U.S. patent application number 15/532650 was filed with the patent office on 2019-03-07 for systems and methods for modulatng nerves or other tissue.
The applicant listed for this patent is Metavention, Inc.. Invention is credited to Bobak Robert Azamian, Jonathan Allen Coe, James G. Hansen, Kevin Robert Hykes, Kelly Justin McCrystle, Rossana Motta, Michael David Perry, Eric Robert Reuland, Scott Raymond Smith, Victor Kelvin Sun, Scott Bradley Vafai, Anthony Ciro Vrba, Mark Wilson Ian Webster.
Application Number | 20190069949 15/532650 |
Document ID | / |
Family ID | 56092488 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190069949 |
Kind Code |
A1 |
Vrba; Anthony Ciro ; et
al. |
March 7, 2019 |
SYSTEMS AND METHODS FOR MODULATNG NERVES OR OTHER TISSUE
Abstract
According to various embodiments, systems, devices and methods
for modulating targeted nerve fibers (e.g., hepatic
neuromodulation) or other tissue are provided. The systems may be
configured to access tortuous anatomy of or adjacent hepatic
vasculature. The systems may be configured to target nerves
surrounding (e.g., within adventitia of or within perivascular
space of) an artery or other blood vessel, such as the common
hepatic artery.
Inventors: |
Vrba; Anthony Ciro; (Maple
Grove, MN) ; Smith; Scott Raymond; (Chaka, MN)
; Azamian; Bobak Robert; (Newport Coast, CA) ;
Vafai; Scott Bradley; (Boston, MA) ; Coe; Jonathan
Allen; (Menlo Park, CA) ; Hansen; James G.;
(Coon Rapids, MN) ; Hykes; Kevin Robert; (Dana
Point, CA) ; McCrystle; Kelly Justin; (Menlo Park,
CA) ; Motta; Rossana; (Eden Prairie, MN) ;
Perry; Michael David; (Los Altos, CA) ; Sun; Victor
Kelvin; (Irvine, CA) ; Webster; Mark Wilson Ian;
(Epsom, Auckland, NZ) ; Reuland; Eric Robert;
(Laguna Niguel, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Metavention, Inc. |
Eden Prairie |
MN |
US |
|
|
Family ID: |
56092488 |
Appl. No.: |
15/532650 |
Filed: |
December 3, 2015 |
PCT Filed: |
December 3, 2015 |
PCT NO: |
PCT/US15/63807 |
371 Date: |
June 2, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62087179 |
Dec 3, 2014 |
|
|
|
62130469 |
Mar 9, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2018/048 20130101;
A61B 2018/00214 20130101; A61M 25/0147 20130101; A61M 25/09
20130101; A61B 18/22 20130101; A61B 2018/00267 20130101; A61B
2218/007 20130101; A61B 2018/1475 20130101; A61B 8/485 20130101;
A61B 2018/00875 20130101; A61B 18/06 20130101; A61B 18/1492
20130101; A61B 2018/00404 20130101; A61B 2018/1467 20130101; A61B
18/02 20130101; A61B 2018/00821 20130101; A61B 18/16 20130101; A61B
17/320068 20130101; A61B 18/24 20130101; A61B 2017/00402 20130101;
A61B 2017/320069 20170801; A61B 2018/00279 20130101; A61B 2018/068
20130101; A61B 2018/1435 20130101; A61B 2018/1861 20130101; A61B
18/1815 20130101; A61B 2018/00023 20130101; A61B 2018/00529
20130101; A61B 2018/00577 20130101; A61B 2018/1425 20130101; A61N
2007/0021 20130101; A61B 8/12 20130101; A61B 17/122 20130101; A61B
2018/00285 20130101; A61B 2018/00434 20130101; A61B 2018/0022
20130101; A61B 2018/0212 20130101; A61B 2017/00867 20130101; A61B
2018/00047 20130101; A61N 2007/0043 20130101 |
International
Class: |
A61B 18/14 20060101
A61B018/14; A61B 17/32 20060101 A61B017/32; A61B 17/122 20060101
A61B017/122; A61B 18/16 20060101 A61B018/16; A61M 25/01 20060101
A61M025/01; A61B 18/02 20060101 A61B018/02; A61B 18/06 20060101
A61B018/06 |
Claims
1-105. (canceled)
106. A method of ablating nerves surrounding a blood vessel
comprising: inserting a neuromodulation device within a blood
vessel, the neuromodulation device comprising a first electrode and
a second electrode spaced apart distal of the first electrode along
a distal end portion of the neuromodulation device and at least one
lesion spacing indicator positioned distal of the second electrode;
causing the first electrode to contact an inner wall of the blood
vessel at a first contact location and the second electrode to
contact the inner wall of the blood vessel at a second contact
location, wherein the first location and the second location are in
different quadrants of the inner wall of the blood vessel and
spaced apart axially from each other by a separation distance;
causing the first electrode and the second electrode to deliver
radiofrequency energy to the inner wall of the blood vessel while
at the contact locations; repositioning the neuromodulation device
axially within the blood vessel using the at least one lesion
spacing indicator; causing the first electrode to contact the inner
wall of the blood vessel at a third contact location and the second
electrode to contact the inner wall at a fourth contact location,
wherein the third contact location and the fourth contact location
are in different quadrants of the inner wall of the blood vessel
and spaced apart axially from each other; and removing the
neuromodulation device from the blood vessel.
107. The method of claim 106, wherein the at least one lesion
spacing indicator is spaced apart axially from the second electrode
by a distance that is equal to the separation distance.
108. The method of claim 106, wherein the at least one lesion
spacing indicator is spaced apart axially from the second electrode
at distance that is twice the separation distance.
109. The method of claim 106, wherein the first contact location
and the second contact location are on opposite sides of the
circumference of the blood vessel.
110. The method of claim 106, wherein the first contact location
and the second contact location are spaced apart circumferentially
by about 180 degrees.
111. The method of claim 106, wherein the first contact location
and the second contact location are spaced apart circumferentially
by between 120 degrees and 210 degrees.
112. The method of claim 106, wherein the first contact location
and the second contact location are spaced apart circumferentially
by about 90 degrees.
113. The method of claim 106, wherein the at least one spacing
indicator comprises two lesion spacing indicators.
114. The method of claim 113, wherein the two lesion spacing
indicators are spaced apart axially along the neuromodulation
device at a distance that is twice the separation distance.
115. The method of claim 113, wherein the two lesion spacing
indicators are spaced apart axially along the neuromodulation
device by an amount equal to the separation distance.
116. The method of claim 113, wherein repositioning the
neuromodulation device axially within the blood vessel comprises
aligning a distal one of the two spaced-apart lesion spacing
indicators with a position of a proximal one of the two lesion
spacing indicators prior to repositioning.
117. The method of claim 106, wherein the separation distance is
between 3 mm and 8 mm.
118.-153. (canceled)
154. A method of modulating nerves in a manner to reduce glucose
production, the method comprising: identifying one or more
locations along a hepatic artery within a specified distance from
an adjacent dense structure using one or more ultrasound
transducers adapted for imaging; and delivering energy sufficient
to modulate nerves to reduce a blood glucose level using the one or
more ultrasound transducers.
155. The method of claim 154, wherein a single ultrasound
transducer is adapted for imaging and for delivering energy to
modulate nerves.
156. The method of claim 154, wherein the one or more transducers
comprises a first one or more transducers adapted for imaging and a
second one or more ultrasound transducers adapted for delivering
energy to modulate nerves.
157. (canceled)
158. The method of claim 154, wherein the energy is sufficient to
ablate the nerves.
159. The method of claim 154, further comprising confirming
modulation of the nerves.
160. The method of claim 154, further comprising adjusting one or
more parameters of the energy delivery based on imaging data
received by the one or more ultrasound transducers.
161. (canceled)
162. (canceled)
163. The method of claim 154, wherein the adjacent dense structures
comprise organs that affect glucose production or storage.
164. The method of claim 163, wherein the adjacent dense structures
comprise at least a portion of one of: a liver, a pancreas, a
stomach, or a small intestine.
165-193. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit of U.S. Provisional
Patent Application No. 62/087,179, filed Dec. 3, 2014, and U.S.
Provisional Patent Application No. 62/130,469, filed Mar. 9, 2015,
each of which is incorporated herein by reference in its
entirety.
FIELD
[0002] The disclosure relates generally to therapeutic tissue
modulation and, more specifically, to embodiments of devices,
systems and methods for therapeutically effecting neuromodulation
of targeted nerve fibers of, for example, the hepatic system, to
treat metabolic diseases or conditions, such as diabetes
mellitus.
BACKGROUND
[0003] Chronic hyperglycemia is one of the defining characteristics
of diabetes mellitus. Hyperglycemia is a condition in which there
is an elevated blood glucose concentration. An elevated blood
glucose concentration may result from impaired insulin secretion
from the pancreas and also, or alternatively, from cells failing to
respond to insulin normally. Excessive glucose release from the
liver is a significant contributor to hyperglycemia. The liver is
responsible for approximately 90% of the glucose production and 33%
of glucose uptake, and derangements in both in type 2 diabetes
contribute to hyperglycemia in the fasting and post-prandial
states.
[0004] Type 1 diabetes mellitus results from autoimmune destruction
of the pancreatic beta cells leading to inadequate insulin
production. Type 2 diabetes mellitus is a more complex, chronic
metabolic disorder that develops due to a combination of
insufficient insulin production as well as cellular resistance to
the action of insulin. Insulin promotes glucose uptake into a
variety of tissues and also decreases production of glucose by the
liver and kidneys; insulin resistance results in reduced peripheral
glucose uptake and increased endogenous glucose output, both of
which drive blood the glucose concentration above normal
levels.
[0005] Current estimates are that approximately 26 million people
in the United States (over 8% of the population) have some form of
diabetes mellitus. Treatments, such as medications, diet, and
exercise, seek to control blood glucose levels, which require a
patient to closely monitor his or her blood glucose levels.
Additionally, patients with type 1 diabetes mellitus, and many
patients with type 2 diabetes mellitus, are required to take
insulin every day. Insulin is not available in a pill form,
however, but must be injected under the skin. Because treatment for
diabetes mellitus is self-managed by the patient on a day-to-day
basis, compliance or adherence with treatments can be
problematic.
SUMMARY
[0006] Several embodiments described herein relate generally to
devices, systems and methods for therapeutically effecting
neuromodulation of targeted nerve fibers to treat various medical
conditions, disorders and diseases. In some embodiments,
neuromodulation of targeted nerve fibers is used to treat, or
reduce the risk of occurrence of symptoms associated with, a
variety of metabolic diseases. For example, neuromodulation of
targeted nerve fibers can treat, or reduce the risk of occurrence
of symptoms associated with, diabetes (e.g., diabetes mellitus) or
other diabetes-related diseases. The methods described herein can
advantageously treat diabetes without requiring daily insulin
injection or constant monitoring of blood glucose levels. The
treatment provided by the devices, systems and methods described
herein can be permanent or at least semi-permanent (e.g., lasting
for several weeks, months or years), thereby reducing the need for
continued or periodic treatment. Embodiments of the devices
described herein can be temporary or implantable.
[0007] In some embodiments, neuromodulation of targeted nerve
fibers as described herein can be used for the treatment of insulin
resistance, genetic metabolic syndromes, ventricular tachycardia,
atrial fibrillation or flutter, arrhythmia, inflammatory diseases,
hypertension (arterial or pulmonary), obesity, hyperglycemia
(including glucose tolerance), hyperlipidemia, eating disorders,
and/or endocrine diseases. In some embodiments, neuromodulation of
targeted nerve fibers treats any combination of diabetes, insulin
resistance, or other metabolic diseases. In some embodiments,
temporary or implantable neuromodulators may be used to regulate
satiety and appetite (e.g., to promote weight loss). In several
embodiments, modulation of nervous tissue that innervates
(efferently or efferently) the liver is used to treat
hemochromatosis, Wilson's disease, non-alcoholic steatohepatitis
(NASH), non-alcoholic fatty liver disease (NAFLD), and/or other
conditions affecting the liver and/or liver metabolism. In some
embodiments, modulation of nervous tissue that innervates
(afferently or efferently) the liver (e.g., hepatic denervation) is
effective for reducing whole-body sympathetic tone and resulting
conditions such as hypertension, congestive heart failure, atrial
fibrillation, obstructive sleep apnea, and/or renal failure,
etc.
[0008] In some embodiments, sympathetic nerve fibers associated
with the liver are selectively disrupted (e.g., ablated,
denervated, disabled, severed, blocked, injured, desensitized,
removed) to decrease hepatic glucose production and/or increase
hepatic glucose uptake, thereby aiding in the treatment of, or
reduction in the risk of, diabetes and/or related diseases or
disorders. The disruption can be permanent or temporary (e.g., for
a matter of several days, weeks or months). In some embodiments,
sympathetic nerve fibers in the hepatic plexus are selectively
disrupted. In some embodiments, sympathetic nerve fibers
surrounding (e.g., within the perivascular space of) the common
hepatic artery proximal to the proper hepatic artery, sympathetic
nerve fibers surrounding the proper hepatic artery, sympathetic
nerve fibers in the celiac ganglion adjacent the celiac artery,
other sympathetic nerve fibers that innervate or surround the
liver, sympathetic nerve fibers that innervate the pancreas,
sympathetic nerve fibers that innervate fat tissue (e.g., visceral
fat), sympathetic nerve fibers that innervate the adrenal glands,
sympathetic nerve fibers that innervate the small intestine (e.g.,
duodenum), sympathetic nerve fibers that innervate the stomach
(e.g., or portions thereof, such as the pylorus), sympathetic nerve
fibers that innervate brown adipose tissue, sympathetic nerve
fibers that innervate skeletal muscle, and/or sympathetic nerve
fibers that innervate the kidneys are selectively disrupted or
modulated (simultaneously or sequentially) to facilitate treatment
or reduction of symptoms associated with hypertension, diabetes
(e.g., diabetes mellitus), or other metabolic diseases or
disorders. In some embodiments, the methods, devices and systems
described herein are used to therapeutically modulate autonomic
nerves associated with any diabetes-relevant organs or tissues. For
example, with respect to the pancreas and duodenum, the nerves that
innervate one or both structures can be neuromodulated (e.g.,
ablated) in addition to or instead of the nerves that innervate the
liver, wherein said neuromodulation affects one or more
symptoms/characteristics associated with diabetes or other
metabolic diseases or disorders. Such symptoms/characteristics
include but are not limited to changes (e.g., increases or
decreases) in glucose levels, cholesterol levels, lipid levels,
triglyceride levels, norepinephrine levels, insulin regulation,
etc. in the blood plasma or liver or other organs. The devices and
methods disclosed herein with respect to hepatic modulation can be
used for neuromodulating the pancreas, duodenum, stomach or other
organs and structures.
[0009] In accordance with several embodiments, any nerves
containing autonomic fibers are modulated, including, but not
limited to, the saphenous nerve, femoral nerves, lumbar nerves,
median nerves, ulnar nerves, vagus nerves, and radial nerves.
Nerves surrounding arteries or veins other than the hepatic artery
may be modulated such as, but not limited to, nerves surrounding
the superior mesenteric artery, the inferior mesenteric artery, the
femoral artery, the pelvic arteries, the portal vein, pulmonary
arteries, pulmonary veins, abdominal aorta, vena cavas, splenic
arteries, gastric arteries, the internal carotid artery, the
internal jugular vein, the vertebral artery, renal arteries, and
renal veins. Celiac arteries may also be modulated according to
several embodiments herein.
[0010] In accordance with several embodiments, a therapeutic
neuromodulation system is used to selectively disrupt sympathetic
nerve fibers. The neuromodulation system can comprise an ablation
catheter system and/or a delivery catheter system (e.g., hollow,
solid, partially hollow, catheter, probe, shaft or other delivery
device with or without a lumen). An ablation catheter system may
use radiofrequency (RF) energy to ablate sympathetic nerve fibers
to cause neuromodulation or disruption of sympathetic
communication. In some embodiments, an ablation catheter system
uses ultrasonic energy to ablate sympathetic nerve fibers. In some
embodiments, an ablation catheter system uses ultrasound (e.g.,
high-intensity focused ultrasound or low-intensity focused
ultrasound) energy to selectively ablate sympathetic nerve fibers.
In other embodiments, an ablation catheter system uses
electroporation to modulate sympathetic nerve fibers. An ablation
catheter, as used herein, shall not be limited to causing ablation,
but also includes devices that facilitate the modulation of nerves
(e.g., partial or reversible ablation, blocking without ablation,
stimulation). In some embodiments, a delivery catheter system
delivers drugs or chemical agents to nerve fibers to modulate the
nerve fibers (e.g., via chemoablation). Chemical agents used with
chemoablation (or some other form of chemically-mediated
neuromodulation) may, for example, include phenol, alcohol, or any
other chemical agents that cause chemoablation of nerve fibers. In
some embodiments, cryotherapy is used. For example, an ablation
catheter system is provided that uses cryoablation to selectively
modulate (e.g., ablate) sympathetic nerve fibers. In other
embodiments, a delivery catheter system is used with brachytherapy
to modulate the nerve fibers. The catheter systems may further
utilize any combination of RF energy, ultrasonic energy, focused
ultrasound (e.g., HIFU, LIFU) energy, ionizing energy (such as
X-ray, proton beam, gamma rays, electron beams, and alpha rays),
electroporation, drug delivery, chemoablation, cryoablation,
brachytherapy, or any other modality to cause disruption or
neuromodulation (e.g., ablation, denervation, stimulation) of
autonomic (e.g., sympathetic or parasympathetic) nerve fibers. As
discussed below, microwave energy or laser energy (or combinations
of two, three or more energy sources) are used in some embodiments.
In some embodiments, energy is used in conjunction with non-energy
based neuromodulation (e.g., drug delivery).
[0011] In some embodiments, a minimally invasive surgical technique
is used to deliver the therapeutic neuromodulation system. For
example, a catheter system (e.g., hollow, solid, partially hollow,
catheter, probe, shaft or other delivery device with or without a
lumen) for the disruption or neuromodulation of sympathetic nerve
fibers can be delivered intra-arterially (e.g., via a femoral
artery, brachial artery, radial artery). In some embodiments, an
ablation catheter system is advanced to the proper hepatic artery
to ablate (completely or partially) sympathetic nerve fibers in the
hepatic plexus. In other embodiments, the ablation catheter system
is advanced to the common hepatic artery to ablate sympathetic
nerve fibers surrounding the common hepatic artery. In some
embodiments, the ablation catheter system is advanced to the celiac
artery or celiac trunk to ablate sympathetic nerve fibers in the
celiac ganglion or celiac plexus (e.g., including nerves downstream
thereof). An ablation or delivery catheter system can be advanced
within other arteries (e.g., left hepatic artery, right hepatic
artery, gastroduodenal artery, gastric arteries, splenic artery,
renal arteries, etc.) in order to disrupt targeted sympathetic
nerve fibers associated with the liver or other organs or tissue
(such as the pancreas, fat tissue (e.g., visceral fat of the
liver), the adrenal glands, the stomach, the small intestine, gall
bladder, bile ducts, brown adipose tissue, skeletal muscle), at
least some of which may be clinically relevant to diabetes. In
several embodiments, neuromodulation (e.g., denervation, stripping,
stimulation) of the celiac ganglion or modulation of celiac
ganglion activity facilitates treatment of hypertension.
[0012] In some embodiments, a therapeutic neuromodulation or
disruption system is delivered intravascularly through the venous
system. For example, the therapeutic neuromodulation system may be
delivered either through the portal vein or through the inferior
vena cava. In some embodiments, the neuromodulation system is
delivered percutaneously to the biliary tree to modulate or disrupt
sympathetic nerve fibers.
[0013] In other embodiments, the neuromodulation system is
delivered transluminally or laparoscopically to modulate or disrupt
sympathetic nerve fibers. For example, the neuromodulation system
may be delivered transluminally either through the stomach, or
through the duodenum.
[0014] In some embodiments, minimally invasive surgical delivery
(e.g., laparoscopic) of the neuromodulation system is accomplished
in conjunction with image guidance techniques. For example, a
visualization device such as a fiberoptic scope can be used to
provide image guidance during minimally invasive surgical delivery
of the neuromodulation system. In some embodiments, fluoroscopic,
computerized tomography (CT), radiographic, optical coherence
tomography (OCT), intravascular ultrasound (IVUS), Doppler,
thermography, and/or magnetic resonance (MR) imaging is used in
conjunction with minimally invasive surgical delivery of the
neuromodulation system. In some embodiments, radiopaque markers are
located at a distal end of the neuromodulation system to aid in
delivery and alignment of the neuromodulation system.
[0015] In some embodiments, an open surgical procedure is used to
access the nerve fibers to be modulated. In some embodiments, any
of the modalities described herein, including, but not limited to,
RF energy, ultrasonic energy, HIFU, thermal energy, light energy,
electrical energy other than RF energy, drug delivery,
chemoablation, cryoablation, steam or hot-water, ionizing energy
(such as X-ray, proton beam, gamma rays, electron beams, and alpha
rays) or any other modality are used in conjunction with an open
surgical procedure to modulate or disrupt sympathetic nerve fibers.
Neuromodulation via microwave energy and laser energy are also
provided in some embodiments and discussed herein. In other
embodiments, nerve fibers are surgically cut (e.g., transected) to
disrupt conduction of nerve signals or otherwise cause nerve
injury.
[0016] In some embodiments, a non-invasive (e.g., transcutaneous)
procedure is used to modulate or disrupt sympathetic nerve fibers
(e.g., nerves that innervate the liver, nerves within or
surrounding the hepatic arteries, the celiac arteries, the
gastroduodenal artery, the splenic artery, nerves that innervate
the pancreas, and/or nerves that innervate the duodenum). In some
embodiments, any of the modalities described herein, including, but
not limited, to RF energy, ultrasonic energy, HIFU energy,
radiation therapy, light energy, infrared energy, thermal energy,
steam, hot water, magnetic fields, ionizing energy, other forms of
electrical or electromagnetic energy or any other modality are used
in conjunction with a non-invasive procedure to modulate or disrupt
sympathetic nerve fibers.
[0017] In accordance with some embodiments, the neuromodulation
system is used to modulate or disrupt sympathetic nerve fibers at
one or more locations or target sites. For example, an ablation
catheter system (e.g., comprising an ablation device or methodology
described herein, for example ultrasound, RF, cryo, etc.) may
perform ablation in a circumferential or radial pattern, and/or the
ablation catheter system may perform ablation at a plurality of
points linearly spaced apart along a vessel length. In other
embodiments, an ablation catheter system performs ablation at one
or more locations in any other pattern capable of causing
disruption in the communication pathway of sympathetic nerve fibers
(e.g., spiral patterns, zig-zag patterns, multiple linear patterns,
etc.). The pattern can be continuous or non-continuous (e.g.,
intermittent). The ablation may be targeted at certain portions of
the circumference of the vessels (e.g., half or portions less than
half of the circumference). In some embodiments, modulation of
(e.g., thermal injury or damage to) the vessel wall is
non-circumferential. Ablation or other treatment may be performed
in one quadrant, two quadrants, three quadrants or four quadrants
of the vessel. In one embodiment, ablation or other treatment is
not performed in more than two quadrants of the vessel. In other
embodiments, ablation or other treatment is performed in sectors of
other increments such as 2, 3, 5 or 6 sections. In some
embodiments, the sector may span a radial distance of 90 degrees to
120 degrees. In other embodiments, the sector may span a radial
distance of 120 degrees to 240 degrees. In various embodiments, the
sectors are radially disposed in increments of approximately 90,
120, 144, or 180 degrees in order to achieve the desired
effect.
[0018] In accordance with embodiments of the invention disclosed
herein, therapeutic neuromodulation to treat various medical
disorders and diseases includes neural stimulation of targeted
nerve fibers. For example, autonomic nerve fibers (e.g.,
sympathetic nerve fibers, parasympathetic nerve fibers) may be
stimulated to treat, or reduce the risk of occurrence of, diabetes
(e.g., diabetes mellitus) or other conditions, diseases and
disorders.
[0019] In some embodiments, parasympathetic nerve fibers that
innervate the liver are stimulated. In some embodiments,
parasympathetic nerve fibers that innervate the pancreas, fat
tissue (e.g., visceral fat of the liver), the adrenal glands, the
stomach (e.g., or portions thereof such as the pylorus), the
kidneys, brown adipose tissue, skeletal muscle, and/or the small
intestine (e.g., duodenum) are stimulated. In accordance with some
embodiments, any combination of parasympathetic nerve fibers
innervating the liver, the pancreas, fat tissue, the adrenal
glands, the stomach, the kidneys, brown adipose tissue, skeletal
muscle, and the small intestine are stimulated to treat, or
alleviate or reduce the risk of occurrence of the symptoms
associated with, diabetes (e.g., diabetes mellitus) or other
conditions, diseases, or disorders. In some embodiments, the organs
or tissue are stimulated directly either internally or externally.
For example, modulation of tissue (or components of tissue, such as
cells, receptors, baroreceptors, etc.) may be accomplished by
several embodiments described herein, and may occur with or without
modulation of nerves.
[0020] In some embodiments, a neurostimulator is used to stimulate
sympathetic or parasympathetic nerve fibers. In some embodiments,
the neurostimulator is implantable. In accordance with some
embodiments, the implantable neurostimulator electrically
stimulates parasympathetic nerve fibers. In some embodiments, the
implantable neurostimulator chemically stimulates parasympathetic
nerve fibers. In still other embodiments, the implantable
neurostimulator uses any combination of electrical stimulation,
chemical stimulation, or any other method capable of stimulating
parasympathetic nerve fibers.
[0021] In other embodiments, non-invasive neurostimulation is used
to effect stimulation of parasympathetic nerve fibers. For example,
transcutaneous electrical stimulation may be used to stimulate
parasympathetic nerve fibers. Other energy modalities can also be
used to affect non-invasive neurostimulation of parasympathetic
nerve fibers (e.g., light energy, ultrasound energy).
[0022] In some embodiments, neuromodulation of targeted autonomic
nerve fibers treats diabetes (e.g., diabetes mellitus) and related
conditions by decreasing systemic glucose. For example, therapeutic
neuromodulation of targeted nerve fibers can decrease systemic
glucose by decreasing hepatic glucose production. In some
embodiments, hepatic glucose production is decreased by disruption
(e.g., ablation) of sympathetic nerve fibers. In other embodiments,
hepatic glucose production is decreased by stimulation of
parasympathetic nerve fibers.
[0023] In some embodiments, therapeutic neuromodulation of targeted
nerve fibers decreases systemic glucose by increasing hepatic
glucose uptake. In some embodiments, hepatic glucose uptake is
increased by disruption (e.g., ablation) of sympathetic nerve
fibers. In other embodiments, hepatic glucose uptake is increased
by stimulation of parasympathetic nerve fibers. In some
embodiments, triglyceride or cholesterol levels are reduced by the
therapeutic neuromodulation.
[0024] In some embodiments, disruption or modulation of the
sympathetic nerve fibers of the hepatic plexus has no effect on the
parasympathetic nerve fibers surrounding the liver. In some
embodiments, disruption or modulation (e.g., ablation or
denervation) of the sympathetic nerve fibers of the hepatic plexus
causes a reduction of very low-density lipoprotein (VLDL) levels,
thereby resulting in a beneficial effect on lipid profile. In
several embodiments, the invention comprises neuromodulation
therapy to affect sympathetic drive and/or triglyceride or
cholesterol levels, including high-density lipoprotein (HDL)
levels, low-density lipoprotein (LDL) levels, and/or
very-low-density lipoprotein (VLDL) levels. In some embodiments,
denervation or ablation of sympathetic nerves reduces triglyceride
levels, cholesterol levels and/or central sympathetic drive. For
example, norepinephrine levels may be affected in some
embodiments.
[0025] In other embodiments, therapeutic neuromodulation of
targeted nerve fibers (e.g., hepatic denervation) decreases
systemic glucose by increasing insulin secretion. In some
embodiments, insulin secretion is increased by disruption (e.g.,
ablation) of sympathetic nerve fibers (e.g., surrounding branches
of the hepatic artery). In other embodiments, insulin secretion is
increased by stimulation of parasympathetic nerve fibers. In some
embodiments, sympathetic nerve fibers surrounding the pancreas may
be modulated to decrease glucagon levels and increase insulin
levels. In some embodiments, sympathetic nerve fibers surrounding
the adrenal glands are modulated to affect adrenaline or
noradrenaline levels. Fatty tissue (e.g., visceral fat) of the
liver may be targeted to affect glycerol or free fatty acid levels.
In some embodiments, insulin levels remain the same or increase or
decrease by less than .+-.5%, less than .+-.10%, less than
.+-.2.5%, or overlapping ranges thereof. In some embodiments,
insulin levels remain constant or substantially constant when a
portion of the pancreas is ablated, either alone or in combination
with the common hepatic artery or other hepatic artery branch. In
various embodiments, denervation of nerves innervating the liver
(e.g., sympathetic nerves surrounding the common hepatic artery)
does not affect a subject's ability to respond to a hypoglycemic
event.
[0026] In accordance with several embodiments of the invention, a
method of decreasing blood glucose levels within a subject is
provided. The method comprises forming an incision in a groin of a
subject to access a femoral artery and inserting a neuromodulation
device (e.g., catheter, ultrasound catheter, etc.) into the
incision. In some embodiments, the method comprises advancing the
neuromodulation device from the femoral artery through an arterial
system to a common or proper hepatic artery and causing a
therapeutically effective amount of energy to thermally inhibit
neural communication along a sympathetic nerve in a hepatic plexus
surrounding the common or proper hepatic artery to be delivered
intravascularly by the ablation catheter to the inner wall of the
proper hepatic artery, thereby decreasing blood glucose levels
within the subject. Other incision or access points may be used as
desired or required. In some embodiments, the neuromodulation
device (e.g., hollow, solid, partially hollow, catheter, probe,
shaft or other delivery device with or without a lumen) is a
focused or unfocused ultrasound ablation catheter.
[0027] In some embodiments, the neuromodulation device (e.g.,
hollow, solid, partially hollow, catheter, probe, shaft or other
delivery device with or without a lumen) is a radiofrequency (RF)
ablation catheter comprising one or more electrodes. In some
embodiments, the neuromodulation catheter is a high-intensity
focused ultrasound ablation catheter. In some embodiments, the
neuromodulation catheter is a cryoablation catheter. The method can
further comprise stimulating one or more parasympathetic nerves
associated with the liver to decrease hepatic glucose production or
increase glucose uptake.
[0028] In accordance with several embodiments, a method of treating
a subject having diabetes or symptoms associated with diabetes is
provided. The method can comprise delivering an RF ablation
catheter (e.g., hollow, solid, partially hollow, catheter, probe,
shaft or other delivery device with or without a lumen) to a
vicinity of a hepatic plexus of a subject and disrupting neural
communication along a sympathetic nerve of the hepatic plexus by
causing RF energy to be emitted from one or more electrodes of the
RF ablation catheter. In some embodiments, the RF ablation catheter
is delivered intravascularly through a femoral artery to a location
within the proper or common hepatic artery branch. In some
embodiments, the RF energy is delivered extravascularly by the RF
ablation catheter.
[0029] In some embodiments, disrupting neural communication
comprises permanently disabling neural communication along the
sympathetic nerve of the hepatic plexus. In some embodiments,
disrupting neural communication comprises temporarily inhibiting or
reducing neural communication along the sympathetic nerve of the
hepatic plexus. In some embodiments, disrupting neural
communication along a sympathetic nerve of the hepatic plexus
comprises disrupting neural communication along a plurality of
sympathetic nerves of the hepatic plexus.
[0030] The method can further comprise positioning the RF ablation
catheter in the vicinity of the celiac plexus of the subject and
disrupting neural communication along a sympathetic nerve of the
celiac plexus by causing RF energy to be emitted from one or more
electrodes of the RF ablation catheter. In some embodiments, the
method comprises positioning the RF ablation catheter in the
vicinity of sympathetic nerve fibers that innervate the pancreas
and disrupting neural communication along the sympathetic nerve
fibers by causing RF energy to be emitted from one or more
electrodes of the RF ablation catheter, positioning the RF ablation
catheter in the vicinity of sympathetic nerve fibers that innervate
the stomach and disrupting neural communication along the
sympathetic nerve fibers by causing RF energy to be emitted from
one or more electrodes of the RF ablation catheter, and/or
positioning the RF ablation catheter in the vicinity of sympathetic
nerve fibers that innervate the duodenum and disrupting neural
communication along the sympathetic nerve fibers by causing RF
energy to be emitted from one or more electrodes of the RF ablation
catheter. In some embodiments, drugs or therapeutic agents can be
delivered to the liver or surrounding organs or tissues.
[0031] In accordance with several embodiments, a method of
decreasing blood glucose levels within a subject is provided. The
method comprises inserting an RF, ultrasound, etc. ablation
catheter (e.g., hollow, solid, partially hollow, catheter, probe,
shaft or other delivery device with or without a lumen) into
vasculature of the subject and advancing the RF ablation catheter
to a location of a branch of a hepatic artery (e.g., the proper
hepatic artery or the common hepatic artery). In one embodiment,
the method comprises causing a therapeutically effective amount of
RF, ultrasound, etc. energy to thermally inhibit neural
communication within sympathetic nerves of a hepatic plexus
surrounding the common or proper hepatic artery to be delivered
intravascularly by the ablation catheter to the inner wall of the
proper hepatic artery, thereby decreasing blood glucose levels
within the subject. In some embodiments, the delivery of the
therapeutically effective amount of RF, ultrasound, etc. energy to
the common or proper hepatic artery also comprises delivery of
energy sufficient to modulate (e.g., ablate, denervate) nerves of
the pancreas and/or duodenum, which may provide a synergistic
effect. In various embodiments, blood glucose levels decrease by
30-60% (e.g., 40-50%, 30-50%, 35-55%, 45-60% or overlapping ranges
thereof) from a baseline level.
[0032] In one embodiment, the therapeutically effective amount of
RF energy at the location of the inner vessel wall of the target
vessel or at the location of the target nerves is in the range of
between about 100 J and about 1 kJ (e.g., between about 100 J and
about 500 J, between about 250 J and about 750 J, between about 300
J and about 1 kJ, between about 500 J and 1 kJ, or overlapping
ranges thereof). In one embodiment, the therapeutically effective
amount of RF energy has a power between about 0.1 W and about 14 W
(e.g., between about 0.1 W and about 10 W, between about 0.5 W and
about 5 W, between about 3 W and about 8 W, between about 2 W and
about 6 W, between about 5 W and about 10 W, between about 8 W and
about 12 W, between about 10 W and about 14 W, or overlapping
ranges thereof). The ranges provided herein can be per electrode,
per energy delivery location, or total energy delivery. The RF,
ultrasound, etc. energy may be delivered at one location or
multiple locations along the target vessel or within multiple
different vessels. In some embodiments, the RF, ultrasound, etc.
energy is delivered sufficient to cause fibrosis of the tissue
surrounding the nerves, thereby resulting in nerve dropout.
[0033] In one embodiment, the RF ablation catheter (e.g., hollow,
solid, partially hollow, catheter, probe, shaft or other delivery
device with or without a lumen) comprises at least one ablation
electrode. The RF ablation catheter may be configured to cause the
at least one ablation electrode to contact the inner wall of the
hepatic artery branch and maintain contact against the inner wall
with sufficient contact pressure while the RF energy is being
delivered. In one embodiment, the RF ablation catheter comprises a
balloon catheter configured to maintain sufficient and continuous
contact pressure of the at least one electrode against the inner
wall of the hepatic artery branch. In one embodiment, the RF
ablation catheter comprises an actuatable (e.g., steerable,
articulatable, expandable) distal tip configured to maintain
sufficient contact pressure of the at least one electrode against
the inner wall of the hepatic artery branch. In various
embodiments, the sufficient contact pressure may range from about
0.1 g/mm.sup.2 to about 100 g/mm.sup.2 (e.g., between about 0.1
g/mm.sup.2 and about 10 g/mm.sup.2). In some embodiments, the RF
ablation catheter comprises at least one anchoring member
configured to maintain sufficient and continuous contact of the at
least one electrode against the inner wall of the hepatic artery
branch. The actuatable distal tip and/or anchoring member may
comprise one or more flexible portions, one or more expandable
members (e.g., balloons, ribbons, cages, baskets, wires, struts),
one or more steerable or articulatable members, one or more
pre-curved shape memory portions, or combinations of the same.
Expandable members may be self-expandable, mechanically expandable,
pneumatically expandable, inflatable, or otherwise expandable.
[0034] In accordance with several embodiments, a method of treating
a subject having diabetes or symptoms associated with diabetes is
provided. In one embodiment, the method comprises delivering an RF
ablation catheter to a vicinity of a hepatic plexus within a
hepatic artery branch (e.g., proper hepatic artery, common hepatic
artery or adjacent or within a bifurcation between the two). In one
embodiment, the RF ablation catheter comprises at least one
electrode. The method may comprise positioning the at least one
electrode in contact with an inner wall of the hepatic artery
branch. In one embodiment, the method comprises disrupting neural
communication of sympathetic nerves of the hepatic plexus
surrounding the hepatic artery branch by applying an electric
signal to the at least one electrode, thereby causing thermal
energy to be delivered by the at least one electrode to heat the
inner wall of the hepatic artery branch. Non-ablative heating,
ablative heating, or combinations thereof, are used in several
embodiments.
[0035] In one embodiment, disrupting neural communication comprises
permanently disabling neural communication of sympathetic nerves of
the hepatic plexus. In one embodiment, disrupting neural
communication comprises temporarily inhibiting or reducing neural
communication along sympathetic nerves of the hepatic plexus. In
some embodiments, the method comprises positioning the RF ablation
catheter in the vicinity of the celiac plexus of the subject and
disrupting neural communication along sympathetic nerves of the
celiac plexus, positioning the RF ablation catheter in the vicinity
of sympathetic nerve fibers that innervate the pancreas and
disrupting neural communication along the sympathetic nerve fibers,
positioning the RF ablation catheter in the vicinity of sympathetic
nerve fibers that innervate the stomach and disrupting neural
communication along the sympathetic nerve fibers, and/or
positioning the RF ablation catheter in the vicinity of sympathetic
nerve fibers that innervate the duodenum and disrupting neural
communication along the sympathetic nerve fibers by causing RF
energy to be emitted from the at least one electrode of the RF
ablation catheter. In several embodiments, a feedback mechanism is
provided to facilitate confirmation of neuromodulation and to allow
for adjustment of treatment in real time. In one embodiment,
ultrasound elastography, ultrasound sonography, echo decorrelation,
Doppler ultrasound, magnetic resonance elastography, and/or
computed tomography is used to track progress or status of
neuromodulation (e.g., ablation) procedures or methods (such as the
methods described herein).
[0036] In accordance with several embodiments, a method of treating
a subject having diabetes or symptoms associated with diabetes
(e.g., high blood glucose or triglyceride levels) is provided. In
one embodiment, the method comprises delivering a neuromodulation
catheter within a hepatic artery to a vicinity of a hepatic plexus
of a subject and modulating nerves of the hepatic plexus by causing
RF, ultrasound, etc. energy to be emitted from one or more
electrodes of the neuromodulation catheter. In one embodiment, the
step of modulating the nerves of the hepatic plexus comprises
denervating sympathetic nerves of the hepatic plexus and/or
stimulating parasympathetic nerves of the hepatic plexus. In one
embodiment, the sympathetic denervation and the parasympathetic
stimulation are performed simultaneously. In one embodiment, the
sympathetic denervation and the parasympathetic stimulation are
performed sequentially. In one embodiment, sympathetic nerves are
modulated without modulating parasympathetic nerves surrounding the
same vessel or tissue.
[0037] In accordance with several embodiments, an apparatus
configured for hepatic neuromodulation is provided. In one
embodiment, the apparatus comprises a balloon catheter configured
for intravascular placement within one or more hepatic artery
branches or adjacent artery branches. In one embodiment, the
balloon catheter comprises at least one expandable balloon and a
bipolar electrode pair. In one embodiment, at least one of the
bipolar electrode pair is configured to be positioned to be
expanded into contact with an inner wall of the hepatic artery
branch upon expansion of the at least one expandable balloon. In
one embodiment, the bipolar electrode pair is configured to deliver
a thermal dose of energy configured to achieve hepatic denervation.
The at least one expandable balloon may be configured to maintain
sufficient contact pressure (e.g., continuous contact pressure)
between the at least one electrode of the bipolar electrode pair
and the inner wall of the hepatic artery branch. In some
embodiments, the balloon catheter comprises two expandable
balloons, each having one electrode of the bipolar electrode pair
disposed thereon. In one embodiment, the balloon catheter comprises
a single expandable balloon and the bipolar electrode pair is
disposed on the expandable balloon. In one embodiment, the balloon
comprises a cooling fluid within a lumen of the balloon.
[0038] In accordance with several embodiments, an apparatus
configured for hepatic neuromodulation is provided. In one
embodiment, the apparatus comprises a catheter comprising a lumen
and an open distal end and a steerable shaft configured to be
slidably received within the lumen of the catheter. In one
embodiment, at least a distal portion of the steerable shaft
comprises a shape memory material having a pre-formed shape
configured to cause the distal portion of the steerable shaft to
change in linear shape (e.g., bend) to contact a vessel wall upon
advancement of the distal portion of the steerable shaft out of the
open distal end of the catheter. In one embodiment, a distal end of
the steerable shaft comprises at least one electrode that is
configured to be activated to deliver a thermal dose of energy
configured to achieve denervation of a branch of a hepatic artery
or other target vessel. In one embodiment, the shape memory
material of the steerable shaft is sufficiently resilient to
maintain sufficient and continuous contact pressure between the at
least one electrode and an inner wall of the branch of the hepatic
artery during a hepatic denervation procedure. The outside diameter
at a distal end of the catheter may be smaller than the outside
diameter at a proximal end of the catheter to accommodate insertion
within vessels having a small inner diameter. In various
embodiments, the outside diameter at the distal end of the catheter
is between about 1 mm and about 4 mm (e.g., 1 mm-3 mm, 1 mm, 2 mm,
3 mm, 4 mm, less than or equal to 3 mm). In one embodiment, the at
least one electrode comprises a coating having one or more windows.
