U.S. patent application number 13/487121 was filed with the patent office on 2012-09-20 for methods for delivering energy to modulate neural structures.
This patent application is currently assigned to Kona Medical, Inc.. Invention is credited to Michael Gertner.
Application Number | 20120238918 13/487121 |
Document ID | / |
Family ID | 56291202 |
Filed Date | 2012-09-20 |
United States Patent
Application |
20120238918 |
Kind Code |
A1 |
Gertner; Michael |
September 20, 2012 |
METHODS FOR DELIVERING ENERGY TO MODULATE NEURAL STRUCTURES
Abstract
In some examples, nerves surrounding arteries or leading to
organs are targeted with energy sources to correct or modulate
physiologic processes. In some examples, different types of energy
sources are utilized singly or combined with one another. In some
examples, bioactive agents or devices activated by the energy
sources are delivered to the region of interest and the energy is
enhanced by such agents or the agents are enhanced by the energy
sources.
Inventors: |
Gertner; Michael; (Menlo
Park, CA) |
Assignee: |
Kona Medical, Inc.
Palo Alto
CA
|
Family ID: |
56291202 |
Appl. No.: |
13/487121 |
Filed: |
June 1, 2012 |
Related U.S. Patent Documents
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Application
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Patent Number |
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12966943 |
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13487121 |
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12902133 |
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12725450 |
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12902133 |
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12685655 |
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12725450 |
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61377908 |
Aug 27, 2010 |
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61347375 |
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61256983 |
Oct 31, 2009 |
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61250857 |
Oct 12, 2009 |
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61261741 |
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61291359 |
Dec 30, 2009 |
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61303307 |
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61256983 |
Oct 31, 2009 |
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61250857 |
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61261741 |
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Current U.S.
Class: |
601/2 |
Current CPC
Class: |
A61B 8/08 20130101; A61B
18/18 20130101; A61B 2018/00404 20130101; A61B 2090/3762 20160201;
A61B 2018/00511 20130101; A61N 2007/0026 20130101; A61N 2007/025
20130101; A61N 2005/063 20130101; A61B 8/485 20130101; A61B 5/489
20130101; A61N 7/02 20130101; A61N 5/0622 20130101; A61N 2/006
20130101; A61B 5/4528 20130101; A61B 6/03 20130101; A61B 5/4035
20130101; A61B 8/4245 20130101; A61B 17/320068 20130101; A61B 8/06
20130101; A61B 5/055 20130101; A61N 5/0601 20130101; A61B 5/412
20130101; A61B 90/37 20160201; A61B 5/4041 20130101; A61B 6/032
20130101; A61B 6/506 20130101; A61N 2007/003 20130101; A61B
2090/378 20160201; A61B 2018/00434 20130101; A61B 2090/374
20160201; A61N 5/00 20130101; A61N 7/00 20130101; A61B 5/4893
20130101; A61B 18/14 20130101; A61B 8/00 20130101; A61N 2007/0078
20130101; A61B 6/037 20130101; A61B 5/4052 20130101; A61B 5/4839
20130101; A61B 5/0225 20130101; A61N 1/0551 20130101; A61N 5/062
20130101; A61B 5/4047 20130101 |
Class at
Publication: |
601/2 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1-148. (canceled)
149. A treatment method, comprising: providing a therapeutic
ultrasonic energy source comprising a transducer outside a patient;
using the transducer to apply ultrasonic energy to a nerve region
containing a blood vessel based on a treatment plan that considers
minimization of energy delivery to a wall of the blood vessel;
wherein the act of using the transducer comprises operating the
transducer to treat tissue in the nerve region on at least two
sides of the blood vessel so that the tissue on the at least two
sides of the blood vessel receives more therapeutic effect than the
blood vessel.
150. The method of claim 149, further comprising tracking a motion
of the blood vessel.
151. The method of claim 149, wherein the tissue in the nerve
region on the at least two sides of the blood vessel comprise
nerves, and wherein the transducer is operated to create a zone of
heat surrounding the blood vessel to create an annular region
around the blood vessel to substantially inhibit the nerves
surrounding the blood vessel.
152. The method of claim 149, wherein the transducer applies power
to the nerve region, the power having a value that is anywhere from
100 W/cm.sup.2 to 2500 W/cm.sup.2.
153. The method of claim 149, further comprising positioning the
transducer relative to the patient so that regions of bone are
avoided by the ultrasonic energy from the transducer.
154. The method of claim 149, wherein the nerve region is an
autonomic nerve region, and the transducer applies the ultrasonic
energy at an energy level to create a reduction in a norepinephrine
output of the autonomic nerve region.
155. The method of claim 149, further comprising tracking speckles
at the nerve region.
156. The method of claim 149, further comprising determining a
three dimensional coordinate of the blood vessel.
157. The method of claim 149, further comprising tracking a doppler
ultrasound signal from the blood vessel.
158. The method of claim 149, wherein the transducer applies the
ultrasonic energy simultaneously to the tissue on the at least two
sides of the blood vessel.
159. The method of claim 149, further comprising visualizing the
blood vessel in the nerve region using an imaging device.
