena cava is accessed and
vibratory energy is passed through the walls of the vena cava and
renal vein to the renal arteries, around which the nerves to the
kidney travel. The veins, having thinner walls, allow energy to
pass through more readily.
[0413] FIG. 21a-b depicts an eyeball 9100. Also depicted are the
zonules of the eye 9130 (the muscles which control lens shape) and
ultrasound transducer 9120. The transducer 9120 applies focused
ultrasound energy to the region surrounding the zonules, or the
zonules themselves, in order to tighten them such that a presbyopic
patient can accommodate and visualize object up close. Similarly,
heat or vibration applied to the ciliary muscles, which then
increases the outflow of aqueous humor at the region of interest so
that the pressure within the eye cannot build up to a high level.
The ultrasound transducer 9120 can also be utilized to deliver drug
therapy to the region of the lens 9150, ciliary body, zonules,
intra-vitreal cavity, anterior cavity 9140, posterior cavity,
etc.
[0414] In some embodiments (FIG. 21b), multiple transducers 9160
are utilized to treat tissues deep within the eye; the ultrasonic
transducers 9170 are focused on the particular region of the eye
from multiple directions so that tissues along the path of the
ultrasound are not damaged by the ultrasound and the focus region
and region of effect 9180 is the position where the waves meet in
the eye. In one embodiment, the transducers are directed through
the pars plana region of the eye to target the macula 9180 at the
posterior pole 9175 of the eye. This configuration might allow for
heat, vibratory stimulation, drug delivery, gene delivery,
augmentation of laser or ionizing radiation therapy, etc. In
certain embodiments, focused ultrasound is not required and generic
vibratory waves are transmitted through the eye at frequencies from
20 kHz to 10 MHz. Such energy may be utilized to break up clots in,
for example, retinal venous or arterial occlusions which are
creating ischemia in the retina. This energy can be utilized in
combination with drugs utilized specifically for breaking up clots
in the veins of the retina.
[0415] FIG. 22 depicts a peripheral joint 9200 being treated with
heat and/or vibrational energy. Ultrasound transducer 9210 emits
waves toward the knee joint to block nerves 9260 just underneath
the bone periostium 92209250 or underneath the cartilage. Although
a knee joint is depicted, it should be understood that many joints
can be treated including small joints in the hand, intervertebral
joints, the hip, the ankle, the wrist, and the shoulder. Unfocused
or focused ultrasonic energy can be applied to the joint region to
inhibit nerve function reversibly or irreversibly. Such inhibition
of nerve function can be utilized to treat arthritis,
post-operative pain, tendonitis, tumor pain, etc. In one preferred
embodiment, vibratory energy can be utilized rather than heat.
Vibratory energy applied to the joint nerves can inhibit their
functioning such that the pain fibers are inhibited.
[0416] FIG. 23a-b depicts closure of a fallopian tube 9300 of a
uterus 9320 using externally applied ultrasound 9310 so as to
prevent pregnancy. MRI or preferably ultrasound can be utilized for
the imaging modality. Thermometry can be utilized as well so as to
see the true ablation zone in real time. The fallopian tube 9300
can be visualized using ultrasound, MRI, CT scan or a laparoscope.
Once the fallopian tube is targeted, external energy 9310, for
example, ultrasound, can be utilized to close the fallopian tube to
prevent pregnancy. When heat is applied to the fallopian tube, the
collagen in the walls are heated and will swell, the walls then
contacting one another and closing the fallopian preventing full
ovulation and therefore preventing pregnancy. Although there is no
doppler signal in the fallopian tube, the technology for
visualization and treatment is similar to that for an artery or
other duct. That is, the walls of the tube are identified and
modeled, then focused ultrasound is applied through the skin to the
fallopian tube to apply heat to the walls of the lumen of the
fallopian tube.
[0417] In FIG. 23b, a method is depicted in which the fallopian
tubes are visualized 9340 using MRI, CT, or ultrasound. HIFU 9350
is applied under visualization with MRI or ultrasound. As the
fallopian tubes are heated, the collagen in the wall is heated
until the walls of the fallopian tube close off. At this point the
patient is sterilized 9360. During the treating time, it may be
required to determine how effective the heating is progressing. If
additional heat is required, then additional HIFU may be added to
the fallopian tubes until there is closure of the tube and the
patient is sterilized 9360. Such is one of the advantages of the
external approach in which multiple treatments can be applied to
the patient, each treatment closing the fallopian tubes further,
the degree of success then assessed after each treatment. A further
treatment can then be applied 9370.
[0418] In other embodiments, ultrasound is applied to the uterus or
fallopian tubes to aid in pregnancy by improving the receptivity of
the sperm and/or egg for one another. This augmentation of
conception can be applied to the sperm and egg outside of the womb
as well, for example, in a test tube in the case of extra-uterine
fertilization.
[0419] FIG. 24 depicts a feedback algorithm to treat the nerves of
the autonomic nervous system. It is important that there be an
assessment of the response to the treatment afterward. Therefore,
in a first step, modulation of the renal nerves 9400 is
accomplished by any or several of the embodiments discussed above.