For embodiments to be used in the hepatic arteries, the steerable
shaft of the catheter can be actuated to have multiple bends (e.g.,
two, three, or more bends) configured to conform to two or more
bends in the hepatic artery branches or neighboring arteries. In
some embodiments, one or more portions of the catheter are
pre-curved to have a particular bend shape. In some embodiments,
one of the multiple bends is pre-formed and one of the multiple
bends is actuated during delivery. In some embodiments, an energy
delivery device (e.g., catheter) comprises a distal portion
constructed of shape memory material and a lumen configured to
receive a guidewire. The shape memory material may be heat- or
shape-set so as to cause a distal end of the energy delivery device
(which may include an energy delivery element such as an electrode)
to contact an inner wall of a target vessel. A guidewire may retain
the distal portion of the energy delivery device in a straight or
substantially straight alignment until the distal portion is
positioned in a desired position within the target vessel. When the
guidewire is withdrawn from the lumen of the energy delivery
device, the shape-memory distal portion deforms to the heat- or
shape-set configuration so as to cause the distal end of the energy
delivery device to contact the inner wall of the target vessel.
[0039] In accordance with several embodiments, a neuromodulation
kit is provided. In one embodiment, the kit comprises a
neuromodulation catheter configured to be inserted within a vessel
of the hepatic system for modulating nerves surrounding the hepatic
artery. In one embodiment, the kit comprises a plurality of energy
delivery devices configured to be inserted within the lumen of the
neuromodulation catheter. In one embodiment, each of the energy
delivery devices comprises at least one modulation element at or
near a distal end of the energy delivery device. In one embodiment,
each of the energy delivery devices comprises a distal portion
comprising a different pre-formed shape memory configuration. The
at least one modulation element may be configured to be activated
to modulate at least a portion of the nerves surrounding the
hepatic artery to treat symptoms associated with diabetes.
[0040] In several embodiments, the invention comprises modulation
of the nervous system to treat disorders affecting insulin and/or
glucose, such as insulin regulation, glucose uptake, metabolism,
etc. In some embodiments, nervous system input and/or output is
temporarily or permanently modulated (e.g., decreased). Several
embodiments are configured to perform one or a combination of the
following effects: ablating nerve tissue, heating nerve tissue,
cooling the nerve tissue, deactivating nerve tissue, severing nerve
tissue, cell lysis, apoptosis, and necrosis. In some embodiments,
localized neuromodulation is performed, leaving surrounding tissue
unaffected. In other embodiments, the tissue surrounding the
targeted nerve(s) is also treated.
[0041] In accordance with several embodiments, methods of hepatic
denervation are performed with shorter procedural and energy
application times than renal denervation procedures. In several
embodiments, hepatic denervation is performed without causing pain
or mitigates pain to the subject during the treatment. In
accordance with several embodiments, neuromodulation (e.g.,
denervation or ablation) is performed without causing stenosis or
thrombosis within the target vessel (e.g., hepatic artery). In
embodiments involving thermal treatment, heat lost to the blood
stream may be prevented or reduced compared to existing denervation
systems and methods, resulting in lower power and shorter treatment
times. In various embodiments, the methods of neuromodulation are
performed with little or no endothelial damage (e.g., less than 20%
ablation of) to the target vessels. In several embodiments, energy
delivery is delivered substantially equally in all directions
(e.g., omnidirectional delivery). In various embodiments of
neuromodulation systems (e.g., catheter-based energy delivery
systems described herein), adequate electrode contact with the
target vessel walls is maintained, thereby reducing power levels,
voltage levels, vessel wall or tissue thermal injury, and treatment
times.
[0042] In accordance with several embodiments, a method for
thermally-induced hepatic neuromodulation is provided. The method
comprises inserting a neuromodulation catheter (e.g., RF ablation
catheter) into vasculature of a subject. In one embodiment, the
neuromodulation catheter is configured to form a first bend to
conform to, or be positioned to correspond with, a first anatomical
bend of a first hepatic artery portion or a first artery branching
into or out from a hepatic artery and is configured to form a
second bend to conform to a second anatomical bend of a second
hepatic artery portion or a second artery branching into or out
from the hepatic artery. The first bend and/or second bend may be
formed by mechanical actuation, magnetic actuation, material
actuation, pneumatic actuation, hydraulic actuation, inflation,
self-expansion, or the like. In one embodiment, the neuromodulation
catheter, the first bend and/or second bend is pre-bent or
pre-curved. Although several catheters and other access/delivery
devices are disclosed herein that are designed (e.g., in shape,
size, flexibility, etc.) for the hepatic artery, such catheters and
other access/delivery devices can also be used for other arteries
and vessels, and in particular, other arteries and vessels that are
tortuous. In addition, although devices may be described herein as
neuromodulation catheters or devices and described with respect to
modulation (e.g., ablation) of nerves, the catheters or other
devices may be used to modulate other types of tissue (e.g., tissue
lining an organ or vessel, muscle tissue, endothelial tissue,
submucosal tissue).
[0043] In some embodiments, the neuromodulation catheter is
advanced to a location within a hepatic artery of the vasculature
or to a location upstream of the hepatic artery (e.g., within the
aorta or celiac trunk or axis). The first bend may be formed and/or
aligned with a first anatomical bend (e.g., an acute bend between
the aorta or celiac trunk and the common hepatic artery, or a first
bend within the common hepatic artery). The second bend may be
formed and/or aligned with a second anatomical bend (e.g., an acute
bend between the common hepatic artery and the proper hepatic
artery or gastroduodenal artery, or a second bend within the common
hepatic artery). In some embodiments, the neuromodulation catheter
is activated or otherwise caused to intravascularly deliver a
therapeutically effective amount of energy (e.g., RF energy,
thermal energy, ultrasound energy) to an inner wall of the hepatic
artery to modulate (e.g., denervate, ablate, injure, stimulate) one
or more sympathetic nerves of a hepatic plexus.
[0044] In one embodiment, the neuromodulation catheter comprises an
RF ablation catheter having at least one electrode. The RF ablation
catheter may advantageously be configured to maintain sufficient
contact pressure of the at least one electrode against an inner
arterial wall of the hepatic artery while RF energy is being
delivered. In one embodiment, the RF ablation catheter comprises a
balloon catheter configured to maintain the sufficient contact
pressure of the at least one electrode against the inner arterial
wall of the hepatic artery. In one embodiment, the RF, ultrasound,
etc. ablation catheter comprises an actuatable distal portion
configured to conform to the first anatomical bend and the second
anatomical bend during said advancing of the RF, ultrasound, etc.
ablation catheter to a location within a hepatic artery. In one
embodiment, the actuatable distal portion comprises shape memory
material configured to form the first bend and the second bend. In
one embodiment, the actuatable distal portion is configured to be
mechanically expanded by one or more pull wires to form the first
bend and the second bend. In one embodiment, the first bend and the
second bend together from an S-shape.
[0045] In one embodiment, the sufficient contact pressure is
between about 0.1 g/mm.sup.2 and about 100 g/mm.sup.2 (e.g.,
between about 0.1 g/mm.sup.2 and about 10 g/mm.sup.2, between about
5 g/mm.sup.2 and about 20 g/mm.sup.2, between about 1 g/mm.sup.2
and about 50 g/mm.sup.2, or overlapping ranges thereof). In one
embodiment, the therapeutically effective amount of RF energy is in
the range of between about 300 J and about 1.5 kJ (e.g., about 300
J to about 1 kJ) per target location or total for all target
locations. The therapeutically effective amount of RF energy may
have a power level between about 0.1 W and about 14 W (e.g.,
between about 0.1 W and about 10 W, between about 3 W and about 8
W, between about 3 W and about 10 W) per target location.
[0046] In some embodiments, the method comprises providing cooling
to a portion of the common hepatic artery that is or is not being
targeted by the RF energy or to the at least one electrode. In one
embodiment, cooling comprises infusing saline within the catheter
or within the blood flow adjacent the at least one electrode. In
one embodiment, cooling comprises obstructing flow upstream of the
at least one electrode to increase the arterial flow rate past the
at least one electrode, thereby providing convective cooling due to
increased blood flow. In some embodiments, flow is diverted or
channeled toward the at least one electrode (e.g., from a center of
the vessel toward a wall of the vessel).
[0047] In accordance with several embodiments, a device for
thermally-induced hepatic neuromodulation is provided. The device
comprises a catheter body having a proximal end and a distal end
and a lumen extending from the proximal end to the distal end. In
one embodiment, the catheter body is configured for percutaneous,
intravascular placement within a hepatic artery branch. The device
may comprise an actuatable portion at the distal end of the
catheter body and at least one electrode disposed on the actuatable
portion. In some embodiments, the actuatable portion is configured
to provide stabilization of the catheter within the hepatic artery
branch and to facilitate contact of the at least one electrode with
an inner arterial wall of hepatic artery branch. The at least one
electrode or transducer may be configured to be activated to
deliver thermal energy sufficient to achieve modulation (e.g.,
denervation, ablation, stimulation) of at least a portion of the
hepatic artery branch (e.g., a segment of the common hepatic artery
having a length of 30 mm or less, 24 mm or less, 20 mm or less, or
between 20 mm and 30 mm). The at least one electrode or transducer
may be repositioned and activated at multiple positions along the
length of and/or around the circumference of the hepatic artery
branch. The at least one electrode or transducer may comprise one
or more monopolar electrodes or one or more bipolar electrode
pairs. In embodiments involving multiple electrodes or transducers,
modulation at different locations or positions may be performed
simultaneously or sequentially. In some embodiments, a
neuromodulation device consists or consists essentially of only two
electrodes or transducers. In some embodiments, a neuromodulation
device consists or consists essentially only of four electrodes or
transducers. In various embodiments, the electrodes or transducers
advantageously facilitate ablation of only two quadrants or
sections of the vessel wall instead of all four quadrants. In some
embodiments, electrodes or transducers are positioned to maintain
180-degree offset between the electrodes or transducers and to
provide spacing between the electrodes or transducers along the
length of the vessel, as desired or required. Other numbers of
electrodes or transducers (e.g., three electrodes, five electrodes,
etc.) and other circumferential offsets (e.g., 30 degrees, 45
degrees, 60 degrees, 72 degrees, 90 degrees, 120 degrees) may be
used in other embodiments. In various embodiments, the electrodes
or transducers may be spaced circumferentially (or radially) and/or
axially (or longitudinally) and may be independently adjustable to
adjust circumferential and/or axial spacing of the electrodes (and
treatment sites) depending on the vessel, patient, or treatment
parameters.
[0048] In one embodiment, the actuatable portion comprises an
inflatable balloon. In one embodiment, the actuatable portion
comprises a deflectable bend segment having a preformed bend shape
such that the distal end of the catheter body bends off-axis
relative to a longitudinal axis of the proximal portion of the
catheter body. In one embodiment, the actuatable portion comprises
shape memory material having one or more pre-formed bend shapes. In
one embodiment, the actuatable portion comprises one or more
flexible bend segments configured to be actuated by one or more
pull wires to form one or more bend shapes to conform to anatomical
bends within the hepatic artery branch or to facilitate access to
the hepatic artery branch. In one embodiment, the actuatable
portion comprises one or more flexible ribbon wires or cables
configured to be expanded outward to contact the inner arterial
wall of the hepatic artery branch at a target location with the at
least one electrode disposed on at least one of said one or more
flexible ribbon wires or cables. The actuatable portion may
comprise a plurality of independently actuatable members. In
various embodiments, the actuatable portion(s) comprises one or
more of the following: shape-memory material, flexible bend
segments, ribbon wires or cables, expandable members, and
inflatable members. In one embodiment, the device comprises an
outer sheath and the catheter body (e.g., probe or shaft) is
configured to be delivered within a lumen of the outer sheath and
is translatable relative to the outer sheath. In one embodiment,
the outer sheath is deflectable. In one embodiment, articulation of
a first bend segment is controlled by a first pull wire and
articulation of a second bend segment is controlled by a second
pull wire. In one embodiment, a first flexible bend segment is
configured to conform to a first arterial bend upon actuation and a
second flexible bend segment is configured to conform to a second
arterial bend. The first bend segment and the second segment may
together form an S-shape upon actuation. In one embodiment, the
device comprises an obstruction element configured to be positioned
adjacent the at least one electrode to increase arterial flow past
the electrode, thereby facilitating cooling of the at least one
electrode. The at least one electrode may comprise a plurality of
electrodes configured to deliver thermal energy to multiple
locations within the hepatic artery branch simultaneously or
sequentially. The target locations may be spaced apart along a
length of a target segment of the hepatic artery (e.g., segment of
less than 30 mm length, 20 mm to 30 mm length, less than 24 mm
length, etc.). In some embodiment, an apparatus for neuromodulation
includes an elongate body having a proximal end and a distal end
that is configured for percutaneous, intravascular placement within
a tortuous artery. The apparatus may also include an actuatable
portion at the distal end of the elongate body. The apparatus may
include at least one electrode disposed on the actuatable portion
that is configured to provide stabilization within the tortuous
artery and configured to facilitate contact of the at least one
electrode with an inner wall of the tortuous artery. In one
embodiment, the at least one electrode is configured to be
activated to deliver thermal energy sufficient to achieve
denervation of at least a portion of the tortuous artery. The
actuatable portion may comprise one or more flexible bend segments
configured to be actuated by one or more pull wires to form one or
more bend shapes to conform to anatomical bends within the artery
or to facilitate access to the tortuous artery, wherein a first
flexible bend segment is configured to conform to a first arterial
bend upon actuation, and wherein a second flexible bend segment is
configured to conform to a second arterial bend upon actuation. In
some embodiments, articulation of the first flexible bend segment
is controlled by a first pull wire and articulation of the second
flexible bend segment is controlled by a second pull wire. The
apparatus may further include an outer sheath, wherein the elongate
body is configured to be delivered within a lumen of the outer
sheath and is translatable relative to the outer sheath. The
elongate body may include a lumen configured to track a guidewire
to facilitate access. In one embodiment, the elongate body
comprises a third and/or fourth bend. In one embodiment, the
elongate body further comprises a pre-formed bend shape.
[0049] In accordance with several embodiments, a method for
thermally-induced hepatic neuromodulation is provided to decrease
blood glucose and/or triglyceride levels within a subject. In one
embodiment, the method comprises identifying a subject having a
metabolic disorder and inserting an RF ablation catheter into
vasculature of the subject. In one embodiment, the method comprises
advancing the RF ablation catheter to a location within a common
hepatic artery of the vasculature. The location may be within the
common hepatic artery between a branch of the celiac artery and a
branch of the common hepatic artery. In one embodiment, the RF
ablation catheter is used to intravascularly deliver a
therapeutically effective amount of RF energy to an inner wall of
the common hepatic artery to ablate one or more sympathetic nerves
of a hepatic plexus, thereby decreasing blood glucose and/or
triglyceride levels within the subject. In one embodiment, the RF
ablation catheter consists, consists essentially of or comprises
two electrodes. The RF ablation catheter may advantageously be
configured to maintain sufficient contact pressure of at least one
of the two electrodes (e.g., an active electrode) against the inner
wall of the common hepatic artery while the RF energy is being
delivered. In one embodiment, the ablation catheter comprises a
balloon catheter configured to maintain the sufficient contact
pressure of the at least one electrode against the inner wall of
the common hepatic artery. In one embodiment, the ablation catheter
comprises a steerable distal tip configured to maintain sufficient
contact pressure of the at least one electrode against the inner
wall of the common hepatic artery. The sufficient contact pressure
may be between about 5 g/mm.sup.2 and about 100 g/mm.sup.2 or
between about 0.1 g/mm.sup.2 and about 10 g/mm.sup.2. In one
embodiment, the RF energy is caused to be delivered to an anterior
180.degree. arc of the inner wall of the common hepatic artery,
thereby ablating sympathetic nerves without ablating
parasympathetic nerves. In some embodiments, the ablation catheter
comprises a force sensor or transducer for measuring the contact
force of the at least one electrode against the inner wall of the
common hepatic artery.
[0050] In one embodiment, a method for thermally-induced hepatic
neuromodulation to decrease blood glucose and/or triglyceride
levels within a subject is provided. The method comprises
delivering an RF ablation catheter comprising two electrodes to a
vicinity of a hepatic plexus within a hepatic artery branch,
positioning at least one of the two electrodes in contact with an
inner wall of the hepatic artery branch and disrupting neural
communication of sympathetic nerves of the hepatic plexus
surrounding the hepatic artery branch by applying an electric
signal to the at least one electrode, thereby causing thermal
energy to be delivered by the at least one electrode to heat the
inner wall of the hepatic artery branch. The hepatic artery branch
may be the proper hepatic artery or the common hepatic artery. In
various embodiments, disrupting neural communication comprises
permanently disabling neural communication of sympathetic nerves of
the hepatic plexus or temporarily inhibiting or reducing neural
communication of sympathetic nerves of the hepatic plexus. In one
embodiment, the method comprises positioning the RF ablation
catheter in the vicinity of the celiac plexus of the subject and
disrupting neural communication of sympathetic nerves of the celiac
plexus by causing RF energy to be emitted from the at least one
electrode of the RF ablation catheter.
[0051] In one embodiment, a method for thermally-induced hepatic
neuromodulation to decrease blood glucose and/or triglyceride
levels within a subject comprises delivering a neuromodulation
catheter within a hepatic artery to a vicinity of a hepatic plexus
of a subject; and modulating nerves of the hepatic plexus by using
said catheter to deliver energy to the hepatic plexus sufficient to
modulate one or more nerves within the hepatic plexus to decrease
at least one of blood glucose levels or triglyceride levels in said
subject. In one embodiment, modulating the nerves of the hepatic
plexus comprises denervating sympathetic nerves of the hepatic
plexus without denervating parasympathetic nerves of the hepatic
plexus. In one embodiment, modulating the nerves of the hepatic
plexus comprises denervating sympathetic nerves of the hepatic
plexus and stimulating parasympathetic nerves of the hepatic
plexus.
[0052] In accordance with several embodiments, a device for hepatic
neuromodulation is provided. In one embodiment, the device
comprises a catheter body having a proximal end and a distal end
and a lumen extending from the proximal end to the distal end and
the catheter body is configured for percutaneous, intravascular
placement within a hepatic artery branch. In one embodiment, the
device comprises an articulatable portion at the distal end of the
catheter body and at least one articulation member (e.g., wire)
extending from the proximal end of the body and being coupled to
the articulatable portion. The at least one articulation wire may
be configured to bend the articulatable portion at the distal end
of the catheter body. In one embodiment, the articulatable portion
and/or a region distal to the articulatable portion comprises one
or more RF electrodes, wherein at least one of the RF electrodes is
configured to be activated to deliver RF energy sufficient to
achieve denervation of the hepatic artery branch, thereby
decreasing blood glucose and/or triglyceride levels within the
subject. In one embodiment, the distal portion of the catheter body
comprises a deflectable bend segment having a preformed bend shape
such that the distal end of the catheter body bends off-axis
relative to a longitudinal axis of the proximal portion of the
catheter body such that the articulatable portion and the
deflectable bend segment facilitate treatment within variable and
tortuous anatomy of or leading to the hepatic artery (such as the
celiac artery branching off the abdominal aorta). In one
embodiment, the articulatable portion is configured to apply and
maintain contact pressure between the at least one active RF
electrode and an inner arterial wall of the hepatic artery branch,
thereby facilitating continuous contact as the hepatic artery
branch moves in response to diaphragm motion. In one embodiment,
the contact pressure is between about 5 g/mm.sup.2 and about 100
g/mm.sup.2 and the RF energy configured to be delivered to achieve
denervation of the hepatic artery branch is between about 100 J and
about 2 kJ (e.g., between about 100 J and 1 kJ, between 500 J and
1.5 kJ, between 1 kJ and 2 kJ, or overlapping ranges thereof).
[0053] In one embodiment, the catheter body has a length sufficient
to extend from a radial or femoral artery to the hepatic artery
branch and the distal end of the catheter body has an outside
diameter sized to fit within the hepatic artery branch. In some
embodiments, the catheter body has a length sufficient to extend
from a femoral artery or a radial artery to an arterial branch
supplying the pancreas, duodenum, stomach, liver, or other
gastrointestinal organs. In one embodiment, the device comprises an
outer sheath and the catheter body is configured to be delivered
within a lumen of the outer sheath and is translatable relative to
the outer sheath. In one embodiment, the deflectable bend segment
of the catheter body is configured to transition to the preformed
bend shape upon retraction of the outer sheath or upon advancement
of the distal end of the catheter body out of the outer sheath. In
one embodiment, the outer sheath is deflectable. In one embodiment,
the device comprises two radiopaque markers positioned along the
distal end of the catheter body configured to be used to adjust the
contact pressure. In one embodiment, the articulatable portion
comprises a plurality of independently controllable bending
segments. In one embodiment, the preformed bend shape of the
deflectable bend segment is configured to correspond to a bend
between a celiac artery or aorta and a common hepatic artery.
Various embodiments of RF ablation catheters and methods of use
provide decreased ablation times and decreased lumenal injury while
providing heat to ablate nerves.
[0054] In accordance with several embodiments, a device for hepatic
neuromodulation is provided. In one embodiment, the device
comprises a catheter body having a proximal end and a distal end
and a lumen extending from the proximal end to the distal end and
the catheter body is configured for percutaneous, intravascular
placement within a hepatic artery branch. In one embodiment, the
device comprises an articulatable portion at the distal end of the
catheter body comprising two independently controllable bending
segments configured to be individually articulated by two
articulation members (e.g., wires) extending from the proximal end
of the catheter body to the two independently controllable bending
segments. In one embodiment, the two independently controllable
bending segments together comprise two or more electrodes, wherein
at least one of the RF electrodes is configured to be activated to
deliver RF energy sufficient to achieve denervation of the hepatic
artery branch, thereby decreasing blood glucose and/or triglyceride
levels within the subject. In one embodiment, articulation of a
first bending segment of the two independently controllable bending
segments is controlled by a first articulation wire and wherein
articulation of a second bending segment of the two independently
controllable bending segments is controlled by a second
articulation wire. The first bending segment may be configured to
articulate to conform to a first arterial bend, and wherein the
second bending segment is configured to conform to a second
arterial bend.
[0055] In accordance with several embodiments, a device for
thermally-induced hepatic neuromodulation is provided. In one
embodiment, the device comprises a catheter body having a proximal
end and a distal end and a lumen extending from the proximal end to
the distal end and the catheter body is configured for
percutaneous, intravascular placement within a hepatic artery
branch. In one embodiment, the catheter body has a length
sufficient to extend from a femoral artery to the hepatic artery
branch and the distal end of the catheter body has an outside
diameter sized to fit within the hepatic artery branch. The distal
end of the catheter body may comprise a deflectable bend segment
having a preformed bend shape such that the distal end of the
catheter body bends off-axis relative to a longitudinal axis of the
proximal portion of the catheter body. The deflectable bend segment
and/or a region distal to the bend segment may comprise one or more
electrodes, wherein at least one of the RF electrodes is configured
to be activated to deliver RF energy sufficient to achieve
denervation of the hepatic artery branch. In one embodiment, the
deflectable bend segment is configured to apply and maintain
contact pressure between the at least one active RF electrode and
an inner arterial wall of the hepatic artery branch, thereby
facilitating continuous contact as the hepatic artery branch moves
in response to diaphragm motion and thereby facilitating treatment
within variable and tortuous anatomy of the hepatic artery. In one
embodiment, the device comprises an outer sheath and the catheter
body is configured to be delivered within a lumen of the outer
sheath and is translatable relative to the outer sheath. The
deflectable bend segment may be configured to transition to the
preformed bend shape upon retraction of the outer sheath or upon
advancement of the distal end of the catheter body out of the outer
sheath.
[0056] In accordance with several embodiments, an apparatus for
hepatic neuromodulation is provided that includes a shaft
comprising a proximal end, a distal end and a lumen and an
electrode positioned at a distal tip of the distal end of the
shaft. In one embodiment, the shaft comprises a first region, a
second region and a third region. The first region may comprise a
resiliently deformable region proximal to the electrode, the second
region may comprise an articulatable region proximal to the
resiliently deformable region and the third region may comprise a
torsionally rigid region proximal to the articulatable region. In
some embodiments, at least one of the first region, the second
region and the third region is configured to navigate a tortuosity
of a hepatic artery. The apparatus may include a pull wire
extending from a distal end of the articulatable region to the
proximal end of the shaft, the pull wire configured to articulate
the electrode at the distal tip toward an inner wall of the hepatic
artery and maintain a consistent contact force of the electrode
against the inner wall, wherein the electrode is configured to be
activated to deliver energy sufficient to achieve denervation of at
least a portion of the hepatic artery. In one embodiment, the
diameter of the electrode is equal to the length of the electrode.
In one embodiment, the torsionally rigid region is flexible and the
torsionally rigid region is torsionally rigid in at least one
direction. The articulatable region may be configured to provide a
cantilever support to facilitate maintenance of the consistent
electrode contact force. The length of the articulatable region may
be between 0.5 and 2 cm. In one embodiment, the shaft comprises a
hypotube and the torsionally rigid region comprises an interrupted
spiral cut pattern that varies along a length of the torsionally
rigid region. In one embodiment, the articulatable region comprises
a spine cut pattern and/or is configured to provide 180-degree
articulation.
[0057] In accordance with several embodiments, a neuromodulation
catheter is provided. The catheter comprises a first end, a second
end and a lumen extending from the first end to the second end. In
one embodiment, the catheter comprises a balloon disposed at the
distal end. The balloon may be disposed about substantially the
entire circumference of the catheter (e.g., between 80% and 90%,
between 75% and 85%, between 85% and 95%, or overlapping ranges
thereof). In one embodiment, the catheter comprises an electrode
disposed at a region of the catheter not covered by the balloon.
Inflation of the balloon may be effective to occlude a portion of
the cross-sectional area of an artery or other vessel into which
the catheter is placed, thereby increasing the blood flow velocity
around the electrode. In one embodiment, the electrode is
configured to deliver energy sufficient to cause denervation of one
or more sympathetic nerves surrounding the artery or other vessel.
In some embodiments, an apparatus adapted for neuromodulation of
nerves surrounding a vessel lumen comprises a tubular shaft
comprising a first end, a second end and a lumen extending from the
first end to the second end. The apparatus may comprise a balloon
positioned at the distal end of the shaft, the balloon configured
to transition from a deflated configuration to an inflated
configuration through introduction of fluid through the lumen of
the shaft. When in the inflated configuration, the balloon may be
disposed around between 85% and 95% of a circumference of the
shaft. The apparatus may comprise an electrode positioned at a
location of the shaft that is not covered by the balloon. In the
inflated configuration the balloon may occlude a portion of a
cross-sectional area of a vessel, thereby increasing blood flow
velocity around the electrode. In one embodiment, the electrode is
configured to deliver energy sufficient to cause denervation of one
or more sympathetic nerves surrounding the vessel. In some
embodiments, the apparatus comprises a plurality of electrodes
positioned along a length of the shaft that is not covered by the
balloon.
[0058] In accordance with several embodiments, a neuromodulation
device configured for intravascular hepatic neuromodulation
comprises an elongated shaft having a proximal end and a distal
end, a first electrode deployment arm coupled to the distal end of
the elongated shaft, a first electrode coupled to a distal end of
the first electrode deployment arm, a second electrode deployment
arm coupled to the distal end of the elongated shaft, and a second
electrode coupled to a distal end of the second electrode
deployment arm. The first electrode deployment arm and the second
electrode deployment arm are positioned 180 degrees apart from each
other about the circumference of the elongated shaft and the first
electrode deployment arm and the second electrode deployment arm
are configured to cause the first electrode and the second
electrode to contact a vessel wall when in a deployed
configuration. In one embodiment, the neuromodulation device
includes two and only two electrode deployment arms each having one
electrode and does not include more than two electrodes. In another
embodiment, the neuromodulation device includes four and only four
electrode deployment arms each having one electrode and does not
include more than four electrodes. In some embodiments, two
electrodes are advantageous because 180 degree offset may be
maintained and vessels having short lengths (e.g., common hepatic
artery having a length of about 30 mm) may be modulated. In another
embodiment, four electrodes are advantageous because of one or more
of the following benefits: (i) increased vessel lengths may be
treated while still maintaining 90-degree or 180 degree offset;
(ii) ability to place multiple electrodes in shortest vessel length
while controlling radial or circumferential spacing between two
electrodes, (iii) increased ability to adjust electrode placement
characteristics in difficult anatomy (e.g., tortuous, short length,
severe tapers); allows operator to work around side branches or
focal disease sites; (iv) allows operator to perform treatments in
multiples of two; (v) reduces treatable territory lost in the
vessel due to incomplete treatment (e.g., ablation) cycles; and/or
(vi) maintains the ability to radially and/or longitudinally offset
space between sets of treatments (e.g., ablations). In some
embodiments using four electrodes, treatment may be better
controlled (e.g., radial and/or length spacing between electrode
pairs may be controlled) and the number of treatment sites or
catheter placements may be reduced to perform four treatments
(e.g., ablations) compared to devices having more than four
electrodes. Using only two electrodes or only four electrodes is
viable in several embodiments due to, for example, the increased
efficiency of the electrodes and the treatment parameters used. If
two electrodes are used, the two electrodes may comprise monopolar
electrodes or a bipolar electrode pair. If four electrodes are
used, the four electrodes may comprise monopolar electrodes or two
bipolar electrode pairs. In some embodiments, a neuromodulation
device configured for intravascular hepatic neuromodulation
comprises an elongated shaft having a proximal end and a distal
end, a first electrode deployment arm coupled at its distal end to
the distal end of the elongated shaft, a first electrode coupled to
a proximal end of the first electrode deployment arm, a second
electrode deployment arm coupled at its distal end to the distal
end of the elongated shaft, and a second electrode coupled to a
proximal end of the second electrode deployment arm.
[0059] In some embodiments, the electrode deployment arms are
coupled to the elongated shaft in a manner such that the electrodes
are brought into contact with the vessel wall at positions spaced
apart along a length of a blood vessel when in the deployed
configuration. In some embodiments, the electrodes are each mounted
on a pivot configured to facilitate an orientation that is in
substantial alignment with the vessel wall. In one embodiment, the
electrode deployment arms comprise shape memory material such that
the electrode deployment arms are configured to automatically
transition to the deployed configuration upon retraction of a
sheath covering the elongated shaft. In one embodiment, the
electrode deployment arms are steerable. For example, the electrode
deployment arms may be collectively actuated by a single pullwire
extending along the length of the elongated shaft or individually
actuated by separate pullwires. In one embodiment, the elongated
shaft comprises a lumen configured to receive a guidewire for
providing trackability of the elongated shaft over the
guidewire.
[0060] In some embodiments, the electrodes comprise curved
electrodes (e.g., having a half-cylindrical shape). In some
embodiments, the electrodes do not comprise spherical electrodes or
flat electrodes. In one embodiment, the neuromodulation device
comprises an inner core member disposed within a lumen of the
shaft. The distal end of the inner core member may comprise a
deployment member configured to deploy the electrode deployment
arms to the deployed configuration. For example, the inner core
member may be translatable relative to the elongated shaft. Upon
retraction of the inner core member in a proximal direction, the
deployment member on the distal end of the inner core member may be
configured to mechanically separate the electrode deployment arms
and cause them to transition to the deployed configuration. In
various embodiments, the electrode deployment arms comprise a
flexible or "soft" segment proximal of an electrode attachment
point configured to enable a pivot of the electrode such that the
contact surface (e.g., side) of the electrode is at least
substantially parallel with the vessel wall. In several
embodiments, the electrode deployment arms are configured to
provide uniform contact force on the vessel wall by the
electrodes.
[0061] In accordance with several embodiments, a neuromodulation
device configured for intravascular hepatic neuromodulation
comprises or consists essentially of an elongated shaft having a
proximal end and a distal end, a first electrode positioned at the
distal end of the elongated shaft and a second electrode positioned
proximal to the first electrode at the distal end of the elongated
shaft (the first electrode and second electrode each comprise a
rounded contact surface, an electrode shaft; and a control element)
and an expansion member positioned within the elongated shaft. The
expansion member is configured to cause the first electrode and the
second electrode to transition between (i) a non-deployed
configuration in which the rounded contact surfaces of the first
electrode and the second electrode are substantially flush with an
outer surface of the elongated shaft and the electrode shafts are
disposed within the elongated shaft and (ii) a deployed
configuration in which the rounded contact surfaces of the first
electrode and the second electrode are brought into contact with a
vessel wall as a result of the electrode shafts being advanced
radially outward of the elongated shaft. The control element is
configured to limit a maximum outward force of the electrode on a
vessel wall and to cause the electrode to return to the
non-deployed configuration once the expansion member is returned to
a non-expanded state. The first electrode and the second electrode
are positioned such that the rounded contact surfaces of the first
electrode and the second electrode are 180 degrees apart from each
other about the circumference of the elongated shaft.
[0062] In various embodiments, the expansion member comprises an
inflatable balloon or a mechanically-actuated scaffold. The control
element may comprise a coil spring disposed about the electrode
shafts of the first electrode and the second electrode. The control
element may comprise other mechanisms configured to restore the
electrode shafts to a non-deployed configuration and to limit the
outward force exerted by the electrodes on the vessel wall. In one
embodiment, the elongated shaft comprises a lumen configured to
receive a guidewire for providing trackability of the elongated
shaft over the guidewire. In one embodiment, the elongated shaft is
steerable.
[0063] In one embodiment, the invention comprises a system that
includes an elongated shaft configured to be intravascularly
advanced to a location within a blood vessel configured to
facilitate modulation of nerves that innervate the liver, pancreas
and/or duodenum (e.g., within a common hepatic artery). The distal
end of the elongated shaft includes two or four radiofrequency
electrodes offset (e.g., by 90 or 180 degrees) about the
circumference of the elongated shaft. The electrodes are configured
to transition between a non-deployed state in which they are
substantially flush with the outer surface of the elongated shaft
and a deployed state in which the electrodes are caused to contact
and maintain contact with a vessel wall. The elongated shaft also
includes a deployment, or expansion member, configured to cause the
electrodes to transition to the deployed state in which they are in
contact with the vessel wall. The deployment, or expansion, member
may be configured to cause the electrodes to maintain contact with
a uniform or consistent force or pressure. The electrodes may be
optionally curved or otherwise shaped or conformable to enhance
surface area contact or otherwise facilitate contact with a target
site (such as a vessel wall). Additionally, the system may be
controllably deployed using pull wires, retraction of a sheath or
other cover, inflatable members such as balloons, or mechanically
actuated expansion members such as scaffolds.
[0064] In accordance with several embodiments, a tissue modulation
device (e.g., neuromodulation device adapted for intravascular
hepatic neuromodulation) having differentially-oriented electrodes
comprises an elongated shaft having a proximal end portion and a
distal end portion. The elongated shaft comprises a guidewire lumen
extending from the proximal end portion to the distal end portion.
The tissue modulation device further comprises a first monopolar
electrode positioned along the elongated shaft and a shape-set
portion located along the distal end portion of the elongated
shaft. The shape-set portion is adapted to transition between a
delivery configuration in which a guidewire extends distal to the
shape-set portion within the guidewire lumen and a deployed
configuration upon retraction of the guidewire proximal to the
shape-set portion. In this embodiment, the shape-set portion
comprises a second monopolar electrode. The shape-set portion may
be adapted such that it forms a non-helical shape in the deployed
configuration. The second monopolar electrode may be positioned at
a position along a length of the non-helical shape of the shape-set
portion such that the second monopolar electrode contacts a vessel
wall of a vessel (e.g., common hepatic artery, renal artery) at a
first location and such that second monopolar electrode (e.g., a
longest aspect or dimension) is oriented substantially
perpendicular to a longitudinal axis of the elongated shaft when
the shape-set portion is in the deployed configuration. In this
embodiment, the first monopolar electrode is adapted to contact the
vessel wall at a second location spaced apart axially and offset
circumferentially from the first location when the shape-set
portion is in the deployed configuration. In some embodiments, the
first location and the second location are on opposite sides of the
vessel wall. In other embodiments, the first location and the
second location are in different quadrants of the vessel wall.
[0065] In one embodiment, the first monopolar electrode is
positioned proximal to the shape-set portion. In another
embodiment, the first monopolar electrode is positioned distal to
the shape-set portion. Some embodiments include a third monopolar
electrode positioned either proximal or distal to the shape-set
portion (e.g., on the opposite side of the shape-set portion as the
first monopolar electrode). The electrode(s) positioned proximal or
distal of the shape-set portion may be cylindrical electrodes
having a longitudinal axis oriented in parallel with a longitudinal
axis of the elongated shaft. In one embodiment, a longest aspect or
dimension of the electrode(s) are oriented in parallel with a
longitudinal axis of the elongated shaft. The electrode on the
shape-set portion (e.g., the second monopolar electrode) may
comprise a cylindrical shape or a trapezoidal shape or may comprise
a slotted or nested configuration (such as a "horseshoe" shape or a
U-shape) to facilitate a reduction in outer profile as the
electrode is nested around a partial circumference of the shape-set
portion. In some embodiments, the non-helical shape-set portion,
when in the deployed configuration, comprises a longitudinal axis
that transitions from a first orientation that is in parallel with
a longitudinal axis of the elongated shaft to a second orientation
that is perpendicular to the longitudinal axis of the elongated
shaft and then back to the first orientation that is parallel with
the elongated shaft. The non-helical shape-set portion may double
back or loop on itself such that at least a first length of the
shape-set portion that is distal of a second length of the
shape-set portion in an undeployed configuration is proximal of the
second length in a deployed configuration.
[0066] The shape-set portion may comprise more than one monopolar
electrode. For example, two monopolar electrodes may be spaced
apart from each other on the shape-set portion and positioned such
that, when in the deployed configuration, the two electrodes are
circumferentially offset by between 90 degrees and 210 degrees
(e.g., between 90 degrees and 120 degrees, between 110 degrees and
140 degrees, between 120 degrees and 160 degrees, between 150
degrees and 180 degrees, between 170 degrees and 200 degrees,
between 180 degrees and 210 degrees, overlapping ranges thereof or
any value of or within the recited ranges, such as 90 degrees or
180 degrees). The two monopolar electrodes may be positioned such
that the two electrodes are circumferentially offset and come into
contact at opposite sides of the vessel wall or at different
quadrants of the vessel wall when in the deployed
configuration.
[0067] The electrodes along the elongated shaft (whether on the
shape-set portion or proximal or distal to the shape-set portion)
may be positioned such that they are spaced apart axially by
between 3 mm and 8 mm (e.g., between 3 and 5 mm, between 4 and 7
mm, between 5 and 8 mm, overlapping ranges thereof or any value of
or within the recited ranges, such as 4 mm or 6 mm) when in the
deployed configuration.
[0068] In some embodiments, the tissue modulation device (e.g.,
neuromodulation device) comprises one or more lesion spacing
indicators positioned along the distal end portion of the elongated
shaft (e.g., distal of the distal-most electrode) to facilitate
controlled spacing of lesion zones. The lesion spacing indicators
may be positioned on a distal extension extending beyond the
shape-set portion. In one embodiment, the device consists of two
spaced-apart lesion indicators. In another embodiment, one of the
electrodes functions as one of the spaced-apart lesion-spacing
indicators. The lesion-spacing indicators may comprise radiopaque
markers visible under fluoroscopy or other imaging technique. The
lesion-spacing indicators may be spaced apart at a distance equal
to the distance between the first monopolar electrode and the
second monopolar electrode when the shape-set portion is in the
deployed configuration or at a distance that is twice the distance
between the first monopolar electrode and the second monopolar
electrode when the shape-set portion is in the deployed
configuration. Other distances may be used as desired and/or
required.
[0069] In some embodiments, the deployment of the shape-set portion
is not triggered by retraction of a guide wire but instead is
triggered by retraction of an outer sheath. In other embodiments,
the shape-set portion is replaced with a deflectable portion that
does not comprise shape-memory or heat-set material and is deployed
by one or more actuation members (e.g., pull-wires) or movement of
two portions of the elongated shaft with respect to each other to
form a three-dimensional curve or other configuration.
[0070] In accordance with several embodiments, a tissue modulation
device (e.g., neuromodulation device adapted for intravascular
hepatic neuromodulation) comprises an elongated shaft comprising a
proximal end portion and a distal end portion and a balloon
positioned at the distal end portion, the balloon being configured
to transition from a non-inflated delivery configuration to an
inflated deployment configuration. In this embodiment, the balloon
comprises a plurality of electrode arrays positioned along an outer
surface of the balloon, each of the electrode arrays comprising a
plurality of spaced-apart electrodes. In this embodiment, each of
the electrode arrays is configured to be connected to a generator
by separate connection wires such that each of the electrode arrays
is individually controllable (e.g., activated or deactivated). The
plurality of electrode arrays are arranged to form a spiral pattern
along the outer surface of the balloon. When in the inflated
deployment configuration, at least one of the plurality of
electrode arrays is adapted to be in contact with a vessel wall
(e.g., a common hepatic artery, proper hepatic artery,
gastroduodenal artery, splenic artery, celiac artery, renal
artery).
[0071] In some embodiments, a size of each of the plurality of
electrode arrays in its longest aspect is less than or equal to a
characteristic length of thermal conduction in body tissue. In some
embodiments, the plurality of spaced-apart electrodes in each array
or group of electrodes are closely-spaced such that the electrodes
are positioned within a region or area having a longest aspect or
dimension that is no more than 6 mm (e.g., when the electrode array
consists of four electrodes). In various embodiments, each
electrode array consists of between two and eight spaced-apart
electrodes (e.g., two, three, four, five, six, seven, eight
electrodes). Each electrode array may have the same number of
electrodes or some electrode arrays may have different numbers of
electrodes than others. In various embodiments, the number of
electrode arrays or groups ranges from two to eight (e.g., two,
three, four, five, six, seven, eight arrays or groups). However,
more than eight arrays or groups may be present in other
embodiments.