160. A treatment method, comprising: providing a therapeutic
ultrasonic energy source comprising a transducer at a location
outside a patient; determining a model of an ultrasound delivery,
wherein the model considers minimization of energy delivery to a
wall of a blood vessel, and controlling the transducer based on the
model to apply ultrasonic energy to autonomic nerves leading to or
from a kidney; wherein the act of controlling transducer comprises
tracking a position associated with the autonomic nerves to thereby
reduce an amount of energy being delivered to the wall of the blood
vessel; and wherein the ultrasonic energy is applied to treat a
first one of the autonomic nerves on a first side of a blood
vessel, and to treat a second one of the autonomic nerves on a
second sided of the blood vessel.
161. The method of claim 160, further comprising adjusting an
aiming by the transducer.
162. The method of claim 161, wherein the aiming by the transducer
is adjusted based on a position of a fiducial located inside the
blood vessel.
163. The method of claim 161, wherein the aiming by the transducer
is adjusted automatically.
164. The method of claim 161, wherein the aiming by the transducer
is adjusted to track the blood vessel.
165. The method of claim 160, wherein the transducer is controlled
also based on a doppler ultrasound signal received from inside the
blood vessel.
166. The method of claim 160, wherein the transducer is controlled
to create an annular zone of heat that at least partially surrounds
a lumen of the blood vessel.
167. A treatment method, comprising: providing a therapeutic
ultrasonic energy source comprising a transducer at a location
outside a patient; controlling the transducer based on a signal
from inside a blood vessel to apply ultrasonic energy to autonomic
nerves around a lumen of the blood vessel; wherein the transducer
is controlled to apply the ultrasonic energy to treat a first one
of the autonomic nerves on a first side of the blood vessel, and to
treat a second one of the autonomic nerves on a second sided of the
blood vessel, so that the first one and the second one of the
autonomic nerves are heated to a temperature above 60 degrees
Celsius.
168. The method of claim 167, further comprising adjusting an
aiming by the transducer.
169. The method of claim 168, wherein the aiming by the transducer
is adjusted based on a position of a fiducial located inside the
blood vessel.
170. The method of claim 169, wherein the fiducial comprises a
passive fiducial.
171. The method of claim 169, wherein the fiducial comprises an
active fiducial.
172. The method of claim 168, wherein the aiming by the transducer
is adjusted automatically.
173. The method of claim 168, wherein the aiming by the transducer
is adjusted automatically to track the blood vessel.
Description
PRIORITY DATA
[0001] This applications 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 of U.S. patent application Ser. No. 12/725,450
filed Mar. 16, 2010, now pending, which is a continuation of U.S.
patent application Ser. No. 12/685,655, filed on Jan. 11, 2010, now
pending, and claims priority to and the benefit of U.S. Provisional
patent application 61/303,307 filed Feb. 10, 2010, now pending,
U.S. Provisional patent application 61/256,983 filed Oct. 31, 2009,
now pending, U.S. Provisional patent application 61/250,857 filed
Oct. 12, 2009, now pending, U.S. Provisional patent application
61/261,741 filed Nov. 16, 2009, now pending, and U.S. Provisional
patent application 61/291,359 filed Dec. 30, 2009, now pending, and
is a continuation of U.S. patent application Ser. No. 12/685,655
filed 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 pending, U.S. Provisional Patent Application No.
61/250,857 filed Oct. 12, 2009, now pending, U.S. Provisional
Patent Application No. 61/261,741 filed Nov. 16, 2009, now pending,
and U.S. Provisional Patent Application No. 61/291,359 filed Dec.
30, 2009, now pending, the disclosures of all of the above
referenced applications are expressly incorporated by reference
herein.
[0002] The following patent applications are also expressly
incorporated by reference herein.
[0003] 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
[0004] 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
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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
[0009] 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.
[0010] In some embodiments, a method of treatment includes placing
an energy source outside a patient, operating the energy source so
that an energy delivery path of the energy source is aimed towards
a nerve inside the patient, wherein the nerve is a part of an
autonomic nervous system, and using the energy source to deliver
treatment energy from outside the patient to the nerve located
inside the patient to treat the nerve.
[0011] In some embodiments, the treatment energy comprises focused
energy.
[0012] In some embodiments, the treatment energy comprises
non-focused energy.
[0013] In some embodiments, the treatment energy comprises HIFU
energy.
[0014] In some embodiments, the treatment energy comprises LIFU
energy.
[0015] In some embodiments, the treatment energy is delivered to
the nerve to achieve partial ablation of the nerve.
[0016] In some embodiments, the treatment energy is delivered to
the nerve to achieve complete ablation of the nerve.
[0017] In some embodiments, the treatment energy is delivered to
achieve paralysis of the nerve.
[0018] In some embodiments, the nerve leads to a kidney.
[0019] In some embodiments, the nerve comprises a renal nerve.
[0020] In some embodiments, the nerve comprises a sympathetic nerve
connected to the kidney.
[0021] In some embodiments, the nerve comprises an afferent nerve
connected to the kidney.
[0022] In some embodiments, the nerve comprises a renal sympathetic
nerve at a renal pedicle.
[0023] In some embodiments, the nerve comprises a nerve trunk
adjacent to a vertebra.
[0024] In some embodiments, the nerve comprises a ganglion adjacent
to a vertebra.