An assessment 9410 then ensues, the assessment determining the
degree of treatment effect engendered; if a complete or
satisfactory response is determined 9420, then treatment is
completed. For example, the assessment 9410 might include
determination through microneurography, assessment of the carotid
sinus reactivity (described above), heart rate variability,
measurement of norepinephrine levels, tilt test, blood pressure,
ambulatory blood pressure measurements, etc. With a satisfactory
autonomic response, further treatment might not ensue or depending
on the degree of response, additional treatments of the nerves 9430
may ensue.
[0420] FIG. 25 depicts a reconstruction of a patient from CT scan
images showing the position of the kidneys 9520 looking through the
skin of a patient 9500. The ribs 9510 partially cover the kidney
but do reveal a window at the inferior pole 9530 of the kidney
9520. Analysis of many of these reconstructions has lead to
clinical paradigm in which the ribs 9510, pelvis 9420, and the
vertebra 9440 are identified on a patient, the kidneys are
identified via ultrasound and then renal arteries are identified
via Doppler ultrasound. A relevant clinical window may have an
access angle of between 40 and 60 degrees.
[0421] As shown in FIG. 26a, once the ribs and vertebra are
identified with the Doppler ultrasound, an external energy source
9600 can be applied to the region. Specifically, focused ultrasound
(HIFU or LIFU) can be applied to the region once these structures
are identified and a lesion applied to the blood vessels (renal
artery and renal nerve) 9620 leading to the kidney 9610. As
described herein, the position of the ultrasound transducer 9600 is
optimized on the posterior of the patient as shown in FIG. 26A.
That is, with the vertebra, the ribs, and the iliac crest bordering
the region where ultrasound is applied. Based on the data above and
specifically the CT scan anatomic information in FIG. 26A, FIG. 26B
depicts a device and system 9650 designed for treatment of this
region (blood vessels in the hilum of the kidney) in a patient. It
contains a 0.5-3 Mhz ultrasound imaging transducer 9675 in its
center and a cutout or attachment location of the ultrasound
ceramic (e.g. PZT) for the diagnostic ultrasound placement. It also
contains a movement mechanism 9660 to control the therapeutic
transducer 9670. The diagnostic ultrasound device 9675 is coupled
to the therapeutic device in a well-defined, known relationship.
The relationship can be defined through rigid or semi-rigid
coupling or it can be defined by electrical coupling such as
through infrared, optical-mechanical coupling and/or
electromechanical coupling. Along the edges of the outer rim of the
device, smaller transducers 9670 can be placed which roughly
identify tissues through which the ultrasound travels. For example,
simple and inexpensive one or two-dimensional transducers might be
used so as to determine the tissues through which the ultrasound
passes on its way to the target can be used for the targeting and
safety. From a safety perspective, such data is important so that
the ultrasound does not hit bone or bowel and that the transducer
is properly placed to target the region around the renal blood
vessels. Also included in the system is a cooling system to
transfer heat from the transducer to fluid 9662 running through the
system. Cooling via this mechanism allows for cooling of the
ultrasound transducer as well as the skin beneath the system. A
further feature of the system is a sensor mechanism 9665 which is
coupled to the system 9650 and records movement of the system 9650
relative to a baseline or a coordinate nearby. In one embodiment, a
magnetic sensor is utilized in which the sensor can determine the
orientation of the system relative to a magnetic sensor on the
system. The sensor 9665 is rigidly coupled to the movement
mechanism 9660 and the imaging transducer 9675. In addition to
magnetic, the sensor might be optoelectric, acoustic, imaging (e.g.
camera), or radiofrequency based.
[0422] Furthermore, the face 9672 of the transducer 9670 is shaped
such that is fits within the bony region described and depicted in
FIG. 26A. For example, in some embodiments, the shape might be
elliptical or aspheric; in other embodiments, the shape may be
triangular or pie shaped. In addition, in some embodiments, the
ultrasound imaging engine might not be directly in the center of
the device and in fact might be superior to the center and closer
to the superior border of the face and closer to the ribs, wherein
the renal artery is visualized better with the imaging probe
9675.
[0423] Given the clinical data as well as the devised technologies
described above (e.g. FIG. 26A-B), FIG. 27 illustrates the novel
treatment plan 9700 to apply energy to the nerves around the renal
artery with energy delivered from a position external to the
patient.
[0424] In one embodiment, the patient is stabilized and/or
positioned such that the renal artery and kidneys are optimally
located 9710. Diagnostic ultrasound 9730 is applied to the region
and optionally, ultrasound is applied from a second direction 9715.
The positioning and imaging maneuvers allow the establishment of
the location of the renal artery, the hilum, and the vein 9720. A
test dose of therapeutic energy 9740 can be applied to the renal
hilum region. In some embodiments, temperature 9735 can be
measured. This test dose can be considered a full dose if the
treatment is in fact effective by one or more measures. These
measures might be blood pressure 9770, decrease in sympathetic
outflow (as measured by microneurography 9765), increase in
parasympathetic outflow, change in the caliber of the blood vessel
9755 or a decrease in the number of spontaneous spikes in a
microneurographic analysis in a peripheral nerve (e.g. peroneal
nerve) 9765, or an MRI or CT scan which reveals a change in the
nervous anatomy 9760. In some embodiments, indices within the
kidney are utilized for feedback. For example, the resistive index,
a measure of the vasoconstriction in the kidney measured by doppler
ultrasound is a useful index related to the renal nerve activity;
for example, when there is greater autonomic activity, the
resistive index increases, and vice versa.