[0072] In some embodiments, the electrode arrays are coupled to the
outer surface of the balloon by an adhesive. In some embodiments,
the electrode arrays are coupled to a flexible substrate. The
balloon may comprise a coating covering an entire outer surface of
the balloon except for active electrode areas of the electrodes or
covering a substantial portion of the outer surface of the balloon
and/or electrodes other than the active electrode areas. In some
embodiments, a portion of the connection wires spanning from the
first electrode to the last electrode in at least one of the
plurality of electrode arrays forms a zig-zag pattern. Each of the
electrode arrays disposed on the outer surface of the balloon may
form the zig-zag pattern of connection wires to reduce overall
spacing and to avoid folds of the balloon in a non-inflated
configuration (e.g., to reduce overall profile). In some
embodiments, the device comprises one or more lesion spacing
indicators positioned along the distal end portion of the elongated
shaft to facilitate controlled spacing of lesion zones. The lesion
spacing indicator(s) (e.g., radiopaque markers) may be positioned
on a distal extension distal of the balloon.
[0073] In accordance with several embodiments, a tissue modulation
device (e.g., neuromodulation device adapted for intravascular
hepatic neuromodulation) comprises an outer tube and an inner tube
concentrically positioned within and longitudinally moveable with
respect to the outer tube, the inner tube having a length to extend
beyond a distal end of the outer tube. The device further comprises
a first deployment arm having a proximal end and a distal end, the
proximal end being coupled to a distal end portion of the outer
tube and the distal end being coupled to a distal end portion of
the inner tube, the first deployment arm being adapted to
transition between a delivery configuration and a deployed
configuration upon movement of the inner tube with respect to the
outer tube. The first deployment arm comprises a first electrode
positioned at a location along a length of the first deployment arm
such that the first electrode is adapted to contact a vessel wall
at a first location when the first deployment arm is in the
deployed configuration.
[0074] In some embodiments, the device comprises a second
deployment arm having a proximal end and a distal end, the proximal
end being coupled to a distal end portion on an opposite side of
the outer tube as the first deployment arm and the distal end being
coupled to a distal end portion of the inner tube on an opposite
side of the inner tube as the first deployment arm. The first
deployment arm is adapted to transition between a delivery
configuration and a deployed configuration upon movement of the
inner tube with respect to the outer tube and wherein, when in the
deployed configuration, the first deployment arm and the second
deployment arm expand outward on opposite sides of a circumference
of the inner tube. In one embodiment, the second deployment arm
comprises a second electrode positioned at a location along a
length of the second deployment arm such that the second electrode
is adapted to contact a vessel wall at a second location on an
opposite side of a circumference of the vessel wall as the first
location when the second deployment arm is in the deployed
configuration.
[0075] In some embodiments, the first electrode is positioned at a
midpoint along the length of the first deployment arm. In
embodiments comprising two deployment arms each comprising an
electrode, the location of the second electrode may be at a
midpoint of the length of the second deployment arm to match the
location of the first electrode on the first deployment arm. In
other embodiments comprising two deployment arms, the location of
at least one of the first electrode and the second electrode is not
at a midpoint of the lengths of the first and/or second deployment
arms, such that the first and second electrodes are configured to
be spaced apart axially along a length of the vessel wall when the
first and second deployment arms are in their deployed
configurations. For example, the location of the first electrode
and the location of the second electrode may be asymmetrical. In
one embodiment, neither the first electrode nor the second
electrode is positioned at a midpoint of the length of the
respective deployment arm.
[0076] In embodiments comprising one or two deployment arms, one or
more electrodes may also be positioned along the distal end portion
of the outer tube proximal to the deployment arm(s) and/or may be
positioned along a distal end portion of the inner tube distal to
the deployment arm(s). In some embodiments, the device comprises a
distal extension coupled to and extending beyond a distal end of
the inner tube, the distal extension comprising a lumen adapted to
receive a guide wire to facilitate trackability. The electrodes may
comprise nested or slotted electrodes to reduce overall profile.
For example, the nested or slotted electrodes may comprise a
half-cylinder shape, a U-shape, a horseshoe shape or other
parabolic or curved shape.
[0077] In some embodiments, the device comprises a second
deployment arm having a proximal end and a distal end, the proximal
end being coupled to a distal end portion of the outer tube and the
distal end being coupled to a distal end portion of the inner tube,
the first deployment arm being adapted to transition between a
delivery configuration and a deployed configuration upon movement
of the inner tube with respect to the outer tube and wherein, when
in the deployed configuration, the first deployment arm and the
second deployment arm expand outward so as to contact the vessel
wall. In this embodiment, the second deployment arm comprises a
second electrode positioned at a location along a length of the
second deployment arm such that the second electrode is adapted to
contact the vessel wall at a second location in a different
quadrant along the circumference of the vessel wall as the first
location when the second deployment arm is in the deployed
configuration (for example, the second location and the first
location are spaced apart circumferentially by at least ninety
degrees). In some embodiments, the second location and the first
location are spaced apart circumferentially by about 180 degrees.
In some embodiments, the second location and the first location are
spaced apart circumferentially by between 120 degrees and 210
degrees (e.g., between 120 and 150 degrees, between 140 and 180
degrees, between 180 and 210 degrees, overlapping ranges thereof or
any value of or within the recited ranges). In some embodiments,
the device comprises one or more lesion spacing indicators (e.g.,
radiopaque markers) positioned along the neuromodulation device to
facilitate controlled spacing of lesion zones as described herein
in connection with other embodiments. The lesion spacing
indicator(s) may be positioned distal of the first electrode.
[0078] In accordance with several embodiments, a tissue modulation
device (e.g., a neuromodulation device configured for intravascular
hepatic neuromodulation) comprises or consists essentially of an
elongated shaft having a proximal end portion and a distal end
portion, a first electrode deployment arm coupled to the distal end
of the elongated shaft, a first electrode coupled to a distal end
of the first electrode deployment arm, a second electrode
deployment arm coupled to the distal end of the elongated shaft
proximal to a location of a coupling of the first electrode
deployment arm to the distal end of the elongated shaft and a
second electrode coupled to a distal end of the second electrode
deployment arm, wherein the first electrode deployment arm and the
second electrode deployment arm are positioned on opposite sides
about the circumference of the elongated shaft and wherein the
first electrode deployment arm and the second electrode deployment
arm are configured to cause the first electrode and the second
electrode to contact a vessel wall at positions on opposite sides
of the vessel wall when in a deployed configuration.
[0079] In some embodiments, the first electrode deployment arm and
the second electrode deployment arm are coupled to the elongated
shaft in a manner such that the first electrode and the second
electrode are brought into contact with the vessel wall at
positions spaced apart along a length of a blood vessel when in the
deployed configuration. In some embodiments, at least one of the
first electrode and the second electrode is mounted on a pivot
configured to facilitate an orientation that is in substantial
alignment with the vessel wall. The electrode deployment arms may
comprise shape memory material such that the electrode deployment
arms are configured to automatically transition to the deployed
configuration upon retraction of a sheath covering the elongated
shaft or upon retraction of a guidewire from a guidewire lumen of
the elongated shaft. In some embodiments, the electrode deployment
arms are steerable (for example, both actuated together by a single
pullwire or other actuation member or individually by separate
pullwires or actuation members). The electrodes may comprise
curved, nested or slotted electrodes. For example, the electrodes
may comprise a half-cylinder shape, a U-shape, a horseshoe shape or
other parabolic or curved shape. In some embodiments, the device
comprises an inner core member disposed within a lumen of the
elongated shaft, a distal end of the inner core member comprising
one or more deployment members configured to deploy the first
electrode deployment arm and the second electrode deployment arm to
the deployed configuration. In one embodiment, the inner core
member is translatable relative to the elongated shaft, and
wherein, upon retraction of the inner core member in a proximal
direction, the deployment member on the distal end of the inner
core member is configured to mechanically separate the first
electrode deployment arm and the second electrode deployment arm
and cause them to transition to the deployed configuration.
[0080] In some embodiments, the first electrode deployment arm and
the second electrode deployment arm comprise a flexible segment
proximal of an electrode attachment point configured to enable a
pivot of the electrode such that the side of the electrode is at
least substantially parallel with the vessel wall. In some
embodiments, the elongated shaft comprises a first slot sized to
house the first electrode deployment arm in a non-deployed
configuration and a second slot sized to house the second electrode
deployment arm in a non-deployed configuration. The first slot and
the second slot may be straight, curved or helical. In one
embodiment, the first slot and the second slot are curved or
helical and the first electrode deployment arm and the second
electrode deployment arm are adapted to have a curved or helical
configuration when in a deployed configuration. In various
embodiments, the first electrode deployment arm and the second
electrode deployment arm are configured to provide uniform contact
force on the vessel wall by the first electrode and the second
electrode. The tissue modulation device may also comprise one or
more lesion spacing indicators (e.g., radiopaque markers)
positioned along the distal end portion of the elongated shaft to
facilitate controlled spacing of lesion zones as described herein
in connection with other embodiments. The lesion spacing
indicator(s) may be positioned distal of the first electrode. In
embodiments consisting of two spacing indicators positioned distal
of the first electrode, the lesion spacing indicators may be spaced
apart at a distance equal to the distance between the first
electrode and the second electrode when the first electrode
deployment arm and the second electrode deployment arm are in the
deployed configuration or at a distance equal to twice the distance
between the first electrode and the second electrode when the first
electrode deployment arm and the second electrode deployment arm
are in the deployed configuration.
[0081] In accordance with several embodiments, a tissue modulation
device a tissue modulation device (e.g., a neuromodulation device
adapted for intravascular hepatic neuromodulation) comprises or
consists essentially of an elongated shaft having a proximal end
and a distal end, a first electrode deployment arm coupled to the
distal end of the elongated shaft, a first electrode coupled to a
distal end of the first electrode deployment arm, a second
electrode deployment arm coupled to the distal end of the elongated
shaft, a second electrode coupled to a distal end of the second
electrode deployment arm, a third electrode deployment arm coupled
to the distal end of the elongated shaft, a third electrode coupled
to a distal end of the third electrode deployment arm, a fourth
electrode deployment arm coupled to the distal end of the elongated
shaft, a fourth electrode coupled to a distal end of the fourth
electrode deployment arm, wherein the first electrode deployment
arm and the second electrode deployment arm are positioned 180
degrees apart from each other about the circumference of the
elongated shaft, wherein the third electrode deployment arm and the
fourth electrode deployment arm are positioned 180 degrees apart
from each other about the circumference of the elongated shaft,
wherein the first electrode deployment arm and the third electrode
deployment arm are positioned in the same quadrant about the
circumference of the elongated shaft, wherein the second electrode
deployment arm and the fourth electrode deployment arm are
positioned in the same quadrant about the circumference of the
elongated shaft, and wherein the four electrode deployment arms are
configured to cause the four electrodes to contact a vessel wall
when in a deployed configuration.
[0082] In some embodiments, the second electrode deployment arm is
spaced proximally of the first electrode deployment arm, the third
electrode deployment arm is spaced proximally of the second
electrode deployment arm, and the fourth electrode deployment arm
is spaced proximally of the third electrode deployment arm such
that the four electrodes contact the vessel wall at spaced-apart
locations along the length of the vessel when in the deployed
configuration. Any or all of the four electrodes may be mounted on
a pivot configured to facilitate an orientation that is in
substantial alignment with the vessel wall. In some embodiments,
the four electrode deployment arms comprise shape memory material
such that the electrode deployment arms are configured to
automatically transition to the deployed configuration upon
retraction of a sheath covering the elongated shaft. In some
embodiments, the four electrode deployment arms are steerable
(e.g., actuated together by a single pullwire or other actuation
member or individually actuated by separate pullwires or actuation
members). In some embodiments, the elongated shaft comprises a
lumen configured to receive a guidewire for providing trackability
of the elongated shaft over the guidewire. The electrodes may
comprise curved, nested or slotted electrodes. For example, the
electrodes may comprise a half-cylinder shape, a U-shape, a
horseshoe shape or other parabolic or curved shape. In some
embodiments, the electrode deployment arms comprise a flexible
segment proximal of an electrode attachment point configured to
enable a pivot of the electrode such that the side of the electrode
is at least substantially parallel with the vessel wall. In various
embodiments, the first electrode deployment arm and the second
electrode deployment arm are configured to provide uniform contact
force on the vessel wall by the first electrode and the second
electrode. The tissue modulation device may also comprise one or
more lesion spacing indicators (e.g., radiopaque markers)
positioned along the distal end portion of the elongated shaft to
facilitate controlled spacing of lesion zones as described herein
in connection with other embodiments. The lesion spacing
indicator(s) may be positioned distal of the distal-most deployment
arm.
[0083] In accordance with several embodiments, a tissue modulation
device a tissue modulation device (e.g., a neuromodulation device
adapted for intravascular hepatic neuromodulation) comprises or
consists essentially of an elongated shaft comprising a proximal
end portion and a distal end portion, wherein the distal end
portion comprises a first electrode a second electrode spaced apart
distally from the first electrode, a first slot between the first
electrode and the second electrode, and a first mechanical
deflection member configured to be contained within the first slot
in an undeployed configuration and to expand outward from the first
slot in a deployed configuration. In the deployed configuration, at
least a portion of the first mechanical deflection member contacts
a vessel wall so as to cause the first electrode and the second
electrode to contact the vessel wall on an opposite side of a
circumference of the vessel wall as a contact location of the first
mechanical deflection member. The first mechanical deflection
member may comprise a ribbon member.
[0084] In some embodiments, the device further comprises a first
actuation wire coupled to a proximal end of the first mechanical
deflection member and configured to cause the first mechanical
deflection member to transition between the undeployed
configuration and the deployed configuration by advancement and
retraction of the first actuation wire, wherein the first actuation
wire extends from the proximal end portion of the neuromodulation
device to the proximal end of the first mechanical deflection
member. In some embodiments, the electrodes comprise cylindrical
monopolar electrodes. In other embodiments, the first electrode and
the second electrode comprise a bipolar electrode pair. The device
may comprise a distal extension distal to the second electrode. The
distal extension may comprise a pair of spaced-apart lesion spacing
indicators (e.g., radiopaque markers). In one embodiment, one of
the electrodes may act as one of the pair of spaced-apart lesion
spacing indicators. The pair of spaced-apart lesion indicators may
be spaced apart at a distance equal to the distance between the
first electrode and the second electrode or at a distance equal to
twice the distance between the first electrode and the second
electrode. Other distances may be used depending on treatment
vessel length or diameter.
[0085] In some embodiments, the tissue modulation device further
comprises a second slot positioned on an opposite side of a
circumference of the distal end portion as the first slot and a
second mechanical deflection member configured to be contained
within the second slot in an undeployed configuration and to expand
outward from the second slot in a deployed configuration, wherein
the second mechanical deflection member is configured to expand
outward in a direction substantially opposite an expansion
direction of the first mechanical deflection member. The second
mechanical deflection member may comprise a ribbon member. In these
embodiments, the device further comprises a second actuation wire
coupled to a proximal end of the second mechanical deflection
member and configured to cause the second mechanical deflection
member to transition between the undeployed configuration and the
deployed configuration by advancement and retraction of the second
actuation wire, wherein the second actuation wire extends from the
proximal end portion of the neuromodulation device to the proximal
end of the second mechanical deflection member.
[0086] In accordance with several embodiments, a method of ablating
nerves surrounding a blood vessel having a controlled lesion
spacing pattern comprises inserting a neuromodulation device within
the blood vessel. The neuromodulation device comprises a first
electrode and a second electrode spaced apart distal of the first
electrode along a distal end portion of the neuromodulation device
and at least one lesion spacing indicator positioned distal of the
second electrode. The method further comprises causing the first
electrode to contact an inner wall of the blood vessel at a first
contact location and the second electrode to contact the inner wall
of the blood vessel at a second contact location, wherein the first
contact location and the second contact location are spaced apart
axially from each other by a separation distance. The method
further comprises causing the first electrode and the second
electrode to deliver radiofrequency energy to the inner wall of the
blood vessel while at the contact locations. The method also
comprises repositioning the neuromodulation device axially within
the blood vessel using the at least one lesion spacing indicator
and causing the first electrode to contact the inner wall of the
blood vessel at a third contact location and the second electrode
to contact the inner wall at a fourth contact location, wherein the
third contact location and the fourth contact location are spaced
apart axially from each other by the separation distance. The
neuromodulation device may then be removed from the blood
vessel.
[0087] In some embodiments, the first location and the second
location are in different quadrants of the inner wall of the blood
vessel with respect to each other and the third location and the
fourth location are in different quadrants of the inner wall of the
blood vessel with respect to each other. The first location and the
third location may be in the same quadrant and the second location
and the third location may be in the same quadrant. For example,
the neuromodulation device may be adapted to deflect or otherwise
change configurations such that one of the first and second
electrodes is in contact with the vessel wall at a first quadrant
while the other of the first and second electrodes is in contact
with the vessel wall at a second quadrant different from the first
quadrant. In some embodiments, the first and second electrodes are
configured to come into contact with the vessel wall in quadrants
on opposite sides of the vessel wall (e.g., contact locations
spaced apart by about 180 degrees). In some embodiments, the first
contact location and the second contact location are spaced apart
circumferentially by between 120 degrees and 210 degrees. In some
embodiments, the first contact location and the second contact
location are spaced apart circumferentially by about 90
degrees.
[0088] In other embodiments, the first location and the second
location are in the same quadrant and the third location and the
fourth location are in the same quadrant. For example, the first
and second electrodes may be positioned into contact with an inner
wall of the blood vessel in a first quadrant and activated to form
spaced apart lesion zones in the first quadrant and then the
neuromodulation device may be retracted or advanced by a distance
using the at least one spacing indicator and the first and second
electrodes may be positioned into contact with an inner wall of the
blood vessel in a second quadrant different from the first quadrant
(e.g., on an opposite side of the vessel circumference).
[0089] In some embodiments, the at least one lesion spacing
indicator is spaced apart axially from the second electrode by a
distance that is equal to the separation distance. In other
embodiments, the at least one lesion spacing indicator is spaced
apart axially from the second electrode at distance that is twice
the separation distance. In embodiments where two spaced-apart
lesion spacing indicators positioned distal to the second electrode
are used, a proximal lesion spacing indicator may be positioned
adjacent the second electrode (e.g., within 2 mm, within 1 mm) and
the spacing between the two spaced-apart lesion spacing indicators
may be equal to or twice the separation distance. In some
embodiments, repositioning the neuromodulation device axially
within the blood vessel comprises aligning a distal one of the two
lesion spacing indicators with a position of a proximal one of the
two lesion spacing indicators prior to repositioning. The
separation distance may be between 3 mm and 8 mm (e.g., 3 mm, 4 mm,
5 mm, 6 mm, 7 mm, 8 mm).
[0090] In accordance with several embodiments, a neuromodulation
system adapted for tissue contact sensing and modulation of tissue
comprises a neuromodulation device including an elongated shaft
having a proximal end portion and a distal end portion and an
electrode assembly positioned at the distal end portion of the
elongated shaft. In one embodiment, the electrode assembly
comprises an inner electrode element and an outer electrode element
separated by an insulation layer, wherein the inner electrode
element is concentric within the outer electrode element. The
electrode assembly is adapted to apply common mode signals to the
inner electrode element and the outer electrode element to cause
delivery of radiofrequency power sufficient to ablate tissue and to
apply differential mode sensing signals between the inner electrode
element and the outer electrode element to generate tissue contact
sensing measurements to be received by a processing device adapted
to determine a level of tissue contact based on the tissue contact
sensing measurements.
[0091] The tissue contact sensing measurements may comprise bipolar
contact impedance measurements between the inner electrode member
and the outer electrode member and/or temperature measurements
obtained by one or more thermocouple leads within the inner
electrode member. In some embodiments, the system comprises a
processing device configured to receive the tissue contact sensing
measurements and to determine whether contact exists or a level of
tissue contact based on the received tissue contact sensing
measurements. The processing device may be configured (e.g.,
specifically programmed) to generate an output indicative of the
level of tissue contact. In some embodiments, the common mode
signals have a frequency range between 400 kHz and 650 kHz (e.g.,
between 400 kHz and 500 kHz, between 450 kHz and 600 kHz, between
550 kHz and 650 kHz, overlapping ranges thereof or any value of or
within the recited ranges). In some embodiments, the differential
mode sensing signals have a frequency outside the frequency range
of the common mode signals. For example, the differential mode
sensing signals have a frequency between 800 kHz and 20 MHz (e.g.,
between 800 kHz and 1 MHz between 1 MHz and 10 MHz, between 5 MHz
and 15 MHz, between 10 MHz and 20 MHz, overlapping ranges thereof
or any value of or within the recited ranges). In several
embodiments, a ratio of a contact surface area of the outer
electrode to a contact surface are of the inner electrode is
between 5:1 and 25:1 (e.g., between 5:1 and 10:1, between 10:1 and
25:1, between 10:1 and 20:1, between 15:1 and 25:1, overlapping
ranges thereof or any value of or within the recited ranges).
[0092] In accordance with several embodiments, a neuromodulation
device adapted for tissue contact sensing and modulation of nerves
or other tissue comprises an elongated shaft comprising a proximal
end portion and a distal end portion and an electrode positioned at
the distal end portion of the elongated shaft. The electrode is
adapted to apply signals to cause delivery of radiofrequency power
sufficient to ablate target tissue. The electrode comprises an
optical window or side port extending from a contact surface of the
electrode to a position within an inner core of the electrode. The
neuromodulation device further comprises an optical sensor
comprising at least one illumination fiber and at least one sensing
fiber. A distal end of the at least one illumination fiber and a
distal end of the at least one sensing fiber are positioned within
the optical window within the inner core of the electrode. A
proximal end of the at least one illumination fiber is configured
to be coupled to an illumination source and a proximal end of the
at least one sensing fiber is configured to be coupled to a
detector.
[0093] In some embodiments, the optical window and/or the distal
ends of the at least one illumination fiber and the at least one
sensing fiber are filled, covered or coated with optical adhesive.
In some embodiments, the optical adhesive has a refractive index
adapted to improve transmission of incident and reflected light
into the target tissue. A system may be provided that comprises the
neuromodulation device and a contact sensing unit comprising the
illumination source and the detector. The contact sensing unit may
be positioned within the elongated shaft or may be a separate,
standalone component configured to be positioned external to a body
of the subject. In some embodiments, the contact sensing unit is
within a same housing as the power or energy source (e.g., RF
generator). The system may also comprise a processing device
configured to generate an output indicative of tissue contact based
on information received from the detector.
[0094] In accordance with several embodiments, the systems, devices
and methods disclosed herein provide consistent disruption of
nerves that innervate organs that influence glucose production
and/or storage regardless of anatomical variation between subjects.
In some embodiments, an ultrasound system adapted for hepatic
neuromodulation comprises a generator and an ultrasound catheter.
The generator may be configured to activate the ultrasound catheter
to deliver acoustic energy sufficient to modulate tissue (e.g.,
nerves) of one or more organs that influence glucose production
and/or storage (such as the liver, pancreas, small intestine,
stomach, etc.).
[0095] In one embodiment, the ultrasound catheter comprises a
proximal end portion, a distal end portion, and an elongate member
extending between the proximal end portion and the distal end
portion. The elongate member and the distal end portion may be
specifically designed and adapted (e.g., configured) to navigate
tortuous vasculature to be positioned in a hepatic artery (e.g., a
common hepatic artery, a proper hepatic artery, a left hepatic
artery, a right hepatic artery) or other artery or blood vessel.
The ultrasound catheter comprises at least one ultrasound
transducer positioned at the distal end portion. The ultrasound
catheter may comprise one, two, three, four, five, six, or any
number of transducers.
[0096] In one embodiment, the ultrasound system is adapted to sense
or visualize adjacent dense structures from a location within a
hepatic artery or other blood vessel and then modulate (e.g.,
ablate) an identified area of interest, such as an area of high
nerve concentration or density caused by the proximity of the
adjacent dense structure. In various embodiments, the at least one
ultrasound transducer is adapted to (a) provide imaging data to the
generator to determine distances to one or more adjacent dense
structures and (b) to deliver acoustic energy sufficient to
modulate nerves. A single ultrasound transducer may be adapted to
provide both diagnostic (e.g., imaging, sensing, visualization,
localization, etc.) capabilities and tissue modulation (e.g., nerve
ablation) capabilities. In some embodiments, one or more ultrasound
transducers are adapted for diagnostic purposes and one or more
ultrasound transducers are adapted for tissue modulation purposes.
For example, the diagnostic transducers may operate in a first
range of frequencies adapted for diagnostic purposes (e.g., 5-60
MHz) and the tissue modulation transducers may operate in a second
range of frequencies adapted for tissue modulation (e.g., 0.5-40
MHz). In some embodiments, diagnostic purposes may be accomplished
at lower frequencies, while tissue modulation may be accomplished
at higher frequencies. In one embodiment, the same range of
frequencies may be used for diagnostic and tissue modulation.
[0097] In some embodiments, the locations of energy delivery within
a hepatic artery are selected based on the determined distances to
the one or more adjacent dense structures or the locations of the
one or more adjacent dense structures determined from images or
data obtained by the ultrasound catheter that are overlaid on
anatomical images. In some embodiments, areas of close proximity to
adjacent dense structures are likely to have a high nerve density
or concentration due to the limited space between the adjacent
dense structure and the hepatic artery or other blood vessel.
Operators may deliver energy at locations having a distance to an
adjacent dense structure that is below a threshold level (e.g.,
within 1 cm, within 9 mm, within 8 mm, within 7 mm, within 6 mm,
within 5 mm). In some embodiments, there may be a minimum threshold
level (e.g., 2 mm, 3 mm, 4 mm, 5 mm) so as to avoid damage to the
adjacent dense structure if it is a dense structure that is not
desired to be ablated or otherwise thermally damaged.
[0098] The generator may be adapted to operate in a diagnostic mode
or a treatment mode. The energy delivered by the ultrasound
transducer(s) in either the diagnostic mode or the treatment mode
may be focused ultrasound (e.g., high-intensity focused ultrasound)
or unfocused ultrasound. An operator may be able to toggle between
the operational modes through interface with the generator (e.g., a
touchscreen interface or physical buttons or switches). In some
embodiments, the generator is adapted to display the determined
distances or images of the adjacent dense structures on a display
of the graphical user interface.
[0099] The generator may be adapted to adjust a frequency of the
energy being delivered by the at least one ultrasound transducer
based on the mode of operation. In one embodiment, the generator is
adapted to adjust one or more parameters of treatment (e.g., power
level, intensity level, duration, target temperature, frequency) of
the at least one ultrasound transducer based on the imaging data or
other feedback received when the generator is in the diagnostic
mode.
[0100] In some embodiments, the ultrasound catheter comprises a
structure adapted to center the at least one transducer within the
hepatic artery or to maintain an offset (e.g., a minimum distance)
between the inner wall of the hepatic artery and a contact surface
of the at least one transducer.
[0101] In some embodiments, the ultrasound catheter comprises one
or more cooling or heat transfer structures adapted to prevent
overheating of the at least one transducer. In one embodiment, the
elongate member of the ultrasound catheter comprises a lumen and
wherein the ultrasound catheter is adapted to be delivered over a
guidewire received in at least a portion of the lumen (e.g., a
majority of the portion within the subject, the distal-most
portion, or a portion distal to the at least one transducer).
[0102] In various embodiments, the at least one transducer
comprises at least one of a resonant cavity transducer, a heat pipe
configuration, or acoustic mirrors or lenses to facilitate cooling,
to control power distribution or focal targets, to improve
efficiency or operation of the transducer(s), and to increase power
without increasing size of the transducer(s). In some embodiments,
the ultrasound catheters comprise structures or mechanisms adapted
to increase circumferential coverage and decrease axial coverage
during energy delivery while maintaining a reduced profile for
introduction to facilitate access to hepatic vasculature or
surrounding vasculature. In some embodiments, the ultrasound
catheters comprise flexible circuits. In some embodiments, the
ultrasound catheters are adapted to pivot a longest dimension of
the at least one transducer from a position generally parallel to a
length of the hepatic artery to a position that is generally
parallel to the circumference of the hepatic artery, thereby
increasing circumferential area of modulation while decreasing
axial length of modulation.
[0103] In accordance with several embodiments, a method of
modulating nerves in a manner to reduce glucose production
comprises identifying one or more locations along a hepatic artery
within a specified distance from an adjacent dense structure using
one or more ultrasound transducers adapted for imaging and
delivering energy sufficient to modulate nerves to reduce a blood
glucose level using the one or more ultrasound transducers. In one
embodiment, a single ultrasound transducer is adapted for imaging
and for delivering energy sufficient to modulate nerves. In other
embodiments, the one or more transducers comprises a first one or
more transducers adapted for imaging and a second one or more
ultrasound transducers adapted for delivering energy to modulate
nerves. The energy sufficient to modulate nerves may be sufficient
to denervate or ablate the nerves in several embodiments.
[0104] In some embodiments, the method comprises confirming
modulation of the nerves (e.g., using a sensing wire coupled to a
radiofrequency electrode on the ultrasound catheter). In some
embodiments, impedance of the tissue may be monitored to determine
whether the tissue in contact with the electrode has been ablated
or not. In some embodiments, the ultrasound catheter is adapted to
deliver both ultrasound energy using the ultrasound transducer(s)
and radiofrequency energy using one or more radiofrequency
electrodes.
[0105] In some embodiments, one or more parameters of the energy
delivery (e.g., power level, intensity level, duration, target
temperature, frequency) are adjusted based on imaging data received
by the one or more ultrasound transducers or based on impedance
measurements obtained by one or more radiofrequency electrodes. In
various embodiments, the method comprises adjusting an orientation
of the one or more ultrasound transducers to adjust a treatment
area within the hepatic artery (e.g., to increase circumferential
coverage while reducing axial coverage). In some embodiments, the
method comprises cooling the one or more ultrasound transducers
(for example, with cooling balloons, with circulating fluid, and/or
with heat plate configurations).
[0106] In accordance with several embodiments, a method of
delivering energy sufficient to ablate nerves innervating the liver
to reduce a glucose level comprises delivering radiofrequency
energy to a target location sufficient to increase a temperature of
tissue to a temperature proximate an ablation threshold using at
least one electrode of an energy delivery device and delivering
acoustic energy to the target location sufficient to raise the
temperature above the ablation threshold using at least one
ultrasound transducer of the energy delivery device. In some
embodiments, the frequency of the radiofrequency energy is between
400 kHz and 60 MHz (e.g., between 400 kHz and 600 kHz, between 500
kHz and 750 kHz, between 600 kHz and 900 kHz, between 700 kHz and 1
MHz, between 1 MHz and 10 MHz, between 10 MHz and 60 MHz, or
overlapping ranges thereof) and wherein the frequency of the
acoustic energy is between 0.5 MHz and 60 MHz (e.g., between 0.5
MHz and 5 MHz, between 1 MHz and 10 MHz, between 2 MHz and 8 MHz,
between 10 MHz and 40 MHz, between 15 MHz and 30 MHz, between 20
MHz and 60 MHz, between 30 MHz and 50 MHz, and overlapping ranges
thereof). In one embodiment, the at least one electrode is
connected in series with the at least one ultrasound transducer. In
another embodiment, the at least one electrode is connected in
parallel with the at least one ultrasound transducer. In another
embodiment, the at least one electrode also serves as an electrode
for the at least one ultrasound transducer. In one embodiment, the
method comprises confirming ablation of the tissue at the target
location using the at least one electrode of the energy delivery
device. The at least one electrode may be the same electrode as the
energy delivery electrode or a separate sensing electrode coupled
directly to a generator. In one embodiment, the at least one
electrode may be an electrode coupled to the ultrasound
transducer.
[0107] In one embodiment, a method of modulating nerves in a manner
to reduce glucose production comprises identifying one or more
locations along a vessel and delivering energy sufficient to
modulate nerves in or surrounding said vessel to directly or
indirectly reduce a glucose level using one or more ultrasound
transducers. The modulation may be performed invasively (e.g.,
within the subject's body) or non-invasively (e.g., from a source
external to a subject's body). In one embodiment, a method of
treating diabetes comprises identifying one or more locations along
a vessel and delivering energy sufficient to modulate nerves in or
surrounding said vessel to directly or indirectly reduce a glucose
level using one or more ultrasound transducers.
[0108] In various embodiments, an ultrasound system adapted for
neuromodulation to reduce blood glucose levels by treating nerves
located in or surrounding a vessel comprises an ultrasound device
comprising a proximal end portion, a distal end portion, and an
elongate member extending between the proximal end portion and the
distal end portion. The elongate member and the distal end portion
are configured to navigate tortuous vasculature to be positioned in
the vessel. The ultrasound device comprises at least one ultrasound
transducer positioned at the distal end portion. The at least one
ultrasound transducer is adapted to deliver acoustic energy
sufficient to modulate nerves of the vessel. In one embodiment, the
frequency of the ultrasound transducer is between 2 MHz and 40 MHz
(e.g., between 2 MHz and 20 MHz, between 10 MHz and 40 MHz) and the
ultrasound transducer is adapted to deliver energy between 0.5 mm
and 10 mm from an internal surface of the vessel. In some
embodiments, ablation of nerves occurs 0.5-5 mm, 1-6 mm, 0.1-10 mm,
1-3 mm, or 2-4 mm from a vessel surface (inner or outer), and
overlapping ranges thereof. The vessel may be a hepatic artery. In
some embodiments, the transducer comprises multiple (e.g., two to
ten or more) transduction elements in a linear or radial pattern.
The transducer may be configured for electronic or phase focusing,
or mechanical focusing. In one embodiment, the transducer is
configured for delivering unfocused ultrasound. In some
embodiments, the ultrasound system comprises an imaging transducer
on the ultrasound device or on a separate device. The ultrasound
system may be used to treat diabetes or other metabolic
conditions.
[0109] Although some embodiments summarized above are described
with respect to hepatic neuromodulation, the embodiments herein
also contemplate neuromodulation or tissue modulation of regions
other than the liver or hepatic vessels. For example, the
catheters, devices and systems described herein may also be used
for renal denervation (e.g., by modulating the nerves in one or
both renal arteries), for glucose or lipid regulation by modulating
the nerves that innervate the pancreas, kidney, duodenum, jejunum
and/or stomach, for cardiac ablation, for pulmonary tissue or
vessel ablation or neuromodulation, as well as other targets and
indications described herein. The devices and systems summarized
above may be used within vessels other than a hepatic artery, such
as a renal artery, a gastroduodenal artery, a celiac artery or a
splenic artery. For example, the devices and systems may be used
within one or more renal arteries or veins and may be suitable for
treating hypertension or other conditions associated with
modulation of nerves surrounding the renal vessels. As another
example, the devices and systems may be used within a
gastroduodenal artery, celiac artery or vessel innervating the
pancreas and the neuromodulation device may be suitable for
treating one or more symptoms of diabetes. As another example, the
devices and systems may be used within a vessel and may be
configured to cause modulation of nerves surrounding the vessel
sufficient to alter sympathetic tone.
[0110] For purposes of summarizing the disclosure, certain aspects,
advantages, and novel features of embodiments of the invention have
been described herein. It is to be understood that not necessarily
all such advantages may be achieved in accordance with any
particular embodiment of the invention disclosed herein. Thus, the
embodiments disclosed herein may be embodied or carried out in a
manner that achieves or optimizes one advantage or group of
advantages as taught or suggested herein without necessarily
achieving other advantages as may be taught or suggested herein.
The methods summarized above and set forth in further detail below
describe certain actions taken by a practitioner; however, it
should be understood that they can also include the instruction of
those actions by another party. Thus, actions such as "delivering a
neuromodulation catheter within a hepatic artery" include
"instructing the delivery of a neuromodulation catheter within a
hepatic artery." With respect to the drawings, elements from one
figure may be combined with elements from the other figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0111] FIG. 1A illustrates the anatomy of a target treatment
location including the liver and hepatic blood supply, in
accordance with an embodiment of the invention.
[0112] FIG. 1B illustrates the anatomy of a target treatment
location including the liver and hepatic blood supply, in
accordance with an embodiment of the invention.
[0113] FIG. 1C illustrates various arteries supplying blood to the
liver and its surrounding organs and tissues and nerves that
innervate the liver and its surrounding organs and tissues.
[0114] FIGS. 2A and 2B illustrate examples of distribution of
nerves surrounding a hepatic artery, as influenced by presence of
an adjacent dense structure.
[0115] FIG. 3 illustrates a schematic drawing of a common hepatic
artery and nerves of the hepatic plexus.
[0116] FIGS. 4A-4C, 5A and 5B, 6 and 7 illustrate embodiments of
compression members configured to facilitate modulation of
nerves.
[0117] FIGS. 8 and 9 illustrate embodiments of electrode
catheters.
[0118] FIGS. 10A and 10B illustrate embodiments of ablation
coils.
[0119] FIGS. 11A-11C, 12A-12E, 13A, 13B, 14, 15A-15C, 16A, 16B,
17A, 17B, 18 and 19A-19C illustrate embodiments of balloon
catheters.
[0120] FIG. 20 illustrates an embodiment of a balloon-based volume
ablation catheter system.
[0121] FIG. 21 illustrates a graph of RF heating versus distance
from the electrode.
[0122] FIGS. 22A-22C, 23A-23C, 24, 25, 26A, 26B, 27A-27D and 28
illustrate devices and methods configured to provide increased
cooling for electrode catheters.
[0123] FIGS. 29A, 29B, 29O-1, 29C-2, 29D, 29E, 29F, 29G-1, 29G-2,
29H, 29I, 29J-1, 29J-2, 29K, 29L-1, 29L-2, 29M-1, 29M-2, 29M-3,
29M-4, 29N-1, 29N-2 and 29O illustrate embodiments of
radiofrequency energy delivery devices for neuromodulation.
[0124] FIG. 30 illustrates several embodiments of catheter distal
tip electrode and guide wire shapes.
[0125] FIGS. 31A-34F illustrate embodiments of radiofrequency
energy delivery devices for neuromodulation.
[0126] FIGS. 35-47B illustrate embodiments of devices and methods
for increasing catheter and/or electrode stabilization of electrode
catheters within target vessels.
[0127] FIGS. 48A-48E illustrate an embodiment of a radiofrequency
energy delivery catheter configured for hepatic denervation.
[0128] FIG. 49 is a schematic illustration of arterial branches
that may be targeted by the methods, devices and systems described
herein.
[0129] FIG. 50 illustrates an embodiment of a catheter configured
to facilitate 180.degree. articulation within vasculature.
[0130] FIGS. 51A-54B illustrate embodiments of devices and methods
for increasing catheter and/or electrode stabilization of electrode
catheters within target vessels.
[0131] FIGS. 55A and 55B illustrate an embodiment of a windowed
ablation catheter.
[0132] FIGS. 56A-62B illustrate embodiments of systems and methods
configured to control lesion formation.
[0133] FIGS. 63A-1 to 63C illustrate various embodiments of
deployment sleeve systems for use in deploying multiple
electrodes.
[0134] FIGS. 64A-1 to 64K illustrate various embodiments of
multi-electrode energy delivery devices.
[0135] FIG. 65 illustrates an embodiment of a pivoting
electrode.
[0136] FIG. 66 illustrates a graph demonstrating the use of pulsed
therapy, in accordance with an embodiment of the invention.
[0137] FIG. 67 illustrates images showing locations of nerves
surrounding the common hepatic artery.
[0138] FIG. 68 illustrates a graph of motion of an electrode
catheter tip indicated by a microwave radiometry sensor.
[0139] FIGS. 69 and 70 illustrate images obtained from a model of
an endovascular ablation within the common hepatic artery.
[0140] FIGS. 71A and 71B illustrate schematic embodiments of a
catheter having a cooled electrode and a thermocouple to provide
temperature feedback at a distance from the cooled electrode.
[0141] FIG. 72 illustrates a graph of electrode tip temperature and
lesion depth as convective blood flow increases.
[0142] FIG. 73 illustrates an embodiment of a catheter having a
thermal mass flow sensor.
[0143] FIG. 74 is a graph illustrating a principle of operation of
the thermal mass flow sensor of FIG. 73.
[0144] FIG. 75 illustrates a flow chart of an embodiment of an
ablation control process.
[0145] FIG. 76 is a flow chart of an embodiment of impedance-based
feedback control.
[0146] FIGS. 77A and 77B illustrate embodiments of an energy
delivery algorithm based on blood flow measurement.
[0147] FIGS. 78A and 78B schematically illustrate embodiments of
intravascular ablation catheters configured to prevent vessel
circumferentiality during ablation therapy.
[0148] FIG. 79 illustrates a schematic representation of a distal
portion of an ultrasound energy delivery device positioned within a
blood vessel at a location corresponding to a location in close
proximity to an adjacent dense structure.
[0149] FIG. 80 illustrates an embodiment of an energy delivery
system.
[0150] FIGS. 81A-81D illustrate embodiments of a pivoting
ultrasound energy delivery device in various pivot conditions.
[0151] FIG. 82A illustrates an embodiment of a distal portion of an
ultrasound energy delivery device having a multiple pivoting
transducers.
[0152] FIG. 82B illustrates an alternative embodiment of an
assembly of multiple pivoting transducers of the ultrasound energy
delivery device of FIG. 82A.
[0153] FIGS. 83A and 83B-1 to 83B-3 illustrate embodiments of a
distal portion of an ultrasound energy delivery device including a
foldable flexible circuit.
[0154] FIGS. 84A-84E illustrate various configurations of the
distal portion of the ultrasound energy delivery device of FIG.
83A.