[0025] In some embodiments, the nerve comprises a dorsal root
nerve.
[0026] In some embodiments, the nerve leads to an adrenal
gland.
[0027] In some embodiments, the nerve comprises a motor nerve.
[0028] In some embodiments, the nerve is next to a kidney.
[0029] In some embodiments, the nerve is behind an eye.
[0030] In some embodiments, the nerve comprises a celiac
plexus.
[0031] In some embodiments, the nerve is within or around a
vertebral column.
[0032] In some embodiments, the nerve extends to a facet joint
[0033] In some embodiments, the nerve comprises a celiac
ganglion.
[0034] In some embodiments, the act of operating the energy source
comprises positioning the energy source.
[0035] In some embodiments, the energy source comprises an
ultrasound energy source.
[0036] In some embodiments, the ultrasound energy source is used to
deliver the treatment energy to the nerve from multiple directions
outside the patient.
[0037] In some embodiments, the treatment energy is delivered to
modulate the nerve without damaging the nerve.
[0038] In some embodiments, the method further includes determining
a position of a renal vessel using an imaging device located
outside the patient.
[0039] In some embodiments, the position of the renal vessel is
used to determine a position of the nerve.
[0040] In some embodiments, the imaging device comprises a CT
device, an 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.
[0041] In some embodiments, the method further includes determining
a position of the nerve inside the patient.
[0042] In some embodiments, the act of determining the position of
the nerve inside the patient comprises determining a position of a
renal vessel to target the nerve that surrounds the renal
vessel.
[0043] In some embodiments, the renal vessel comprises a renal
artery.
[0044] In some embodiments, the act of determining the position of
the nerve inside the patient comprises using a Doppler
triangulation technique.
[0045] In some embodiments, the imaging device comprises a MRI
device.
[0046] In some embodiments, the imaging device comprises a CT
device.
[0047] In some embodiments, the treatment energy comprises HIFU
energy, and the imaging device comprises a MRI device.
[0048] In some embodiments, the treatment energy comprises HIFU
energy, and the imaging device comprises an ultrasound device.
[0049] In some embodiments, the nerve leads to a kidney, and the
imaging device comprises a MRI device.
[0050] In some embodiments, the nerve leads to a kidney, and the
imaging device comprises an ultrasound device.
[0051] In some embodiments, the nerve leads to a kidney, and the
imaging device is used to obtain a doppler signal.
[0052] In some embodiments, the treatment energy is delivered to a
kidney to decrease a sympathetic stimulus to the kidney, decrease
an afferent signal from the kidney to an autonomic nervous system,
or both.
[0053] In some embodiments, the method further includes delivering
testing energy to the patient to determine if there is a reaction
resulted therefrom, wherein the testing energy is delivered before
the treatment energy is delivered from the energy source.
[0054] In some embodiments, the testing energy comprises heat or
vibratory energy, and the method further comprises performing a
test to detect sympathetic nerve activity.
[0055] In some embodiments, the testing energy comprises a stimulus
applied to a skin, and the method further comprises detecting an
output from the patient.
[0056] In some embodiments, the output comprises a heart rate.
[0057] In some embodiments, the test energy is delivered to
stimulate a baroreceptor complex, and the method further includes
applying pressure to a carotid artery, and determining whether a
blood pressure decreases after application of the pressure to the
carotid artery.
[0058] In some embodiments, the test energy is delivered using an
ultrasound device that is placed outside the patient.
[0059] In some embodiments, the treatment energy from the energy
source is delivered if the blood pressure decreases or if the blood
pressure decreases at a rate that is above a prescribed
threshold.
[0060] In some embodiments, the treatment energy is delivered to
treat hypertension.
[0061] In some embodiments, the treatment energy is delivered to
treat glaucoma.
[0062] In some embodiments, the energy source is operated so that
the energy source aims at a direction that aligns with a vessel
that is next to the nerve.
[0063] In some embodiments, the method further includes tracking a
movement of a treatment region containing the nerve.
[0064] In some embodiments, the energy delivery path of the energy
source is aimed towards the nerve by using a position of a blood
vessel that is surrounded by the nerve.
[0065] In some embodiments, the method further includes delivering
a device inside the patient, and using the device to determine a
position of the nerve inside the patient, wherein the energy source
is operated based at least in part on the determined position so
that the energy delivery path is aimed towards the nerve.
[0066] In some embodiments, the device is placed inside a vessel
that is surrounded by the nerve, and the position of the nerve is
determined indirectly by determining a position of the vessel.
[0067] In some embodiments, a system for treatment includes an
energy source for placement outside a patient, wherein the energy
source is configured to aim an energy delivery path towards a nerve
that is a part of an autonomic nervous system inside the patient,
and wherein the energy source is configured to deliver treatment
energy from outside the patient to the nerve located inside the
patient to treat the nerve.
[0068] In some embodiments, the energy source is configured to
provide focused energy.
[0069] In some embodiments, the energy source is configured to
provide non-focused energy.
[0070] In some embodiments, the energy source is configured to
provide HIFU energy.
[0071] In some embodiments, the energy source is configured to
provide LIFU energy.
[0072] In some embodiments, the energy source is configured to
provide the treatment energy to achieve partial ablation of the
nerve.