[0425] Completion of the treatment 9745 might occur when the blood
pressure reaches a target value 9770. In fact, this might never
occur or it may occur only after several years of treatment. The
blood pressure might continually be too high and multiple
treatments may be applied over a period of years . . . the concept
of dose fractionation. Fractionation is a major advantage of
applying energy from a region external to a region around the renal
arteries in the patient as it is more convenient and less expensive
when compared to invasive treatments such as stimulator
implantation and interventional procedures such as catheterization
of the renal artery.
[0426] Another important component is the establishment of the
location and position of the renal artery, renal vein, and hilum of
the kidney 9720. As discussed above, the utilization of Doppler
ultrasound signaling allows for the position of the nerves to be
well approximated such that the ultrasound can be applied to the
general region of the nerves. The region of the nerves can be seen
in FIGS. 29A-D. FIGS. 29A-C are sketches from actual histologic
slices. The distances from the arterial wall can be seen at
different locations and generally range from 0.3 mm to 10 mm.
Nonetheless, these images are from actual renal arteries and nerves
and are used so as to develop the treatment plan for the system.
For example, once the arterial wall is localized 9730 using the
Doppler or other ultrasound signal, a model of the position of the
nerves can be established and the energy then targeted to that
region to inhibit the activity of the nerves 9720. Notably, the
distance of many of these nerves from the wall of the blood vessel
indicate that a therapy which applies radiofrequency to the wall of
the vessel from the inside of the vessel likely has great
difficulty in reaching a majority of the nerves around the blood
vessel wall.
[0427] For example, FIG. 29D depicts a schematic from a live human
ultrasound. As can be seen, the ultrasound travels through skin,
through the subcutaneous fat, through the muscle and at least
partially through the kidney 8935 to reach the hilum 8941 of the
kidney and the renal blood vessels 8937. This direction was
optimized through clinical experimentation so as to not include
structures which tend to scatter ultrasound such as bone and lung.
Experimentation lead to the optimization of this position for the
imaging and therapy of the renal nerves. The position of the
ultrasound is between the palpable bony landmarks on the posterior
of the patient as described above and below. The vertebrae are
medial, the ribs superior and the iliac crest inferior.
Importantly, the distance of these structures 8943 is approximately
8-12 cm and not prohibitive from a technical standpoint. These
images from the ultrasound are therefore consistent with the
results from the CT scans described above as well.
[0428] FIG. 29E depicts the surface area 8760 available to an
ultrasound transducer for two patients out of a clinical study. One
patient was obese and the other thinner. Quantification of this
surface area 8762 was obtained by the following methodology: 1)
obtain CT scan; 2) mark off boundary of organs such as the
vertebrae, iliac crest, and ribs; 3) draw line from renal blood
vessels to the point along the edge of the bone; 4) draw
perpendicular from edge bone to the surface of the skin; 5) map the
collection of points obtained along the border of the bone. The
surface area is the surface area between the points and the maximum
diameter is the greatest distance between the bony borders. The
collection of points obtained with this method delimits the area on
the posterior of the patient which is available to the ultrasound
transducer to either visualize or treat the region of the focal
spot. By studying a series of patients, the range of surface areas
was determined so as to assist in the design which will serve the
majority of patients. The transducers modeled in FIG. 30 have
surface areas of approximately 11.times.8 cm or 88 cm.sup.2 which
is well within the surface area 8762 shown in FIG. 29E, which is
representative of a patient series. Furthermore the length, or
distance, from the renal artery to the skin was quantified in
shortest ray 8764 and longest ray 8766. Along with the angular data
presented above, these data enable design of an appropriate
transducer to achieve autonomic modulation and control of blood
pressure.
[0429] In a separate study, it was shown that these nerves could be
inhibited using ultrasound applied externally with the parameters
and devices described herein. Pathologic analysis revealed that the
nerves around the artery were completely inhibited and degenerated,
confirming the ability of the treatment plan to inhibit these
nerves and ultimately to treat diseases such as hypertension.
Furthermore, utilizing these parameters, did not cause any damage
within the path of the ultrasound through the kidney and to the
renal hilum.
[0430] Importantly, it has also been discovered via clinical trials
that when ultrasound is used as the energy applied externally, that
centering the diagnostic ultrasound probe such that a cross section
of the kidney is visualized and the vessels are visualized, is an
important component of delivering the therapy to the correct
position along the blood vessels. One of the first steps in the
algorithm 9700 is to stabilize the patient in a patient stabilizer
custom built to deliver energy to the region of the renal arteries.
After stabilization of the patient, diagnostic ultrasound is
applied to the region 9730 to establish the extent of the ribs,
vertebrae, and pelvis location. Palpation of the bony landmarks
also allows for the demarcation of the treatment zone of interest.