[0155] FIG. 85 illustrates an embodiment of a distal portion of an
ultrasound energy delivery device configured to deploy by unrolling
a flexible circuit.
[0156] FIG. 86 illustrates another embodiment of a distal portion
of an ultrasound energy delivery device comprising multiple
interlocking mounting elements.
[0157] FIGS. 87A-87F illustrate various embodiments of acoustic
mirrors and/or lenses to control distribution of acoustic energy
delivered by an ultrasound transducer.
[0158] FIG. 88 illustrates a schematic representation of an
embodiment of a resonant cavity ultrasound transducer.
[0159] FIG. 89 illustrates an embodiment of an ultrasound
transducer comprising a heat pipe to increase heat transfer.
[0160] FIG. 89A illustrates a close-up view of a portion of a
cooling plate of the ultrasound transducer heat pipe of FIG.
89.
[0161] FIG. 89B illustrates various embodiments of texture patterns
of the surfaces of the ultrasound transducer heat pipe of FIG.
89.
[0162] FIG. 90 illustrates an embodiment of an energy delivery
system configured to deliver ultrasound and radiofrequency energy
to target tissue using a single energy delivery device.
[0163] FIG. 91 illustrates an embodiment of a microwave-based
ablation catheter system.
[0164] FIG. 92 illustrates an embodiment of an induction-based
ablation catheter system.
[0165] FIG. 93 illustrates an embodiment of a steam ablation
catheter.
[0166] FIG. 94 illustrates an embodiment of a hot water balloon
ablation catheter.
[0167] FIG. 95 illustrates an embodiment of a "telescoping" system
for facilitating delivery of a low-profile neuromodulation catheter
to a hepatic artery branch.
[0168] FIG. 96 illustrates an embodiment of use of the system of
FIG. 95 to access a target neuromodulation location within a
hepatic artery.
[0169] FIGS. 97A and 97B illustrate embodiments of a vascular
access system comprising a guide sheath or captive sleeve.
[0170] FIGS. 98A and 98B illustrate an embodiment of a wedge-type
expanding anchor that can be used to secure a guide catheter or
guide extension catheter in place.
[0171] FIGS. 99A and 99B illustrate embodiments of devices (and
methods of using such devices) specifically designed to facilitate
access to tortuous hepatic vasculature.
[0172] FIGS. 100-110 illustrate embodiments of catheter systems and
associated methods configured to provide catheter
stabilization.
[0173] FIG. 111 illustrates an example of poor wall-electrode
contact and an example of good wall-electrode contact.
[0174] FIGS. 112A-118 illustrate embodiments of neuromodulation
catheters configured to provide catheter stabilization within
tortuous vasculature or within vasculature subject to movement
during respiration.
[0175] FIGS. 119A-119D illustrate embodiments of split electrode
assemblies for tissue contact sensing.
[0176] FIGS. 120A and 120B illustrate an embodiment of a fiberoptic
sensor for tissue contact sensing.
[0177] FIG. 121 illustrates an embodiment of a system comprising a
controller (e.g., generator) positioned outside of a subject's body
that is communicatively coupled (via wired or wireless connection)
to an energy delivery device.
[0178] FIG. 122 illustrates a portion of a human anatomy
surrounding the liver.
[0179] FIGS. 123A-1, 123A-2, 123B and 124 illustrate graphs of data
from hepatic denervation studies, in accordance with embodiments of
the invention.
[0180] FIG. 125 illustrates the effect on liver norepinephrine
levels following a hepatic denervation procedure during an animal
study.
[0181] FIGS. 126A-126D illustrate geometric models.
[0182] FIG. 127 illustrates a schematic two-dimensional
representation of lesion depth, in accordance with an embodiment of
the invention.
[0183] FIG. 128 is a graph illustrating maximum power as a function
of arterial flow rate, in accordance with an embodiment of the
invention.
[0184] FIG. 129 is a graph of a least-square curve fitting for the
relation between maximum power and arterial flow rate, in
accordance with an embodiment of the invention.
[0185] FIG. 130 is a graph illustrating change in lesion
temperature as electrode size changes, in accordance with an
embodiment of the invention.
[0186] FIG. 131 is a graph illustrating change in temperature over
time for different power levels of RF energy, in accordance with an
embodiment of the invention.
[0187] FIGS. 132-134 are graphs illustrating relationships between
various treatment parameters, in accordance with embodiments of the
invention.
[0188] FIG. 135 illustrates an embodiment of a power control
process incorporating impedance feedback control.
[0189] FIG. 136 illustrates how phase shifts can cause inaccurate
measurement of current and/or voltage.
[0190] FIG. 137 illustrates components of impedance in an
embodiment of an endovascular ablation procedure.
[0191] FIG. 138 illustrates an effect on impedance measurements by
subtracting a background impedance signal, in accordance with an
embodiment of the invention.
DETAILED DESCRIPTION
I. Introduction and Overview
[0192] Embodiments of the invention described herein are generally
directed to therapeutic neuromodulation of targeted nerve fibers to
treat, or reduce the risk of occurrence or progression of, various
metabolic diseases, conditions, or disorders, including but not
limited to diabetes (e.g., diabetes mellitus). While the
description sets forth specific details in various embodiments, it
will be appreciated that the description is illustrative only and
should not be construed in any way as limiting the disclosure.
Furthermore, various applications of the disclosed embodiments, and
modifications thereto, which may occur to those who are skilled in
the art, are also encompassed by the general concepts described
herein. Although several figures set forth below are described with
respect to hepatic neuromodulation, the embodiments herein also
contemplate neuromodulation or tissue modulation of regions other
than the liver or hepatic vasculature. For example, the catheters,
devices and systems described herein may also be used for renal
denervation (e.g., by modulating the nerves in one or both renal
arteries), for glucose or lipid regulation by modulating the nerves
that innervate the pancreas, duodenum, jejunum and/or stomach, for
cardiac ablation, for pulmonary tissue or vessel ablation or
neuromodulation, as well as other targets and indications described
herein.
[0193] The autonomic nervous system includes the sympathetic and
parasympathetic nervous systems. The sympathetic nervous system is
the component of the autonomic nervous system that is responsible
for the body's "fight or flight" responses, those that can prepare
the body for periods of high stress or strenuous physical exertion.
One of the functions of the sympathetic nervous system, therefore,
is to increase availability of glucose for rapid energy metabolism
during periods of excitement or stress, and to decrease insulin
secretion.
[0194] The liver can play an important role in maintaining a normal
blood glucose concentration. For example, the liver can store
excess glucose within its cells by forming glycogen, a large
polymer of glucose. Then, if the blood glucose concentration begins
to decrease too severely, glucose molecules can be separated from
the stored glycogen and returned to the blood to be used as energy
by other cells. The liver is a highly vascular organ that is
supplied by two independent blood supplies, one being the portal
vein (as the liver's primary blood supply) and the other being the
hepatic artery (being the liver's secondary blood supply).
[0195] The process of breaking down glycogen into glucose is known
as glycogenolysis, and is one way in which the sympathetic nervous
system can increase systemic glucose. In order for glycogenolysis
to occur, the enzyme phosphorylase must first be activated in order
to cause phosphorylation, which allows individual glucose molecules
to separate from branches of the glycogen polymer. One method of
activating phosphorylase, for example, is through sympathetic
stimulation of the adrenal medulla. By stimulating the sympathetic
nerves that innervate the adrenal medulla, epinephrine is released.
Epinephrine then promotes the formation of cyclic AMP, which in
turn initiates a chemical reaction that activates phosphorylase. An
alternative method of activating phosphorylase is through
sympathetic stimulation of the pancreas. For example, phosphorylase
can be activated through the release of the hormone glucagon by the
alpha cells of the pancreas. Similar to epinephrine, glucagon
stimulates formation of cyclic AMP, which in turn begins the
chemical reaction to activate phosphorylase.
[0196] Another way in which the liver functions to maintain a
normal blood glucose concentration is through the process of
gluconeogenesis. When the blood glucose concentration decreases
below normal, the liver will synthesize glucose from various amino
acids and glycerol in order to maintain a normal blood glucose
concentration. Increased sympathetic activity has been shown to
increase gluconeogenesis, thereby resulting in an increased blood
glucose concentration.
[0197] The parasympathetic nervous system is the second component
of the autonomic nervous system and is responsible for the body's
"rest and digest" functions. These "rest and digest" functions
complement the "fight or flight" responses of the sympathetic
nervous system. Stimulation of the parasympathetic nervous system
has been associated with decreased blood glucose levels. For
example, stimulation of the parasympathetic nervous system has been
shown to increase insulin secretion from the beta-cells of the
pancreas. Because the rate of glucose transport through cell
membranes is greatly enhanced by insulin, increasing the amount of
insulin secreted from the pancreas can help to lower blood glucose
concentration. Neuromodulation (e.g., denervation or stimulation)
of sympathetic and/or parasympathetic nerves surrounding other
organs or tissues (such as the pancreas, small intestine, duodenum,
and/or portions of the stomach) may also be performed in
combination with modulation of nerves innervating the liver to
treat diabetes or the symptoms associated with diabetes (e.g., high
blood glucose levels, high triglyceride levels, high cholesterol
levels, low insulin secretion levels). Several embodiments
described herein are adapted to modulate (e.g., ablate, stimulate,
etc.) the parasympathetic system alone or in conjunction with the
sympathetic system. In some embodiments, one system is activated
and the other deactivated. Alternatively, both systems can be
activated or deactivated. In some embodiments, stimulation of the
parasympathetic nerves innervating the pancreas is combined with
denervation of sympathetic nerves innervating the liver to treat
diabetes or the symptoms associated with diabetes (e.g., high blood
glucose levels, high triglyceride levels, high cholesterol levels,
low insulin secretion levels). Stimulation and/or denervation of
sympathetic and/or parasympathetic nerves surrounding other organs
or tissues (such as the pancreas, duodenum and/or portions of the
stomach) may also be performed in combination.
[0198] FIG. 1A illustrates a liver 101 and vasculature of a target
hepatic treatment location 100. The vasculature includes the common
hepatic artery 105, the proper hepatic artery 110, the right
hepatic artery 115, the left hepatic artery 120, the right hepatic
vein 125, the left hepatic vein 130, the middle hepatic vein 135,
and the inferior vena cava 140. In the hepatic blood supply system,
blood enters the liver by coursing through the common hepatic
artery 105, the proper hepatic artery 110, and then either of the
left hepatic artery 120 or the right hepatic artery 115. The right
hepatic artery 115 and the left hepatic artery 120 (as well as the
portal vein, not shown) provide blood supply to the liver 101, and
directly feed the capillary beds within the hepatic tissue of the
liver 101. The liver 101 uses the oxygen provided by the oxygenated
blood flow provided by the right hepatic artery 115 and the left
hepatic artery 120. Deoxygenated blood from the liver 101 leaves
the liver 101 through the right hepatic vein 125, the left hepatic
vein 130, and the middle hepatic vein 135, all of which empty into
the inferior vena cava 140.
[0199] FIG. 1B illustrates a liver 101 and target vasculature of
hepatic neuromodulation methods and systems to treat diabetes or
symptoms associated with diabetes or glucose production. The target
vasculature may include a hepatic artery 105, which branches off
from a celiac artery 210 originating at the abdominal aorta 205.
The hepatic artery 105 supplies blood to the liver. The splenic
artery 235 is also illustrated, which also branches off from the
celiac artery 210 to provide blood to the spleen 145. Other organs
or dense structures positioned adjacent the hepatic artery 105 may
include the pancreas 150, the stomach 155, and portions of the
bowel 160 (including the small intestine). As will be discussed in
further detail below, systems and methods may be provided to
identify locations along the hepatic artery 105 that are in close
proximity to adjacent structures (e.g., organs) which may influence
glucose production and to modulate tissue at or near the identified
locations (e.g., delivering energy using radiofrequency, ultrasound
or microwave energy delivery devices sufficient to modulate nerves
that innervate the liver and/or other adjacent structures that may
influence glucose production (such as the pancreas 150, stomach
155, and/or small intestine 160)). The modulation provided may be
sufficient to reduce glucose levels (e.g., blood glucose levels),
lipid levels, cholesterol levels, etc. In various embodiments,
portions of multiple adjacent structures (e.g., organs) may be
denervated or otherwise modulated (either from a single location or
from multiple locations along a portion of the hepatic artery 105
or arteries connected or adjacent to the hepatic artery 105, such
as the celiac artery 210, splenic artery 235, and gastroduodenal
artery). Several embodiments of the invention are particularly
advantageous in that disruption of sympathetic nerves that
innervate organs that influence glucose production and storage may
be performed consistently regardless of anatomical variations
between subjects.
[0200] FIG. 1C illustrates various arteries surrounding the liver
and the various nerve systems 200 that innervate the liver and its
surrounding organs and tissue. The arteries include the abdominal
aorta 205, the celiac artery 210, the common hepatic artery 215,
the proper hepatic artery 220, the gastroduodenal artery 222, the
right hepatic artery 225, the left hepatic artery 230, and the
splenic artery 235. The various nerve systems 200 illustrated
include the celiac plexus 240 and the hepatic plexus 245. Blood
supply to the liver is pumped from the heart into the aorta and
then down through the abdominal aorta 205 and into the celiac
artery 210. From the celiac artery 210, the blood travels through
the common hepatic artery 215, into the proper hepatic artery 220,
then into the liver through the right hepatic artery 225 and the
left hepatic artery 230. The common hepatic artery 215 branches off
of the celiac trunk, or artery 210. The common hepatic artery 215
gives rise to the gastric and gastroduodenal arteries. The nerves
innervating the liver may include portions of the celiac plexus 240
and the hepatic plexus 245. The celiac plexus 240 wraps around the
celiac artery 210 and continues on into the hepatic plexus 245,
which wraps around the proper hepatic artery 220, the common
hepatic artery 215, and may continue on to the right hepatic artery
225 and the left hepatic artery 230. In some anatomies, the celiac
plexus 240 and hepatic plexus 245 adhere tightly to the walls (and
some of the nerves may be embedded in the adventitia) of the
arteries supplying the liver with blood, thereby rendering
intra-to-extra-vascular neuromodulation particularly advantageous
to modulate nerves of the celiac plexus 240 and/or hepatic plexus
245. In several embodiments, the media thickness of the vessel
(e.g., hepatic artery) ranges from about 0.1 cm to about 0.25 cm.
In some anatomies, at least a substantial portion of nerve fibers
of the hepatic artery branches are localized within 0.5 mm to 1 mm
from the lumen wall such that modulation (e.g., denervation) using
an endovascular approach is effective with reduced power or energy
dose requirements. In some embodiments where radiofrequency energy
is used, low-power or low-energy (e.g., less than 10 W of power
output and/or less than 1 kJ of energy delivered to the inner wall
of the target vessel or to the target nerves) intravascular energy
delivery may be used because the nerves are tightly adhered to or
within the outer walls of the arteries supplying the liver with
blood (e.g., hepatic artery branches).
[0201] With continued reference to FIGS. 1A, 1B, and 10, the
hepatic plexus 245 is the largest offset from the celiac plexus
240. The hepatic plexus 245 is believed to carry primarily afferent
and efferent sympathetic nerve fibers, the stimulation of which can
increase blood glucose levels by a number of mechanisms. For
example, stimulation of sympathetic nerve fibers in the hepatic
plexus 245 can increase blood glucose levels by increasing hepatic
glucose production. Stimulation of sympathetic nerve fibers of the
hepatic plexus 245 can also increase blood glucose levels by
decreasing hepatic glucose uptake. Therefore, by disrupting (e.g.,
blocking, terminating, denervating, ablating) sympathetic nerve
signaling in the hepatic plexus 245, blood glucose, triglyceride,
norepinephrine, lipid (e.g., lipoprotein), and/or cholesterol
levels can be decreased or reduced. In some embodiments, blood
glucose levels are reduced from baseline by 10-80% (e.g., 10-20%,
20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 30-60%, 40-70%,
20-50%, or overlapping ranges thereof). Triglyceride,
norepinephrine, lipid and/or cholesterol levels may also be reduced
by similar amounts.
[0202] In several embodiments, any of the regions (e.g., arteries,
nerves) identified in FIGS. 1A, 1B, and 10 may be modulated
according to embodiments described herein. Alternatively, in one
embodiment, localized therapy is provided to the hepatic plexus,
while leaving one or more of these other regions unaffected. In
some embodiments, multiple regions (e.g., of organs, arteries,
nerve systems) shown in FIGS. 1A, 1B, and 10 may be modulated in
combination (simultaneously or sequentially), which may provide one
or more synergistic effects. For example, in some embodiments,
methods of metabolic neuromodulation treatment involve forming
ablation lesions in the common hepatic artery as well as in the
celiac, splenic and/or other portions or branches of the hepatic
artery (e.g., proper hepatic artery, left hepatic artery, right
hepatic artery) to facilitate denervation of complementary
metabolic organs and structures (e.g., pancreas, stomach, duodenum)
in addition to the liver, even in the instance of a shortened
common hepatic artery and/or unusual branch vessel anatomy. In some
embodiments, if a subject has a short common hepatic artery (e.g.,
less than 30 mm), ablation of other vessels or portions of the
hepatic artery may be desired and/or required to achieve an
effective treatment. In other embodiments, treatment of
complementary metabolic organs and structures by delivering energy
in the celiac artery, splenic artery, gastroduodenal artery and/or
other portions of the hepatic artery (e.g., proper hepatic artery,
right hepatic artery, left hepatic artery) may advantageously
provide one or more synergistic effects. Although several
access/delivery devices are described herein that are configured
for (e.g., in shape, size, flexibility, etc.) the hepatic artery,
such access/delivery devices can also be used for other arteries
and vessels, and in particular, other tortuous vasculature. In
addition, although devices may be described herein as
neuromodulation catheters or devices and described with respect to
modulation (e.g., ablation) of nerves, the catheters or other
devices may be used to modulate other types of tissue (e.g., tissue
lining an organ or vessel, muscle tissue, endothelial tissue,
connective tissue, submucosal tissue).
[0203] Sympathetic nerves may be distributed around the hepatic
artery (or other arteries, such as the celiac artery, the splenic
artery, the gastroduodenal artery), and several embodiments of the
invention are adapted to treat these vessels. The hepatic artery
passes by many adjacent structures from its origin at the celiac
artery to its termination at the liver. The distance that the
nerves are away from the hepatic artery or the density of nerves
can be influenced by the proximity of adjacent dense structures,
such as the liver, pancreas, stomach, small intestine). In
accordance with several embodiments, it may be advantageous to
modulate tissue at locations along the hepatic artery that are in
sufficiently close proximity (e.g., less than 1 cm away from the
inner wall of the hepatic artery) to adjacent dense structures
(e.g., liver, pancreas, stomach, small intestine, muscle, and/or
connective tissue). For example, locations along the hepatic artery
that are close to adjacent structures may be associated with highly
dense concentrations of nerves, the modulation of which could
reduce glucose levels or provide other effects associated with
treatment of diabetes in an efficient and effective manner. FIG. 2A
illustrates a schematic representation of distribution of nerves
165 surrounding a hepatic artery 105 with limited adjacent
structure 170 influence (e.g., where the adjacent dense structure
170 is greater than 1 cm away from the inner wall of the hepatic
artery 105) and FIG. 2B illustrates a schematic representation of
distribution of nerves 165 surrounding a hepatic artery 105 with
significant adjacent structure 170 influence (e.g., wherein the
adjacent dense structure 170 is less than 1 cm away from the inner
wall of the hepatic artery 105). As can be seen, the distribution
of nerves 165 in FIG. 2B is very highly concentrated around the
hepatic artery 105 due to the limited space between the hepatic
artery 105 and the adjacent structure 170. The illustrated example
may represent an area of the hepatic artery 105 that is generally
encapsulated by the pancreas.
[0204] The anatomy of the vascular branches distal of the celiac
plexus may be highly disparate between subjects. In accordance with
several embodiments, systems and methods are provided to identify
locations along the hepatic artery 105 where the hepatic artery 105
is in close proximity to (e.g., less than 1 cm, less than 5 mm
from) an adjacent dense structure 170 and to provide energy to the
identified locations in a manner that disrupts the nerves 165
surrounding the hepatic artery 105 (e.g., nerves 165 between the
medial layer of the hepatic artery 105 and the adjacent dense
structure 170). In some embodiments, the locations where the
hepatic artery 105 is in close proximity to an adjacent dense
structure 170 are matched with locations determined to be ideal
candidates for neuromodulation (e.g., locations having a proper
vessel diameter, sufficient treatment length without much
tortuosity, etc.).
[0205] FIG. 3 is a schematic illustration of the nerve fibers of
the hepatic plexus 300. A portion of the common hepatic artery 305
(or, alternatively, the proper hepatic artery) is shown with the
hepatic plexus 300 wrapping around the artery. Some of the nerve
fibers of the hepatic plexus may be embedded within the
perivascular space (e.g., adventitia) of the common hepatic artery
305 (or proper hepatic artery), or at least tightly adhered to or
within the outer vascular walls. As shown, there is a vessel
lumenal axis that follows the center of the artery lumen. The
hepatic plexus 300 is comprised of parasympathetic nerves 310 and
sympathetic nerves 315. In some anatomies, the parasympathetic
nerves 310 tend to course down one half of the circumference of an
artery and the sympathetic nerves 315 tend to course down the other
half of the artery.
[0206] As shown in FIG. 3, the portion of the common hepatic artery
305 is roughly cylindrical, with parasympathetic nerves 310
innervating approximately a 180.degree. arc of the cylinder, and
the sympathetic nerves of the hepatic plexus 315 innervating the
opposite approximately 180.degree. arc of the cylinder. In some
anatomies, there is very little overlap (if any) between the
parasympathetic nerves 310 and the sympathetic nerves 315 of the
hepatic plexus. Such discretization may be advantageous in
embodiments where only sympathetic nerves 315 or parasympathetic
nerves 310 of the hepatic plexus are to be modulated. In some
embodiments, modulation of the sympathetic nerves 315 of the
hepatic plexus may be desirable while modulation of the
parasympathetic nerves 310 of the hepatic plexus may not be
desirable (or vice-versa).
[0207] In some embodiments, only selective regions of the
perivascular space (e.g., adventitial layer) of target vasculature
is modulated. In some subjects, parasympathetic and sympathetic
nerves may be distributed distinctly on or within the adventitial
layer of blood vessels. For example, using an axis created by the
lumen of a blood vessel, parasympathetic nerves of the hepatic
plexus may lie in one 180 degree arc of the adventitia while
sympathetic nerves may lie in the other 180 degree arc of the
adventitia, such as shown in FIG. 3. Generally, the sympathetic
nerve fibers tend to run along the anterior surface of the hepatic
artery, while the parasympathetic nerve fibers are localized toward
the posterior surface of the hepatic artery. In these cases, it may
be advantageous to selectively disrupt either the sympathetic or
the parasympathetic nerves by modulating nerves in either the
anterior region or the posterior region, respectively.
[0208] In some subjects, sympathetic nerve fibers may run along a
significant length of the hepatic artery, while parasympathetic
nerve fibers may join toward the distal extent of the hepatic
artery. Research has shown that the vagus nerve joins the liver
hilus near the liver parenchyma (e.g., in a more distal position
than the nerves surrounding the hepatic arterial tree). As the
vagal nerves are parasympathetic, the nerves surrounding the
hepatic artery proximally may be predominantly sympathetic. In
accordance with several embodiments, modulation (e.g., ablation) of
the proper hepatic artery towards its proximal extent (e.g.,
halfway between the first branch of the celiac artery and the first
branch of the common hepatic artery) is performed when it is
desired to disrupt sympathetic nerves in the hepatic plexus.
Ablation of the proximal extent of the hepatic artery could
advantageously provide the concomitant benefit of avoiding such
critical structures as the bile duct, pancreas and portal vein
(which approaches the hepatic artery as it courses distally towards
the liver), in accordance with one embodiment of the invention.
[0209] In one embodiment, only the anterior regions of the hepatic
artery are selectively modulated (e.g., ablated). In one
embodiment, approximately 180 degrees of the arterial circumference
(which may include the corresponding adventitial layer) is ablated.
In some embodiments, it is desirable to ablate in the range of
about 60.degree. to about 240.degree., about 80.degree. to about
220.degree., about 100.degree. to about 200.degree., about
120.degree. to about 180.degree., about 140.degree. to about
160.degree., or overlapping ranges thereof. In some embodiments,
the portion of the vessel wall not being targeted opposite the
portion of the vessel wall being targeted is actively cooled during
the modulation procedure (e.g., as described, for example, in
connection with FIGS. 56A and 56B). Such cooling may decrease
collateral injury to the nerve fibers not intended for treatment.
In many embodiments, cooling is not used.
[0210] In embodiments in which only selective portions of the
vessel wall are to be treated, a zig-zag, overlapping semicircular,
spiral, lasso, or other pattern of ablation may be used to treat
only selective regions of nerve tissue in the adventitia or other
perivascular space. An example of a spiral ablation pattern Z, in
accordance with one embodiment, is shown in FIG. 3. In some
embodiments, one or more ablation electrodes having an inherent
zig-zag, spiral or other pattern are used. In some embodiments, a
single point ablation electrode (regardless of electrode pattern)
is advanced longitudinally and circumferentially about
substantially 180 degrees of the vessel circumference to ablate in
a zig-zag, spiral or other pattern, thereby selectively ablating
only approximately 180 degrees of the vessel wall and the
accompanying nerve tissues. In some embodiments, other patterns of
electrode configurations are used. In some embodiments, other
patterns of ablation electrode movement (regardless of inherent
conformation) are used. In some embodiments, lesion zones are
created that do not overlap with each other. In various
embodiments, lesion zones are spaced apart axially and/or
radially.
[0211] In some embodiments, where only selective regions of the
vessel wall are to be modulated (e.g., ablated or stimulated) it
may be helpful to have a high degree of device (e.g., catheter)
control, stability and/or precision. To achieve the control
necessary for a high degree of precision, a guide catheter may be
used to engage the osteum of a nearby branch (e.g., the branch of
the common hepatic artery off of the celiac artery, or celiac
trunk) to provide a constant reference point from which to position
an energy delivery (e.g., ablation) catheter. Alternatively, the
catheter (e.g., probe) could also be anchored in other branches,
either individually or simultaneously, to further improve control
and/or stabilization. Simultaneous anchoring may be achieved by
means of a compliant, inflatable balloon (e.g., having a shape and
size configured to match an osteum or another portion of a
particular vessel), which may substantially occlude the vascular
lumen (e.g., osteum), thereby anchoring the catheter and providing
increased stability. Such an approach may obviate the need for
angiography to map the course of treatment, including the
concomitant deleterious contrast agent and x-ray exposure, because
treatment guidance can be performed relative to a reference
angiogram, with distance of the neuromodulation catheter from the
guide catheter measured outside of the patient. In some
embodiments, the inflatable balloon may have a size and shape
configured to engage multiple ostia or to be anchored in multiple
branches (simultaneously or sequentially). In some embodiments,
occlusion of a vessel results in increased arterial blood flow at a
target location, thereby providing more effective convective
cooling. In one embodiment, a balloon catheter is configured to
deliver a controlled amount of energy within a defined region of an
arterial wall irrespective of low and/or variable flow within the
artery (e.g., hepatic artery).
[0212] The anatomy of the vascular branches distal of the celiac
plexus may be highly disparate between subjects and variations in
the course of the sympathetic and parasympathetic nerves tend to be
associated predominantly with branches distal of the celiac plexus,
rather than being associated with any specific distance distally
along the hepatic artery. In some embodiments, a neuromodulation
location is selected based on a position relative to the branching
anatomy rather than on any fixed distance along the hepatic artery
in order to target the sympathetic nerve fibers; for example,
within the common hepatic artery and about 1 cm-6 cm (e.g., about 2
cm-3 cm, or substantially at the midpoint of the common hepatic
artery) from the branching of the celiac axis or 1 mm-1 cm (e.g., 1
mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm) from the
branching of the splenic artery or from the branching of the
gastroduodenal artery.
[0213] Parasympathetic and sympathetic nerve fibers tend to have
opposing physiologic effects, and therefore, in some embodiments,
only the sympathetic nerve fibers and not the parasympathetic nerve
fibers are disrupted (e.g., denervated, ablated) in order to
achieve the effects of reducing endogenous glucose production and
increasing hepatic and peripheral glucose storage. In some
embodiments, only the parasympathetic nerve fibers and not the
sympathetic nerve fibers are stimulated in order to achieve the
effects of reducing endogenous glucose production and increasing
hepatic and peripheral glucose storage. In some embodiments, the
sympathetic nerve fibers are denervated while the parasympathetic
nerve fibers are simultaneously stimulated in order to achieve the
effects of reducing endogenous glucose production and increasing
hepatic and peripheral glucose storage. In some embodiments, the
denervation of the sympathetic nerve fibers and the stimulation of
the parasympathetic nerve fibers are performed sequentially.
[0214] In accordance with several embodiments, methods of
therapeutic neuromodulation for preventing or treating disorders
(such as diabetes mellitus) comprise modulation of nerve fibers
(e.g., the sympathetic nerve fibers of the hepatic plexus). In one
embodiment, neuromodulation decreases hepatic glucose production
and/or increases hepatic glucose uptake, which in turn can result
in a decrease of blood glucose levels, triglyceride levels, lipid
levels, norepinephrine levels, and/or cholesterol levels.
Disruption of the nerve fibers can be effected by ablating,
denervating, severing, destroying, removing, desensitizing,
disabling, reducing, crushing or compression, or inhibiting neural
activity through, blocking, or otherwise modulating (permanently or
temporarily) the nerve fibers or surrounding regions. In some
embodiments, the disruption is carried out using one or more energy
modalities that are delivered for example, intravascularly,
extravascularly, or noninvasively (e.g., transcutaneously) from an
extracorporeal location. Energy modalities include, but are not
limited to, acoustic or sound energy such as ultrasonic energy,
unfocused ultrasound, focused ultrasound such as high-intensity or
low-intensity focused ultrasound, microwave energy, radiofrequency
(RF) energy, thermal energy (e.g., cryoenergy, heat provided by a
hot fluid or gas, such as steam), electrical energy, infrared
energy, laser energy, phototherapy or photodynamic therapy (e.g.,
in combination with one or more activation agents), plasma energy,
ionizing energy delivery (such as X-ray, proton beam, gamma rays,
electron beams, and alpha rays), mechanical energies delivered by
cutting or abrasive elements, cryoablation, and chemical energy or
modulation (e.g., chemoablation), or any combination thereof. In
some embodiments, the disruption of the sympathetic nerve fibers is
carried out by chemicals or therapeutic agents (for example, via
drug delivery), either alone or in combination with an energy
modality. In various embodiments different energy modalities may be
used in combination (either simultaneously or sequentially).
[0215] In some embodiments, a catheter system is configured to
extravascularly and selectively disrupt target nerves. In some
embodiments, a catheter is advanced through a cardiovascular system
to the target site. The catheter may be passed transluminally to
the extravascular space or may create a virtual space between the
vascular media and adventitia of the vessel. In some embodiments,
the catheter, once positioned at the desired location is activated
to selectively modulate or disrupt the target nerve or nerves. The
selective disruption may be accomplished or performed through
chemo-disruption, such as supplying any type of nerve destroying
agent, including, but not limited to, neurotoxins or other drugs
detrimental to nerve viability. In some embodiments, selective
disruption is performed through energy-induced disruption, such as
thermal or light ablation (e.g., radiofrequency ablation,
ultrasound ablation, or laser ablation). In one embodiment, a
camera or other visualization device (e.g., fiberoptic scope) is
disposed on a distal end of the catheter to ensure that nerves are
targeted and not surrounding tissue. If a target location is
adjacent the branch between the common hepatic artery and the
proper hepatic artery, a less acute catheter bend may be required
due to the angulation between the bifurcation of the common hepatic
artery and the proper hepatic artery. In some embodiments, the
catheter comprises a side port, opening or window, thereby allowing
for delivery of fluid or energy to denervate or ablate nerves with
the longitudinal axis of the catheter aligned parallel or
substantially parallel to the target vessel portion. In some
embodiments, the catheter or probe is inserted percutaneously and
advanced to the target location for extravascular delivery of
energy or fluid.
[0216] In accordance with several embodiments disclosed herein, the
invention comprises modulation of nerve fibers instead of or in
addition to nerve fibers in the hepatic plexus to treat diabetes or
other metabolic conditions, disorders, or other diseases. For
example, sympathetic nerve fibers surrounding (e.g., within the
intima, media, perivascular space (e.g., adventitia) of the common
hepatic artery proximal to the proper hepatic artery or other
branch of the hepatic artery, sympathetic nerve fibers surrounding
the celiac artery (e.g., the celiac ganglion or celiac plexus,
which supplies nerve fibers to multiple organs including the
pancreas, stomach, and small intestine), sympathetic nerve fibers
that innervate the pancreas, sympathetic nerve fibers that
innervate the adrenal glands (e.g., the renal plexus or suprarenal
plexus), sympathetic nerve fibers that innervate the gut, bowel,
stomach or small intestine (e.g., the duodenum or jejunum),
sympathetic nerve fibers that innervate brown adipose tissue,
sympathetic nerve fibers that innervate skeletal muscle, the vagal
nerves, the phrenic plexus or phrenic ganglion, the gastric plexus,
the splenic plexus, the splanchnic nerves, the spermatic plexus,
the superior mesenteric ganglion, the lumbar ganglia, the superior
or inferior mesenteric plexus, the aortic plexus, or any
combination of sympathetic nerve fibers thereof may be modulated in
accordance with the embodiments herein disclosed. In some
embodiments, instead of being treated, these other tissues are
protected from destruction (e.g., ablation or denervation) during
localized neuromodulation of the hepatic plexus. In some
embodiments, one or more sympathetic nerve fibers (for example, a
ganglion) can be removed (for example, pancreatic sympathectomy).
The nerves (sympathetic or parasympathetic) surrounding the various
organs described above may be modulated in a combined treatment
procedure (either simultaneously or sequentially), which may
provide one or more synergistic effects.
[0217] In some embodiments, modulation of the nerves (e.g.,
sympathetic denervation) innervating the stomach results in
reduction of ghrelin secretion and greater satiety, decreased
sympathetic tone leading to increased motility and/or faster food
transit time, thereby effecting a "neural gastric bypass." In some
embodiments, modulation of the nerves (e.g., sympathetic
denervation) innervating the pylorus results in decreased efferent
sympathetic tone, leading to faster transit time and effecting a
"neural gastric bypass." In some embodiments, modulation of the
nerves (e.g., sympathetic denervation) innervating the duodenum
results in disrupted afferent sympathetic activity leading to
altered signaling of various receptors and hormones (e.g., gut
hormones, GLP-1, gastric inhibitory peptide (GIP), cholecystokinin
(CCK), peptide YY (PYY), 5-hydroxytryptamine (5-HT)), thereby
causing increased insulin secretion and insulin sensitivity, and/or
decreased efferent sympathetic tone leading to faster transit time,
thereby effecting a "neural duodenal bypass."
[0218] In some embodiments, modulation of the nerves (e.g.,
sympathetic denervation) innervating the pancreas results in
decreased efferent sympathetic tone, thereby causing increased beta
cell insulin production and beta cell mass, and decreased alpha
cell glucagon production. In some embodiments, modulation of the
afferent sympathetic nerves innervating the liver results in
reflexive decreased sympathetic tone to the pancreas,
gastrointestinal tract, and/or muscle. In some embodiments,
modulation of the afferent sympathetic nerves innervating the liver
results in an increase in a hepatokine hormone with systemic
effects (e.g., hepatic insulin sensitizing substance). In some
embodiments, stimulation of the common hepatic branch of the vagus
nerves could result in similar effects.
[0219] Several embodiments of the invention are particularly
advantageous because they include one, several or all of the
following benefits: (i) consistent and maintained contact with
vessel walls; (ii) fewer treatment locations due to increased
efficacy; (iii) ability to effectively treat a short vessel length
such as the common hepatic artery; (iv) reduction in blood glucose,
cholesterol and/or triglyceride levels, (v) reduction in lipid
and/or norepinephrine levels in the liver, pancreas, and/or
duodenum; (vi) confirmation of treatment efficacy; (vii)
denervation of multiple organs or tissue structures from a single
location; (viii) effective denervation of nerves in a perivascular
region while maintaining minimal heating of, or thermal injury to,
the inner vessel wall; (ix) higher likelihood of successful
neuromodulation due to modulation of areas of high nerve density;
(x) increased likelihood of modulation having an effect on glucose
production due to modulation of areas of high nerve density or
concentration; and/or (xi) increased circumferential vessel
coverage with reduced axial vessel length coverage.
II. Types of Neuromodulation
A. Mechanical Neuromodulation
[0220] The selective modulation or disruption of nerve fibers may
be performed through mechanical or physical disruption, such as,
but not limited to, cutting, severing, ripping, tearing,
transecting, or crushing. Several embodiments of the invention
comprise disrupting cell membranes of nerve tissue. Several
embodiments involve selective compression of the nerve tissue and
fibers. Nerves being subjected to mechanical pressure, such as, but
not limited to, selective compression or crushing forces may
experience effects such as, but not limited to, ischemia, impeded
neural conduction velocity, and nervous necrosis. Such effects may
be due to a plurality of factors, such as decreased blood flow.
[0221] In several embodiments, many of the effects due to selective
compression or mechanical crushing forces are reversible. Beyond
using mechanical compression to selectively and reversibly modulate
neural response, mechanical compression may be used to permanently
modulate neural response through damage to select myelin sheaths
and individual nerve fascicles. In some embodiments, the level of
neural modulation is tuned by modulating the mechanical compressive
forces applied to the nerve. For example, a large compressive force
applied to a nerve may completely inhibit neural response, while a
light compressive force applied to the same nerve may only slightly
decrease neural response. In some embodiments, a mechanical
compressive force or crushing force may be applied to a nerve, such
as a sympathetic nerve in the hepatic plexus, with a removable
crushing device. In some embodiments, the removable crushing device
is removed and replaced with a stronger or weaker removable
crushing device depending on the individual needs of the subject
(e.g., the strength of the removable crushing device being keyed to
the needed neural response levels). The ability of such removable
crushing devices to be fine-tuned to selectively modulate neural
response is advantageous over the binary (e.g., all or nothing)
response of many types of neural ablation.
[0222] In various embodiments, the compressive or crushing forces
necessary to compress or crush nerves or cause ischemia within the
hepatic artery or other vessels may range from about 1 to about 100
g/mm.sup.2, from about 1 g/mm.sup.2 to about 10 g/mm.sup.2, from
about 3 g/mm.sup.2 to about 5 g/mm.sup.2 (e.g., 8 g/mm.sup.2), from
about 5 g/mm.sup.2 to about 20 g/mm.sup.2, from about 10 g/mm.sup.2
to about 50 g/mm.sup.2, from about 20 g/mm.sup.2 to about 80
g/mm.sup.2, from about 50 g/mm.sup.2 to about 100 g/mm.sup.2, or
overlapping ranges thereof. These compressive forces may be
effected by the various embodiments of mechanical neuromodulation
devices or members described herein.
[0223] FIGS. 4A-4C, 5A, 5B, 6 and 7 illustrate various embodiments
of mechanical neuromodulation devices or members. FIGS. 4A-4C
illustrate embodiments of a shape memory compression clip 400. In
some embodiments, the shape memory compression clip 400 is used to
mechanically compress target nerves. In some embodiments, the shape
memory compression clip 400 is removable. FIG. 4A illustrates a
resting conformation of the shape memory compression clip 400. FIG.
4B illustrates a strained conformation of the shape memory
compression clip 400, which looks like a capital "U" in the
illustrated embodiment The shape memory compression clip 400 may be
applied to a nerve, such as a nerve of the hepatic plexus by
forcibly placing the shape memory compression clip 400 in its
strained conformation, placing the target nerve in the bottom well
of the shape memory compression clip 400, and then allowing the
shape memory compression clip 400 to return to its resting
conformation, thereby applying the desired compressive forces to
the target nerve by causing it to be crushed or pinched. FIG. 4C
illustrates an alternative embodiment of a shape memory compression
clip 420 in which the bottom well forms an acute bend instead of
being curvate when in a resting shape. The compression clip 400,
420 may be allowed to return to a resting configuration through
either removal of external forces biasing the compression clip in a
strained configuration (e.g., utilizing superelastic properties of
shape memory materials) or heating the compression clip above a
transition temperature, thereby allowing the compression clip to
assume a native or resting configuration in an austenitic phase
above the transition temperature.
[0224] In some embodiments, mechanical compressive forces are held
at substantially constant levels after application. In some
embodiments, the shape memory compression clip 400 may be tailored
to the anatomy of different target nerves. In some embodiments, the
shape memory compression clip 400 varies in size or shape to
compensate for anatomical variance. In some embodiments, varying
sizes or shapes of shape memory compression clips may be used, in
addition to compensating for anatomical variance, to selectively
apply varying levels of compressive stresses to the target nerve
(e.g., smaller clip or stronger material for higher forces and
larger clip or weaker material for smaller forces). In one
embodiment, the shape memory material is nitinol. In various
embodiments, the shape memory material is a shape memory polymer or
any other appropriate material having shape memory material
properties. In some embodiments, compression members comprise
simple spring clips or any other devices capable of applying a
substantially constant force. In some embodiments, a compression
member is configured to clamp the entire artery and the nerves in
the adventitial layer, thereby applying the desired compressive
forces to both the target nerves and the artery around which the
target nerves travel.
[0225] Applying compressive, occlusive or collapsing forces to
hepatic arteries is uniquely feasible, in some embodiments, because
the liver is supplied with blood from both the hepatic arteries,
around which many of the target nerves described herein may travel,
as well as the portal vein. If at least one of the hepatic arteries
is clamped (for the purpose of applying compressive forces to the
nerves in its adventitia), the liver would lose the blood supply
from that artery, but would be fully supplied by the portal vein,
thereby leaving the liver viable and healthy.