[0073] In some embodiments, the energy source is configured to
deliver the treatment energy to achieve complete ablation of the
nerve.
[0074] In some embodiments, the energy source is configured to
deliver the treatment energy to achieve paralysis of the nerve.
[0075] In some embodiments, the energy source comprises an
ultrasound energy source.
[0076] In some embodiments, the ultrasound energy source is
configured to deliver the treatment energy to the nerve from
multiple directions outside the patient while the ultrasound energy
source is stationary relative to the patient.
[0077] In some embodiments, the energy source is configured to
deliver the treatment energy to modulate the nerve without damaging
tissues that are within a path of the treatment energy to the
nerve.
[0078] In some embodiments, the nerve comprises a renal nerve, and
the system further includes a processor located outside the
patient, wherein the processor is configured for receiving an input
related to a position of a renal artery, determining an output
related to a position of the renal nerve based on a model that
associates artery position with nerve position, and providing the
output to a positioning system for the energy source so that the
positioning system can cause the energy source to deliver the
treatment energy from the outside of the patient to the renal nerve
to treat the renal nerve.
[0079] In some embodiments, the system further includes a processor
for determining a position of a renal vessel located outside the
patient.
[0080] In some embodiments, the system further includes an imaging
device for providing an image signal, wherein the processor is
configured to determine the position based on the image signal.
[0081] In some embodiments, the imaging device 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.
[0082] In some embodiments, the position of the renal vessel is
used during the treatment energy delivery to target the nerve that
surrounds the renal vessel.
[0083] In some embodiments, the position is determined using a
Doppler triangulation technique.
[0084] In some embodiments, the renal vessel comprises a renal
artery.
[0085] In some embodiments, treatment energy is delivered to a
kidney to decrease a sympathetic stimulus to the kidney, decrease
an afferent signal from the kidney to an autonomic nervous system,
or both.
[0086] In some embodiments, the energy source is also configured to
deliver testing energy to the patient to determine if there is a
reaction resulted therefrom.
[0087] In some embodiments, the energy source is configured to
deliver the treatment energy to treat hypertension.
[0088] In some embodiments, the energy source is configured to
deliver the treatment energy to treat glaucoma.
[0089] In some embodiments, the energy source has an orientation so
that the energy source aims at a direction that aligns with a
vessel that is next to the nerve.
[0090] In some embodiments, the energy source is configured to
track a movement of the nerve.
[0091] In some embodiments, the energy source is configured to
track the movement of the nerve by tracking a movement of a blood
vessel next to the nerve.
[0092] In some embodiments, the energy source is configured to aim
at the nerve by aiming at a vessel that is surrounded by the
nerve.
[0093] In some embodiments, the system further includes a device
for placement inside the patient, and a processor for determining a
position using the device, wherein the energy source is configured
to aim the energy delivery path towards the nerve inside the
patient based at least in part on the determined position.
[0094] In some embodiments, the device is sized for insertion into
a vessel that is surrounded by the nerve.
[0095] In some embodiments, a system to deliver energy from a
position outside a skin of a patient to a nerve surrounding a blood
vessel inside the patient, includes a processor configured to
receive image signal, and determine a three dimensional coordinate
of a blood vessel based on the image signal, and an energy source
configured to deliver energy from the position outside the skin of
the patient to the nerve surrounding the blood vessel, wherein the
processor is also configured to control the energy source based on
the determined coordinate.
[0096] In some embodiments, the system further includes an imaging
device for providing the image signal.
[0097] In some embodiments, the imaging device comprises a MRI
device.
[0098] In some embodiments, the imaging device comprises an
ultrasound device.
[0099] In some embodiments, the energy comprises focused
energy.
[0100] In some embodiments, the energy comprises focused
ultrasound.
[0101] In some embodiments, the energy source comprises an
ultrasound array that is aligned with the vessel.
[0102] In some embodiments, the system further includes an imaging
device for providing a B-mode ultrasound for imaging the blood
vessel.
[0103] In some embodiments, a system to deliver energy from a
position outside a skin of a patient to a nerve surrounding a blood
vessel includes a fiducial for placement inside the blood vessel, a
detection device to detect the fiducial inside the blood vessel, a
processor configured to determine a three dimensional coordinate of
the detected fiducial, and an energy source configured to transmit
energy through the skin and to focus the energy at the region of
the blood vessel, wherein the processor is configured to operate
the energy source based on the determined three dimensional
coordinate of the fiducial, and information regarding the blood
vessel.
[0104] In some embodiments, the energy source comprises an
ultrasound device, and wherein the blood vessel is a renal
artery.
[0105] In some embodiments, the system further includes an
ultrasound imaging system.
[0106] In some embodiments, the fiducial is placed inside the blood
vessel and is attached to an intravascular catheter.
[0107] In some embodiments, the fiducial is a passive fidicial that
is configured to respond to an external signal.
[0108] In some embodiments, the fiducial is an active ficucial,
transmitting its position to the detection device.
[0109] In some embodiments, a method to treat hypertension in a
patient includes obtaining an imaging signal from a blood vessel in
the patient, planning a delivery of energy to a wall of the blood
vessel, and delivering energy from outside a skin of the patient to
an autonomic nerve surrounding the blood vessel.