The external ultrasound system is then placed within these regions
so as to avoid bone. Then, by ensuring that a portion of the
external energy is delivered across the kidney (for example, using
ultrasound for visualization), the possibility of hitting bowel is
all but eliminated. The ultrasound image in FIG. 29D depicts a soft
tissue path from outside the patient to the renal hilum inside the
patient. The distance is approximately 8-16 cm. Once the patient is
positioned, a cushion 9815 is placed under the patient. In one
embodiment, the cushion 9815 is simply a way to prop up the back of
the patient. In another embodiment, the cushion 9815 is an
expandable device in which expansion of the device is adjustable
for the individual patient. The expandable component 9815 allows
for compression of the retroperitoneum (where the kidney resides)
to slow down or dampen movement of the kidney and maintain its
position for treatment with the energy source or ultrasound.
[0431] A test dose of energy 9740 can be given to the region of the
kidney hilum or renal artery and temperature imaging 9735,
constriction of blood vessels 9755, CT scans 9760, microneurography
9765 patch or electrode, and even blood pressure 9770. Thereafter,
the treatment can be completed 9745. Completion might occur
minutes, hours, days, or years later depending on the parameter
being measured.
[0432] Through experimentation, it has been determined that the
region of the renal hilum and kidneys can be stabilized utilizing
gravity with local application of force to the region of the
abdomen below the ribs and above the renal pelvis. For example,
FIGS. 28A-C depict examples of patient positioners intended to
treat the region of the renal blood vessels.
[0433] FIG. 28A is one example of a patient positioned in which the
ultrasound diagnostic and therapeutic 9820 is placed underneath the
patient. The positioner 9810 is in the form of a tiltable bed. A
patient elevator 9815 placed under the patient pushes the renal
hilum closer to the skin and can be pushed forward in this manner;
as determined in clinical trials, the renal artery is approximately
2-3 cm more superficial in this type of arrangement with a range of
approximately 7-15 cm in the patients studied within the clinical
trial. The weight of the patient allows for some stabilization of
the respiratory motion which would otherwise occur; the patient
elevator can be localized to one side or another depending on the
region to be treated. Alternative approaches (in the case where the
physician wants to maintain the patient in a flat position) are to
place a positioning device under the patient's legs and maintain
the upper torso substantially flat.
[0434] FIG. 28B detects a more detailed configuration of the
ultrasound imaging and therapy engine 9820 inset. A patient
interface 9815 is utilized to create a smooth transition for the
ultrasound waves to travel through the skin and to the kidneys for
treatment. The interface is adjustable such that it is customizable
for each patient.
[0435] FIG. 28C depicts another embodiment of a positioner device
9850, this time meant for the patient to be face down. In this
embodiment, the patient is positioned in the prone position lying
over the patient elevator 9815. Again, through clinical
experimentation, it was determined that the prone position with the
positioner under the patient pushes the renal hilum posterior and
stretches out the renal artery and vein allowing them to be more
visible to ultrasound and accessible to energy deposition in the
region. The positioner underneath the patient might be an
expandable bladder with one or more compartments which allows for
adjustability in the amount of pressure applied to the underside of
the patient. The positioner might also have a back side which is
expandable 9825 and can push against the posterior side of the
patient toward the expandable front side of the positioner thereby
compressing the stretched out renal blood vessels to allow for a
more superficial and easier application of the energy device. These
data can be seen in FIGS. 7G and 7H where the renal artery is quite
a bit closer to the skin (7-17 cm down to 6-10 cm). The position of
the energy devices for the left side 9827 of the patient and right
side 9828 of the patient are depicted in FIG. 28C. The ribs 9829
delimit the upper region of the device placement and the iliac
crest 9831 delimits the lower region of the device placement. The
spinous processes 9832 delimit the medial edge of the region where
the device can be placed and the region between 9828 is the
location where the therapeutic transducer is placed.
[0436] FIGS. 28D-28E depict a system implementation of the
description above. Belt 9853 is fixed to the transducer 9855.
Bladder 9857 is an adaptable and fillable cavity which can be used
to help stabilize the flank region of the patient by pressing the
posterior skin against the belt and transducer 9855. The transducer
incorporates many of the embodiments described herein. For example,
in the illustrated embodiments, the transducer is designed and
manufactured with such a specification that it applies energy
directed to the region of the renal artery and nerves. The
transducer may be shaped like a pizza slice with annular
components, or multiple elements forming into a global shape, like
a pizza slice (as described herein). The transducer may also
provide imaging and motion tracking capability such as with a
pulse-echo detection system or with integral ultrasound imaging.
The imaging aid might detect an indwelling vascular catheter or an
implant. Nonetheless, the imaging aid can both detect the target
track its motion. The therapeutic aspect of the transducer 9855 may
generate focused ultrasound at a frequency of 0.5 MHz to 3 MHz
depending on the specific configuration or pattern desired. Monitor
9862 is utilized to monitor the progress of the therapy throughout
the treatment regimen.
[0437] Thus, in one embodiment of the system, as depicted in FIGS.
28D and 28E, the system comprises a belt which circumscribes the
patient and applies a bladder (optionally) on one side of the
patient to limit excursion of the abdominal organs and at least
partially stabilize the abdominal organs, such as the kidney.
Additionally, imaging and tracking may be utilized to maintain the
positioning of the therapeutic energy focus. The stabilized focused
energy system can then be automatically directed (e.g., by a
processor) to track and follow the blood vessels and carry out a
treatment according to a treatment plan, e.g., to treat tissue
(nerves) surround the vessels leading to the kidney. The bladders
may be filled automatically. In some cases, motion controllers may
be utilized to direct the therapeutic energy focus to regions close
to or within the hilum of the kidney.