[0226] In some embodiments, mechanical compressive forces are
variable across time following application. In some embodiments,
the mechanical compressive forces are varied according to a pre-set
duty cycle, thereby titrating the effects of the neuromodulation.
One or more embodiments may comprise a transcutaneous delivery of
energy to a circuit coupled to a compression member (e.g., a
nitinol clip) having a transition between martensitic and
austenitic states at a specific temperature induced by a
temperature that is substantially different from body temperature.
In several embodiments, a variance in temperature is provided
through, but is not limited to: a thermocouple (e.g., a Peltier
junction) thermally coupled to the compression member to which the
circuit may apply power, or a heating element thermally coupled to
the compression member to which the circuit may apply resistive
power, thereby altering the physical conformation of the
compression member and varying (either increasing or decreasing
depending on the power applied) the compressive forces generated by
the compression member. In one embodiment, the compression member
itself acts as a resistive element and the circuit is coupled
directly to the compression member to apply resistive power to the
compression member, thereby altering the physical conformation of
the compression member and varying (either increasing or decreasing
depending on the power applied) the compressive forces generated by
the compression member. Other embodiments combine the compression
member with a thermocouple or other temperature-measurement device
to allow the selective application of electric power to vary the
compressive stresses created by the compression member.
[0227] FIGS. 5A and 5B illustrate another embodiment of a
compression device. FIG. 5A illustrates a catheter-based vascular
wall compression system 500 including a vascular wall clamp 515 in
an open conformation. The catheter-based vascular wall compression
system 500 includes a detachable insertion catheter 505, suction
holes 510, an engagement portion 515A of the vascular wall clamp
515, an anchoring mechanism 520, a receiving portion 515B of the
vascular wall clamp, and an anchoring mechanism accepting portion
530. In operation, the vascular wall clamp 515 may be inserted into
the target vessel on the distal end of the detachable insertion
catheter 505. In one embodiment, the receiving portion 515B of the
vascular wall clamp 515 is located at the distal end of the
detachable insertion catheter 505, while the engagement portion
515A of the vascular wall clamp 515 is located slightly proximal to
the receiving portion 515B. The surface of the detachable insertion
catheter 505 between the receiving portion 515B and the engagement
portion 515A may include a plurality of suction holes 510.
[0228] In further operation, once the vascular wall clamp 515 is
placed at the desired target location, the suction holes 510, in
one embodiment, create a vacuum, or suction, which brings the walls
of the target vessel in substantially direct apposition to the
surface of the detachable insertion catheter portion that includes
the plurality of suction holes 510. While maintaining suction, and
therefore the position of the vessel wall in apposition to the
detachable insertion catheter 505, the engagement portion 515A is
moved toward the receiving portion 515B (or vice versa), thereby
pinching the vascular wall which remained in direct apposition to
the detachable insertion catheter between the receiving portion
515B and the engagement portion 515A.
[0229] The anchoring mechanism 520, which is attached to the
engagement portion 515A engages the anchoring member accepting
portion 530 of the receiving portion 515B, thereby securing the
receiving portion 515B to the engagement portion 515A and clamping
the vascular wall portion that remains in direct apposition to the
detachable insertion catheter 505 between the receiving portion
515B and the engagement portion 515A. Once the receiving portion
515B has fully engaged with the engagement portion 515A, the
detachable insertion catheter 505 may be disengaged from the
vascular wall clamp 515 and removed by the same path it was
inserted.
[0230] FIG. 5B illustrates the vascular wall clamp 515 in a closed
conformation. In FIG. 5B, the anchoring mechanism 520, which is
attached to the engagement portion 515A of the vascular wall clamp
515 has engaged the anchoring member accepting portion 530 of the
receiving portion 515B of the vascular wall clamp 515, thereby
clamping a portion of the vascular wall between the receiving
portion 515B and the engagement portion 515A. FIG. 5B shows that
the detachable insertion catheter 505 has already been removed.
[0231] In some embodiments, the engagement portion 515A and the
receiving portion 515B of the vascular wall clamp 525 both include
a hollow center. In these embodiments, when the detachable
insertion catheter 505 is removed, the hole at the center of the
engagement portion 515A of the vascular wall clamp 515 and the hole
at the center of the receiving portion 515B of the vascular wall
clamp 525 creates a patent lumen between the receiving portion 515B
and the engagement portion 515A, thereby allowing continued blood
flow from one side to the other. In some embodiments, the
detachable insertion catheter 505 is attached to either the
engagement portion 515A or the receiving portion 515B of the
vascular wall clamp 515 by means of a threaded portion, which may
be unthreaded once the receiving portion 515B and engagement
portion 515A have engaged, and the detachable insertion catheter
505 is no longer needed.
[0232] In some embodiments, the vascular wall clamp 515 is inserted
to the target anatomy using an over-the-wire approach. In some
embodiments, the detachable insertion catheter 505 is hollow and
has suction holes 510 in communication with an internal hollow
lumen of the detachable insertion catheter 505. The suction holes
510 may be a series of small openings, a screen, or any other
structure which allows a lower pressure area to be created between
the receiving portion 515B and the engagement portion 515A of the
vascular wall clamp 515 to bring the vessel wall and perivascular
tissue in substantially direct apposition with the detachable
insertion catheter 505. In some embodiments, the vascular wall
clamp 515 is deployed by pulling proximally on the detachable
insertion catheter 505, thereby bringing the distal receiving
portion 515B of the vascular wall clamp 525 into engagement with
the proximal engagement portion 515A of the vascular wall clamp
515, thereby compressing and/or severing arterial and nerve tissue
captured therein. In some embodiments, rotation of the catheter 505
is effective to disengage the catheter 505 from the vascular wall
clamp 515. In some embodiments, removal of the detachable insertion
catheter 505 from the vascular wall clamp 515 leaves a patent lumen
permitting blood flow to the liver.
[0233] In some embodiments, the engagement mechanism 520 comprises
at least one spear-shaped clip and the engagement accepting portion
530 comprises at least one hole aligned to accept the at least one
spear shaped clip and to engage the at least one spear shaped clip
engagement mechanism 520 as it enters the at least one hole
engagement accepting portion 530 and snaps into place. In some
embodiments, the engagement mechanism 520 and engagement accepting
portion 530 are simply magnets which hold the receiving portion
515B of the vascular wall clamp 515 and the engagement portion 515A
of the vascular wall clamp 515 together. In still other
embodiments, the engagement mechanism 520 and the engagement
accepting portion 530 are any structures that allow the engagement
portion 515A to engage the receiving portion 515B and remain in
that engaged conformation. In some embodiments, the vascular wall
clamp 515 comprises a biologically inert material with decreased
thrombogenicity, such as Teflon.RTM..
[0234] FIG. 6 illustrates an embodiment of an extravascular
compression coil 600 inserted within a vessel. In operation, the
extravascular compression coil 600 may be advanced through a hole
in the vascular wall 610 in a spiraling intra-vascular to
extra-vascular manner into the vessel adventitia, thereby placing
the extravascular compression coil 600 around the target vessel. In
some embodiments, the extravascular compression coil 600 has the
effect of compressing the nerves located within the vascular wall
of the target vessel. In some embodiments, to prevent or inhibit
occlusion and stenosis, an intravascular stent is subsequently
placed within the lumen of the target vessel, thereby both propping
open the vessel for continued flow and providing a resilient
surface against which the target nerves may be compressed.
[0235] In embodiments where stenosis is of particular concern, a
stent is placed in the target vessel after treatment to retain
patency. In some embodiments, the placement of a stent within the
lumen of the target vessel provides the added benefit of
compressing the vascular wall to a higher degree, thereby
disrupting the target nerves even more. In some embodiments, a
stent is placed in the portal vein due to the risk of portal vein
stenosis from hepatic arterial ablation procedures. In some
embodiments, to protect the portal vein from possible stenosis,
anal cooling is used because the gut venous flow travels to the
portal system (in some embodiments, anal cooling has the direct
result of cooling the portal vein and decreasing the likelihood of
stenosis due to treatment of the hepatic artery).
[0236] In some embodiments, magnets may be delivered separately
into the portal vein and hepatic artery. Upon placement of the two
magnets, opposite poles of the two magnets will attract each other
and subsequently mate, thereby resulting in substantial compression
of the nerves disposed between the two magnets. The force created
by the mating of the two magnets may be selectively modulated by
increasing or decreasing the strength of magnets used for any given
patient morphology, as desired or required.
[0237] FIG. 7 illustrates an embodiment of a fully occluding
balloon 700 inserted within a target blood vessel. In operation, a
fully occluding balloon 710 is inserted into a target vessel,
inflated and used to expand or stretch the vascular lumen to
sufficiently stretch the surrounding nerves to either the point of
ischemia or physical disruption. The fully occluding balloon 710
may be removed after physical disruption or after the target nerves
have been destroyed due to ischemia. Alternatively, the fully
occluding balloon 710 may be left in place permanently because, as
discussed previously, the liver is supplied by blood from the
portal vein as well, rendering the hepatic artery at least somewhat
redundant. In some embodiments, the level of balloon compression is
adjusted in an ambulatory fashion, thereby allowing for titration
of the neuromodulation effect.
[0238] In some embodiments, rather than using a fully occluding
balloon 710, a non-occluding balloon or partially occluding balloon
is inserted into a target vessel, inflated, and used to expand or
stretch the vascular lumen to sufficiently stretch the surrounding
nerves to the point of ischemia or physical disruption. The
non-occluding or partially occluding balloon may have similar
structural features as the fully occluding balloon 710, but may
include at least one hollow lumen (e.g., a central lumen) to allow
for continued blood flow after placement. In some embodiments, the
level of balloon compression can be adjusted in an ambulatory
fashion, thereby allowing for titration of the neuromodulation
effect.
[0239] In some embodiments, similar to the occlusion techniques
described above, a balloon catheter may be inserted into the target
vessel and then filled with a fluid which is infused and withdrawn
at a specific frequency (e.g., pressurized in an oscillating
fashion), thereby causing mechanical disruption of the nerve fibers
surrounding (e.g., within a wall of, such as within the intima,
media or adventitia of) the target vessel (e.g., hepatic artery).
In some embodiments, the fluid used to fill the balloon catheter
may be a contrast agent to aid in visualization of the arterial
structure (and thereby limiting the amount of contrast agent used
in the procedure).
[0240] In some embodiments, a fluid is injected into the
interstitial space surrounding the vasculature around which the
target nerve lies, thereby applying compressive forces to the nerve
bundle which surrounds the vessel(s). In some embodiments, the
fluid is air. In some embodiments, the fluid is any noble gas
(e.g., heavy gas), including but not limited to: helium, neon,
argon, krypton, and xenon. In some embodiments, the fluid is
nitrogen gas. In some embodiments, the fluid is any fluid capable
of being injected to apply the desired compressive forces. In some
embodiments, the fluid is injected by a catheter inserted
transluminally through a blood vessel in substantially close
proximity to the target site (e.g., location where nervous
compression is desired). In some embodiments, the fluid is injected
by a needle or trocar inserted transdermally through the skin and
surrounding tissues to the target site. Any method of fluid
injection may be used to deliver the requisite amount of fluid to
the target site in order to create compressive forces that are
applied to the target nerve, such as nerves of the hepatic
plexus.
[0241] In some embodiments, a target vessel is completely
transected, thereby causing a complete and total physical
disruption of the vessel wall and the surrounding nerves in the
adventitial tissues. The target vessel may then be re-anastamosed,
thereby allowing continued perfusion through the vessel. The nerve
tissue either does not reconnect, or takes a significant amount of
time to do so. Therefore, all neural communication surrounding the
transected vessel may temporarily or permanently the disrupted. In
some embodiments, a cutting device is advanced in a catheter
through the subject's vasculature until it reaches a target vessel.
The cutting device may then be twisted along the axis of the target
vessel to cut through the target vessel from the inside out. In
some embodiments, an expandable element, such as a balloon
catheter, is inserted into the vessel to compress the vessel wall
and provide a controlled vessel thickness to permit transection. A
rotational cutter may then be advanced circumferentially around the
expandable element to effect transection of the vessel and the
nerves disposed within the adventitia of the vessel. In one
embodiment, the target vessel is transected during open
surgery.
[0242] Re-anastomoses of vessels could be achieved using any of
several methods, including laser, RF, microwave, direct thermal, or
ultrasonic vessel sealing. In some embodiments, thermal energy may
be delivered through an expandable element to effect anastomosis of
the vessel under the mechanical pressure provided by the expandable
element. The combination of pressure, time, and temperature (e.g.,
60.degree. C., 5 seconds, and 120 psi in one embodiment) may be an
effective means to seal vessels such as the hepatic arteries.
B. Energy-Based Neuromodulation
1. Radiofrequency
[0243] In some embodiments, a catheter system comprises an ablation
device coupled to a generator (for example, pulse-generating device
or power generator). For example, the ablation device may be an
ablation catheter. The ablation catheter may have a proximal end
portion and a distal end portion. In some embodiments, the distal
end portion of the ablation catheter comprises one or more
electrodes (e.g., one electrode, two electrodes, three electrodes,
four electrodes, five electrodes, six electrodes, more than six
electrodes). In some embodiments, the ablation catheter consists of
only two electrodes. In other embodiments, the ablation catheter
consists of only four electrodes. The one or more electrodes can be
positioned on an external surface of the ablation catheter or can
extend out of the distal end portion of the ablation catheter. In
some embodiments, the electrodes comprise monopolar electrodes. In
some embodiments, the electrodes comprise one or more active
electrodes and one or more return electrodes that cooperate to form
bipolar electrode pairs. In some embodiments, the distal end
portion of the ablation catheter comprises at least one bipolar
electrode pair and at least one monopolar electrode. One or more
electrically conductive wires (for example, thermocouple wires) may
connect one or more electrodes located at the distal end of the
ablation catheter to the generator (for example, pulse-generating
device). In some embodiments, multiple electrodes can extend from
the ablation catheter on multiple wires or deployment arms to
provide multiple energy delivery locations or points within a
vessel (e.g., a hepatic artery, a renal artery) or other body lumen
or within an organ (e.g., pancreas, stomach, small intestine).
[0244] In some embodiments, the generator (for example,
pulse-generating device) applies power or delivers electrical
(e.g., radiofrequency (RF)) signals or pulses to the electrodes
located at or near the distal end portion of the ablation catheter.
The electrodes may be positioned to deliver RF energy in the
direction of sympathetic nerve fibers in the hepatic plexus to
cause ablation due to thermal energy. In some embodiments, the
electrodes are positioned on top of reflective layers or coatings
to facilitate directivity of the RF energy away from the ablation
catheter. In various embodiments, the electrodes are curved or
flat. The electrodes can be dry electrodes or wet electrodes. In
some embodiments, a catheter system comprises one or more probes
with one or more electrodes. For example, a first probe can include
an active electrode and a second probe can include a return
electrode. In some embodiments, the distal ends of the one or more
probes are flexible. The ablation catheter can comprise a flexible
distal end portion. Variable regions of flexibility or stiffness
along a catheter length are provided in some embodiments. In
various embodiments, a first flexible portion is actuated to have a
first bend shape configured to conform to a first anatomical bend
(e.g., a first bend of a hepatic artery branch) and a second
flexible portion is actuated to have a second bend shape configured
to conform to a second anatomical bend (e.g., a second bend of a
hepatic artery branch).
[0245] In one embodiment, a pair of bipolar electrodes is disposed
at a location that is substantially tangential to the inner lumen
of the hepatic artery, each individual electrode having an arc
length of 20 degrees, with an inter-electrode spacing of 10
degrees. In one embodiment, the arc length and electrode spacing
are configured to deliver thermal energy to a region within 1-3 mm
of a hepatic artery lumen. The edges of the two electrodes may have
radii sufficient to reduce current concentrations. In some
embodiments, the two electrodes are coated with a thin layer of
non-conductive material to reduce current concentrations such that
energy is delivered to target tissue via capacitive coupling. The
arc length and spacing of the bipolar electrodes may be varied to
alter the shape of the energy delivery zones and thermal lesions
created by the delivery of energy from the electrodes.
[0246] In some embodiments, peripheral active or grounding
conductors are used to shape an electric field. In one embodiment,
a grounding needle is positioned perivascularly to direct ablative
current towards nerves within the perivascular space. In a
non-invasive embodiment to accomplish the same effect, high ion
content material is infused into the portal vein. In another
embodiment, a shaping electrode is positioned within the portal
vein using percutaneous techniques such as employed in transjugular
intrahepatic portosystemic (TIPS) techniques. In one embodiment, a
second shaping electrode is positioned in the biliary tree
endoscopically.
[0247] In some embodiments, a plurality of electrodes are spaced
apart longitudinally with respect to a center axis of the ablation
catheter (e.g., along the length of the ablation catheter). In some
embodiments, a plurality of electrodes are spaced apart radially
around a circumference of the distal end of the ablation catheter.
In some embodiments, a plurality of electrodes are spaced apart
both longitudinally along a longitudinal axis of the ablation
catheter and radially around a circumference of the ablation
catheter from each other. In various embodiments, the electrodes
are positioned in various other patterns (e.g., spiral patterns,
checkered patterns, zig-zag patterns, linear patterns, randomized
patterns).
[0248] One or more electrodes can be positioned so as to be in
contact with the inner walls (e.g., intima) of the blood vessel
(e.g., common hepatic artery or proper hepatic artery) at one or
more target ablation sites adjacent the autonomic nerves to be
disrupted or modulated, thereby providing intravascular energy
delivery. In some embodiments, the electrodes are coupled to
expandable and collapsible structures (e.g., self-expandable or
mechanically expandable) to facilitate contact with an inner vessel
wall. The expandable structures can comprise coils, springs,
prongs, tines, scaffolds, wires, stents, balloons, cages, baskets
and/or the like. The expandable electrodes can be deployed from the
distal end of the catheter or from the external circumferential
surface of the catheter. The catheter can also include insulation
layers adjacent to the electrodes or active cooling elements. In
some embodiments, cooling elements are not required. In some
embodiments, the electrodes can be needle electrodes configured to
penetrate through a wall of a blood vessel (e.g., a hepatic artery)
to deliver energy extravascularly to disrupt sympathetic nerve
fibers (e.g., the hepatic plexus). For example, the catheter can
employ an intra-to-extravascular approach using expandable needle
electrodes having piercing elements. The electrodes can be
disposable or reusable.
[0249] In some embodiments, the catheter includes electrodes having
a surface area of about 2 to about 5 mm.sup.2, 5 to about 20
mm.sup.2, about 7.5 to about 17.5 mm.sup.2, about 10 to about 15
mm.sup.2, overlapping ranges thereof, less than about 5 mm.sup.2,
greater than about 20 mm.sup.2, 4 mm.sup.2, or about 12.5 mm.sup.2.
In some embodiments, the catheter relies only on direct blood
cooling. In some embodiments, the surface area of the electrodes is
a function of the cooling available to reduce thrombus formation
and endothelial wall damage. In some embodiments, lower temperature
cooling is provided. In some embodiments, higher surface areas are
used, thereby increasing the amount of energy delivered to the
perivascular space, including surface areas of about 5 to about 120
mm.sup.2, about 40 to about 110 mm.sup.2, about 50 to about 100
mm.sup.2, about 60 to about 90 mm.sup.2, about 70 to about 80
mm.sup.2, overlapping ranges thereof, less than 5 mm.sup.2, or
greater than 120 mm.sup.2. In some embodiments, the electrodes
comprise stainless steel, copper, platinum, gold, nickel,
nickel-plated steel, magnesium, or any other suitably conductive
material. In some embodiments, positive temperature coefficient
(PTC) composite polymers having an inverse and highly non-linear
relationship between conductivity and temperature are used. In some
embodiments, PTC electrodes (such as the PTC electrodes described
in U.S. Pat. No. 7,327,951, which is hereby incorporated herein by
reference) are used to control the temperature of RF energy
delivered to the target tissue. For example, PTC electrodes may
provide high conductivity at temperatures below 60.degree. C. and
substantially lower conductivity at temperatures above 60.degree.
C., thereby limiting the effect of energy delivery to tissue above
60.degree. C.
[0250] a. Hydrogel-Coated Electrode Catheters
[0251] FIG. 8 illustrates a self-repairing ablation catheter 800.
The self-repairing ablation catheter 800 comprises a catheter body
805, a needle electrode 810, and a vascular wall plug 815. In one
embodiment, the needle electrode 810 is placed at or near the
distal end of the catheter body 805 and used to heat tissue (which
may result in nerve ablation). The vascular wall plug 815 may be
placed around the needle electrode 810 such that when the needle
electrode 810 is pushed into or through the vascular wall, the
vascular wall plug 815 is pushed into or through the vascular wall
as well. Upon retracting the self-repairing ablation catheter 800,
the needle electrode 810 fully retracts in some embodiments,
leaving the vascular wall plug 815 behind, and thereby plugging or
occluding the hole left by the needle electrode 810.
[0252] In embodiments used to modulate (e.g., ablate)
extravascularly, the vascular wall plug 815 may comprise a hydrogel
jacket or coating disposed on the needle electrode 810. In some
embodiments, the vascular wall plug 815 is glued or otherwise
adhered or fixed in a frangible manner at its distal end to the
needle electrode 810, yet may be sufficiently thin so it does not
prevent or inhibit smooth passage of the needle electrode 810 as it
is advanced into the perivascular space. In some embodiments, once
the proximal end of the vascular wall plug 815 passes out of the
guiding lumen, it cannot be pulled proximally. Therefore, upon
ablation completion, removal of the needle electrode 810 from the
perivascular space places the hydrogel jacket in compression in the
hole made by the needle electrode 810 in the vessel wall, thereby
forming a plug which prevents or reduces the likelihood of vessel
leakage or rupture. In some embodiments, the vascular wall plug 815
is made of a hydrogel that swells when exposed to tissues, such as
polyvinyl alcohol, or a thrombogenic material, such as those
employed during interventional radiology procedures to coil off
non-target vessels.
[0253] FIG. 9 illustrates an embodiment of a hydrogel-coated
electrode catheter 900. The hydrogel-coated electrode catheter 900
includes a catheter body 905, an ablation electrode 910, and a
hydrogel coating 915. In one embodiment, the ablation electrode 910
is attached to the distal end of the catheter body 905 and the
hydrogel coating 915 coats the electrode 910.
[0254] In some embodiments, the hydrogel coating 915 is a
previously-desiccated hydrogel. Upon insertion into the target
anatomy, the hydrogel coating 915 on the ablation electrode 910 may
absorb water from the surrounding tissues and blood. Ions drawn in
from the blood (or included a priori in the hydrogel coating 915)
may impart conductive properties to the hydrogel coating 915,
thereby permitting delivery of energy to tissue. In accordance with
several embodiments, the hydrogel-coated electrode catheter 900
requires less cooling during ablation, as the hydrogel coating
resists desiccation. A smaller catheter size may also be used, as
construction requirements and number of components may be reduced.
In some embodiments, the electrode impedance replicates native
tissue impedance for better impedance matching. In some
embodiments, temperature measurements at the surface of the
hydrogel-coated electrode are possible.
[0255] b. Balloon Catheters
[0256] Energy delivery catheters may comprise balloon catheters
configured to modulate nerves or other tissue. In some embodiments,
a balloon catheter comprises a catheter body and a distal balloon.
The catheter body comprises a lumen configured to continuously
infuse saline or other fluid into the balloon. The distal balloon
comprises one or more hydrogel portions spaced around the
circumference of the distal balloon. In one embodiment, if saline
is used, any water that vaporizes from the surface of the distal
balloon is replenished by diffusion from the balloon lumen, thereby
preventing or inhibiting free saline to travel into the vessel
interface and reducing any undesired effects of saline
infusion.
[0257] In accordance with several embodiments, the branches of the
forks between the common hepatic artery, the proper hepatic artery
and the gastroduodenal artery are advantageously simultaneously or
sequentially targeted (e.g., with RF energy) because sympathetic
nerves supplying the liver and pancreas are generally tightly
adhered to or within the walls of these arteries. Forks between
other arteries or vessels may similarly be simultaneously or
sequentially be targeted (e.g., with RF energy). In some
embodiments, coiled electrodes opposing the artery walls are
used.
[0258] FIG. 10A illustrates an embodiment of a single ablation coil
1000 device. The single ablation coil device 1000 may be inserted
into target vasculature and activated to ablate the nerves within
or surrounding the vasculature. To ablate a vascular fork, it may
be necessary to insert the single ablation coil 1000 into one
branch of the fork (e.g., proper hepatic artery branch) and ablate
that branch, then insert the single ablation coil 1000 into the
other branch of the fork (e.g., gastroduodenal artery branch or
left or right hepatic artery branch) and ablate that branch.
[0259] FIG. 10B illustrates a forked ablation coil device 1050. The
forked ablation coil device 1050 comprises two ablation coils, a
first ablation coil 1055 and a second ablation coil 1060. In
accordance with several embodiments, the forked ablation coil
device 1050 allows an entire vascular fork to be ablated
simultaneously. In operation, the forked ablation coil device 1050
may be inserted to the target vasculature by overlapping the first
ablation coil 1055 and the second ablation coil 1060 (effectively
creating a single double helix coil). Once the target fork is
reached, the first ablation coil 1055 and the second ablation coil
1060 may be separated and the first ablation coil 1055 inserted
into a first branch of the target fork and the second ablation coil
1060 inserted into a second branch of the target fork. The branches
of the target vessel fork (and the nerves within or surrounding the
vessels of the fork branches) may then be simultaneously
ablated.
[0260] In some embodiments, the coiled electrodes (e.g., ablation
coil device 1000 or forked ablation coil device 1050) are created
out of a memory material, such as nitinol or any other shape memory
material. In some embodiments, energy may be delivered by the one
or more coiled electrodes in a manner so as not to cause nerve
ablation (temporary or permanent). In some embodiments, the thermal
dose delivered may modulate nerves without causing ablation. The
ablation coils may be delivered by one or more catheters. The
ablation coils may be coupled to a catheter such that the ablation
coils may be removed or repositioned following ablation of a target
location. Balloon electrodes or other ablation elements may be used
instead of ablation coils. In some embodiments, a single balloon
with multiple electrodes may be used instead of the coiled
electrodes. A portion of the balloon with an electrode may be
positioned in each of the branches. In other embodiments, each of
the branches may be occluded with an occlusion member and fluid may
be infused to create a wet electrode effect for ablation.
[0261] In some embodiments, energy is delivered between two
ablation elements positioned to span a vessel bifurcation in a
bipolar manner, thereby concentrating delivery of energy and
denervation between the ablation elements in a bifurcation region
where a higher density of nerve fibers may exist.
[0262] FIGS. 11A-11C illustrate embodiments of balloon ablation
catheters. FIG. 11A illustrates an embodiment of a single balloon
ablation catheter 1100, FIG. 11B illustrates an embodiment of a
forked double balloon ablation catheter 1125, and FIG. 11C
illustrates an embodiment of a forked balloon ablation catheter
1175. In various embodiments, a balloon ablation catheter comprises
a bipolar balloon catheter.
[0263] The single balloon ablation catheter 1100 of FIG. 11A
comprises an electrode balloon 1105 having at least one electrode
1110 (e.g., one electrode, two electrodes, three electrodes, four
electrodes, five to ten electrodes, ten to twenty electrodes, or
more than twenty electrodes). The electrode patterns and
configurations shown in FIGS. 11A-110 illustrate various
embodiments of electrode patterns and configurations; however,
other patterns and configurations may be used as desired or
required. In some embodiments, a high dielectric constant material
may be used in the place of at least one electrode. The single
balloon ablation catheter 1100 may be inserted into target
vasculature and then inflated and used to ablate the vasculature
(and thereby ablate the nerves within or surrounding the vessel,
such as within the perivascular space). To ablate a vascular fork,
it may be necessary to insert the single balloon ablation catheter
1100 into one branch of the fork and ablate that branch, then
retract the single balloon ablation catheter 1100 from that branch
and insert the single balloon ablation catheter 1100 into the other
branch of the fork and ablate that branch.
[0264] The forked two balloon ablation catheter 1125 of FIG. 11B
includes a first electrode balloon 1130 and a second electrode
balloon 1135. The first electrode balloon 1130 includes at least a
first electrode 1140, and the second electrode balloon 1135
includes at least a second electrode 1145. In several embodiments,
the forked two balloon ablation catheter 1125 allows an entire
vascular fork (e.g., all branches) to be ablated simultaneously. In
operation, the forked two balloon ablation catheter 1125 is
inserted into the vasculature and advanced to the target fork. Once
the target fork is reached, the left electrode balloon 1130 and the
right electrode balloon 1135 may be inflated and the left electrode
balloon 1130 inserted into the left branch of the target fork and
the right electrode balloon 1135 inserted into the right branch of
the target fork (or vice versa). The target fork may then be
simultaneously ablated. As discussed above, the first balloon and
the second balloon can comprise a plurality of electrodes, or in
some embodiments, at least one of the electrodes is replaced with a
high dielectric constant material. The one or more electrodes may
be individually connected to a generator via one or more leads or
thermocouple wires. By selectively and/or sequentially activating
one or more electrode pair simultaneously, energy delivery to the
surrounding tissue can be uniquely directed toward target anatomy
with respect to balloon position. For example, referring now to
FIG. 11C, energy could be directed between electrode 1190A and
electrode 1190B in order to create a focused lesion within the
vessel wall, or between electrode 1190C and 1190D to focus energy
delivery at the vessel bifurcation.
[0265] The forked balloon ablation catheter 1175 of FIG. 11C
includes a single balloon which has a left fork 1180 and a right
fork 1185 with at least one balloon electrode 1190. In some
embodiments, the forked balloon ablation catheter 1175 comprises at
least one balloon electrode for each balloon fork. The electrodes
can be spaced and distributed along the balloon to facilitate
positioning of at least one balloon electrode in each branch of the
target fork. The forked balloon ablation catheter 1175 operates in
the same manner as the forked double balloon ablation catheter
1125; however, it may advantageously allow for more effective
ablation of the crotch of the vascular fork. In some embodiments,
the balloon of the forked balloon ablation catheter 1175 is
substantially the shape of the target fork or is configured to
conform to the shape of the target fork. In some embodiments, the
forked balloon ablation catheter 1175 is configured to be used in
vessels having forks with three or more branches (such as the fork
between the common hepatic artery, proper hepatic artery and the
gastroduodenal artery). In some embodiments, each of the branches
of the vessel fork may be occluded with an occlusion member and
fluid may be infused to form a wet electrode for ablation. In
various embodiments, the bifurcation devices described herein are
used to modulate nerves at the bifurcation of the common hepatic
artery and the gastroduodenal artery or the bifurcation of the
proper hepatic artery into the right and left hepatic arteries.
[0266] An electrode balloon may be used to ablate (or otherwise
modulate) target vasculature. In some embodiments, the electrode
balloon is inserted via a catheter and inflated such that the
balloon is in contact with substantially all of the fork intimal
walls. In some embodiments, the electrode balloon is substantially
oval. A two-step approach may be used to ablate the entire surface
of the fork: first, the balloon can be put in place in one branch
of the fork (e.g., the proper hepatic artery branch), inflated, and
then used to ablate; second, the balloon can be retracted and then
advanced into the other fork (e.g., the gastroduodenal artery
branch or right or left hepatic artery branch), inflated, and then
used to ablate. In some embodiments, the electrode balloon
comprises ablation electrodes on an external surface in sufficient
density that simultaneous ablation of the entire intimal wall in
contact with the electrode balloon is possible. In some
embodiments, the ablation electrodes on the surface of the
electrode balloon are arranged in a predetermined pattern. In some
embodiments, the ablation electrodes on the surface of the
electrode balloon are activated simultaneously. In some
embodiments, the ablation electrodes on the surface of the
electrode balloon are individually addressable (e.g., actuatable),
thereby allowing selective areas to be ablated as desired. In some
embodiments, at least one electrode on the electrode balloon is an
ablation electrode and at least one electrode on the electrode
balloon is a sensing electrode (used, for example, to sense
impedance, temperature, etc.).
[0267] In some embodiments, the electrode balloon comprises a
proximal electrode and a distal electrode configured to be
individually actuatable and configured to be used in a stimulation
mode, ablation mode, and/or sensing mode. The proximal electrode
and distal electrode may be positioned in two different branches
(e.g., the proximal electrode in the proper hepatic artery and the
distal electrode in the gastroduodenal artery). The electrode
balloon may be deployed from a guide catheter positioned in the
common hepatic artery. In one embodiment, the proximal electrode is
stimulated and the distal electrode is sensed and if the correct
territory is identified (e.g., nerve fibers emanating to the proper
hepatic artery but not the gastroduodenal artery), then the
proximal electrode may be activated for ablation. The electrode
balloon may be used to map and selectively ablate or otherwise
treat various vessel portions.
[0268] In some embodiments, a round electrode balloon may be used
to selectively ablate only a select area. In some embodiments, the
round electrode balloon has approximately the same electrode
properties as described above, including electrode density, and the
presence of at least one ablation electrode. In some embodiments,
the round electrode balloon comprises at least one sensor electrode
or temperature-measurement device (e.g., thermocouple).
[0269] In some embodiments, a dielectric ablating balloon is used.
The dielectric ablating balloon may have the same shape
characteristics as do the other electrode balloon embodiments
described herein. In some embodiments, the dielectric ablating
balloon comprises at least one piece of a high conductivity
material on its outer surface. In some embodiments, use of the
dielectric ablating balloon comprises advancing the dielectric
ablating balloon into position in the target vessel through methods
described herein and inflating the dielectric ablating balloon so
that its outer surface is proximate to the intimal walls of the
target vessel. In some embodiments, a microwave generator is then
placed near the surface of the body of the subject and microwaves
are directed from the microwave generator toward the dielectric
ablating balloon within the subject such that the microwaves
interact with the at least one piece of a high conductivity
material to create heat in a manner such that the heat created
thermally ablates the region (e.g., vessel wall surface) proximate
to the at least one high conductivity material. In some
embodiments, the dielectric ablating balloon comprises a plurality
of (e.g., two, three, four or more than four) pieces or portions of
high conductivity material on its outer surface.
[0270] FIG. 12A illustrates a schematic representation of an
embodiment of a radiofrequency energy delivery device 1200
comprising a balloon 1205. The balloon 1205 is adapted to be
partially or substantially occlusive and comprises multiple
electrodes 1210 positioned at one or more locations along the outer
surface of the balloon 1205. The balloon 1205 may be sized to cover
the entire length of the vessel (e.g., common hepatic artery) to be
treated (e.g., ablated or denervated) or may be shorter in order to
treat a portion of the vessel. In one embodiment, the balloon 1205
is 5 mm in diameter by 20 mm long; however other balloons may range
from 3 mm to 8 mm (e.g., 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5.5 mm,
6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm) in diameter and from 10 mm to 40
mm (e.g., from 10 mm to 20 mm, from 15 mm to 25 mm, from 20 mm to
30 mm, from 25 mm to 35 mm, from 30 mm to 40 mm) in length as
desired or required based on vessel length. The electrode area may
range from 1 mm.sup.2 to 6 mm.sup.2 (e.g., from 1 mm.sup.2 to 3
mm.sup.2, from 2 mm.sup.2 to 4 mm.sup.2, from 3 mm.sup.2 to 6
mm.sup.2). The electrodes 1210 may be comprised of a single
electrode element or member or may be comprised of one or more
arrays of a plurality of separate electrode elements (e.g.,
clusters or groups of four electrodes). For example, at least one
array of electrode elements may be proximate an area of tissue in
thermal communication such that RF power delivered via the
electrodes 1210 acts to heat a substantially continuous volume of
tissue. The electrodes 1210 may be from 0.5 mm to 3 mm in diameter
(e.g., from 0.5 mm to 1 mm, from 1 mm to 1.5 mm, from 1.5 mm to 2
mm, from 2 mm to 2.5 mm, from 2.5 mm to 3 mm, overlapping ranges
thereof, or any value of or within the recited ranges). The at
least one array of electrodes may be linear, zig zag, curved,
rectangular, polygonal, or circular. Other shapes and patterns may
also be used as desired or required. The size of the electrode
array may be from 0.1 mm to 3 mm (e.g., from 0.1 mm to 0.5 mm, from
0.3 mm to 1 mm, from 0.5 mm to 1.5 mm, from 0.8 mm to 2 mm, from 1
mm to 3 mm, from 1.5 mm to 3 mm, overlapping ranges thereof, or any
value of or within the recited ranges) in its narrowest aspect and
from 1 mm to 5 mm (from 1 mm to 3 mm, from 2 mm to 4 mm, from 3 mm
to 5 mm, overlapping ranges thereof, or any value of or within the
recited ranges) in its longer aspect. In some embodiments the
electrode array may be from 10 mm to 20 mm in its longest aspect.
The individual electrodes 1210 comprising the array may be from 0.1
mm to 2 mm (e.g., from 0.1 mm to 0.5 mm, from 0.3 mm to 1 mm, from
0.5 mm to 1.5 mm, from 0.8 mm to 2 mm, overlapping ranges thereof,
or any value of or within the recited ranges) in their narrowest
aspect and from 0.5 mm to 5 mm (e.g., from 0.5 mm to 2.5 mm, from 2
mm to 4 mm, from 3 mm to 5 mm, overlapping ranges thereof, or any
value of or within the recited ranges) in their longest aspect. In
some embodiments the longest aspect of the electrode elements may
be from 5 mm to 20 mm. In some embodiments, 0.5 W-3 W (e.g., 0.5 W,
1 W, 1.5 W, 2 W, 2.5 W, 3 W) of RF power may be delivered though
the electrode or electrodes.
[0271] In various embodiments, electrodes or arrays may be affixed
to the balloon 1205 along with one or more connecting wires 1215.
Two embodiments of electrode arrays with connecting wires are
illustrated in FIGS. 12B and 12C. In accordance with various
embodiments, the connecting wires 1215 supply RF current to the
electrode(s) 1210. In some embodiments, the connecting wires 1215
carry a signal for measuring the temperature. In some embodiments,
the connecting wires 1215 carry both RF current for ablation or
other treatment and signals to measure temperature. In some
embodiments, the connecting wires 1215 form a thermocouple (e.g.
bifilar thermocouple). The balloon 1205 may consist of two, three,
four, five, six or more than six electrode arrays. Each array may
consist of two, three, four, five, six, seven, eight or more than
eight electrodes.
[0272] In some embodiments, the electrodes 1210 together with their
one or more connecting wires 1215 are affixed to the balloon with
adhesives such as epoxy, cyanoacrylate, silicone, acrylic,
polyamide, polyurethane, pressure sensitive adhesive, and hot melt
adhesives. In one embodiment, the entire balloon and electrode
assembly, except for active electrode areas, may be encapsulated in
a coating. In another embodiment, the coating covers only portions
of the balloon and electrode assembly. FIG. 12B illustrates an
embodiment of an electrode array 1202 comprising an adhesive body
1220 that is adapted to be adhered to the balloon 1205. In other
embodiments, the electrodes may be attached directly to the balloon
1205. FIG. 12C illustrates an electrode array having a zig-zag
arrangement with the connecting wires 1215 coupled between each
individual electrode. The zig-zag arrangement may advantageously
reduce the spacing between the electrodes and reduce the overall
size or array occupied by the electrode array while maintaining a
generally spiral pattern. In some embodiments, the electrodes of
the electrode array are affixed to a flexible substrate. In some
embodiments, the electrodes, connecting wires and flexible
substrate together comprise a flex circuit. FIG. 12D illustrates an
embodiment of a balloon catheter 1200 having a plurality of
electrode arrays 1202 comprising electrodes 1210 and connecting
wires 1215 arranged in a spiral pattern around the outer surface of
the balloon 1205. The connecting wires 1215 may be coupled to a
source of RF power or energy (such as a generator). Each electrode
array or group of electrodes may have separate connecting wires
such that each electrode array or group is individually
controllable by an RF power source.
[0273] In accordance with several embodiments, a balloon of a
balloon electrode catheter includes at least one group of
diagonally or circumferentially oriented electrodes formed of a
plurality of electrode elements connected in parallel, where the
size of the electrode group in its longest aspect is less than or
equal to a characteristic length of thermal conduction or diffusion
in tissue. Larger lesions require more power, therefore greater
electrode surface area is required to keep current density within
acceptable levels (for example, >3 mm.sup.2). However, large
electrodes (for example, >1.5 mm in a largest aspect) degrade
flexibility, trackability and foldability of balloons.
Circumferential or diagonal orientation of electrodes may further
interfere with balloon folding; however, the electrodes may be
positioned so as to be arranged around folds. In accordance with
several embodiments, closely-spaced electrode arrays as illustrated
and described in connection with FIGS. 12A-12C create locally
inhomogeneous current density near the electrodes (e.g., near
field) and current density evens out at farther distances from the
electrode (e.g., far field). In addition, thermal conduction within
the tissue tends to even out temperature within the near field.
When electrodes are closely spaced and the length of the electrode
is not too long, current density distribution over the electrode
surface is predictable and a single temperature measurement can
represent the temperature of the entire electrode. For example,
temperature may still vary, but in a predictable fashion. In
accordance with several embodiments, "closely-spaced" means that
the total electrode area is in a region that is no more than 6 mm
in its longest aspect.
[0274] FIG. 12E illustrates an embodiment of a balloon 1205 of a
balloon catheter 1200 comprising four individual electrode members
offset by 180 degrees from each other and spaced apart
longitudinally along the surface of the balloon 1205 so as to
provide a desired ablation or treatment pattern designed to provide
increased perivascular treatment while reducing vessel wall injury
or damage. In some embodiments, the electrodes 1205 exhibit a
circumferential aspect ratio. In some embodiments, the array of
electrodes is oriented in a diagonal direction with respect to the
axis of the artery or other body lumen, thereby increasing the
circumferential extent of the lesion while avoiding interference
between the electrodes 1210 when the balloon 1205 is in a
collapsed, deflated configuration. Greater frequency and extent of
ablated tissue increases the degree of neuromodulation or other
tissue modulation (e.g., ablation, denervation). The degree of
circumferential orientation to the electrode of an electrode array
is reflected by the shape of the lesion created by the heating
generated by the electrode. Staggered, oblique lesions can
advantageously be packed tightly (for example, spaced apart by
between 2 mm and 8 mm, e.g., 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8
mm) along the vessel to increase the circumferential coverage of
the lesion without overlapping lesions.