[0110] In some embodiments, the method further includes selectively
modulating an afferent nerve within a sympathetic nerve bundle.
[0111] In some embodiments, the method further includes utilizing
microneurography after the delivery of the energy to determine an
effect of the energy delivery on a sympathetic nervous system.
[0112] In some embodiments, the blood vessel extends to or from a
kidney, and the method further comprises locating the blood vessel
with doppler ultrasound.
[0113] In some embodiments, a system to modulate an autonomic nerve
in a patient utilizing transcutaneous energy delivery, the system
includes a processor comprising an input for receiving information
regarding energy and power to be delivered to a treatment region
containing the nerve, and an output for outputting a signal,
wherein the processor is configured to determine a position of a
reference target from outside the patient to localize the nerve
relative to the reference target, a therapeutic energy device
comprising a transducer for delivering energy from outside the
patient, a controller to control an aiming of the transducer based
at least in part on the signal from the processor, and an imaging
system coupled to the processor or the therapeutic energy
device.
[0114] In some embodiments, the processor is configured to
determine the position during an operation of the therapeutic
energy device.
[0115] In some embodiments, the system further includes a patient
interface configured to position the therapeutic device so that the
transducer is aimed toward a blood vessel connected to a kidney
from a position between ribs superiorly, a iliac crest inferiorly,
and a vertebral column medially.
[0116] In some embodiments, the therapeutic energy device is
configured to deliver focused ultrasound.
[0117] In some embodiments, the reference target is at least a
portion of a blood vessel traveling to or from a kidney, and the
nerve is a renal nerve.
[0118] In some embodiments, the transducer is configured to focus
energy at a distance from 6 cm to 18 cm.
[0119] In some embodiments, the transducer is configured to deliver
the energy in a form of focused ultrasound to a renal blood vessel
at an angle ranging between about -10 degrees and about -48 degrees
relative to a horizontal line connecting transverse processes of a
spinal column.
[0120] In some embodiments, the energy from the therapeutic energy
device ranges between 100 W/cm2 and 2500 W/cm2.
[0121] In some embodiments, the reference target is an indwelling
vascular catheter.
[0122] In some embodiments, the imaging system is a magnetic
resonance imaging system and the therapeutic energy device is an
ultrasound device.
[0123] In some embodiments, the imaging system is an ultrasound
imaging system.
[0124] In some embodiments, the processor is a part of the
therapeutic energy device.
[0125] In some embodiments, the processor is a part of the imaging
system.
[0126] In some embodiments, a method to deliver energy from a
position outside the skin of a patient to a nerve surrounding a
blood vessel, includes placing a device inferior to ribs, superior
to an iliac crest, and lateral to a spine, and using the device to
maintain an energy delivery system at a desired position relative
to the patient so that the energy delivery system can deliver
energy through the skin without traversing bone.
[0127] In some embodiments, the energy delivery system comprises a
focused ultrasound delivery system.
[0128] In some embodiments, a device for use in a system to deliver
focused ultrasound energy from a position outside a skin of a
patient to a nerve surrounding a blood vessel, includes a
positioning device configured to maintain an energy delivery system
at a desired position relative to the patient so that the energy
delivery system can deliver energy through the skin without
traversing bone, wherein the positioning device is configured to be
placed inferior to ribs, superior to an iliac crest, and lateral to
a spine.
[0129] In some embodiments, the energy delivery system comprises a
focused ultrasound delivery system.
[0130] In some embodiments, the positioning device is configured to
maintain an angle of the focused ultrasound delivery system such
that bony structures are not include in an ultrasound field.
[0131] In some embodiments, a system for treatment includes a
treatment device configured to deliver energy from outside a
patient to a nerve inside the patient, a catheter configured for
placement inside a vessel surrounded by the nerve, the catheter
configured to transmit a signal, and a processor configured to
receive the signal and determine a reference position in the
vessel, wherein the treatment device is configured deliver the
energy to the nerve based on the determined reference position.
[0132] In some embodiments, the treatment device comprises an
ultrasound device.
[0133] In some embodiments, a method of inhibiting the function of
a nerve traveling with an artery includes providing an external
imaging modality to determine the location of the artery of a
patient, placing the artery in a first three dimensional coordinate
reference based on the imaging, placing or associating a
therapeutic energy generation source in the first three dimensional
coordinate reference frame, modeling the delivery of energy to the
adventitial region of the artery or a region adjacent to the artery
where a nerve travels, delivering therapeutic energy from the
therapeutic energy source, from at least two different angles,
through the skin of a patient, to intersect at the artery or the
region adjacent to the artery, and at least partially inhibiting
the function of the nerve traveling with the artery.
[0134] In some embodiments, the imaging modality is one of:
ultrasound, MRI, and CT.
[0135] In some embodiments, the therapeutic energy is
ultrasound.
[0136] In some embodiments, the artery is a renal artery.
[0137] In some embodiments, placing the artery in a three
dimensional reference frame comprises locating the artery using a
doppler ultrasound signal.
[0138] In some embodiments, the method further includes utilizing a
fiducial wherein the fiducial is placed internal to the
patient.
[0139] In some embodiments, said fiducial is temporarily placed in
a position internal to the patient.
[0140] In some embodiments, said fiducial is a catheter placed in
the artery of the patient.