[0438] FIGS. 28E-G depict a more complete picture of the transducer
to be applied to the back of the patient 9855 within the belt 9853
FIG. 28F depicts a 6 dimensional movement mechanism for the
transducer platform with a positionable arm and its fit into the
system configuration 9860. Six degrees of freedom are available for
movement, which includes rotation and translation of the
transducer. The platform is able to move in 6 degrees of freedom
and the bottom mover allows for the transducer to be pressed
against the skin of the patient.
[0439] FIG. 28H depicts a patient treatment system 9800 in which a
catheter 9805 is inserted into the patient 9810 and the system 9820
is placed behind the patient. Coupling applicator 9815 is pressed
against the patient to maintain coupling contact between the
therapeutic system 9820 and the patient. Catheter 9805 can be
utilized to assist in targeting of the blood vessels and nerves
being treated by the therapeutic system. Maintaining the
therapeutic system behind the patient 9820 allows the patient's
weight to be utilized in maintaining coupling between the system
9820 and patient 9810.
[0440] FIG. 28I is a close up picture of the transducer 9820.
Elements 9809 are depicted with different phasings patterns to meet
at the intersection 9807. Elements 9809 can also translate or
rotate within the transducer allowing for a multi-modality.
[0441] FIG. 28J depicts a component 9865 to apply pressure to
specific anatomic regions of the patient. Individual bladders 9860
can be inflated 9860 or deflated 9863 depending on the region of
the patient for which pressure is applied. Such a system aids with
conforming the applicator to the patient. In FIG. 28K, another
configuration of a system to apply therapeutic energy to the region
of the renal hilum is depicted. Transducer 9875 is depicted on the
portion of the table which is positioned under the patient to be
treated. Angiogram 9874 is visible in the case where a catheter is
utilized for targeting. Therefore in one embodiment, the system to
apply energy to the renal artery region is described in which a
typical OR or cath lab table is retrofitted for a therapeutic
ultrasound underneath the patient. The therapeutic ultrasound array
contains a movement mechanism to maintain the array in contact with
the skin of the patient, wherein the mechanism is able to translate
to the left side of the patient or the right side of the patient.
The movement mechanism can operate (e.g., to track a target) based
on an image (e.g., a doppler image) of a blood vessel.
[0442] FIG. 28K depicts the movement mechanism 9875 within a table
9870 to treat a patient who is positioned in the supine position.
The table elevation is on the front side of the patient, pushing
upward toward the renal hilum and kidneys. The head of the table
may be dropped or elevated so as to allow specific positioning
positions. The elevated portion may contain an inflateable
structure which controllably applies pressure to one side or
another of the torso, head, or pelvis of the patient.
[0443] FIG. 29A-C depicts the anatomical basis 9900 of the
targeting approach described herein. These figures are derived
directly from histologic slides. Nerves 9910 can be seen in a
position around renal artery 9920 and vein 9922. The range of
radial distance from the artery is out to 2 mm and even out to 10
mm. Anatomic correlation with the modeling in FIG. 16B reveals the
feasibility of the targeting and validates the approach based on
actual pathology; that is, the approach of applying therapy to the
renal nerves by targeting the adventitia of the artery, and using
the kidney as both a conduit and fiducial for the focused energy
(e.g., focused ultrasound energy). This is important because the
methodology used to target the nerves is one of detecting the
Doppler signal from the artery and then targeting the vessel wall
around the doppler signal. Nerves 9910 can be seen surrounding the
renal artery 9920 which puts them squarely into the temperature
field shown in 16B indicating the feasibility of the outlined
targeting approach in FIG. 27 and the lesion configuration in FIG.
16A. Further experimentation (utilizing similar types of pathology
as well as levels of norepinephrine in the kidney) reveals that the
required dose of ultrasound to the region to affect changes in the
nerves is on the order of 100 W/cm.sup.2 for partial inhibition of
the nerves and 1-2 kW/cm.sup.2 for complete inhibition and necrosis
of the nerves. These doses or doses in between them might be chosen
depending on the degree of nerve inhibition desired in the
treatment plan. Importantly, it was further discovered through the
experimentation that an acoustic plane through the blood vessels
was adequate to partially or completely inhibit the nerves in the
region. That is to say, that a plane through which the blood
vessels travels perpendicularly is adequate to ablate the nerves
around the artery as illustrated in FIG. 16B. Until this
experimentation, there had been no evidence that ultrasound would
be able to inhibit nerves surrounding an artery by applying a plane
of ultrasound through the blood vessel. Indeed, it was proven that
a plane of ultrasound essentially could circumferentially inhibit
the nerves around the blood vessel.
[0444] FIG. 29D depicts a treatment combining the technical factors
described herein. An ultrasound image with a doppler is shown with
a blood vessel 8941 leading to a kidney 8935. The blood vessel
(doppler signal and image) is targeted 8937 in three dimensions and
the kidney 8935 is used as a conduit to conduct the focused energy
(in this case ultrasound) toward the blood vessel. The kidney is
further used as a fiducial, which indicates the direction, and
indicates that the correct vessel is indeed targeted. A treatment
paradigm is created in which a program is generated to move the
focal plane around the target in three dimensions. Data generated,
both theoretically and in pre-clinical models, reveals that the
kidney indeed can be used as a conduit to conduct HIFU energy
because the ability of the kidney to transmit ultrasound without
heating is outstanding due to its high blood flow. Therefore, one
preferred embodiment is that the kidney is utilized as a fiducial
to direct the focused ultrasound, as well as allowing transmission
through to the blood vessels of the kidney.