[0275] The electrodes of the balloon catheters (e.g., balloon
catheters 1200) may be circular, rectangular or oblong. In some
embodiments, the electrodes may be disk shaped. In one embodiment,
the electrodes may be comprised of metals selected from a list
including, without limitation, gold, platinum, stainless steel,
layered composites of gold or platinum, gold or platinum plated
base metals such as copper, stainless steel, nickel. In some
embodiments, the connecting wires 1215 are continuous with the
electrode(s) 1210. In other embodiments, the connecting wires 1215
may be attached to the electrode(s) 1210 by means such as welding,
soldering, crimping, or swaging.
[0276] In some embodiments, the balloon material is of a low
compliance material selected from a list of materials comprising,
without limitation: PET, polyester, polyolefin, nylon, high
durometer polyurethane and polyether block amide. In some
embodiments, the balloon material is comprised of a compliant
material such as low durometer polyurethane, kraton, latex,
silicone, and/or thermoplastic elastomer.
[0277] In some embodiments, lower power and longer duration
ablations are used for ablation procedures involving occlusion
within the hepatic arteries than for ablation procedures in other
arteries, such as the renal arteries. Such treatment may be
uniquely possible because of the liver's dual source blood supply
(as described above). Balloon ablation of the hepatic vessels
(e.g., common hepatic artery) may employ full occlusion for a
substantial period of time, not previously possible or not
previously attempted in other locations for safety reasons (e.g.,
to avoid potential stroke due to ischemia). In some embodiments,
balloons may be inflated and used for ablation in the range of
about 1 to about 10 minutes, about 10 minutes to about 20 minutes,
about 20 minutes to about 60 minutes, about 15 minutes to about 45
minutes, about 10 minutes to about 40 minutes, about 15 minutes,
about 20 minutes, about 25 minutes, about 30 minutes, about 35
minutes, about 40 minutes, about 45 minutes, about 50 minutes,
about 55 minutes, about 60 minutes. Longer ablation times may have
several advantages in accordance with several embodiments. First,
longer exposure times mean that lower treatment temperatures may be
used because tissue and nerve death is a function of both
temperature and time. In some embodiments, temperatures are used in
the ranges of about 30.degree. C. to about 80.degree. C., about
40.degree. C. to about 70.degree. C., or about 50.degree. C. to
about 60.degree. C. In one embodiment, temperatures greater than
45.degree. C. and less than 60.degree. C. are used.
[0278] In some embodiments, the vessel (e.g., arterial) lumen is
simultaneously protected by infusing a low temperature coolant
through the balloon cavity (thereby keeping the intima cool) while
focusing RF energy and thermal heating at the level of the
adventitia or perivascular space (where the target nerves are
located). Second, balloon occlusion may facilitate improved contact
and contact pressure between the electrodes disposed on the outside
of the balloon and the arterial wall. Third, balloon occlusion may
compress the tissues of the vessel wall and thereby reduce the
distance from the electrode(s) to the target nerves, which improves
the efficiency of thermal energy delivery to the target nerves.
Fourth, less contrast/imaging agent may be required by using a
balloon catheter because an occluding device is reliably and
accurately positioned (and maintains that position once in place),
and serves as a reliable marker of device and therapy placement.
Additionally, when a balloon engages the vascular wall, heating of
the blood is avoided entirely (because energy is transferred
directly from the electrode(s) to the vessel wall without directly
contacting the blood), thereby reducing the risk of vapor bubble
formation or thrombosis (e.g., clot formation).
[0279] An embodiment of a balloon catheter is illustrated in FIGS.
13A and 13B. The balloon catheter may advantageously be configured
to provide flow to cool one or more electrodes without having or
without requiring the electrode(s) in contact with blood. In some
embodiments, the balloon is a c-shaped balloon as shown in FIGS.
13A and 13B, having an inflatable region 1302 about a substantial
portion of the balloon circumference and a small non-inflatable
region 1304 (e.g., "webbed region") comprising less than 1/18 (or
alternatively, less than 1/10, less than 1/12, less than 1/14, less
than 1/16, less than 1/20, less than 1/22, less than 1/24, less
than 1/25) of the total circumference of the balloon in order for
the balloon to maintain a substantially circular shape upon
inflation. A plurality of electrodes may be disposed along the
longitudinal axis of the balloon on the non-inflatable webbed
region, configured to deliver RF energy to the hepatic artery or
other target vessel or tissue. The c-shaped balloon of the design
illustrated in FIG. 13 defines a lumen upon inflation that may
permit the flow of blood therethrough. In one embodiment, a thin
membrane of the webbed region provides electrical isolation to
ensure that the applied RF energy is delivered substantially to the
target tissue (and hence to the nerves surrounding the hepatic
artery or other target vessel or tissue) and not lost to the blood.
In one embodiment, the balloon design illustrated in FIGS. 13A and
13B advantageously provides the ability for the blood to cool the
electrode by means of the limited thermal insulation offered by the
thin membrane of the webbed region, thereby increasing the
effective power that can be delivered to the target tissue.
[0280] FIG. 14 illustrates how the c-shaped balloon electrode
design of FIGS. 13A and 13B could be attached to an interventional
catheter. In one embodiment, the inflatable region 1402 of the
c-shaped balloon is in fluidic communication with an inflation
manifold 1403, which may be disposed proximally toward a shaft of
the interventional catheter. The inflation manifold 1403 can define
a lumen 1404 terminating in a flange 1406 configured for attachment
to the catheter. The flange 1406 of the inflation manifold 1403 may
be adhered to a side-exiting lumen disposed along a portion of or
substantially the entire length of the catheter using suitable
adhesion means (e.g., UV cured adhesives, RF welding, adhesives,
heat sealing), thereby permitting fluidic communication between the
catheter lumen and the inflatable region of the c-shaped balloon
1401. In order to structurally attach the c-shaped balloon 1401 to
the catheter, a plurality of struts may be provided. In one
embodiment, the struts are formed of a resilient material such as
nitinol and biased towards a position that would tend to expand the
balloon into a cylindrical shape. The struts may be joined to the
catheter and c-shaped balloon using any suitable means. In one
embodiment, the struts are overmolded into the catheter and glued
to the balloon 1401.
[0281] An exemplary method for fabricating the c-shaped balloon and
electrode is highlighted in FIGS. 15A-15C. The balloon may be
fabricated using two pieces of flat or substantially flat stock
material (e.g., polyurethane sheet of about 0.003'' in thickness).
The two layers may be bonded using suitable techniques in the
regions illustrated (e.g., RF welding, adhesives, heat sealing,
etc.), and then rolled and sealed into a cylinder to form the
non-inflatable webbed region. In one embodiment, the webbed region
1504 is formed using flexible electronics manufacturing techniques
(e.g., "Flextronics"), where the electrode is laminated between two
dielectric layers, such as polyimide. The Flextronics strip can
then be adhered to each edge of the thin film balloon structure to
form the cylindrical, c-shaped balloon.
[0282] FIGS. 16A and 16B illustrate an embodiment of a balloon
catheter 1600 configured to deliver RF energy. In one embodiment,
the catheter is comprised of a polymeric shaft 1605 having a lumen
1610 disposed along a portion or substantially the entire length in
communication at a proximal end portion with a pressure source
(e.g., capable of creating between 0-600 mmHg within a balloon at a
distal end of the catheter). In one embodiment, the lumen 1610
exits through a transverse surface of the shaft 1605 near the
distal tip of the shaft 1605. As shown, a balloon 1615 is disposed
about the lumen exit and a portion of the shaft. In various
embodiments, the balloon 1615 is disposed about a substantial
(e.g., greater than 30%, greater than 40%, greater than 50%,
greater than 60%, about 40%, about 50%, about 60%, about 70%, about
80%, or about 90%, of the circumference of the shaft 1605.
[0283] In one embodiment, the balloon 1615 is disposed about the
entire circumference of the shaft 1605 not covered by an electrode
or other energy delivery member. In one embodiment, the balloon
1615 is expandable to a diameter of 1 mm to 8 mm (e.g., 1 mm to 5
mm, 1 mm to 4 mm, 2 mm to 5 mm, 3 mm to 8 mm, 1 mm to 6 mm, 4 mm to
8 mm, or overlapping ranges thereof) and is disposed about a length
of 5 mm to 30 mm (e.g., 5 mm to 20 mm, 5 mm to 15 mm, 10 mm to 20
mm, 10 mm to 30 mm, 5 mm to 25 mm, 15 mm to 25 mm, 20 mm to 30 mm,
or overlapping ranges thereof) along a distal portion of the shaft
1605. In one embodiment, substantially opposite the balloon 1615 an
electrode (e.g., half-cylindrical electrode) or other energy
delivery member 1620 is bonded or otherwise affixed to the shaft
and in electrical communication with a wire (e.g., thermocouple
wire) through either the lumen or routed along an exterior surface
of the catheter 1600, which is connected to an RF generator and a
thermocouple (e.g., type T thermocouple) reading circuit to permit
the delivery of RF energy and assessment of electrode or tissue
temperature. In one embodiment, the electrode 1620 is positioned
within 1 cm of the distal tip of the catheter 1600. The electrode
1620 is advantageously flush or substantially flush with the
catheter surface, in one embodiment.
[0284] FIGS. 17A and 17B illustrate another arrangement of the
balloon catheter of FIGS. 13A and 13B. In one embodiment, an energy
delivery catheter 1700 includes a perfusion balloon 1705 enabling
occlusion of a vessel lumen and redirection of the blood flow
through a perfusion lumen 1710. The perfusion lumen 1710 provides a
constant diameter flow pathway which directs the blood flow over an
exposed electrode surface within the perfusion lumen 1710, thereby
allowing for a more predictable cooling effect. The catheter
embodiments described herein may be used in conjunction with an
over-the-wire, rapid exchange or steerable catheter approach.
[0285] At the distal end of the catheter 1700, an atraumatic,
flexible tip 1720 is incorporated on or adjacent to a distal
opening 1725 of the perfusion lumen 1710. In one embodiment,
proximal to the distal tip 1720 is a balloon attachment region
1730, where the perfusion balloon 1705 is attached to the perfusion
lumen 1710. The balloon attachment region 1730 may advantageously
be optimized to provide a smooth flexibility transition. In various
embodiments, the perfusion balloon 1705 is attached by adhesive or
thermal joining or bonding methods and materials. The balloon
attachment region 1730 may encompass the full or partial
circumference of the perfusion lumen 1710 and/or guide wire lumen.
The balloon material may be a compliant or non-compliant type. The
balloon 1705 can be made of a single material or incorporate layers
of different materials or grades of the same material. Similarly,
the balloon 1705 can be formed of a polymer blend.
[0286] The shape of the balloon 1705 may be tapered or
non-concentric. Cross sectional shapes may range from round to
crescent shaped. In accordance with several embodiments, the
balloon 1705 is formed and attached to the perfusion lumen 1710
such that it occludes the natural vessel lumen and maintains
electrode contact with the vessel wall. The balloon diameter in the
expanded state can range from about 2 mm to about 10 mm, (e.g.,
from 2 mm to 8 mm, from 3 mm to 6 mm, from 4 mm to 10 mm, and
overlapping ranges thereof).
[0287] In some embodiments, at least one electrode 1715 resides
within the length of the perfusion lumen 1710. The electrode 1715
may be placed or positioned such that the exterior side of the
electrode 1715 is able to contact the vessel wall and the internal
side (e.g., the side exposed within the perfusion lumen 1710) is
flush or within the lumen formed by the internal diameter of the
perfusion lumen 1710. The one or more electrodes 1715 are connected
via conductive wires to an external energy source, such as an RF
generator. The electrodes 1715 may be individually controlled or
jointly controlled to deliver energy independently or
simultaneously at the same or different levels.
[0288] Proximal to the electrode location is a second balloon
attachment point or region 1735. Materials and joining methods may
advantageously be selected to optimize the flexibility transition.
Cross-sectionally at the attachment point or region 1735, the
balloon 1705, the perfusion lumen 1710, an inflation lumen, a guide
wire lumen, and/or conductive wires are contained. Proximal to the
second balloon attachment point or region 1735 is a perfusion lumen
exit or opening (not shown). The length of the perfusion lumen 1710
can range from about 5 mm to about 80 mm (e.g., 5 mm to 40 mm, 10
mm to 50 mm, 20 mm to 60 mm, 30 mm to 80 mm, 5 mm to 20 mm, or
overlapping ranges thereof). The balloon length may generally be
shorter than the length of the perfusion lumen 1710. The perfusion
lumen 1710 may be insulated from the electrode 1715 by an
insulation layer to avoid direct contact of the electrode 1715 with
the blood, as described in connection with FIGS. 90A and 90B.
[0289] Proximal or corresponding with the perfusion lumen proximal
opening the catheter construction may be optimized for flexibility,
torque and push force capability while maintaining a lumen or
lumens for balloon inflation, guide wire containment, and/or
conductive wire pathways.
[0290] In some embodiments, a handle or manifold (not shown) is
located proximally on the shaft that enables conductive wire
connections to the energy source (e.g., RF generator), attachment
to a balloon inflation device, and/or access to a guide wire lumen
and/or a mechanism to deflect the distal steerable segment.
[0291] In a rapid exchange embodiment, a guide wire port may be
located 10 to 20 cm proximal of the distal tip. In one embodiment,
the guide wire port is constructed to maintain a flexibility
transition that is kink resistant while efficiently transferring
push force to the distal assembly. Proximal to the guide wire port,
the shaft maybe be constructed of a hypotube that is sheathed in
polymer and includes an inflation lumen and protects the conductive
wires.
[0292] In some embodiments, the shaft proximal to the proximal
perfusion lumen opening comprises an inflation lumen, a lumen
containing the shielded conductive wires, a guide wire lumen, a
pull wire, and/or a polymer that encapsulates or sheaths the
aforementioned lumens. The polymer encasement or sheath may be an
extruded or deposition formed tube or a thermoplastic that has been
reflowed to reduce profile. In some embodiments, the catheter is
steerable and contains a pull wire assembly that can deflect the
distal assembly, as described elsewhere in the disclosure.
[0293] Balloon ablation catheter systems may be advantageous for
denervating nerves surrounding (e.g., within a wall of, such as
within the intima, media or adventitia of) the hepatic artery
branches in that the hepatic artery branches (e.g., common hepatic
artery) can be occluded by one or more balloons and then coolant
can be circulated in the region of the ablation (e.g., through a
lumen of a balloon). In various embodiments, balloon ablation
catheters advantageously facilitate both higher power net energy
through larger electrode surface area (enabled, for example, by
large electrode sizes that can be included on a balloon) and
increased deposition time (which may be permitted by the ability to
occlude flow to the hepatic artery for longer periods of time). In
some embodiments, the risk of damage to the endothelial wall is
mitigated by the flow of coolant even with an increase in energy
density through higher power. Accordingly, higher power energy
delivery (e.g., about 40 to 50% higher power) may be used than
denervation systems used for denervation of other vessels or organs
without risk of damage to the endothelial region of the hepatic
artery due to maintained less than hyperthermic temperatures up to
1 mm from the lumen of the hepatic artery.
[0294] In some embodiments, an actively-cooled balloon catheter is
used to ablate target vasculature. A pump sufficient to deliver
high flow coolant to the cooling element may be used to facilitate
the active cooling. In several embodiments, the range of drive
pressures to deliver an appropriate flow rate (e.g., between about
100 and 500 mL/min) of coolant into a 4 to 6 Fr balloon catheter to
maintain an appropriate temperature is between about 25 and about
150 psi. The flow rate may be adjusted on the basis of the actual
temperature inside the balloon. In some embodiments, the desired
coolant temperature in the balloon is between about 5.degree. C.
and about 10.degree. C. In some embodiments,
temperature-measurement devices (e.g., thermocouples) are included
inside the balloon to constantly monitor the coolant temperature.
The pump output may be increased or decreased based on the
difference between the desired temperature and the actual
temperature of the coolant.
[0295] FIG. 18 illustrates an embodiment of an actively-cooled
balloon catheter 1800. The balloon catheter comprises a main shaft
1802 having a lumen, a balloon 1805 coupled to a distal end of the
main shaft 1802 and in fluid communication with the lumen, a
plurality of electrodes 1810 disposed around the circumference of
the balloon 1805, electrode leads 1812 coupled to the electrodes
1810 and extending to a proximal end of the main shaft 1802, and an
outlet tube 1815. Nonconductive coolant solution may be pumped into
an inlet of the balloon 1805 by a pump (not shown) and the
nonconductive coolant solution may exit the balloon 1805 through
the outlet tube 1815. The main shaft 1802 may comprise an
insulating sheath or cover 1820 to prevent or inhibit heat
transfer. The nonconductive coolant solution may advantageously
provide cooling to the electrodes 1810 on the balloon 1805, while
also shielding adjacent tissues from RF energy.
[0296] FIGS. 19A-19C illustrate a distal end portion of another
embodiment of a balloon catheter 1900 configured to provide cooling
to an electrode 1910 of the balloon catheter 1900. In the
illustrated embodiment, the balloon catheter 1900 is a tube
comprising a balloon 1912 that expands when infused with coolant,
pulling taut an internal diaphragm 1915 which directs the flow 1914
(illustrated by arrows) of the coolant from at least one inlet to
at least one outlet. A circular surface centered on the electrode
1910 may comprise a heat conducting surface 1920, while the rest of
the catheter 1900 may comprise a heat-insulating material
configured to prevent or inhibit warming of the coolant 1914 while
traveling to a target ablation area. When the cooling balloon 1912
is infused with coolant, the balloon 1912 expands, thereby pressing
the electrode 1910 and the cooling balloon 1912 against the vessel
wall. In one embodiment, the coolant cools the vessel wall at the
target ablation area, thereby preventing against or reducing the
likelihood of excessive vessel wall damage.
[0297] In some embodiments, the neuromodulation catheter (e.g.,
ablation catheter) designs described herein advantageously provide
effective modulation of nerves innervating branches of the hepatic
artery or other vessel without causing, or at least minimizing
endothelial damage, if desired. For example, the catheters
described herein can occlude the hepatic artery (e.g., using a
balloon) and then circulate coolant in the region of the ablation
(e.g., within the lumen of the balloon). In some embodiments, the
catheters provide the unique advantage of both higher power net
energy offered through larger electrode surface area (which may be
enabled by the larger electrode sizes that can be manufactured on a
balloon) and increased deposition time (which may be permitted by
the ability to occlude flow to the hepatic artery for longer
periods of time). In accordance with several embodiments, the
increase in energy density through higher power mitigates the risk
of damage to the endothelial wall by the flow of coolant within the
balloon.
[0298] FIG. 20 is an embodiment of a balloon-based volume ablation
system 2000, which can be used, for example, in the celiac, common
hepatic, and proper hepatic arteries. In the illustrated
embodiment, the balloon-based volume ablation system 2000 comprises
a plurality of occlusive balloons 2025, a plurality of balloon
guide wires 2030, a catheter 2050, and an electrode 2040. FIG. 20
also illustrates the abdominal aorta 2005, the celiac artery 2006,
the common hepatic artery 2007, the splenic artery 2008, the proper
hepatic artery 2009, the right hepatic artery 2010, and the left
hepatic artery 2011 as an example of a target treatment site. In
operation, the balloon-based volume ablation system 2000 may be
inserted to the target treatment site through the abdominal aorta
2005 and into the celiac artery 2006. Individual occlusive balloons
2025 may then be advanced into subsequent vessels, such as the
splenic artery 2008, the right hepatic artery 2010 and the left
hepatic artery 2011. When the appropriate occlusive balloons 2025
have been placed such that they define the desired volume of
vasculature to be ablated, the occlusive balloons 2025 may be
inflated, thereby occluding the vessels in which they have been
placed. In one embodiment, the target volume is then filled with
saline and the electrode 2040 is activated to deliver electrical
energy to heat the entire target volume simultaneously. The
electrode 2040 may be configured to deliver sufficient energy to
the target volume to ablate all or at least a portion of the nerves
of the vessels within the target treatment site. Upon completion,
the occlusive balloons 2025 may be deflated and the entire
balloon-based volume ablation system 2000 may be retracted.
[0299] In some embodiments, it may be advantageous to
simultaneously ablate a region of nerves innervating a portion of
all, or a subset of all, arteries arising from the celiac artery
(such as the left gastric artery, the splenic artery, the right
gastric artery, the gastroduodenal artery, and the hepatic artery).
In some embodiments, ablation is achieved by using balloon
catheters or other occlusion members deployed from a guide catheter
within the celiac artery or abdominal aorta to block off or occlude
portions of vessels not to be ablated (the target volume may be
adjusted by inflating balloons or placing occlusion members
upstream and downstream of the desired volume, thereby creating a
discrete volume), filling the target volume with saline solution
through a guide catheter, and applying RF or other energy to the
saline to thereby ablate the tissues surrounding the target volume
in a manner that maintains vessel patency with hydraulic pressure
while also providing for direct cooling of the endothelial surfaces
of the vessels through circulation of chilled saline. In some
embodiments, the described "saline electrode" system is used to
pressurize the target arteries with saline. The contact pressure of
the saline electrode system against the arterial walls can be
assessed by measurement of the arterial diameter on angiography and
utilizing the pre-defined relationship between arterial diameter
and fluid pressure or by using one or more pressure sensors, which
in one embodiment, are included as a component of the saline
electrode system. The saline electrode system may advantageously
facilitate omnidirectional delivery of energy.
[0300] In some embodiments, hypertonic (e.g., hyperosmolar) saline
is used in the ablation of the target volume. Using hypertonic
saline may cause "loading" of the endothelial cells with ions,
effectively increasing their conductivity. The loading of the
endothelial cells with ions may have one or more of the following
effects: decreasing ion friction in the endothelial lining (and
other cells affected along the osmosis gradient, such as those in
the media); reducing the heat deposited in the endothelial cell
locations; preventing or inhibiting significant thermal damage to
the endothelial cells; and increasing current density as a result
of the increased conductivity in the region near the electrode,
which may advantageously increase the efficiency of heating deeper
in the vessel wall where the target nerves may be located. In one
embodiment, "loading" of the vessel reduces the impact of the bile
duct and/or portal vein structures on an ablation profile
shape.
[0301] Saline slug electrodes, such as the embodiment described in
FIG. 20, can be configured to circulate chilled fluid with constant
infusion to maintain constant temperature at a lumen surface. In
some embodiments, the difference between the inlet and outlet
coolant flow can be measured to gauge the amount of energy
delivered. Because a saline slug is by definition conformable to
any shape or size lumen, the use of multiple compliant balloons
(which may lead to delamination of the electrodes mounted on the
respective balloons, is not required to accommodate variations in
lumen size of various blood vessels. In accordance with several
embodiments, the saline electrodes described herein advantageously
provide improved electrode contact independent of device design,
function, or operator variability. In several embodiments, the
saline slug electrode employs catheter designs that interventional
cardiologists are familiar with using in practice on a daily basis
(e.g., balloons), whereas only electrophysiologists may be
comfortable and trained using "point electrode" ablation
catheters.
[0302] In several embodiments, by precisely controlling the
convective heat transfer coefficient (h) in saline slug electrode
(or metal electrode) configurations (e.g., by precisely controlling
flow rate within the slug region), energy delivery can be
interrupted, and by measuring the thermal decay (time constant) at
a point within the slug, the depth of ablation can be assessed,
where a longer time constant generally corresponds to a larger
depth of ablation.
[0303] In accordance with several embodiments, electrode and vessel
wall temperature are carefully monitored and controlled during
vessel ablation. Depth of ablation may be monitored. In several
embodiments, temperatures at the arterial wall are limited or
reduced to avoid vessel spasm, thrombus formation, and stenosis.
The ability to affect the convective cooling of the electrode and
contacted tissue can be particularly advantageous in various
embodiments. Electrode temperature can affect the depth of the
lesion. In some embodiments, a main mechanism affecting electrode
cooling is convective cooling from blood flow past the electrode
and contacted vessel wall. Ablation of the renal artery has a flow
rate of 550 mL/min. Flow through the common hepatic artery is
.about.100-200 mL/min (e.g., 150 mL/min), which is much slower than
typical flow rates in renal arteries (.about.550 mL/min), where
ablations have been performed with minimal or no electrode cooling.
Because of the low and/or variable flow rate within the hepatic
arteries, methods and systems aimed at increasing electrode cooling
are provided herein. FIG. 21 illustrates an example of challenges
of endovascular ablation given the reduced flow rates in the common
hepatic artery. FIG. 21 illustrates a plot of the reduction in RF
heating as the distance from the electrode surface increases. In
some embodiments, reduced heating at the electrode surface requires
a reduction in overall power, which can result in reduced heating
at the therapeutic target (e.g., hepatic nerves, renal nerves or
other peripheral nerves).
[0304] In one embodiment, the mass flow rate around the electrode
and contacted tissue at the therapeutic target is increased, as
illustrated, for example, in FIGS. 22A-22C. For example, by
reducing the cross-sectional area around the electrode (e.g., by
partially occluding a vessel using a plug or other obstruction or
occlusion device), the average flow velocity increases and the peak
velocity flow line is moved closer to the electrode and contacted
tissue, as shown in the transverse cross-section in FIG. 22B and in
FIG. 22C. The shading in FIGS. 22A and 22B illustrates fluid
velocity--the darker the shading, the higher the flow velocity. As
shown, by at least partially occluding flow, the blood flow
adjacent to the electrode is increased over unobstructed or
unoccluded flow. FIG. 22C illustrates a longitudinal cross-section
view of an obstruction or occluding element 2205 within a blood
vessel (e.g., hepatic artery). The obstruction or occluding element
2205 may have an opening or notch or indentation 2210 that is at
least substantially aligned with an electrode 2215. The obstruction
or occluding element 2205 with the aligned opening 2210 may cause
flow line density downstream of the electrode 2215 to be more dense
than upstream of the electrode 2215. The increased blood flow may
result in increased cooling of the electrode 2215.
[0305] In one embodiment, the obstruction element (e.g., balloon)
is effective to apply a reaction force as close to the electrode as
possible (in a direction perpendicular to the surface defined by
the contact of the electrode and the tissue surface, in one
embodiment). In one embodiment, the balloon is disposed directly
opposite the electrode. In order to limit motion of a balloon
within the artery as an artifact of diaphragmatic motion, the
balloon may be comprised of materials having higher coefficients of
friction between the balloon and arterial components, such as
endothelial tissue. In one embodiment, the balloon is comprised of
silicone.
[0306] In various embodiments, the balloon is configured to occlude
at least 50% of the arterial cross-sectional area. Suitable ranges
may include 50-60%, 50-70%, 50-80%, 60-80%, and 70-90% occlusion,
or overlapping ranges thereof. In some embodiments, the power
required to reach a target electrode temperature is higher when the
vessel lumen is substantially occluded compared to the unoccluded
configuration, increasing the efficiency of energy delivery.
[0307] Referring now to FIGS. 23A-23C, one embodiment of an
occlusive or obstruction element is a compliant balloon 2305 (e.g.,
made of silicone, polyurethane, or other suitable compliant
material) bonded to a distal end of a catheter shaft 2310 and to a
distal point of the overall catheter (e.g., which includes an
electrode or other activation member). In one embodiment, a portion
of the balloon's circumferential arc 2315 is constrained by a less
compliant material (e.g., PEBAX, Nylon, PE, Nitinol, stainless
steel, or other suitably less compliant material) that spans a
significant distance of the balloon's axial length. In some
embodiments, the constrained section or portion of the catheter is
an extension of the catheter shaft 2310 and may be constructed so
that it can bend. In the illustrated embodiment, the constrained
section incorporates physical design elements, such as notches or
flexure-like regions 2320 to permit bending.
[0308] As shown in FIG. 23B, during inflation of the balloon 2305,
the balloon material would expand evenly until it hit the vessel
wall everywhere except near the constrained section. In some
embodiments, although the constrained section would move out
radially, the constrained section would still restrict the
compliant balloon 2305, thereby creating a gap between the vessel
(e.g., artery) wall and the balloon 2305 on either side of the
constrained section arc 2315. The size of this gap may be pressure
dependent (as it is related to the expansion of the compliant
balloon). In some embodiments, the gap size is characterized as a
function of balloon pressure by experimentation where the compliant
balloon (with a constrained arc) is expanded within a
semi-compliant tube and the cross-sectional area is measured
visually or as a function of fluid resistance.
[0309] In various embodiments, the cross-section of the gap is
advantageously smaller than the natural vessel cross-section,
thereby increasing the fluid velocity at that cross-section. In
some embodiments, the midpoint of the cross-section (e.g., region
of highest velocity flow lines) would be moved closer to the
constrained arc 2315.
[0310] In some embodiments, when the balloon 2305 is inflated, it
expands evenly, except around the strip of catheter material, where
it has to bend (requiring more pressure to stretch the material in
that area). Through a range of pressures, the balloon 2305 may
expand to press against the opposing vessel wall while leaving a
gap around the electrode. In various embodiments, this pressure
range could be experimentally defined.
[0311] In one embodiment, the balloon 2305 is inflated by a syringe
at the proximal end of the catheter. The physician or other
clinician may self-inflate the balloon, using his/her tactile sense
(and potentially a pressure gauge in the syringe), and adjust the
applied pressure. In one embodiment, the pressure is limited by a
release valve or by a set volume placed in the syringe before
inflating the balloon. In one embodiment, the balloon becomes the
mechanism for applying the electrode force, and this mechanism has
tactile feedback (e.g., the syringe). The balloon may be filled
with cold fluid to enhance the overall cooling effect.
[0312] In various embodiments, the electrode(s) are bonded (e.g.,
physically with an overmold, chemically with adhesive, or other
suitable bonding method) onto the constrained section. The wire(s)
from the electrode(s) may run outside, within or inside the
constrained section. In one embodiment, the constrained section is
made of a thin, flexible circuit with wire(s) and electrode(s)
embedded within the circuit encasing material.
[0313] In various embodiments, capacitive coupling or resistive
heating catheter devices are used to deliver thermal energy. In one
embodiment, a capacitive coupling catheter device comprises a
balloon comprising a bipolar electrode pair arranged in a
capacitive coupling configuration with an insulation layer between
the two electrodes. In one embodiment, the insulation layer coats
the two electrodes. In one embodiment, the balloon comprises a
non-conductive balloon filled with saline that is capacitively
coupled to the target tissue through the dielectric layer formed by
the substantially non-conductive balloon membrane. The capacitive
coupling catheter device may advantageously not require direct
electrode contact with the target tissue, thereby reducing current
density levels and edge effects required by other devices.
Capacitive coupling devices or methods similar to those described
in U.S. Pat. No. 5,295,038, incorporated herein by reference, may
be used. A return electrode path may also be provided.
[0314] In one embodiment, a resistive heating energy delivery
catheter comprises a balloon catheter having a resistive heating
element disposed thereon. For example, the balloon catheter may
comprise spiral resistive heater that wraps around the balloon.
Instead of inducing RF currents in the vascular tissue, DC or AC/RF
currents can be used to generate heat in the balloon catheter
itself and the heat can be transmitted to the surrounding vascular
tissue (e.g., hepatic arterial tissue) by conduction.
[0315] c. Electrode Cooling
[0316] In accordance with several embodiments, the surface area of
the electrode or a region in thermal proximity to the electrode can
be increased. The increased temperatures can be achieved by
increasing the length or diameter of the electrode, as convective
cooling according to Newton's law is proportional to the surface
area. In one embodiment, increasing the surface area of the
electrode is achieved by adding fins 2405 or thermally connecting
the electrode to another section of the catheter 2410 (as
illustrated in FIG. 24). In various embodiments, the finned region
of the catheter 2410 might either be in direct electrical
communication with the electrode or electrically isolated from the
electrode by means of a thin dielectric layer. In accordance with
several embodiments, electric insulation (for example a thin
0.001'' layer of polyimide) does not substantially reduce the
thermal communication between the finned region and the electrode
because the rate of thermal conduction through a thin material is
greater than that through a thicker material.
[0317] In various embodiments, instead of fins, the surface of the
electrode can also be microstructured, for example bead-blasted,
microfractured, or etched. In some embodiments, small solder bumps
are welded or riveted onto the surface of the electrode. In one
embodiment, gold or other radiopaque material solder bumps are
particularly advantageous to increase the radiopacity of the
electrode.
[0318] In one embodiment, electrode cooling is increased by
effectively increasing the surface area of the lumen of the vessel
(as opposed to increasing the surface area of the electrode),
thereby increasing the heat transfer rate from the tissue to the
blood. In an embodiment shown in FIG. 25, increasing the heat
transfer rate from the tissue to the blood is achieved by placing a
thermally conductive pad 2505 in contact with the tissue
surrounding the electrode 2510. For example, a stent or ring may be
deployed before the ablation energy dosage. The deployable stent or
ring may place a thermally conductive structure (e.g., "pad")
around the ablation site. In one embodiment, the pad 2505 is a
pre-formed structure comprised of gelatin, hydrogel, or other high
thermal conductivity material. In order to prevent or inhibit
non-targeted ablation of tissue, it may be necessary to
electrically insulate the pad 2505 from the electrode. Electrical
insulation may be achieved by leaving space between the electrode
2510 and the conductive pad 2505 (thereby preventing or inhibiting
contact between the pad 2505 and the electrode 2510) through
accurate placement of the electrode 2510 or a placement-guiding
mechanism such as a funnel. Electrical insulation may also be
achieved by placing a thin layer of an electrical insulator on the
surface of the pad 2505 exposed to the electrode 2510. The layer of
electrical insulation may also be attached to the catheter between
the electrode 2510 and the pad 2505.
[0319] In accordance with various embodiments, it would be
advantageous for the pad to have a large surface area. Fins, as
shown and described in FIG. 24, are one way to increase the surface
area and to increase heat dissipation.
[0320] In some embodiments, an ablation region is precooled using
cold infusion techniques (e.g., iced saline infused directly into
the vessel) or using a chilled balloon. In some embodiments, blood
flow may also be restricted during pre-cooling to increase
residence time and achieve desired heat transfer. The pre-cooling
of the ablation region may advantageously lower the initial
temperature for the ablation and allow more power to be delivered
locally, thereby enabling steeper temperature gradients and deeper,
tighter lesions. The pre-cooling may also result in lower
conductivity in the cooled region, further concentrating power into
locally heated regions. In one embodiment, a balloon having one or
more electrodes is inserted to a target ablation site within a
blood vessel or organ (e.g., within a common hepatic artery).
Coolant may be circulated through the balloon for a period of time
(e.g., 20-60 seconds, 30-50 seconds, 20-40 seconds, 30 seconds)
prior to initiating ablation via the one or more electrodes. In
some embodiments, the pre-cooling of the target ablation site may
advantageously allow for delivery of ablative energy at a higher
power level than if the target ablation site was not pre-cooled,
thereby enabling deeper, more narrow lesions to be formed.
[0321] In one embodiment, electrode and/or tissue cooling is
increased by decreasing the temperature of the blood in order to
increase heat conduction by increasing the temperature delta
between the blood and the electrode and surrounding tissue. In
several embodiments, electrode and/or tissue cooling is achieved by
placing thermoelectrics on the catheter and proximal to the
electrode. Using the Peltier effect, a current driven through a
junction of two different conductors can be used to remove heat
from (cool) the junction. Because the catheter is inserted into the
hepatic artery in an antegrade fashion, blood flows along the
catheter towards the electrode (or ablation site). In one
embodiment, the region of the catheter proximal to the electrode is
upstream of the ablation (other site and the blood could be cooled
along the catheter before it reaches the ablation site. In one
embodiment, multiple thermoelectric coolers (e.g., the MD03 series
or MDL06 series) are placed in the catheter proximal to the
electrode and used to cool the blood. Since increasing the thermal
conductance of the thermoelectric sites improves the efficiency of
the thermoelectric elements, the thermoelectric elements may be
placed to maximize or increase surface area (e.g., fins), minimize
or otherwise reduce wall thickness, and/or maximize or increase
location near the max velocity flow lines. In some embodiments,
cold fluid injections upstream of the ablation site are used
instead of thermoelectrics to achieve the same goal of reducing the
blood temperature at the ablation site.
[0322] In some embodiments, a saline hyperphysiologic flow catheter
is used to increase fluid flow within a target artery (e.g., common
hepatic artery). FIGS. 26A and 26B illustrate schematic embodiments
of a saline hyperphysiologic flow catheter. FIG. 26A illustrates an
embodiment of a saline hyperphysiologic flow catheter configured to
provide increased antegrade flow control at the electrode-vessel
contact location (e.g., of about 500 mL/min). FIG. 26B illustrates
an embodiment of a saline hyperphysiologic flow catheter configured
to provide increased retrograde or reverse flow past the
electrode-vessel contact location. In one embodiment, the vessel
flow may be partially or completely stopped proximally or distally
of the electrode and/or lower power can be used. The saline flow
may cause flow within the vessel to be increased by two, three,
four, five, six times or more. In one embodiment, a flow sensor is
placed at a distal tip of the catheter to provide feedback of the
convective cooling rate so that a desired temperature can be
achieved.
[0323] In accordance with several embodiments, redirecting high
velocity blood flow from a higher-flow region (e.g., center) of the
vessel to the vessel wall (or to an electrode in contact with the
vessel wall) increases the removal of heat generated during
ablation. FIGS. 27A-27D Illustrate embodiments of devices
configured to redirect or divert high velocity blood flow from the
center of a vessel toward an electrode in contact with the vessel
wall. FIG. 27A illustrates an embodiment of an inflatable cone
2705, which can be placed above an electrode 2710 to redirect flow
toward the electrode 2710. In one embodiment, the inflatable cone
2705 may be introduced into and delivered to the location through a
separate catheter. The cone 2705 can be inflated to give room for
blood flow around the cone 2705 and may be positioned in the center
of the vessel, thereby resulting in a laminar high velocity flow
along the walls of the vessel, and thereby cooling the electrode
2710 and vessel lumen. FIGS. 27B-27D illustrate an embodiment of a
funnel 2720 configured to divert flow toward an electrode 2710 at a
distal end of a catheter 2725 (e.g., probe or shaft). FIG. 27D is a
cross-section view of FIG. 27C. The funnel 2720 may be affixed or
coupled to the catheter 2725 by a joint or hinge at a location near
the electrode 2710 (however, other coupling techniques may be used
as desired and/or required). The funnel 2720 may be configured to
collect higher blood flow at the center of the vessel and divert
the flow directly across the electrode 2710. In some embodiments,
the funnel 2720 comprises a flexible material. The cooling provided
by the increased blood flow may facilitate formation of deeper
lesions without causing charring or spasm, may reduce the
likelihood of excessive superficial injury, and may provide more
control over ablations. In one embodiment, flaps may capture and
divert flow over the electrode to enhance cooling and direct the
electrode toward an upstream location in the vessel (e.g., artery).
The flaps may enable the electrode to be directed by the flow
against the vessel wall, thereby enhancing or enabling wall
contact. In one embodiment, a proximal catheter shaft can be
extremely flexible to enable traversing extreme tortuosity. The
flow-directed wall contact may enable electrode contact in
situations where there is a desire to neuromodulate (e.g., ablate)
on tight bends. In one embodiment, a "cup" may be created for blood
capture, thereby enabling flow directed tracking and flow directed
wall contact.
[0324] In accordance with several embodiments, branches of a main
vessel other than those leading to a target vessel (e.g., the
common hepatic artery) are partially or completely occluded to
increase blood flow to the target vessel. For example, the left
gastric artery and splenic artery (which branch off of the
abdominal aorta upstream of the origin of the common hepatic
artery) may be occluded temporarily during treatment of a common
hepatic artery to increase blood flow through the common hepatic
artery, thereby increasing electrode cooling and reducing the
likelihood of spasms, notching and charring. In some embodiments,
the partial or total occlusion of the branch vessels may be
provided by a guide catheter. The guide catheter may be modified to
add extensible and adjustable plates that may be retracted during
insertion and removal of the guide catheter and deployed upon
advancement of the guide catheter to an appropriate location
adjacent a target vessel (e.g., within the abdominal aorta adjacent
an origin of the common hepatic artery). Once the guide catheter is
in position, the plates may be deployed and positioned to occlude a
portion or the entire entrance to the branch arteries upstream of
the target artery, thereby increasing flow into the target artery,
which in turn increases the cooling of the electrode and of the
arterial wall.
[0325] In accordance with some embodiments, buried and/or shielded
electrode designs are used to prevent or inhibit cooling. FIG. 28
illustrates an example of burying the electrode to substantially
shield the electrode from cooling by blood flow within the artery,
thereby increasing electrical aperture. In some embodiments, the
electrode can be pushed against or into the media of the arterial
wall to create a "false lumen" between the intima and the media to
shield the electrode from blood flow. In one embodiment, a flat or
substantially flat electrode can be used that is placed such that
the electrode is parallel or substantially parallel to the vessel
wall, thereby shielding the electrode from cooling due to blood
flow. In one embodiment, the electrode comprises a finger-like
electrode with a hemisphere covered with insulation to prevent or
inhibit blood cooling.
[0326] d. Deflectable, Steerable, Deployable or Expandable
Structures
[0327] The hepatic artery anatomy is generally more tortuous and
variable than anatomies of other vessels in other areas.
Maintaining good contact of electrodes or other energy delivery
elements in the tortuous hepatic artery anatomy can be difficult
and may require the use of different catheter devices than existing
catheter devices for nerve ablation. FIGS. 29A and 29B illustrate
an embodiment of a low-profile ablation catheter 2900 that may
advantageously facilitate contact of electrodes or other energy
delivery elements with the inner walls of arteries of the tortuous
hepatic vascular anatomy. The low-profile ablation catheter 2900
comprises an inner electrode member 2910 and an outer sheath 2915.