[0141] In some embodiments, said catheter is detectable using a
radiofrequency signal and said imaging modality is ultrasound.
[0142] In some embodiments, the therapeutic energy from the energy
source is delivered in a distribution along the length of the
artery.
[0143] In some embodiments, the therapeutic energy is ionizing
radiation.
[0144] In some embodiments, a system to inhibit the function of a
nerve traveling with a renal artery includes a detector to
determine the location of the renal artery and renal nerve from a
position external to a patient, an ultrasound component to deliver
therapeutic energy through the skin from at least two directions to
the nerve surrounding the renal artery, a modeling algorithm
comprising an input and an output, said input to the modeling
algorithm comprising a three dimensional coordinate space
containing a therapeutic energy source and the position of the
renal artery in the three dimensional coordinate space, and said
output from the modeling algorithm comprising the direction and
energy level of the ultrasound component, a fiducial, locatable
from a position outside a patient, adapted to be temporarily placed
in the artery of the patient and communicate with the detector to
determine the location of the renal artery in a three dimensional
reference frame, the information regarding the location
transmittable as the input to the model.
[0145] In some embodiments, the fiducial is a passive reflector of
ultrasound.
[0146] In some embodiments, the fiducial generates radiofrequency
energy.
[0147] In some embodiments, the fiducial is activated to transmit
energy based on a signal from an ultrasound or magnetic field
generator.
[0148] In some embodiments, the output from the model instructs the
ultrasound component to deliver a lesion on the artery in which the
major axis of the lesion is longitudinal along the length of the
artery.
[0149] In some embodiments, the output from the model instructs the
ultrasound component to deliver multiple lesions around an artery
simultaneously.
[0150] In some embodiments, the output from the model instructs the
ultrasound component to deliver a circumferential lesion around the
artery.
[0151] In some embodiments, the lesion is placed around the renal
artery just proximal to the bifurcation of the artery in the hilum
of the kidney.
[0152] In some embodiments, a method to stimulate or inhibit the
function of a nerve traveling to or from the kidney includes
identifying an acoustic window at the posterior region of a patient
in which the renal arteries can be visualized, transmitting a first
energy through the skin of a patient from the posterior region of
the patient, imaging an arterial region using the first transmitted
energy, and applying a second transmitted energy to the arterial
adventitia by coupling the imaging and the second transmitted
energy.
[0153] In some embodiments, the method further includes tracking
the image created by the first transmitted energy.
[0154] In some embodiments, a method to locate the position of a
blood vessel in the body of a patient includes applying a first
wave of ultrasound, from a first direction, to a region of a blood
vessel from outside of the patient and detecting its return signal,
comparing the applied first wave and its return signal,
simultaneously, or sequentially, applying a second wave of
ultrasound from a second direction to the blood vessel and
detecting a its return signal, and integrating the return signals
from the first wave and the return signals from the second wave to
determine the position, in a three dimensional coordinate
reference, of the blood vessel.
[0155] In some embodiments, the method further includes the step of
instructing a therapeutic ultrasound transducer to apply energy to
the position of the blood vessel.
DESCRIPTION OF FIGURES
[0156] FIGS. 1a-b depict the focusing of energy sources on nerves
of the autonomic nervous system.
[0157] FIG. 1c depicts an imaging system to help direct the energy
sources.
[0158] FIG. 2 depicts targeting and/or therapeutic ultrasound
delivered through the stomach to the autonomic nervous system
posterior to the stomach.
[0159] FIG. 3a depicts focusing of energy waves on the renal
nerves.
[0160] FIG. 3b depicts a coordinate reference frame for the
treatment.
[0161] FIG. 3C depicts targeting catheters placed in any of the
renal vessels.
[0162] FIG. 3D depicts an image detection system of a blood vessel
with a temporary fiducial placed inside.
[0163] FIG. 3E depicts a therapy paradigm for the treatment and
assessment of hypertension.
[0164] FIG. 4a depicts the application of energy to the autonomic
nervous system surrounding the carotid arteries.
[0165] FIG. 4B depicts the application of energy to through the
vessels of the renal hilum.
[0166] FIGS. 5a-b depicts the application of focused energy to the
autonomic nervous system of the eye.
[0167] FIG. 6 depicts the application of constricting lesions to
the kidney deep inside the calyces of the kidney.
[0168] FIGS. 7a depicts a patient in an imaging system receiving
treatment with focused energy waves.
[0169] FIG. 7b depicts visualization of a kidney being treated.
[0170] FIG. 7c depicts a close up view of the renal nerve region of
the kidney being treated.
[0171] FIG. 7d depicts an algorithmic method to treat the autonomic
nervous system using MRI and energy transducers.
[0172] FIG. 7e depicts a geometric model obtained from
cross-sectional images of the area of the aorta and kidneys.
[0173] FIG. 7F depicts a close up image of the region of
treatment.
[0174] FIG. 7G depicts the results of measurements from a series of
cross sectional image reconstructions.
[0175] FIG. 7H depicts the results of measurements from a series of
cros-sectional images from a patient in a more optimized
position.
[0176] FIG. 7I depicts an algorithmic methodology to apply
treatment to the hilum of the kidney and apply energy to the renal
blood vessels.