[0445] FIGS. 30A-I depict three dimensional simulations from a set
of CT scans from the patient model shown in FIG. 26A. Numerical
simulations were performed in three dimensions with actual human
anatomy from the CT scans. The same CT scans utilized to produce
FIGS. 7E, 19, and 25 were utilized to simulate a theoretical
treatment of the renal artery region considering the anatomy of a
real patient. Utilizing the doses shown in the experimentation
above (FIGS. 29A-D) combined with the human anatomy from the CT
scans, it is shown with these simulations that the ability exists
to apply therapeutic ultrasound to the renal hilum from a position
outside the patient. In combination with FIG. 29, which as
discussed, depicts the position of the nerves around the blood
vessels as well as the position of the vessels in an ultrasound,
FIG. 30A-I depicts the feasibility of an ultrasound transducer
which is configured to apply the required energy to the region of
the hilum of the kidney without damaging intervening structures.
These simulations are in fact confirmation for the proof of concept
for this therapy and incorporate the knowledge obtained from the
pathology, human CT scans, human ultrasound scans, and the system
designs presented previously above.
[0446] In one embodiment, FIG. 30A, the maximum intensity is
reached at the focus 10010 is approximately 186 W/cm.sup.2 with a
transducer 10000 design at 750 MHz; the transducer is approximately
11.times.8 cm with a central portion 10050 for an ultrasound
imaging engine. The input wattage to the transducer is
approximately 120 W-150 W depending on the specific patient
anatomy. The input voltage might be as high as 1000 W depending on
the desired peak intensity at the focus. For example, for a peak
intensity of 2 kW/cm.sup.2, it may be desirable to have an input
wattage of approximately 600-800 W.
[0447] FIGS. 30B and 30C depict the acoustic focus 10020, 10030 at
a depth of approximately 9-11 cm and in two dimensions.
Importantly, the region (tissues such as kidney, ureter, skin,
muscle) proximal (10040 and 10041) to the focus 10020, 10030 do not
have any significant acoustic power absorption indicating that the
treatment can be applied safely to the renal artery region through
these tissues as described above. Importantly, the intervening
tissues are not injured in this simulation indicating the
feasibility of this treatment paradigm.
[0448] FIGS. 30D-F depict a simulation with a transducer 10055
having a frequency of approximately 1 MHz. With this frequency, the
focal spot 10070, 10040, 10050 size is a bit smaller (approximately
2 cm by 0.5 cm) and the maximum power higher at the focus,
approximately 400 W/cm.sup.2 than shown in FIGS. 30A-C. In the
human simulation, this is close to an optimal response and dictates
the design parameters for the externally placed devices. The
transducer in this design is a rectangular type of design
(spherical with the edges shaved off) so as to optimize the working
space in between the posterior ribs of the patient and the superior
portion of the iliac crest of the patient. Its size is
approximately 11 cm.times.8 cm which as described above and below
is well within the space between the bony landmarks of the back of
the patient.
[0449] FIGS. 30G-I depict a simulation with similar ultrasound
variables as seen in FIGS. 30D-F. The difference is that the
transducer 10090 was left as spherical with a central cutout rather
than rectangular with a central cutout. The spherical transducer
setup 10090 allows for a greater concentration of energy at the
focus 1075 due to the increased surface area of vibratory energy.
Indeed, the maximum energy from this transducer (FIG. 30G) is
approximately 744 W/cm.sup.2 whereas for the transducer in FIG.
30d, the maximum intensity is approximately 370 W/cm.sup.2. FIG.
30H depicts one plane of the model and 30I another plane. Focus
10080, 10085 is depicted with intervening regions 10082 and 10083
free from acoustic power and heat generation, similar to FIG.
30A-F.
[0450] These simulations confirm the feasibility of a therapeutic
treatment of the renal sympathetic nerves from the outside without
damage to intervening tissues or structures such as bone, bowel,
and lung. Hypertension is one clinical application of this therapy.
A transducer with an imaging unit within is utilized to apply
focused ultrasound to a renal nerve surrounding a renal artery.
Both the afferent nerves and efferent nerves are affected by this
therapy.
[0451] Other transducer configurations are possible. Although a
single therapeutic transducer is shown in FIG. 30A-I,
configurations such as phased array therapy transducers (more than
one independently controlled therapeutic transducer) are possible.
Such transducers allow more specific tailoring to the individual
patient. For example, a larger transducer might be utilized with 2,
3, 4 or greater than 4 transducers. Individual transducers might be
turned on or off depending on the patients anatomy. For example, a
transducer which would cover a rib in an individual patient might
be turned off during the therapy.
[0452] Although the central space is shown in the center of the
transducer in FIGS. 30A-I, the imaging transducer might be placed
anywhere within the field as long as its position is well known
relative to the therapy transducers. For example, insofar as the
transducer for therapy is coupled to the imaging transducer
spatially in three dimensional space and this relationship is
always known, the imaging transducer can be in any orientation
relative to the therapeutic transducer.