The inner electrode member 2910 may comprise a reversibly
deflectable, pre-shaped cylindrical shaft comprising resilient
(e.g., shape memory) material and at least one electrode 2920. In
one embodiment, the outer sheath 2915 comprises a guide catheter
having a lumen. The inner electrode member 2910 may be configured
to be delivered within the lumen of the outer sheath 2915 and to be
translatable relative to the outer sheath 2915 such that the inner
electrode member 2910 may be advanced out of a distal end of the
outer sheath 2915 and retracted back in. In one embodiment, the
inner electrode member 2910 assumes a generally deflected (e.g.,
off-axis) configuration when advanced out of the distal end of the
outer sheath 2915, as shown in FIG. 29B. In this unconstrained
state, the distal end of the inner electrode member 2910 deviates
from a longitudinal axis defined by the proximal portion of the
electrode. When the inner electrode member 2910 is retracted within
the outer sheath 2915, the inner electrode member 2910 is
resiliently deformed to assume a substantially straight shape
defined by the substantially straight shape of the lumen of the
outer sheath 2915, as shown in FIG. 29A. In some embodiments, when
the inner electrode member 2910 is advanced out of the distal end
of the outer sheath 2915, the distal end portion of the inner
electrode member 2910 deflects to contact a vessel wall (e.g.,
arterial wall). The shape of the distal end of the inner electrode
member 2910 in the unconstrained state may be pre-formed to ensure
contact with the vessel wall.
[0328] In some embodiments, the outer sheath 2915 has a diameter of
less than about 4 mm, less than about 3 mm, less than about 2 mm,
or less than about 1 mm. In some embodiments, the inner electrode
member 2910 comprises a shaft formed, at least partly, of memory
material such as a nickel titanium alloy material. The inner
electrode member 2910 may have an outer cross-sectional dimension
that is substantially equal to the outside diameter of the outer
sheath 2915 or may have an outer cross-sectional dimension that is
smaller or larger than the outside diameter of the outer sheath
2915. In some embodiments, when the inner electrode member 2910 is
slid out of the outer sheath 2915 past a pre-formed step 2925 at or
near its distal end, the step 2925 at or near the distal end places
the surface of the distal end of the inner electrode member 2910
away from the natural axis of the outer sheath 2915. In some
embodiments, the step 2925 near the distal end of the inner
electrode member 2910 places the surface of the inner electrode
member 2910 between about the same plane as the outer surface of
the outer sheath 2915 and about double the diameter from the center
of the outer sheath 2915 to the outer surface of the outer sheath
2915. In some embodiments, the outer sheath 2915 is
deflectable.
[0329] In some embodiments, the magnitude of the off-axis
deflection created in the step 2925 near the distal end is tailored
to satisfy varying anatomic requirements (e.g., larger step near
the distal end for larger blood vessels and smaller step near the
distal end for smaller blood vessels). In some embodiments, the
inner electrode member 2910 is interchangeable and may be replaced
with a different inner electrode member with different size
parameters. The different sizes of inner electrode members or
electrode members with different pre-formed shapes may be provided
in a kit and an appropriate inner electrode member may be selected
after evaluating patient anatomy (for example, by CT, fluoroscopy,
or ultrasound imaging methods). In some embodiments, the inner
electrode member 2910 is rotated within the catheter body.
[0330] In some embodiments, the at least one electrode 2920 of the
inner electrode member 2910 comprises one or more monopolar,
bipolar or multipolar electrodes (the addition of additional
pre-shaped electrodes may enable bipolar and multi-polar RF energy
delivery). Any combination of electrodes may be incorporated into
the design of the inner electrode member 2910 to create a catheter
with any desired properties.
[0331] In some embodiments, the shaft of the inner electrode member
2910 comprises an insulation member to prevent or inhibit heat
transfer away from or electrically insulate portions of the inner
electrode member 2910. In some embodiments, the insulation member
is a tubing, coating or heat shrink comprised of polyamide,
polytetrafluoroethylene, polyetheretherketone, polyethylene, or any
other high dielectric material. The insulation member may comprise
one or more openings to expose portions of the distal end portion
of the inner electrode member 2910. In some embodiments, the
insulation member is used to define specific electrode geometries
by selective removal of the insulation member in whatever geometry
is desired. In other embodiments, the inner electrode member 2910
comprises a shape memory polymer or shape-biased polymer with one
or more electrode leads disposed therein. In one embodiment, the
low-profile ablation catheter 2900 comprises a catheter coextruded
with a shape memory electrode spine, where the extruded catheter
provides electrical insulation. In one embodiment, the at least one
electrode 2920 comprises a spherical electrode. In one embodiment,
the distal end of the inner electrode shaft comprises a series of
electrodes.
[0332] In some embodiments, the low-profile ablation catheter 2900
comprises a radial window or slot in a side portion near the distal
end of the ablation catheter. In one embodiment, the distal end of
the inner electrode member 2910 is configured to be deployed out of
the radial window or slot. In one embodiment, the lumen of the
ablation catheter 2900 comprises a ramp leading up to the radial
window or slot to direct the distal end of the inner electrode
member out of the radial window or slot.
[0333] In accordance with several embodiments, the low-profile
ablation catheter 2900 advantageously provides a device that
comprises a low profile (e.g., small outer cross-sectional
dimension) and uses the same mechanism to actuate the electrode
deflection as well as the electrode itself, thereby reducing the
number of distinct components. The inner electrode 2910 of the
low-profile ablation catheter 2900 may also advantageously be at
least partially deployed to facilitate navigation by providing a
variety of tip curvature options for "hooking" vascular branches or
navigating tortuous vessels during catheter insertion. In
accordance with several embodiments, the low-profile ablation
catheter 2900 advantageously facilitates solid and continuous
contact with the vessel wall, thereby allowing for substantially
constant voltage to maintain a desired electrode tip
temperature.
[0334] FIGS. 29C-29K Illustrate various embodiments of energy
delivery devices configured to facilitate maintained contact of an
energy delivery member (e.g., an electrode) against a vessel wall
(e.g., a wall of a common hepatic artery) despite motion due to
respiration or blood flow.
[0335] FIGS. 29C-1 and 29C-2 illustrate an embodiment of an
ablation catheter system 2900C comprising a shaft 2901 having one
or more expandable intravascular structures 2902 configured to
expand into contact with a vessel wall upon expansion. The ablation
catheter system 2900C may advantageously be used to provide vessel
centering for embodiments involving an electrode-tipped catheter.
In some embodiments, the expandable structures 2902 allow for
minimal restriction to blood flow while supporting an electrode
2904 for a controlled vertical presentation to a desired treatment
site. The expandable intravascular structures 2902 may comprise a
scaffold, frame, cage or basket formed of multiple lobes or tines
constructed from a flexible, durable and/or flex resilient material
(such as Nitinol, Inconel or other shape memory materials). In one
embodiment, expansion of the structures 2902 from the unexpanded
state to the expanded state involves compression, or
foreshortening, by way of a pull wire being retracted. As shown in
the illustrated embodiment, the shaft 2901 may comprise two
expandable intravascular structures 2902. The electrode-tipped
catheter may comprise a cylindrical probe or tube having an
electrode tip 2904 that is advanced through a lumen of the shaft
2901 and out of a port or side opening 2903 of the shaft 2901. In
one embodiment, the electrode tip 2904 is advanced through the
lumen of the shaft 2901 until it reaches a deflection ramp
positioned between (e.g., at the midpoint between) the expandable
intravascular structures 2902 that forces the electrode tip 2904
out of the port or side opening 2903 of the shaft 2901 at a 90
degree angle relative to the longitudinal axis of the shaft 2901
until the electrode tip 2904 contacts the vessel wall.
[0336] FIG. 29D illustrates an embodiment of an ablation catheter
system 2900D comprising a dual-lumen catheter 2911. A distal end of
the dual-lumen catheter 2911 comprises an expandable structure 2912
and an electrode 2916. In the illustrated embodiment, the
expandable structure 2912 is mechanically expanded by a pull-wire
2914 extending from a proximal end of one of the lumens to the
expandable structure 2912 at the distal end. The expandable
structure 2912 may advantageously comprise a scaffold or basket
having an open pattern that facilitates free, unrestricted flow of
blood while the scaffold or basket is in an expanded state. The
expandable structure 2912 may have a configuration that enables the
structure 2912 to be deployed and secured within any of a number of
target vessels having different diameters (e.g., for the purpose of
creating a lesion) without the influence of movement due to
respiration or blood flow (e.g., piston-like axial movement),
thereby providing consistent and focused electrode wall contact
during energy delivery. As an example embodiment of a method of
use, an operator may place the dual-lumen catheter 2911 in a target
vessel, advance it to a target site within the target vessel, and
deploy the expandable structure 2912 using the mechanical pull-wire
2914. Energy may be delivered via the electrode 2916. Once the
energy cycle is complete, the expandable structure 2912 may be
retracted and the catheter 2911 may be withdrawn or moved to a
different target site. In some ablative embodiments, the improved
precision of lesion creation and minimization of axial lesion
extension reduces likelihood of lesion overlap and improves
vascular safety profile.
[0337] FIG. 29E illustrates an embodiment of a radiofrequency
energy delivery catheter 2900E that is configured to harness the
energy of blood flow through a vessel to facilitate maintained
contact of an electrode against the vessel wall. The catheter 2900E
comprises a deflectable shaft segment 2921, a pull wire 2924, a
distal tip electrode 2926, an elastic membrane 2927 and a push wire
2928 configured to expand the elastic membrane 2927. As actuation
of the deflectable shaft segment 2921 occurs upon pulling of the
pull wire 2924, the same action pushes the push wire 2928, thereby
expanding the elastic membrane 2927. The elastic membrane 2927
extends around a portion (e.g., 180 degrees of the shaft
circumference) of the deflectable shaft segment 2921, and forms a
"sail" that takes advantage of the force provided by blood flow to
provide increased electrode contact force and stability. The design
of catheter 2900E may minimize or otherwise reduce shaft profile by
eliminating actuation structures. In some embodiments, the push
wire 2928 and the pull wire 2924 are actuated independently.
[0338] In accordance with several embodiments, energy delivery
devices (e.g., catheters) comprise a distal portion constructed of
shape memory material and a lumen configured to receive a
guidewire. The shape memory material may be heat or shape set so as
to cause an electrode positioned on the distal portion of the
energy delivery device to contact an inner wall of a target vessel.
A guidewire may retain the distal portion of the energy delivery
device in a straight or substantially straight alignment until the
distal portion is positioned in a desired position within the
target vessel. When the guidewire is withdrawn from the lumen of
the energy delivery device, the shape-memory distal portion deforms
to the heat- or shape-set configuration so as to cause an electrode
of the energy delivery device to contact the inner wall of the
target vessel. In some embodiments, energy delivery devices (e.g.,
catheters may have one or more pre-formed configuration portions
configured to transition to a pre-formed configuration upon being
advanced out of a sheath or introducer catheter and one or more
pre-formed configuration portions configured to transition to a
pre-formed configuration upon removal or withdrawal of a
guidewire.
[0339] FIG. 29F illustrates an embodiment of an RF energy delivery
system 2900F comprising a device (e.g., catheter) 2931 having a tip
electrode 2936 and a guidewire 2938. The distal portion of the
catheter 2931 is shape set during manufacture to have a pre-formed
pigtail (e.g., spiral or corkscrew) shape. The distal portion of
the catheter 2931 remains in a straight or substantially straight
shape as it is advanced to a target location over the guidewire.
Upon retraction of the guidewire, the distal portion of the
catheter 2931 assumes the pre-formed pigtail shape, thereby causing
contact of the distal portion of the catheter 2931 at multiple
locations along the length and circumference of the vessel wall,
including at the electrode tip 2936. Re-insertion of the guidewire
straightens the distal portion of the catheter 2931 and facilitates
removal of the catheter 2931.
[0340] FIGS. 29G-1 and 29G-2 illustrate another embodiment of an RF
energy delivery system 2900G for neuromodulation or other tissue
modulation. The energy delivery system 2900G comprises an over-the
wire treatment catheter 2931 and a guidewire 2938. The treatment
catheter 2931 of FIGS. 29G-1 and FIGS. 29G-2 comprises two
electrodes 2936 on a shape-set portion 2932 and a lumen sized and
adapted to receive the guidewire 2938. The shape-set portion 2932
is coupled to a proximal portion 2937 and a distal portion 2939 of
a main shaft of the treatment catheter 2931. The distal portion
2939 may comprise an extension to facilitate trackability over the
guidewire 2938.
[0341] As described above in connection with FIG. 29F, a portion of
the catheter 2931 of FIGS. 29G-1 and 29G-2 is shape set during
manufacture to have a preformed pigtail (e.g., spiral or corkscrew)
shape. The shape-set portion 2932 of the treatment catheter 2931
remains in a straight or substantially straight configuration as it
is advanced to a target location over the guidewire 2938. Once the
treatment catheter is positioned at the target location, the
guidewire 2938 may be retracted or withdrawn, which allows the
shape-set portion 2932 of the treatment catheter 2931 to "spring"
into a three-dimensional curve (as shown in the deployed
configuration of FIG. 29G-2), thereby causing the electrodes 2936
on the shape-set portion 2932 to contact an inner vessel wall at
multiple spaced-apart locations along the length and circumference
of the vessel wall. Re-insertion of the guidewire 2938 straightens
the shape-set portion 2932 and facilitates removal of the treatment
catheter 2931. The three dimensional curve can be spiral-shaped, as
shown. The spiral may have varying pitch and or diameter or may be
helical, of uniform diameter and pitch. The shape-set portion 2932
may be formed by incorporating a shaped elastic member, such as
from a metal or metal alloy (e.g., nitinol), or may be formed with
a thermoplastic material using heat shaping techniques. The
shape-set portion 2932 may be formed by heat-setting or
pre-stressing methods or techniques.
[0342] The shape-set portion 2932 may comprise two or more
electrodes (e.g., two, three, four, more than four). In the case
where two electrodes are included, the electrodes 2936 can be
positioned at approximately 180 degrees of circumferential angular
separation on the shape-set portion 2932, as shown in FIG. 29G-2.
The 180 degree offset puts the electrodes 2936 longitudinally
spaced, but at opposing sides when deployed within a treatment
vessel. The electrodes 2936 may be positioned in any manner along
the shape-set portion, as desired and/or required. In various
embodiments, the positioning of the electrodes 2936 and the shape
of the three-dimensional curve are configured such that a first
electrode contacts the vessel wall in an axial or longitudinal
orientation (e.g., as determined by a longest aspect of the first
electrode) and the second electrode contacts the vessel wall in an
oblique orientation (offset perpendicularly with respect to a
longitudinal axis of the vessel or catheter shaft), as shown in
FIG. 29G-2. For example, the first electrode and the second
electrode may be differentially oriented 90 degrees or
substantially perpendicular to each other. In one embodiment, the
three-dimensional curve is non-helical. The non-helical curve or
shape-set portion 2932 may be configured to transition from a
proximal longitudinal portion connected to a proximal portion of
the catheter shaft to a proximal oblique portion to a central
longitudinal portion to a distal oblique portion and then back to a
distal longitudinal portion connected to a distal portion of the
catheter shaft, as shown in FIG. 29G-2. In the illustrated
embodiment, a first electrode is positioned on the central
longitudinal portion and a second electrode is positioned on the
distal oblique portion. The contact portions of the longitudinal
and oblique portions may be configured to be 180 degrees offset
from each other. In some embodiments, the second electrode may be
positioned on the proximal oblique portion or electrodes may be
positioned on each of the proximal and distal oblique portions,
with each of the obliquely-oriented electrodes being offset by 180
degrees from the axially-oriented electrode. In some embodiments,
electrodes may be positioned on one or both of the proximal and
distal longitudinal portions or on the catheter shaft adjacent the
proximal and distal longitudinal portions, in addition to or
instead of on the middle longitudinal portion. The electrodes 2936
may be configured to be spaced apart axially by 2 mm, 3 mm, 4 mm, 5
mm, 6 mm.
[0343] FIG. 29H illustrates an embodiment of a catheter shaft 2931
adapted to form a helical configuration along a portion of the
length of the catheter shaft 2931. The catheter shaft 2931
comprises two electrodes 2936 positioned at spaced-apart locations
along the helical portion so as to contact a vessel wall at
locations spaced apart axially and circumferentially (e.g., 180
degrees apart). In some embodiments, one or more electrodes are
located on non-deflectable (for example, non-helical) portions of
the shaft proximal and/or distal of the deflectable portion of the
shaft. In one embodiment, a catheter shaft consists of a single
electrode on a deflectable (for example, shape memory, steerable
via pull-wire) portion and one or more electrodes on a main,
non-deflectable portion of the shaft.
[0344] FIG. 29I illustrates an embodiment of a catheter shaft
comprising two electrode members 2936 on a flexible, deflectable
portion of the catheter shaft. The catheter shaft may also comprise
one or more electrodes positioned at locations along the
non-deflectable main shaft portion. In some embodiments, flush
contact may be achieved by two spaced-apart electrode portions on
the deflectable portion due to variability in the flexibility
and/or material of the catheter shaft. The deflectable portion may
comprise sub-portions or lengths having varying degrees of
flexibility. For example sub-portions 2933 immediately adjacent
(proximal and distal of) the electrodes 2936 may comprise a
more-flexible portion than sub-portion 2934 extending from
sub-portion 2933 to a non-deflectable main shaft portion. The
various sub-portions of the deflectable portion may be specifically
adapted and designed to cause the electrodes 2936 to contact the
vessel wall in a straight, flush or substantially straight or flush
manner.
[0345] In some embodiments, one or more additional electrodes may
be positioned along the main shaft portion proximal and/or distal
of the deflectable portion. The electrodes 2936 may comprise
cylindrical or non-cylindrical electrodes (e.g., slotted, C-shaped,
D-shaped electrodes). The deflectable portion may comprise
shape-memory material (heat-set thermoplastic or a shape-memory
metal or metal alloy) or may be controlled by one or more pullwires
or other actuation members.
[0346] FIGS. 29J-1 and 29J-2 illustrate another embodiment of a
self-deploying treatment catheter 2931. As with the embodiment of
FIGS. 29G-1 and 29G-2, the treatment catheter 2931 comprises a
shape-set portion 2932 configured to transition to a three
dimensional shaped configuration upon retraction of an internal
guidewire 2938. However, in this embodiment, the proximal electrode
2936A is not on the shape-set portion 2932, but positioned on the
proximal portion 2937 of the main shaft. The distal electrode 2936B
may be mounted on the shape-set portion 2932 such that when the
shape-set portion 2932 is in its deployed configuration (FIG.
29J-2), the distal electrode 2936B is on the opposing side of the
vessel. The shape-set portion 2932 may comprise a non-helical
shape. For example, in one embodiment, the shape-set portion
comprises a proximal longitudinal portion connected to a proximal
portion of the catheter shaft, which transitions to a central
oblique portion and then back to a distal longitudinal portion. The
contact portions of the longitudinal and oblique portions may be
configured to be 180 degrees offset from each other. As shown in
FIGS. 29J-1 and 29J-2, the proximal electrode 2936A on the main
catheter shaft is axially oriented or aligned (e.g., parallel with
the longitudinal axis of the catheter or vessel) and the distal
electrode 2936B is obliquely oriented or aligned (e.g., offset
perpendicularly with respect to a longitudinal axis of the vessel
or catheter shaft). As shown, the proximal electrode 2936A and the
distal electrode 2936B may also be positioned so as to contact the
vessel wall at locations offset circumferentially (e.g., 180
degrees offset). In one embodiment, an electrode may be positioned
on the distal portion 2939 of the catheter shaft, either instead of
or in addition to the proximal electrode 2936A. The shape-set
portion 2932 may be formed by heat-setting or pre-stressing methods
or techniques.
[0347] In accordance with several embodiments, the electrode(s) may
advantageously be positioned on a side of a low-profile catheter
(e.g., probe or shaft), thereby providing a longer segment of
electrode contact with the vessel wall than a tip electrode. The
side placement may allow for reduced catheter dimensions for
equivalent energy delivery.
[0348] FIG. 29K illustrates an embodiment of an energy delivery
catheter (e.g., shaft or probe) 2900K comprising a distal end
portion 2941 having a pre-formed bend shape and comprising a side
electrode 2946. The energy delivery catheter 2900K may comprise (1)
a core wire 2944 having the pre-formed bend shape that is
configured to transition to the pre-formed bend shape upon being
advanced out of a sheath or catheter or (2) a hollow sheath having
the pre-formed bend shape that is configured to be advanced over a
guidewire and then "deployed" upon retraction of the guidewire. In
some embodiments, the catheter 2900K comprises an insulating and/or
protective layer between the core wire 2944 and the electrode 2946
and the electrode lead wire(s) 2948.
[0349] FIGS. 29L-1 and 29L-2 illustrate an embodiment of an energy
delivery catheter (e.g., shaft, probe, or wire) 2900L comprising a
distal end portion 2951 having a pre-formed bend shape and
comprising a side electrode 2956. FIG. 29L-1 illustrates that a
segment 2957 of the energy delivery catheter is flattened. The side
electrode 2956 is positioned at a distance from a distal terminus
of the distal end portion 2951 at the location of the flattened
segment 2957. FIG. 29L-2 illustrates the pre-formed bend shape of
the distal end portion 2951 that is heat- or shape-set during
manufacture. The pre-formed bend shape facilitates contact of the
side electrode 2956 with a vessel wall upon being advanced out of
an outer sheath (e.g., guide extension catheter or guide
catheter).
[0350] FIGS. 29M-1 to 29M-4 illustrate embodiments of an energy
delivery system 2900M comprising a catheter 2961 having a distal
end portion 2962 with a pre-formed bend shape or configuration and
a side electrode 2966 and a guidewire 2963 (e.g., 0.014'' wire).
The distal end portion 2962 remains in a substantially straight
configuration while being advanced over the guidewire 2963 and
transitions to a "cobra-head" configuration upon retraction of the
guidewire 2963, thereby causing the side electrode 2966 to contact
the vessel wall. The side electrode 2966 is positioned at or near a
distal terminus in FIGS. 29M-1 and 29M-2 and at a location spaced
from the distal terminus in FIGS. 29M-3 and 29M-4. The guidewire
2963 can be re-advanced to straighten the distal end portion 2962
to facilitate removal of the catheter 2961.
[0351] FIGS. 29N-1 and 29N-2 illustrate embodiments of an energy
delivery system 2900N comprising a low-profile catheter 2971 and a
guidewire 2973. The catheter 2971 comprises a main shaft 2972, a
distal shaft tip 2974 and an electrode 2976. The proximal end of
the electrode 2976 is coupled to the distal portion of the main
shaft 2972 and the distal end of the electrode 2976 is coupled to
the proximal portion of the distal shaft tip 2974. The catheter
2971 is advanced over the guidewire 2973 to a target treatment site
within a target vessel. The guidewire 2973 may then be retracted,
allowing the electrode 2976 to transition to a configuration in
which the electrode 2976 contacts the vessel wall. The embodiment
of the energy delivery system 2900N advantageously provides for
lower profile at the electrode location.
[0352] FIG. 29O illustrates a cross-section view of an embodiment
of an energy delivery catheter 29000. The catheter 29000 may be
delivered over a guidewire 2983 such that at least a portion of the
catheter 29000 having a shape-memory configuration remains in a
substantially straight configuration. The catheter 29000 may
comprise a central lumen 2984 configured to receive the guidewire
2983, a braided wall 2985 formed of shape-memory material (e.g.,
nitinol) extending along all or a portion of the catheter length,
and an electrode 2986 and a temperature-measurement device 2987
(e.g., thermistor, thermocouple) embedded in an outer layer 2988 of
the catheter 29000.
[0353] FIG. 30 illustrates various embodiments of distal tip
electrode and guide wire shapes 3000. The distal tip electrode and
guide wire shapes 3000 may include an "L" shaped tip 3005, a "J"
shaped tip 3010, a "shepherds crook"-shaped tip 3015, a "hook"
shaped tip 3020, a "line" shaped tip 3025, a "key" shaped tip 3030,
a "circle" shaped tip 3035, a "square hook" shaped tip 3040, or a
"step" shaped hook 3045. A spiral-shaped tip (such as shown in FIG.
10A) may also be used. In one embodiment, a lasso-shaped tip is
used. The lasso-shaped tip may have a similar configuration to the
"circle" shaped tip 3035 but with the "circle"- or "lasso"-shaped
tip portion being oriented substantially perpendicular to the
straight line portion. The various shapes illustrated in FIG. 30
may advantageously be selected from and used in conjunction with
the low-profile ablation catheter 2900 or other catheter devices to
facilitate contact of electrodes or other energy delivery elements
with the inner walls of arteries of the tortuous hepatic vascular
anatomy (e.g., based on the particular vascular anatomy of the
subject being treated or the particular vessels being treated). Any
of the shapes 3000 shown in FIG. 30 may comprise a plurality of
electrodes arranged in different patterns. The various distal tip
shapes or designs may be provided in a kit and can increase the
ability to treat the wide variety of hepatic artery anatomies or
other target anatomies between subjects.
[0354] In some embodiments, the distal tip electrode itself, or a
guide wire, may be partially or fully extended from an insertion
catheter, to aid in navigation, thereby providing for a variety of
tip curvature options for "hooking" vascular branches during
catheter insertion. In some embodiments, shape-memory electrodes
may be interchangeable by a clinician-user. For example, the
clinician may select the most appropriate shape conformation for
the patient's unique anatomy from a kit of different shaped
devices, rather than being bound to a single device conformation or
configuration. In one embodiment, the particular shape is selected
based on angiography or other imaging modalities of the target
treatment region. The various shaped tips may advantageously be
selected to optimize the ability for the one or more electrodes or
energy delivery elements to contact the target vessel due to the
tortuosity and variability of the vascular anatomy at and/or
surrounding the target vessel. The electrode assembly may also
include a sensing element, such as a thermal sensing element (e.g.,
thermistor or thermocouple) to permit measurement of tissue
temperatures and energy delivery during the treatment. The sensing
element may provide feedback regarding confirmation of denervation
or blocking of nerve conduction and/or regarding the contact force
applied to the vessel wall and whether or not the contact force is
sufficient to enable effective neuromodulation.
[0355] In accordance with several embodiments, once a particular
shape is selected, forces (F) can be applied to the proximal end of
the electrode to adjust the contact force F' against a vessel wall.
In some embodiments, the degree of strain of the electrode distal
portion is proportional to the force applied to the vessel wall.
Radiopaque markers may be placed along the length of the inner
electrode 1410 and the relative angle 1) between lines drawn
between two of the radiopaque markers can be designed such that
F'=f(P(F)). A clinician may then adjust the force on the proximal
end of the electrode to achieve the desired contact force.
[0356] In some embodiments, electrode contact force and/or
electrode articulation is provided through the use of
electromagnetic elements disposed within the neuromodulation
catheter (e.g., ablation catheter). As shown in FIGS. 31A and 31B,
an embodiment of an ablation catheter device is comprised of at
least an electrode 3115, a flexible shaft 3110, and a segment that
is capable of carrying current and that is significantly close to
the electrode to effect movement of the electrode in response to an
applied magnetic field. In some embodiments, the ablation catheter
device is positioned in a vessel and a magnetic field is applied
through the vessel (for example, applied external to the patient).
When the current is turned on, an electro-magnetic force is applied
to the current-carrying segment per the Lorentz force law:
F=I.times.B. The location of the magnetic field may be moved so
that the direction of the force (and hence the location of the
applied force within the vessel) can be adjusted. The magnitude and
the current or magnetic field may be adjusted to adjust the
magnitude of the force. The direction of the current and magnetic
field can be used to adjust the magnitude of the force, as the
magnitude of a cross product is dependent on direction of the
crossed vectors. In various embodiments, one or more
current-carrying segments, one or more electrodes and/or one or
more flexible catheter segments may be used.
[0357] In one embodiment, shown in FIGS. 32A and 32B, a
neuromodulation device (e.g., ablation catheter) is comprised of at
least an electrode 3215, a flexible shaft 3210, and a segment or
element 3218 that is capable of carrying a magnetic field (for
example, a ferromagnetic material) and that is significantly close
to the electrode to effect movement of the electrode in response to
one or more applied magnetic fields. The ablation catheter device
may be positioned in a vessel at a particular location and a
magnetic field may then be applied through the vessel in
conjunction with application of the magnetic field of the magnetic
segment, thereby causing the opposite poles of the magnetic fields
to attract. The location and/or direction of the magnetic fields
may be moved to adjust the direction of the force. The magnitude of
the magnetic fields may be adjusted to adjust the magnitude of the
force. In various embodiments, the number of magnetic
field-carrying segments may vary (e.g., one, two, three, four or
more) and/or the number of electrodes and flexible catheter
segments may vary (e.g., one, two, three, four or more). In some
embodiments, the magnetic segment 3218 comprises a ferromagnet
and/or electro-magnet.
[0358] With reference to FIGS. 33A and 33B, in some embodiments, a
neuromodulation device (e.g., ablation catheter) is comprised of at
least an electrode 3315, a flexible shaft 3310, and two segments or
elements 3318 that are capable of carrying a magnetic field and
that are significantly close to the electrode to effect movement of
the electrode in response to one or more applied magnetic fields.
In some embodiments, the two magnetic segments are configured to
generate magnetic fields having opposite poles. The device may be
positioned in a vessel at a particular target location. Magnetic
fields may be applied through the magnetic segments, causing the
opposite poles of the magnetic fields of the two magnetic segments
to attract (e.g., magnetic fields align), thereby leading to at
least one bending moment in the flexible shaft. As shown in FIG.
33B, multiple bends can be created in the distal portion of the
catheter. The location and/or direction of the magnetic fields may
be moved to adjust the direction of the force and/or bending
moment(s). The magnitude of the magnetic fields may be adjusted to
adjust the magnitude of the force and/or bending moment(s). In
various embodiments, the number of magnetic field-carrying segments
may vary (e.g., one, two, three, four or more) and/or the number of
electrodes and flexible catheter segments may vary (e.g., one, two,
three, four or more). In some embodiments, one or more of the
magnetic segment comprises a ferromagnet and/or electro-magnet.
[0359] The embodiments illustrated in and described in connection
with FIGS. 31 through 33 may advantageously allow a force to be
applied directly to a segment of the ablation catheter device that
is significantly close to the electrode(s), thereby improving
control of the electrode(s) and control of the electrode-vessel
force when the ablation catheter device is placed in a tortuous or
otherwise difficult-to-navigate anatomy.
[0360] In some embodiments, a catheter having an outer diameter
substantially matching the target vessel's inner diameter is used,
thereby minimizing mechanical and footprint requirements for
precise targeting. A catheter may be selected from a kit of
catheters having various outside diameter dimensions based on a
measured inner diameter of the target vessel. In some embodiments,
the outside diameter of a catheter can be modified using spacers
provided in a procedure kit. The catheter may be advanced through
the patient's vasculature (the inner diameter of which may decrease
as the target location nears). Once the catheter is advanced to the
target vessel location, it may then advantageously engage the
vessel wall with substantially uniform contact pressure about its
circumference. In some embodiments, because application of energy
to the entire circumference of the vessel is undesirable (due to
the risk of stenosis,) any of the designs herein disclosed that
employ selective electrode placement or electrode "windows" are
used, thereby allowing the delivery of energy in discrete locations
about the vessel wall.
[0361] Turning to FIGS. 34A-34C, embodiments of an RF electrode
ablation catheter (e.g., probe) 3400 are illustrated. The RF
ablation catheter 3400 may comprise a tip electrode 3402 configured
to contact a vessel wall provide more focused, more directed energy
delivery to a target ablation site, thereby reducing
circumferential heating of extraneous tissues and surrounding
blood. The RF ablation catheter 3400 in FIG. 34A comprises a flat
plate electrode and the RF ablation catheter 3400 in FIG. 34B
comprises a semi-sphere electrode. With reference to FIG. 34C, the
distal-most portion 3401 of the RF ablation catheter 3400 may be
actuated to position a contact surface of the tip electrode flush
or substantially flush with the vessel wall (e.g., such that the a
longitudinal axis of the distal-most portion 3401 is perpendicular
or substantially perpendicular to the vessel wall) by cantilevering
off the opposite vessel wall (e.g., via one or more pull-wires and
one or more flexible, steerable and/or shape-memory deformable
portions of a main shaft 3402 of the RF ablation catheter
3400).
[0362] FIGS. 34D and 34E illustrate an embodiment of an RF
treatment catheter 3400' comprising two electrodes 3402. A distal
deflection region 3405 extends between the two electrodes 3402 and
a proximal deflection region 3406 extends proximal of the proximal
electrode 3402B. The deflection regions 3405, 3406 may be
constructed of an articulating structure actuated by an internal
deflection wire (not shown). The RF treatment catheter 3400' can be
navigated to a treatment vessel (e.g., common hepatic artery)
utilizing techniques described herein. When the electrodes 3402 are
in a desired treatment position, the distal deflection segment 3405
is actuated into a curved shape, which presses the distal electrode
3402A toward a quadrant of the vessel lumen, thereby urging the
proximal electrode 3402B to the opposite quadrant (side) of the
vessel lumen (as shown in FIG. 34D). A flexible region 3407 extends
proximal to the proximal deflection region 3406 to allow the
catheter shaft further proximal to extend generally parallel to the
vessel lumen rather than be forcibly apposed to the opposite wall.
Distal and/or proximal electrodes 3402 may further include rounded
surfaces, as shown, to maintain consistent and uniform contact with
the vessel lumen, even when the electrodes 3402 are not lying
parallel to the lumen surface. With both electrodes 3402 in the
longitudinally spaced and diametrically opposed position, two
treatment zones can be created without longitudinal or rotational
manipulation of the catheter. Three or more treatment zones can be
created with longitudinal manipulation and reactivation of the
treatment catheter 3400'. The electrodes 3402 may be activated
simultaneously or sequentially, or a single electrode may be
activated. In some embodiments, the distal electrode 3402A is
configured to contact the vessel wall in an oblique or generally
perpendicular orientation and the proximal electrode 3402B is
adapted to contact the vessel wall in a parallel orientation.
[0363] In one embodiment, the treatment catheter 3400' is of a
"non-over-the-wire" design. In this embodiment, a wire lumen is not
provided, and the distal electrode may simply have a closed off
distal surface. Delivery of such a non-over-the-wire embodiment may
be performed through a guide catheter positioned at the ostium of
the celiac artery, or through a guide catheter positioned deeper,
for example at the ostium of the common hepatic artery. The
treatment catheter 3400' could alternatively be positioned in other
vessel segments, and catheter delivery could be performed by
placement of a guide catheter at the ostium of any appropriate
vessel.
[0364] The embodiment of the RF treatment catheter 3400'
illustrated in FIGS. 34D and 34E can also be of a "self-deploying"
design. For example, instead of having active deflection regions,
such regions can be pre-curved to attain the desired shape shown in
FIG. 34E. The RF treatment catheter 3400'' may comprise a lumen
configured to receive a guide wire 3408. When utilized with an
internal guide wire 3408 (as shown in FIG. 34F), the RF treatment
catheter 3400'' is relatively straight when the guide wire 3408 is
advanced distally of the deflection regions. Upon retraction of the
guide wire 3408, the "deployment" regions elastically self-deflect
to the curved condition, thereby placing the electrodes 3402 in the
spaced and opposing configuration. In use, the RF treatment
catheter 3400'' would be relatively straight due to the presence of
the guide wire 3408. Once in a desired position, the guide wire
3408 may be retracted to allow the distal portion of the RF
treatment catheter 3400'' to take on the serpentine shape, which
may place the electrodes 3402 against the vessel lumen for
activation. The guide wire 3408 may be readvanced to reposition the
catheter 3400'' for subsequent treatments, or withdrawal of the
catheter 3400'' from the subject.
[0365] FIGS. 35, 36A, 36B, 37A, 37B, 38, 39, 40, 41A, 41B, 41C,
41D, 42A, 42B, 43A, 43B, 44, 45A, 45B, 46A, 46B, 47A, 47B, 53A,
53B, and 54A-54C illustrate embodiments of electrode catheters or
catheter modifications configured to provide enhanced catheter
stabilization and/or electrode contact with vessel walls at
therapeutic target locations (e.g., within hepatic arteries). FIG.
35 illustrates one embodiment of an electrode catheter with a
retractable stabilization segment 3505 configured to anchor to the
inner wall of a vessel (e.g., artery), in the opposite direction of
the electrode 3510. To provide friction, the stabilization segment
3505 may comprise an anti-slip surface. In one embodiment, the
stabilization segment 3505 only protrudes or is deployed once in
place so that the friction does not significantly affect the
ability to insert the catheter. In one embodiment, the anti-slip
surface is achieved by modifying the outer layer of silicone so
that it is no longer smooth but has an array of longitudinal and
transversal small size dents. The extensible stabilization segment
3505 presses into the arterial wall without poking a hole in it, as
its tip extends parallel to the arterial wall, in order to
distribute the stress on a larger surface. In one embodiment, the
catheter with the stabilization segment causes at least a slight
vessel (e.g., arterial) deformation as a result of the
stabilization forces.
[0366] Because of the tortuous anatomy of the hepatic arteries or
vasculature leading to the hepatic arteries or other vasculature,
it may be difficult to apply a repeatable force to the electrode of
an RF electrode catheter at various locations along the length of
the artery. Cantilever flex catheters are catheters that apply a
bending moment along a distal section of the catheter by
compressing the inner arc with a pull wire. The bending moment
moves the catheter tip towards the vessel wall. In order for the
bending moment to apply a force through the catheter tip and into
the vessel wall, a reactionary force must be applied at another
section of the catheter. This reactionary force is likely between
the catheter and vessel wall opposite of the catheter distal tip
and through a segment of the catheter proximal to the distal tip.
With tortuous anatomy and sharp bends, this "reaction force" may
not be repeatable. Several embodiments of the devices, systems and
methods described herein are configured to provide a repeatable
and/or continuous contact force. In several embodiments of
catheters and methods of use described herein, pulsatile contact is
advantageously provided.
[0367] In one embodiment, instead of applying a moment at the
distal tip and relying on a reaction force between the vessel and a
proximal segment of the catheter, one could use a wire or ribbon to
apply the reaction force closer to the bending moment and
cantilevered tip. The objective is to create a reaction force (or
multiple reaction forces) as close to the electrode contact as
possible, thereby anchoring the distal region of the catheter
relative to the vessel wall to provide a reaction moment against
the flex mechanism (e.g., cantilever flex catheter) that applies
the electrode into the vessel wall with a bending moment. Referring
now to FIG. 36A, two openings are made in a cantilever flex
catheter 3605 opposite of the location where the bending moment is
applied (e.g., where a pull wire is attached to the catheter shaft)
and a ribbon 3610 is threaded through these openings so that the
ribbon 3610 is outside of the catheter 3605 between these two
openings. The ribbon may 3610 be fixed to a point in the catheter
3605 that is distal to the most distal opening and able to be
pushed at the proximal end of the catheter. When the ribbon 3610 is
pushed, it moves out of the proximal opening and creates a loop.
This loop is enlarged until it presses against the wall of the
vessel opposite of the bending moment. An optional additional
feature that may be added to reduce slack in the system (since the
ribbon is being pushed, it will want to fill all of the empty space
in the catheter) is a divider 3620 that runs along the length of
the catheter 3605 and rests near the midpoint of the cross-section,
as shown in FIG. 36B. Because the divider is at the cross-sectional
midpoint in some embodiments, the divider would not significantly
affect the catheter's flexibility towards and away from the ribbon
3610; therefore, the divider 3620 could run through the distal flex
section 3608 without affecting the bending moment.
[0368] In various embodiments, modifications and improvements to
the catheter of the sort described in connection with FIG. 36A may
be made. For example, in one embodiment, instead of using a pull
wire to create the bending moment at the catheter tip 3607, the
ribbon 3610, which is pushed along the outer arc of the catheter
3605, could place the outer arc of the flex region in tension and
create the bending moment. This embodiment would simplify the
design by reducing the redundant pull wire.
[0369] In accordance with several embodiments, RF electrode
treatment catheters may have one or more deployment segments that
do not themselves carry the electrodes. FIG. 36C illustrates an
embodiment of an RF electrode treatment catheter 3605 comprising
two electrodes 3601. The electrodes 3601 are fixedly coupled to a
main catheter shaft 3602 and a deflection segment 3610 extends
between the two electrodes 3601 and is configured to deploy
radially outward from a slot 3603 in the main catheter shaft 3602.
Because the electrodes 3601 are fixedly coupled to the main
catheter shaft 3602, their longitudinal position will remain
stable, independent of the radial extent that the deployment
segment 3610 is deployed. The deployment segment 3610 may be of a
ribbon configuration, such as a metallic ribbon. The deployment
segment 3610 may be deployed radially by advancing a proximal
portion relative to the proximal catheter shaft. Alternatively, as
best seen in FIG. 36D (which is a cross-section of FIG. 36C), the
deployment segment 3610 may be deployed by relative retraction of
an inner catheter 3604, to which a distal end of the deployment
segment 3610 is coupled or secured.
[0370] The deployment segment 3610 may also have a pre-set shape in
a radially extended shape, and can be "held" in a pre-deployment
shape generally parallel to the catheter shaft 3602 during tracking
of the treatment catheter 3605 to a treatment site. Once at or near
the treatment site, the deployment segment 3610 can be allowed to
self-deploy by relative advancement of a proximal portion relative
to the proximal catheter shaft. A combination of self-deployment
and active deployment is also contemplated. For example, the
deployment segment 3610 may be pre-shaped to self-deploy to a
certain radial distance from the catheter shaft 3602, but further
relative advancement of the proximal portion of the deployment
segment 3610 may extend it further radially.