[0177] FIG. 8a depicts a percutaneous approach to treating the
autonomic nervous system surrounding the kidneys.
[0178] FIG. 8b depicts an intravascular approach to treating or
targeting the autonomic nervous system.
[0179] FIG. 8C depicts a percutaneous approach to the renal hila
using a CT scan and a probe to reach the renal blood vessels.
[0180] FIGS. 9a-c depicts the application of energy from inside the
aorta to regions outside the aorta to treat the autonomic nervous
system.
[0181] FIG. 10 depicts steps to treat a disease using HIFU while
monitoring progress of the treatment as well as motion.
[0182] FIG. 11a depicts treatment of brain pathology using cross
sectional imaging.
[0183] FIG. 11b depicts an image on a viewer showing therapy of the
region of the brain being treated.
[0184] 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.
[0185] FIG. 12 depicts treatment of the renal nerve region using a
laparoscopic approach.
[0186] FIG. 13 depicts a methodology for destroying a region of
tissue using imaging markers to monitor treatment progress.
[0187] FIG. 14 depicts the partial treatment of portions of a nerve
bundle using converging imaging and therapy wave.
[0188] FIG. 15a-b depicts the application of focused energy to the
vertebral column to treat various spinal pathologies including
therapy of the spinal or intravertebral nerves.
[0189] FIG. 16A depicts the types of lesions which are created
around the renal arteries to affect a response.
[0190] FIG. 16B depicts a simulation of ultrasound around a blood
vessel I support of FIG. 16A.
[0191] FIG. 16C depicts data from ultrasound energy applied to the
renal blood vessels and the resultant change in norepinephrine
levels.
[0192] FIG. 17A depicts the application of multiple transducers to
treat regions of the autonomic nervous system at the renal
hilum.
[0193] FIGS. 17B-C depict methods for using imaging to direct
treatment of a specific region surrounding an artery as well as
display the predicted lesion morphology.
[0194] FIG. 17D depicts a method for localizing HIFU transducers
relative to Doppler ultrasound signals.
[0195] FIG. 17E depicts an arrangement of transducers relative to a
target.
[0196] FIG. 17F depicts ablation zones in a multi-focal region in
cross-section.
[0197] FIG. 18 depicts the application of energy internally within
the kidney to affect specific functional changes at the regional
level within the kidney.
[0198] FIG. 19A depicts the direction of energy wave propagation to
treat regions of the autonomic nervous system around the region of
the kidney hilum.
[0199] 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.
[0200] FIG. 20 depicts the application of ultrasound waves through
the wall of the aorta to apply a therapy to the autonomic nervous
system.
[0201] FIG. 21A depicts application of focused energy to the
ciliary muscles and processes of the anterior region of the
eye.
[0202] 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.
[0203] FIG. 22 depicts the application of focused energy to nerves
surrounding the knee joint to affect nerve function in the
joint.
[0204] FIGS. 23A-B depicts the application of energy to the
fallopian tube to sterilize a patient.
[0205] 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.
[0206] FIG. 25 depicts an optimized position of a device to apply
therapy to internal nerves.
[0207] FIG. 26A depicts positioning of a patient to obtain
parameters for system design.
[0208] FIG. 26B depicts a device design based on the information
learned from feasibility studies.
[0209] FIG. 27 depicts a clinical paradigm for treating the renal
nerves of the autonomic nervous system based on feasibility
studies.
[0210] FIG. 28 A-C depicts a treatment positioning system for a
patient incorporating a focused ultrasound system.
[0211] FIG. 29 A-D depicts results of studies applying focused
energy to nerves surrounding arteries and of ultrasound studies to
visualize the blood vessels around which the nerves travel.
[0212] FIG. 29E depicts the results of design processes in which
the angle, length, and surface area from CT scans is
quantified.
[0213] FIGS. 30A-I depicts results of simulations to apply focused
ultrasound to the region of a renal artery with a prototype device
design based on simulations.
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, incorporated by reference
herein).
[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
incorporated by reference). 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 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.
[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, herein incorporated by
reference). 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.
[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 510 (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 sumpathetic 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 energies 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 of 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. 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.
[0238] 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.
[0239] 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.
[0240] 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.
[0241] 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.
[0242] Yet another embodiment of the present invention 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:
[0243] 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.
[0244] A preferred embodiment of this invention contemplates a
method for transcutaneous ultrasonic therapy of a target tissue,
where the target tissue is close to a blood vessel.
[0245] Other preferred embodiments of this invention 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 t of this invention
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 of the present invention 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
of this invention contemplates that the photosensitizing agent is
indocyanine green (ICG).
[0246] Other embodiments of the present invention 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 of the present invention 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, adventitiaof arteries, arterial plaques,
vascular smooth muscle cells and/or the extracellular matrix of the
site to be treated.
[0249] A further preferred embodiment of this invention
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 of the present invention 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-etio-purpurin,
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 mW/Cm.sup.2 whereas HIFU (thermal
modulation), by definition generates heat at a focus, 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.
[0256] 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. 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).
[0257] 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.
[0258] Imaging 600 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 in
which the coordinate space of the imaging system. 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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.
[0264] 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.
[0265] 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 730,731 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.
[0266] 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.