[0453] Another embodiment of a customized transducer 11030 is
depicted in FIGS. 30J-30K. Importantly, this transducer is
specifically designed to accommodate the anatomy shown above for
the kidney anatomy. The pizza slice shape 11000 is unique to treat
the anatomy in which the ribs, spine and pelvis are considered.
Sensors 11040 are located along the edges of the transducer and
allow for imaging or otherwise to detect the direction of the
ultrasound system as it travels through the patient toward its
target. At the tip of the system, 11050, an ultrasound imaging
probe is included where the probe is coupled to the therapeutic
ultrasound array 11030 and 11020. The number of elements 11030
determines the spatial resolution of the array and the degree to
which the focus can be electronically controlled.
[0454] The sensors around the side 11040 may be small 1D imaging
transducers or contain a single plane. Alternatively, they may be
acoustic time of flight sensors for measuring the distance to the
target or a combination of the two different techniques.
[0455] FIGS. 30L-N depicts additional views of the transducer in
which the imaging component is in the center 11070, side cutout
11075, and within the pie slice shape 11085. The pizza slice shape
does not necessarily have to be shaped as a slice but might be a
larger array in which a slice shape is produced by turning on or
off any number of transducers. The transducers in such an
embodiment can have square, annular, or rectangular elements each
of which has its own controller for imaging or therapeutic
uses.
[0456] FIG. 30O-Q depicts a transducer with several elements
arranged into a fixed focus 11130. Each of the 6 elements 11150 can
be tuned to focus on a spot a given focal length from the
transducer. The pizza slice shape can be fit into the region
between the ribs and spine and the pelvis to apply therapy to a
blood vessel such as the renal artery or the renal vein. FIG. 30Q
depicts discreet movers 11141, 11143, 11145 which dictate the
degree of overlap at the focus 11147.
[0457] FIG. 30R-S depicts a transducer 11200 with many elements
11230. Again, although shaped like a slice of a pie 11220, the
shape can be created by turning on transducers from a larger
cutout. A cross section 11210 is shown as well (FIG. 30R) revealing
a thickness of the array which can range from several mm to a few
cm. The profile is produced such that the transducer can be adapted
to fit into the acoustic window of a human patient with anatomy
described herein.
[0458] FIG. 30V is an expanded version of a transducer 11300 in
which discrete bowls are fit together to simulate a larger bowl
11310 approximation. In this arrangement, the individual bowls
11324, 11324, 11326 each provide a piece of the curvature of a
larger bowl, which would otherwise be very difficult to
manufacture.
[0459] FIG. 30W depicts the assembly of the configuration 11350
with the bowls in combination which when powered, creates a single
focus 11355. By moving each individual bowl slightly, the focus can
be made to be elongate or circular.
[0460] FIGS. 30T-U depict simulations of the annular array
transducers shown in FIGS. 30J-K. The simulation reveals that the
focus can be electronically controlled between less than 10 cm
distance 11510 to greater than 14 cm 11500. These distances are
compatible with the blood vessels leading to the kidney and are
delivered from within the envelope of the window on the posterior
portion of the patient's back.
[0461] FIG. 30V depicts an exploded view of an assembly of a
transducer 11300. A base 11310 might contain a motion control
system for x-y-z motion, and optionally a pivot for rotation of the
ultrasound array. Array 11322 is comprised of one or more
ultrasound emanating crystals 11324 with different curvatures
11326, 11320 to focus energy. Housing 11330 might contain a
nosecone or other directional structure to direct the ultrasound
energy to a focus. Covering 11340 is a coupling structure with an
integral membrane to couple the ultrasound energy to the patient.
The transducer 11322 might provide a combination of phasing and
mechanical movement for its operation.
[0462] FIG. 31A depicts a perspective view of a transducer device
customized for the anatomy of the blood vessels leading to the
kidney. This design is based on the anatomic, biologic, and
technical issues discovered and described above specific for the
clinical treatment of nerves surrounding the blood vessels which go
to the kidney. Transducer 11650 has multiple elements and is also
able to be pivoted and translated. The individual elements of the
array can be phased so that different depths of foci can be
achieved 11600, 11610 to treat regions around a blood vessel 11620.
An imaging transducer 11710 is attached to, or integrated with, the
device 11700. Although the ultrasound imaging transducer has been
described, in other embodiments, MRI, CT, or fluoroscopy can also
be linked to the system 11700. The device further contains elements
described above such as a mover to move the entire device as a
complete unit, motion tracking to track its global motion in three
dimensional space, and a water circulation system to maintain the
temperature of the skin and the transducer to acceptable
levels.
[0463] Angle 11652 is important to the anatomy which is being
treated. It represents the envelope of the therapeutic beam and is
incorporated into the design of the system. It is represented in
one plane in this figure and would cover approximately 40 to 70
degrees in this figure which allows for a treatment depth of
between 6 cm and 15 cm. For the short dimension (into the drawing),
the angle (not shown) would be 35 to 65 degrees. The treatment
depth may be desirably adjusted with different phasing from the
transducer; however, the shape of the focus is not substantially
affected. The position in X and Y may be adjusted using mechanical
manipulation but can also be adjusted via phasing elements.
Therefore, in one embodiment, an ultrasound transducer is described
within which a multi-element array is disposed, the transducer
devised to allow for electrical focusing of a focused ultrasound
beam at an angle 11652 to the central axis of the transducer to
move the beam focus in the direction perpendicular to the plane of
the transducer but at an angle to the central axis of the
transducer. The angle is customized for the anatomy being treated.
For example, when treating a region such as the renal artery and
nerve going to the kidney, the blood vessels are located at an
angle from a plane of the skin when the transducer is place between
the ribs, iliac crest, and spine (for example, see FIG. 31A, angle
11652, transducer 11650 is placed on the skin underneath the ribs,
lateral to the spine and superior to the iliac crest). A mover may
also be provided, which moves the transducer in the plane of the
transducer and perpendicular to the central axis of the
transducer.
[0464] FIG. 31B depicts another embodiment of a transducer 11700
designed to deliver focused ultrasound specifically to the region
of the kidney and associated blood vessels 11770. The transducer
has multiple small bowl shaped transducers 11720 fitted together
for a deep focus 11740 of the ultrasound. The smaller bowl
transducers 11720 are each movable utilizing a mechanical
manipulator 11780 so as to create foci with different sizes at the
target. A water cooling system is present as well 11730, which
ensures that the skin and the transducers are maintained at a
predetermined temperature. The variations in foci include
elongated, spiral, and annular, each with different depths 11740.
In this embodiment, imaging is a component of the transducers
11720. ATOF (acoustic time of flight) receivers 11710 can
optionally receive signals from transducers 11750 on an indwelling
vascular catheter 11760, which contains piezoelectric transducers
capable of transmitting information through the patient to
receivers 11710.
[0465] FIG. 31C depicts a two component mover mechanism (termed
upper and lower movers) 11820 with a patient table 11800 to house
the transducer arrangement and hold a patient. A mover 11850 is
responsible for placing the transducer 11840 against the skin of
the patient inside of the cutout 11830 in the table; clinical
studies have shown that up to 50 pounds of pressure can be applied
by the lower transducer to the skin of the patient to maintain
coupling. The mover 11850 is also responsible for lowering the
upper transducer 11840. The upper transducer 11840 is positioned at
the angle and position required to treat a region such as the renal
nerves around a renal blood vessel. Electronic focusing might be
utilized for some components of the system, including the z
direction which is the vertical direction through the central axis
of the transducer and would generally be pointing in the direction
in and out of the patient being treated. With electronic focusing,
the distance can be automatically determined and calibrated
relative to the transducer. In some embodiments, X and Y motions
are altered electronically with various phasing patterns created
through the transducer. In some embodiments, a combination of
electronic phasing and mechanical movement is utilized to achieve
the proper focusing and positioning of the system on the patient.
The transducers being used for the therapeutic application of
energy to the patient might also be utilized for detection of
ultrasound signals which can be used for imaging detection. A
separate imaging transducer can be utilized to augment the therapy
transducer. For example, acoustic time of flight can be utilized or
B mode or Doppler imaging can be utilized. Therefore, in one
embodiment, the transducer is positioned at the proper angle to
reach the renal blood vessels
[0466] FIG. 31D depicts a system and subsystem overview of one
configuration. A transducer belt 12010 can be applied to a patient,
wherein the belt includes an applicator 12020 with transducer
containing a membrane assembly, packaging, temperature sensors, and
coupling attachments for coupling to the skin of the patient.
Within the transducer assembly is a carveout for an imaging engine
12180, which can be an annular array for imaging in the same
package as the therapy transducer, or it can be a separate array
12040 tuned for a different frequency specific for imaging. Within
the transducer belt is a mover for the applicator, for example, a
mover 12030 which can translate in X-Y-Z and rotate around a pivot
to deliver an ultrasound focus to any position within a space
around a blood vessel. Alternatively, in another embodiment, phased
array transducers may be utilized in for treatment, imaging, or
both. A cooling subsystem 12060 is a component of the system,
wherein the cooling subsystem is configured to maintain the
transducer and membrane temperature at a pre-specified level. An
optional targeting catheter 12170 is included in the system,
wherein the targeting catheter may be used in characterizing the
energy being delivered from the focused ultrasound as well as in
assisting and verifying the targeting accuracy of the imaging and
the coupling of the imaging to the motion control 12030. The
targeting catheter can also include sensors to determine the amount
of energy applied to the vessel, the temperature of the vessel and
surroundings, the acoustic power flux, and the degree of motion of
the vessel during, before, or after treatment. A user interface is
also included, the user interface comprising a track ball, a mouse,
a touch screen, or a keyboard to allow user interaction with the
system. The system is powered using power supplies 12150 which can
be switched or non-switched depending on which subsystem is being
activated at any given time.
[0467] FIGS. 30R and 30S depict the active shape of the transducer,
and 30T and 30U depict the simulation of the focused ultrasound at
the depth of treatment. The perspective view of the focus 11600 is
shown in FIG. 31A and the annular transducer 11650 which delivers
the ultrasound to a blood vessel 11620 and surrounding nerves 11610
is shown as well. An imaging array 11710 is included in the system
11700 as well.
* * * * *