[0267] Temporary neurostimulators can also be placed through the
tube, 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.
[0268] 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 no re-grow as quickly as the efferent fibers, if at
all.
[0269] 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.
[0270] 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 herein
incorporated by reference). 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. 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.
[0271] 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.
[0272] 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.
[0273] The original imaging modality can be utilized to locate the
renal sympathetic region 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. 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.
[0274] 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.
[0275] 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 temporary fiducial might be a mechanical,
optical, electromechanical, a radiofrequency radiotransmitter,
global positioning tracking (GPS) device, or ultrasound responsive
technology. Similar devices might be found in U.S. Pat. Nos.
6,656,131 and 7,470,241 which are incorporated by reference
herein.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] 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. 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.
[0280] In some embodiments, only the temperature determination is
utilized. That is, the temperature sensing embodiments and
algorithms 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.
[0281] 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.
[0282] 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.
[0283] 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.
[0284] 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, and the like.
[0285] 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 1020 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 1020 region. 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.).
[0286] 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, 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.
[0287] 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] 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.
[0294] 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.
[0295] 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.
[0296] 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.
[0297] 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.
[0298] 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, 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).
[0299] 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.
[0300] 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.
[0301] 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.
[0302] 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.
[0303] 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.
[0304] 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.
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.
[0305] 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.
[0306] 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 of the vessels
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.
[0307] Alternatively, in another embodiment, ultrasound is utilized
and the ultrasound image 4510 can be directly correlated to the
origin of the imaging transducer. 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.
[0308] 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.
[0309] 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.
[0310] 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 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.
[0311] 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 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.
[0312] 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 pharmaceutical 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.
[0313] 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.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] 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.
[0318] 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.
[0319] 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.
[0320] 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.
[0321] 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.
[0322] 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.
[0323] 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 in order to "see" the renal artery under the
rib.
[0324] 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 4640 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.
[0325] 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 4640).
[0326] 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.
[0327] 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.
[0328] 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.
[0329] FIG. 8A depicts a percutaneous procedure and device 5010 in
which the region around the renal artery 5030 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, and 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. 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.
[0330] 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.
[0331] 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.
[0332] 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
[0333] 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.
[0334] 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, only
facilitates 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
transducted 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.
[0335] 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.
[0336] 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.
[0337] 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
denvervate the region. The data presented below indicates the
feasibility of this approach as far as ultrasound enabling
denervation of the vessels quickly and easily.
[0338] 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.
[0339] 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.
[0340] 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.
[0341] 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.
[0342] 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.
[0343] 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.
[0344] 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.
[0345] 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.
[0346] 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.
[0347] 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.
[0348] 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.
[0349] 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.
[0350] 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.
[0351] 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.
[0352] 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 spike 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 suturing 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, PP. Effects of Focused
Ultrasound Radiation on Peripheral Nerve, with Observations on
Local Heating. Experimental Neurology 8, 47-83 1963 incorporated by
reference).
[0353] 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.
[0354] 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.
[0355] 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.
[0356] 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.
[0357] 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.
Simulations are shown in FIG. 16B 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. In these
experiments which were performed, the norepinephrine levels
approached zero 8782 versus controls 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). It is important that the renal artery and vein
walls were 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.
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 FIG. 16B. Histological results also confirm the annular nature
of the lesions and limited collateral damage as predicted by the
modeling in 16B.
[0358] 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 by use of a model to
approximate the position of the nerves based on the position of the
blood vessel.
[0359] 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
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 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.
[0360] 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.
[0361] 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 shaped 1150. This lesion is generated by a
spherical or semi-spherical type of ultrasound array in a preferred
embodiment. Multiple cigar shaped lesion as shown in FIG. 17C leads
to a ring type of lesion 1350.
[0362] 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, or might be based on a simulation
of the position of the lesion 1150. 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.
[0363] 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 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.
[0364] 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 difference frequencies or angles might be required.
[0365] 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.
[0366] 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.
[0367] 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.
[0368] 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.
[0369] 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:
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
[0370] 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.
[0371] 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
[0372] 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.
[0373] 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.
[0374] 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.
[0375] 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.
The transducer(s) can be spherical or aspherical, they can be
couple 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.
[0376] 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.)
[0377] 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.
[0378] 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.
[0379] 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.
[0380] 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.
[0381] 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.
[0382] 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.
[0383] 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.
[0384] 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.
[0385] 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, 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.
[0386] 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.
[0387] 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.
[0388] 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 electro-mechanical 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, or radiofrequency based.
[0389] 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, the shape might be elliptical or aspheric ro
in some cases shperic. 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.
[0390] 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.
[0391] 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.
[0392] 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 and 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 stimulator implantation
and interventional procedures such as catheterization of the renal
artery.
[0393] 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.
[0394] 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.
[0395] 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 shown in FIG. 29E 8762 which is
representative of a patient series. Further more 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.
[0396] 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.
[0397] 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.
[0398] 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.
[0399] 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.
[0400] 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.
[0401] 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.
[0402] 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.
[0403] 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.
[0404] 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. 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. 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.
[0405] 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.
[0406] 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.
[0407] 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.
[0408] 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.
[0409] 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 301 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.
[0410] 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.
[0411] 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.
[0412] 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.
* * * * *