[0371] As both electrodes 3601 are mounted on the catheter shaft
3602, when the deployment segment 3610 is deployed, both electrodes
3601 will be on the same side of the vessel lumen. If both
electrodes 3601 are activated simultaneously, two longitudinally
spaced treatment zones will be created on one side of the vessel.
If it is desired to create two longitudinally spaced treatment
zones, but on opposite sides of the vessel, a single electrode may
be activated (for example, the distal electrode). After that, the
catheter 3605 may be rotated by torqueing 180 degrees, then
re-deploying the deployment segment 3610, and then activating a
single electrode (for example, the proximal electrode). In one
embodiment, this approach is referred to as a "leapfrog" approach.
If it is desired to create more than two treatment zones, the
catheter 3605 may be advanced or withdrawn to another longitudinal
position, and the same steps above repeated. In some
implementations, a total of 4 longitudinally-spaced treatment
zones, alternating on opposite sides of the vessel lumen may be
desired, as shown in FIG. 61A. Such a pattern of treatment zones
can be created with the embodiment of FIG. 36C, by initially
placing the catheter 3605 at a first location, deploying the
deployment segment 3610 and energizing both the distal and proximal
electrodes 3601. Then, the catheter 3605 is advanced or withdrawn a
distance of approximately half the distance between the electrodes
3601, rotated, deployed, and both electrodes 3601 activated. In
some embodiments, the catheter 3605 comprises a distal extension
3609 to facilitate trackability.
[0372] In some embodiments, multiple ribbons 3710 could be used as
shown in FIGS. 37A-37D. These embodiments increase the number of
contact points and increase catheter stability. In one embodiment,
a balloon could be used alone or in combination with the one or
more ribbons. FIGS. 37C and 37D illustrate an embodiment of an RF
electrode treatment catheter 3705 similar to the RF treatment
catheter 3605 of FIGS. 36C and 36D; however, the embodiment of the
RF treatment catheter 3705 of FIGS. 37C and 37D comprises two
deployment segments (upper deployment segment 3710A and lower
deployment segment 3710B). This embodiment facilitates treatment of
opposite sides of the vessel (e.g., formation of lesion zones
offset by 180 degrees) without having to torque or rotate the RF
electrode treatment catheter 3705. For example, the catheter 3705
may be advanced to a first treatment position and the upper
deployment segment 3710A may be deployed to a deployed
configuration such that the electrodes 3701 contact the vessel wall
on the opposite side of the vessel. The lower deployment segment
3710B remains in an undeployed configuration. One or both of the
electrodes 3701 may then activated to deliver energy to the vessel
wall. In embodiments where ablative energy is delivered, one or two
lesion zones may be formed at the first treatment position
(depending on whether the electrodes are monopolar or bipolar and
whether one or both electrodes are activated). The upper deployment
segment 3710A is then transitioned to an undeployed configuration.
The catheter 3705 may then be advanced or retracted to a second
treatment position spaced longitudinally, or axially, from the
first treatment position and the lower deployment segment 3710B may
be deployed to a deployed configuration such that the electrodes
3701 contact the vessel wall on the opposite side of the vessel.
One or both of the electrodes 3701 may then activated to deliver
energy to the vessel wall. In embodiments where ablative energy is
delivered, one or two lesion zones may be formed at the second
treatment position (depending on whether the electrodes are
monopolar or bipolar and whether one or both electrodes are
activated) that are circumferentially offset from the lesion
zone(s) created at the first treatment position. The embodiment of
the RF electrode treatment catheter 3705 may be used to form 4
longitudinally-spaced treatment zones, alternating on opposite
sides of the vessel lumen, as shown in FIG. 61A. In some
embodiments, the catheter 3705 comprises a distal extension 3709 to
facilitate trackability.
[0373] In one embodiment, instead of providing multiple contact
points in a line along the circumference, one could create contact
points (also shown in FIGS. 37A and 37B) that contact the vessel at
different locations along the vessel's length and/or circumference.
Creating multiple points separated by a distance may enable these
points to resist a torque (because their applied force is separated
by a distance).
[0374] The "ribbon" is not limited to a specific material or
geometric configuration. For example, metallic, polymer, or shape
memory materials may be used. In some embodiments, flat wires
(ribbons) could be replaced with wires or any other geometry (e.g.,
cylindrical, triangular, rectangular, diamond).
[0375] In accordance with several embodiments, applying the
"reaction force" closer to the bending moment and cantilevered tip
reduces the length required to apply the electrode force when
compared to a standard cantilever flex catheter, which may
advantageously improve the repeatability of the applied "electrode
force" in tortuous vessels. Moving reaction forces or contact
points towards the electrode may also increase the stability near
the electrode and reduce electrode movement during use. Increasing
the normal force applied to the vessel may also increase the
stability of the catheter electrode in the target anatomy.
[0376] In some embodiments, instead of applying a moment at the
distal tip of the catheter and relying on a reaction force between
the vessel and a proximal segment of the catheter, one could apply
the reaction force perpendicular to the electrode force (also
interchangeably referred to as the catheter tip force). Referring
now to FIG. 38, a structure comprising four hinge points connected
by members resembling a square or parallelogram could be disposed
at the distal end of a catheter. Assuming the members connecting
these points have a constant length, if two opposite hinge points
are pulled towards each other (e.g., pt1 and pt3) the other pair of
opposite points will move away from each other (e.g., pt2 and pt4).
In one embodiment, this opposing motion could be achieved by fixing
pt1 against the distal end of a catheter and pulling pt3 towards
pt1. The electrode can be placed at one of the other hinge points
(pt2 or pt3) and both of these hinge points can apply a force
against the vessel wall, as illustrated in FIG. 39.
[0377] In one embodiment, as shown in FIG. 40, the hinge points
comprise flexures (e.g., thin, flexible segments connecting larger
segments) or the members and opposite hinge points (pt2 and pt4)
could be replaced by a flexible, continuous length of wire or
ribbon, forming "virtual" or "living" hinges. Using flexible
ribbons 4010 may eliminate the need for explicit hinge points (pt2
and pt4) and it would also eliminate the need for explicit hinges
at pt1 and pt3. Instead, pt1 could be an opening in the catheter
and pt3 could be the bond point for the ribbons. In this
embodiment, the electrode can be fixed on at least of one of the
ribbons in a location substantially in contact with the vessel
wall.
[0378] In accordance with several embodiments, the "reaction force"
vector is opposite of (180 degrees from) the "electrode force" and
the "reaction force" is applied at the same segment of the vessel
as the "electrode force," thereby reducing the length required to
apply the electrode force when compared to a cantilever flex
catheter, and thereby improving the repeatability of the applied
"electrode force" in tortuous vessels. Moving reaction forces or
contact points towards the electrode may also increase the
stability near the electrode and reduce electrode movement during
use.
[0379] In another preferred embodiment illustrated in FIGS. 42A and
42B, a plurality of ribbons may be formed by cutting slits 4205
through the wall of a tube formed of flexible electronics, or
electronic devices mounted on flexible plastic substrate, such as
polyimide. For example, two layers of polyimide having a plurality
of copper or silver leads (preferably at least one) embedded
between the two layers can be rolled into a tube structure,
defining a cylindrical structure. A plurality of openings
(preferably at least one) can be cut into the polyimide layer
comprising the outer surface of the cylinder to define individual
electrodes 4215 that can be connected to a generator, including but
not limited to an electrosurgical (RF) generator in either a
monopolar or bipolar or multipolar fashion. To define the ribbons
described previously, slits 4205 can be cut along substantially the
longitudinal axis of the tube. The tube structure can be mounted on
a catheter as shown in FIGS. 42A and 42B, with marker bands 4210
(e.g., radiopaque marker bands) defining the proximal and distal
extents of the tube structure. In one embodiment, the ribbon or
wire or like device (such as a thin nitinol ribbon) is jacketed
with polyimide in a manner to provide the substrate to mount the
flexible electronics. The nitinol or other higher modulus material,
may provide integrity to an expandable structure while it is in the
expanded and unexpanded states. In one embodiment, a guidewire
housing is disposed at the distal end of the catheter, in
communication with a lumen extending through substantially the
entire length of the catheter. In one embodiment, the catheter
device is passed or introduced over a locking guidewire 4220
containing a detent feature designed to interface with the
guidewire housing, such that moving the guidewire and the catheter
in opposite directions creates a compression force on the tube
structure that causes expansion of the ribbons. The detent may be
designed such that upon exceeding a maximum detent force, the
locking guidewire 4220 is retracted into the guidewire housing. In
this manner, this maximum contact force applied to tissue can be
limited; for example, the detent force (and hence the force applied
to tissue) can be controlled by varying the dimensional
interference defined by an outer dimension of the detent feature
and an inner dimension of the guidewire housing.
[0380] One particular advantage of the embodiment of the flexible
circuit design described above is the ability to isolate the
delivery of energy from the blood flow while still achieving the
beneficial effects of convective cooling from the blood. Because of
the high dielectric properties of flex circuit materials such as
polyimide, polyether ether ketone (PEEK) or polyester, only a thin
layer of material may be required to electrically isolate any one
of the plurality of electrodes from the arterial blood flow,
effectively limiting the amount of energy "lost" to the blood, and
providing a more repeatable and measurable titration of electrical
and thermal energy to the target tissues surrounding the artery. In
some embodiments, the thin construction of the electrical isolation
layer permits enhanced heat transfer from the electrode, through
the isolation layer, and to the arterial blood to limit the
temperature of the electrode, thereby advantageously allowing for
higher power energy delivery, deeper ablations, and reduced
treatment times, for example.
[0381] Referring now to FIGS. 43A and 43B, the force applied to the
vessel wall may also be limited by a torque limiter 4305 in the
handle of the catheter to deploy one or more ribbons of an
expandable structure 4310. For example, the pull wire 4307 might be
wrapped around the capstan of a torque-wrench mechanism having a
pre-defined torque slip value.
[0382] In yet other embodiments, modifications and improvements to
the catheter of the sort described in FIGS. 40-43 are provided. For
example, in one embodiment, instead of using two ribbons (one to
apply the electrode force, the other to apply the reaction force),
multiple ribbons are used to apply the reaction force (e.g., 3, 4,
5, 6 or more contact points against the vessel wall). The "ribbon"
is not limited to a specific material or geometric configuration.
In various embodiments, metallic, polymer, or shape memory
materials may be used. In some embodiments, flat wires (ribbons)
could be replaced with wires or any other geometry (e.g.,
cylindrical, triangular, rectangular, diamond).
[0383] In various embodiments, a stage could be used to support the
electrode, as illustrated in FIGS. 41A and 41B. The stage may be
connected to pt1 (catheter end) with a flexible ribbon and it can
act like pt3 (distal connection point for the other ribbon). In one
embodiment, the stage could be connected to pt1 (catheter end) and
a separate pt3 (distal connection point for the other ribbon) with
a flexible ribbon.
[0384] In one embodiment, instead of applying a moment at a distal
tip of the steerable catheter and relying on a reaction force
between the vessel and a segment of the steerable catheter, one
could force the catheter to bend at specific locations (e.g.,
creating an s-curve) and/or apply larger reaction forces at
multiple locations. Referring now to FIG. 44, multiple bending
moments can be provided that force the catheter into the vessel and
apply a force through the electrode to the vessel wall. The
electrode(s) may advantageously be disposed at locations in contact
with the vessel wall.
[0385] FIG. 45A illustrates an embodiment of a "self-deploying"
catheter 4500 adapted to transition to a shape to facilitate
contact of two electrodes 4502 spaced apart along a length of the
catheter 4500 at treatment locations on opposite sides (e.g., 180
degrees apart) of a vessel wall. As shown, a distal portion of the
catheter is shaped into a generally serpentine shape. The
serpentine or otherwise curved shape extends laterally away from a
generally longitudinal axis, creating an apex which defines a span
dimension. Two electrodes 4502 may be positioned in the distal
portion, one at or near the distal end of the curve, and one at or
near the apex. The catheter 4500 may further include a guide wire
lumen for use with a guide wire 4503. The lumen may be extended
distally with a distal extension 4504, as shown, distal of the
distal electrode to enhance trackability of the catheter. The
distal extension 4504 may transition in lateral stiffness, being
more flexible in the distal direction. In use, the guide wire may
be retracted once the electrodes 4502 are in a desirable location
so as not to hinder the deflection or create electrical anomalies
during subsequent electrical activation of the electrodes 4502. It
may be desirable for the stiffness of the extension 4504, even near
the distal electrode, to be low enough to allow for the extension
to flex easily away from the vessel wall when the catheter is in
its deflected state. The distal extension 4504 may also incorporate
kink resisting structures, such as a coil or braid to prevent
kinking near the distal electrode. The distal extension 4504 may be
constructed of an elastomeric material, such that if it does kink
near the distal electrode, it can recover after the deflection is
reversed.
[0386] One or both of the electrodes 4502 may have a generally
trapezoidal side profile, as shown in FIG. 45B. In order for the
guide wire lumen to remain patent (e.g., not kinked or crimped),
the serpentine shape preferably has smooth curves and not sharp
curves. If the span desired for the serpentine shape is relatively
large in comparison to the longitudinal spacing, the length of the
electrodes 4502 is preferably relatively short to maximize the
available length of the distal portion of the catheter 4500 to take
on the serpentine shape. However, it may still be desirable for the
electrodes to present a relatively large surface area to the
contact the vessel wall. In accordance with one embodiment, a
trapezoidal shape allows for reducing the impact on the serpentine
shape of the catheter while presenting a relatively large surface
to the treatment vessel lumen. Any embodiments of treatment
catheters or devices including electrodes described herein may
incorporate a trapezoidal shape for one or more of the
electrodes.
[0387] One or both electrodes 4502 may be configured with an inner
cavity or hole to facilitate mounting of the electrode 4502 to the
catheter shaft while retaining a substantially cylindrical outer
aspect. In some embodiments, this cavity or hole may be placed
eccentrically so that the contact surface of the electrode lies
farther from the catheter axis. FIG. 45B also shows additional
elements that may be incorporated into any of the embodiments of
treatment catheters or devices having electrodes described herein.
Each electrode may have a lead wire 4512 connecting to it. One or
both electrodes 4502 may have thermocouples or other temperature
sensors connected to them. If an electrode has a temperature sensor
connected to it, one of the lead wires of the sensor may actually
be used to power the electrode as well. Additionally, an internal
lumen for use with a guide wire may be provided. The lumen may be
formed from an internal tube 4514. One or more electrodes may be
mechanically coupled or secured to an outer tube 4515. A coil
structure 4516 between the inner tube 4514 and the outer tube 4515
may be provided for some or all the length of the catheter to
provide kink resistance, and may also be pre-shaped in the
serpentine shape. FIG. 45B shows the distal portion of the
treatment catheter 4500 in a straight configuration, such as when
an internal guide wire (not shown) is present.
[0388] FIGS. 46A and 46B illustrate one embodiment of a catheter
having an s-curve (e.g., having two bends). A hypotube-supported
catheter may be laser cut (as shown in FIG. 46A) to create two
highly flexible sections close to the distal tip and the electrode.
In one embodiment, the two sections are separated by a distance and
are offset by 180 degrees or about 180 degrees, such that the two
sections bend opposite of each other and within the same plane. For
example, the two sections can facilitate 180-degree articulation of
the catheter. In one embodiment, two pull wires 4607A, 4607B run
down the length of the catheter (see FIG. 46B), perpendicular to
the bending plane until they each reach their corresponding
flexible section. Through a pull wire's flex section, the pull wire
runs in the bending plane and along the catheter wall with the flex
cuts. The pull wire may then be bonded to the catheter shaft (e.g.,
just distal to its flex cuts). Orienting the pull wires in this
manner may advantageously prevent or inhibit opposing forces from
each pull wire that would otherwise resist multi-segment,
multi-direction flexing.
[0389] In various embodiments, modifications and improvements to
the device (e.g., catheter) of the sort described in FIGS. 40-43
may be made. For example, some embodiments may comprise one or more
of the following: [0390] 1. Instead of using two pull wires, one
pull wire could be used to cause both bending moments (e.g.,
compression of the inner arc length of each bend). Causing both
bending moments with a single pull wire can be performed, for
example, by placing the pull wire in a spiral pattern along the
inside of the catheter and orienting the pull wire with the flex
cuts or, alternatively, one pull wire could run loosely within the
catheter until the location of the flex cuts, where the pull wire
would enter through loops connected to each of the flex cut
sections. [0391] 2. Instead of using the single pull wire to
compress the inner arc length of each bend, one pull wire could
pass outside of the catheter through a hole, extend outside of the
catheter lumen along a section of the catheter length, and then
re-enter the catheter lumen through a second hole (see, for
example, FIGS. 47A and 47B). In one embodiment, the pull wire is
fixed distal to both holes and can be pulled by a mechanism
proximal to both holes. The catheter may have a flexible region at
least extending proximally and distally from the holes. Upon
pulling the pull wire, the two holes may move towards each other,
thereby causing the catheter to bend in an arc away from the holes.
[0392] 3. Multiple flex sections (>1, >2, >3, >4) could
be used to improve stability and apply force through the electrode
with more repeatability. [0393] 4. Instead of bending in one plane
(because the flex cuts are oriented 180 degrees apart), the
catheter could bend in multiple (e.g., two, three, four or more)
planes. In one embodiment, the catheter bends into a helical shape
(e.g., a pigtail or corkscrew shape). [0394] 5. In one embodiment,
the catheter could be cut or configured so that pulling a distal
point of a pull wire would cause the catheter to elastically
collapse into a coil or helical shape. Once the tension in the pull
wire is released, the catheter may elastically straighten out.
[0395] FIGS. 48A-48C illustrate embodiments of a catheter 4800
having a longitudinal axis and an internal lumen disposed about a
substantial portion of the longitudinal axis. In the illustrated
embodiment, an electrode 4805 is disposed at a distal tip or
towards the distal end of the catheter 4800, with a resiliently
deformable region 4810 disposed proximal to the electrode 4805, a
deflectable or articulatable region 4815 disposed proximal to the
resiliently deformable region 4810, and a torsionally-rigid but
flexible region 4820 (torsionally rigid in at least one rotational
direction) disposed proximal to the deflectable region 4815. The
remaining length of the catheter 4800 (proximal solid tubing
portion 4825) may be substantially torsionally and flexually rigid.
The catheter 4800 may comprise a hypotube with the resiliently
deformable region 4810 and the deflectable region 4815 having a
spine cut pattern and the torsionally-rigid but flexible region
4820 having a spiral cut pattern (interrupted or continuous).
[0396] The dimensional characteristics of each catheter region may
be tailored to the specific anatomy targeted for the
neuromodulation. For example, the catheter 4800 may be used to
access any portions of the arteries illustrated in FIG. 49. In one
embodiment, the catheter 4800 is configured to access and modulate
nerves surrounding (e.g., within a wall of, such as within the
intima, media or adventitia of, or within the perivascular space
around) the common hepatic artery. Treatment of the common hepatic
artery can be particularly difficult due to the tortuosity and
routing variance of the vasculature in this region. In one
embodiment, the diameter of the electrode 4805 is 2 mm (6 Fr) with
a length of 2 mm, though other combinations of electrode diameter
(e.g., 0.5-1 mm, 1-1.25 mm 1-1.5 mm, 1.5-2 mm, 2-2.5 mm, 2.5-3 mm)
and length (e.g., 0.5-1 mm, 1-1.25 mm, 1-1.5 mm, 1.5-2 mm, 2-2.5
mm, 2.5-3 mm) may be desirable. In order to provide and maintain an
effective contact force (such as the contact forces and pressures
described herein) and cantilever support, the length of the
resiliently deformable region 4810, in one embodiment, is covered
with a reflow polymer (e.g., 40D Pebax.RTM. of 35D Hytrel.RTM.,
0.042'' OD.times.0.038'' ID and between 0.250'' and 0.350'' in
length (or alternatively, 30 mm.+-.1 mm in length)). In one
embodiment, the catheter 4800 is configured to repeatably apply an
effective contact force or pressure (e.g., 0.1-100 g/mm.sup.2,
0.1-10 g/mm.sup.2, 5-20 g/mm.sup.2) to the inner wall of the common
hepatic artery. The resiliently deformable region 4810 may be
designed to provide the cantilever support to provide a consistent
and effective contact force or pressure. The catheter 4800 may be
used to deliver 8-14 Watts of power (e.g., 8 W, 10 W, 12 W) for 1
to 4 minutes (e.g., 1 minute, 90 seconds, 2 minutes, 150 seconds, 3
minutes) to deliver energy between 480 J to 2520 J (e.g., about 1
kJ, about 1500 J, about 2000 J) at each ablation or heating
location.
[0397] In order to facilitate contact in the tortuous anatomy of
the common hepatic artery or other arterial branches, increased
ranges of deflection may be required in some embodiments, in
contrast to relatively straight vascular beds such as the renal
artery, where 90 degrees (by definition) is the minimum required
deflection required to deflect a line off of its longitudinal axis
to a point directly perpendicular to the longitudinal axis. In
regions of increased vascular curvature or tortuosity (such as the
vasculature proximate or within the common hepatic artery), the
required deflection angle may be 90 degrees plus an amount
proportional to the radius of curvature of the vessel. For example,
in one embodiment, the deflectable or articulatable region 4815 is
capable of 180 degrees of deflection, as shown in FIG. 50. The 180
degree deflection may advantageously improve the coupling of
reaction forces between the electrode to tissue contact surface
(defining an electrode to tissue contact force/pressure) and
deflectable region segment to tissue contact surface. The coupling
of reaction forces can serve to prevent or inhibit motion of the
distal catheter region within the hepatic artery during
diaphragmatic motion. In some embodiments, in order to ensure that
the deflectable region 4815 can reliably remain wholly within the
length of the common hepatic artery, thereby providing the
appropriate contact force or pressure, the length of the
deflectable region 4815 plus the resiliently deformable region 4810
is less than 2 cm or other length corresponding to the mean common
hepatic artery length (which, from studies has been determined to
be 27 mm.+-.8.5 mm) minus one standard deviation, thereby ensuring
that the majority of common hepatic artery anatomies will be
accessible by the catheter 4800. In some embodiments, this combined
length is between 0.5 and 2 cm. The length of the deflectable
region 4815, in some embodiments, is between about 0.4 inches and
0.5 inches. In one embodiment, a pull wire can be coupled to a
distal end of the deflectable or articulatable region 4815 to
effect deflection, articulation, or steerability.
[0398] One embodiment of the torsionally-rigid yet flexible or
floppy section 4820 is shown in FIG. 48C. The section 4820 may
advantageously include interrupted spiral cuts in a hypotube (e.g.,
stainless steel hypotube) to permit flexural bending for entrance
into the tortuous anatomy of the celiac axis and common hepatic
artery. In some embodiments, the length of the region 4820 is at
least 5.+-.3 cm in order to permit catheter access to a wide range
of variable celiac and common hepatic anatomies found in human
subjects. The embodiment illustrated in FIG. 48C, owing to its
spiral cut hypotube design, is advantageously torsionally-rigid in
at least one direction (or in a preferred direction), as the spiral
is wound when rotated in the counter-clockwise direction and is
measurably stiffer from a torsional perspective. Other tubing cut
designs are possible, including continuous spiral cut and those
with a) opposing double interrupted helix cuts (torsionally rigid
in both directions), b) a pattern of holes drilled through a
transverse axis of the tube, offset along the longitudinal axis of
the tube by an angle (for example, 180 degrees), and other
patterns. In one embodiment, the cut pattern is a spiral cut having
a pitch or spine width of between 0.012'' and 0.015'' (e.g., 012'',
0.013'', 0.014'', 0.015''). In one embodiment, the cut pattern is
uniform along the entire length. In one embodiment, the cut pattern
varies along its length, as shown in FIG. 48A. In one embodiment,
the cut pattern includes a highly flexible interrupted spiral cut
pattern along a first distal portion (e.g., 8.5 cm) and a
transition (either an abrupt or gradual transition) to a less
flexible, wider-pitch interrupted spiral cut pattern along a second
proximal portion (11.5 cm). For example, the pitch of the first
distal portion can be 0.015'' and then gradually transition to a
0.220'' inch pitch. In some embodiments, the transition between the
torsionally rigid yet flexible region 4820 and the solid tubing
proximal region 4825 is supported by a thermoset heat shrink
material (e.g., PET heat shrink tubing) to reduce the chance of
kinking the catheter in this region. In one embodiment, the width
of the cuts is 0.002''; however, the width may range from about
0.001'' to about 0.005'', from about 0.0015'' to about 0.0025'',
from about 0.002'' to about 0.004'', or overlapping ranges
thereof.
[0399] The catheter 4800 may advantageously be configured to have
sufficient push efficiency to push the distal tip and electrode
through at least two tight bends of about 0.5 cm radius. The
catheter length of any of the catheters described herein (including
the catheter 4800) may range from 50 cm to 150 cm (e.g., 50 cm to
100 cm, 80 cm to 120 cm, 90 cm to 130 cm, 100 cm, 110 cm, 120 cm)
in various embodiments. In one embodiment, the catheter 4800 has a
length of 110 cm. In one embodiment, the catheter 4800 comprises a
smooth, low-friction material such as polytetrafluoroethylene
(PTFE). The kink radius of the catheter 4800 may be less than 0.5
cm. The length of the electrode 4805 can be less than 0.25 inches.
In various embodiments, the outer diameter of the catheter 4800 is
less than 8 Fr, less than 7 Fr, 6 Fr or less, or less than 5 Fr.
The electrode 4805 is advantageously flush or substantially flush
with the catheter surface, in one embodiment. In some embodiments,
the electrode 4805 has sufficient torque efficiency provided by the
catheter 4800 to be configured to contact the inner wall of a
vessel at four points (or fewer or more than four points as desired
or required) around the circumference of the vessel (e.g., 4 points
90 degrees apart) after navigating through two or more tight
(approximately 0.5 cm) bends. In various embodiments, the catheter
4800 is configured to deliver energy at multiple locations without
having to reposition the catheter. The catheter 4800 may be
introduced within vasculature through a vascular access system that
includes a guide sheath or a guide catheter and (optionally) a
guide extender. In some embodiments, a temperature-measurement
device (e.g., thermocouple) is bonded to the electrode 4805 by
soldering, spot welding and/or an adhesive.
[0400] FIGS. 48D and 48E illustrate another embodiment of a
catheter 4800 configured to provide uniform and consistent contact
by multiple electrodes 4805 positioned along a length of a distal
end portion of the catheter 4800. The catheter 4800 of FIGS. 48D
and 48E consists of two electrodes; however, other embodiments may
include more than two electrodes (e.g., three, four, five, six or
more than six electrodes). The catheter 4800 comprises a distal
electrode 4805A and a proximal electrode 4805B spaced proximal to
the distal electrode. A deflection mechanism activated with an
internal pull wire may be incorporated.
[0401] Referring to FIG. 48E, an embodiment of an internal
structure to effect deflection is shown. The catheter shaft may
comprise segmented stiffness, or segments having varying degrees of
flexibility or stiffness, to effect the distal deflection. The
primary structural element of the catheter shaft may be a tube such
as a hypotube, wherein a pattern is cut or etched. The deflectable
portion 4806 of the treatment catheter 4800 may incorporate a
slotted pattern with a spine on the side that becomes the outer
portion of the curved deflected portion. The deflectable portion
4806 may have a uniform degree of flexibility determined by the
spacing and width of the slots as well as the material of the
shaft. Proximal of the deflectable portion 4806 is a relatively
flexible region 4808 which may be formed by cutting a spiral
pattern into the tube. The relatively flexible region 4808
comprises a different slot or slit pattern than the deflectable
portion 4806 and may be less flexible than the distal length of the
deflectable portion 4806. The variable flexibility of the catheter
lengths and the positioning of the two electrodes 4805 may be
adapted so as to cause both of the electrodes 4805 to be positioned
against a vessel wall at spaced-apart locations.
[0402] As illustrated, both electrodes 4805 are positioned on the
deflectable portion 4806, with the distal electrode 4805 positioned
at a distal end of the deflectable portion 4806 and the proximal
electrode positioned at a proximal end of the deflectable portion
4806. In some embodiments, both electrodes 4805 are positioned so
that a side of the electrode is flush or generally parallel to a
vessel wall surface. In other embodiments, the distal electrode
4805A may be positioned in generally perpendicular or an oblique
contact with the vessel wall at a first location while the proximal
electrode 4805B is positioned in generally parallel contact with
the vessel wall at a second location. The electrodes 4805 may
comprise monopolar electrodes each separately adapted to apply
power or energy to the vessel wall. In other embodiments, the
proximal electrode 4805B is not positioned on the deflectable
portion 4806 but is positioned on the relatively flexible portion
4808 portion. The catheter shaft may be reinforced with stainless
steel and/or polyimide.
[0403] In some embodiments, the catheter 4800 comprises a guidewire
lumen that is extended distally with a distal extension 4809
extending distal of the distal electrode 4805A to enhance
trackability of the catheter 4800. The distal extension 4809 may
transition in lateral stiffness, being more flexible in the distal
direction. In use, the guide wire may be retracted once the
electrodes 4805 are in a desirable location, so as not to hinder
the deflection or create electrical anomalies during subsequent
electrical activation of the electrodes 4805. It may be desirable
for the stiffness of the distal extension 4809, even near the
distal electrode 4805A, to be low enough to allow for the extension
4809 to flex easily away from the vessel wall when the catheter is
in its deflected state. The distal extension 4809 may also
incorporate kink resisting structures, such as a coil or braid to
prevent kinking near the distal electrode 4805A. The distal
extension 4809 may be constructed of an elastomeric material, such
that if it does kink near the distal electrode 4805A, it can
recover after the deflection is reversed. In some embodiments, the
catheter 4800 comprises an outer sheath or covering 4811.
[0404] In accordance with several embodiments, forcing the catheter
to oppose the electrode force (the secondary s-bend) would reduce
the length required to apply the electrode force and would improve
the repeatability of the applied "electrode force" in tortuous
vessels. Moving reaction forces or contact points towards the
electrode may also increase the stability near the electrode and
reduce electrode movement during use. Increasing the normal force
applied to the vessel may also increase the stability of the
catheter electrode in the target anatomy and increase the amount of
energy delivered to target nerves surrounding (e.g., within a wall
of, such as within the intima, media or adventitia of) the hepatic
artery (e.g., common or proper hepatic artery or other arteries,
veins or other vessels or organs). In accordance with several
embodiments, directing the path of the pull wire as described
herein provides a predictable bending direction for a given
rotational catheter orientation.
[0405] In one embodiment, instead of applying a moment at the
distal tip of the catheter and relying on a reaction force between
the vessel and a segment of the catheter, one could apply the
reaction force perpendicular to the electrode force (previously
referred to as the catheter tip force), and instead of applying the
force at one point, or multiple discrete points, it could be
applied around the circumference of the vessel. For example, a
balloon or stent-like member could be used to apply reaction forces
and electrode forces to the circumference of the vessel. As an
alternative, a "reverse" Tuohy Borst-type mechanism could be used.
A Tuohy Borst is an example of a seal mechanism where a
compressible polymer shaped like a thick hollow cylinder is placed
within a cylindrical sleeve and compressed from either end of the
sleeve. The compression can cause the compressible hollow cylinder
to collapse on itself and reduce its inner diameter. Looking at the
inverse, one could place a compressible hollow cylinder over a rod
and compress it, thereby causing its outer diameter to expand. In
one embodiment, creating longitudinal cuts in the material
exaggerates this mechanism.
[0406] Referring now to FIGS. 51A and 51B, a cylinder 5102 of a
soft and flexible material (e.g., low Young's modulus material such
as silicone or polyurethane) is placed between a catheter shaft
5105 and a distal plug 5110, with a pull rod or pull wire 5107
running through the center of the material. In some embodiments,
one or more electrodes are disposed near or at the mid-point of the
longitudinal length of the cylinder such that the electrode(s) are
exposed beyond the outer surface of the cylinder and are
subsequently brought into contact with the vessel wall upon
expansion of the cylinder. The electrode(s) may be fixed to the
cylinder using an over-molding process or bonded to the cylinder
with adhesive. In various embodiments, the wire(s) connected to the
electrode(s) run along the outer surface of the cylinder, through
the cylinder material (over-molded onto the wires), or inside the
cylinder. In one embodiment, the wire(s) are replaced with a
flexible, printed circuit. Pulling the distal plug 5110 relative to
the catheter shaft 5105 causes the cylinder material to be deformed
outward and brings the electrodes into contact with the vessel
wall. In some embodiments, creating longitudinal cuts in the
material exaggerates this mechanism.
[0407] Applying the reaction force around a circumference in the
same plane as the electrode force may reduce the length required to
apply the electrode force and improve the repeatability of the
applied "electrode force" in tortuous vessels. Moving reaction
forces or contact points towards the electrode may also increase
the stability near the electrode and reduce electrode movement
during use. Increasing the normal force applied to the vessel may
increase the stability of the catheter electrode in the target
anatomy. As compared to the balloon or stent, a slit, "reverse
Tuohy Borst" may enable the designer to direct blood flow to
particular areas and control the mass flow rate through those
areas, as illustrated in FIGS. 52A-52C.
[0408] In the case of denervating the common hepatic artery, unique
vessel tortuosity (e.g., multiple acute turns or bends) can make
force or torque transfer from the proximal end of the device to the
distal end difficult. For example, torque may initially be lost due
to translation of a catheter shaft until it contacts a tortuous
vessel wall, and a pull wire locked in one plane of the catheter
shaft can cause straightening or bending of the shaft through bends
in that plane, leading to a loss of force along those bends prior
to the flexing of the distal segment intended for articulation.
Several embodiments described herein advantageously use a form of
energy that does not experience a loss as it travels through
tortuous bends.
[0409] In some embodiments, mechanism other than pull wires can be
used to actuate structures such as cantilever flex catheters as
described herein. For example, hydraulic or pneumatic means can be
utilized to effect bending of a flex catheter, as illustrated, for
example, in FIGS. 53A and 53B. In some embodiments, a
neuromodulation device (e.g., ablation catheter) is comprised of at
least an electrode 5315, a flexible shaft, and a segment 5318 that
is adjacent to the electrode (e.g., located at the distal end
portion of the device) and that is exposed to a medium surrounding
the shaft and/or to a fluid within the shaft. In one embodiment,
the segment 5318 comprises a compliant balloon 5320 made of a
material with a low elastic modulus (e.g., silicone or
polyurethane) or a balloon made of a less compliant material (e.g.,
Nylon, PET, silicone, etc.) and processed to have circumferential
ribs or folds (e.g., similar to a bendable straw). When the
internal pressure is greater than the external pressure, the
balloon may expand axially. If one side is constrained, the
expansion can cause the balloon and constrained segment to bend
towards the constrained segment or vessel wall.
[0410] Referring now to FIGS. 54A and 54B, in one embodiment, a
neuromodulation device (e.g., ablation catheter) is comprised of at
least an electrode 5415, a flexible shaft, an articulating (e.g.,
expandable) section in communication with a plunger 5417, and two
pressure chambers separated by a seal or plunger. In one
embodiment, at least one chamber is filled with a compressible
fluid or is filled with a non-compressible fluid and is also in
communication with another chamber such as a syringe. In one
embodiment, the plunger 5417 is driven by changing the pressure on
either side of the plunger 5417, thereby transferring energy into
the articulating section that is in communication with the plunger
5417. The articulating section illustrated in FIGS. 54A and 54B may
be similar in structure and/or operation to the structure and/or
operation of the expanding structure illustrated in and described
in connection with FIGS. 42A, 42B, and 43A.
[0411] e. Controlled Lesion Formation
[0412] FIGS. 55A and 55B illustrate an embodiment of a windowed
ablation catheter 5500.
[0413] The windowed ablation catheter 5500 comprises a catheter
body 5505, an inner sleeve 5510 having a first window 5520 and at
least one ablation electrode 5530 and an outer sleeve 5515 having a
second window 5525. FIG. 55A shows a view of the distal end of the
windowed ablation catheter 5500 and FIG. 55B shows a detailed
cut-away view of the distal end of the windowed ablation catheter
5500.
[0414] In some embodiments, the ablation electrode 5530 is disposed
within a lumen of the inner sleeve 5510. The inner sleeve 5510 is
rotatably received within the outer sleeve 5515 such that the outer
sleeve 5515 is rotatable about the inner sleeve 5510. Energy can be
delivered by the catheter by aligning the second window 5525 of the
outer sleeve 5515 with the first window 5520 of the inner sleeve
5510 by rotating the inner sleeve 5510 with respect to the outer
sleeve 5515, or vice-versa. In one embodiment, the inner sleeve
5510 comprises a dielectric covering to provide insulation.
[0415] In some embodiments, when the first window 5520 of the inner
sleeve 5510 and the second window 5525 of the outer sleeve 5515
overlap, the ablating electrode 5530 is exposed to the outside of
the outer sleeve 5515 (which may be placed against the wall of the
target vessel). In one embodiment, energy only reaches the wall of
the target vessel when the first window 5520 and the second window
5525 overlap, or are at least partially aligned. The degree of
overlap may be controlled by the rotation or translation of the
inner sleeve 5510 relative to the outer sleeve 5515. In one
embodiment, the catheter is inserted by a user, the inner sleeve
5510 is turned based on user control, and the outer sleeve 5515 is
turned based on user control, thereby allowing selective
application of energy generated by the at least one ablation
electrode to substantially any portion of the target vessel.
[0416] In some embodiments, the inner sleeve 5510 comprises
multiple openings spaced along the length of the inner sleeve 5510
at different locations. For example, the inner sleeve 5510 may have
openings spaced linearly along the axis of the inner sleeve 5510
and openings rotated about the axis of the inner sleeve 5510. In
one embodiment, the openings of the inner sleeve 5510 define a
spiral pattern. As shown in FIG. 55B, the external surface of the
inner sleeve 5510 and the internal surface of the outer sleeve 5515
may be threaded such that the inner sleeve 5510 is translated with
respect to the outer sleeve 5515 by rotation of the outer sleeve
5515 relative to the inner sleeve 5510. In some embodiments,
relative rotation of the outer sleeve 5515 with respect to the
inner sleeve 5510 serves to both translate and rotate window 5525
of the outer sleeve 5515, sequentially exposing vascular tissue to
the ablation electrode 5535 through each of the openings of the
inner sleeve 5510. In accordance with several embodiments, a
windowed ablation catheter as described herein may facilitate
creation of a spiral lesion along a length of the vessel wall. By
selectively creating openings in the inner sleeve 5510, and
rotating the outer sleeve 5515 with respect to the inner sleeve
5510, substantially any pattern of ablation along a helical path
may be created.
[0417] To improve ablation catheter-vascular wall contact and
thereby improve treatment efficacy, some embodiments include a
window on the distal tip of the ablation catheter, or incorporated
into one or more of the electrode windows, to provide suction (or
vacuum pressure). The suction provided to the lumen wall places the
artery in direct contact with the device to thereby achieve more
efficient and less damaging ablation.
[0418] In accordance with several embodiments, the common hepatic
artery is a target of ablation using an RF electrode catheter. For
some subjects, a length of the common hepatic artery may limit the
number of possible ablation sites. In some embodiments, minimizing
the size of the lesions created along the longitudinal length of
the common hepatic artery increases the number of ablation sites
available within the vessel. In order to decrease the width of the
lesions parallel to the vessel longitudinal axis while maintaining
sufficient depth of the lesions and maximizing a surface of the
electrode exposed to blood flow or cooling fluid for cooling, the
electrode(s) of the RF electrode catheter may be constructed to
have a diameter that is greater than or equal to its length. For
example, if the electrode is generally 6 French in diameter (0.080
inches), then the length of the electrode may be 0.080 inches or
less.
[0419] In accordance with several embodiments, consistency in
lesion size is desired without being dependent on variations in
vessel size, which may vary for the same target vessel across
different subjects. For example, the inner diameter of the common
hepatic artery may vary from 3 mm to 7 mm. In addition, overlap in
lesion formation may be undesirable. Overlap in lesion formation
can be difficult to avoid or prevent if a target treatment length
is sufficiently short (e.g., due to patient anatomy) and multiple
spaced-apart lesions are required to be formed along the vessel
length.
[0420] For situations where there is an intrinsic limit in the
number of ablations that can be performed at a defined spacing due
to patient-specific anatomy limitations, a target vessel may be
stretched out while being ablated. In one embodiment, the target
vessel may be stretched by placing a spring in the vessel during
ablation to stretch the vessel to a desired length and then may be
removed upon completion of ablation. In one embodiment, a balloon
is inserted within the vessel and expanded to straighten and thus
stretch the vessel. The balloon may be a balloon of a balloon
ablation catheter. In some embodiments, the length and the area of
the vessel may be increased by the balloon, resulting in no
increase in resistance of the vessel. In accordance with several
embodiments, stretching of the vessel enables more lesions to be
formed across the length of the target vessel or a portion of the
target vessel at a given spacing, thereby resulting in potential
greater effectiveness of therapy. In some embodiments, because
cells are stretched by the vessel stretching while tissue
conductivity remains constant, the energy plume or cone targets
fewer cells within the vessel wall while still reaching the same
density of nerve fibers within or surrounding the vessel wall
(e.g., within the adventitia).
[0421] Turning to FIGS. 56A and 56B, a metabolic neuromodulation
system 5600 configured to provide consistency in lesion size
regardless of vessel diameter while utilizing a single energy
protocol is illustrated. In one embodiment, the metabolic
neuromodulation system 5600 advantageously allows for a single
ablation protocol to be developed for a full range of vessel
diameters that ensures a desired circumferentiality (e.g., 60-80%
of vessel circumference) while reducing the risk of lesion tail
overlap between spaced-apart lesions (e.g., reduces the risk of
complete circumferentiality due to overlapping lesion zones). In
some embodiments, the metabolic neuromodulation system 5600 may
allow for reduction in the number of lesions necessary to ensure
full circumferential treatment in multiple different planes. The
metabolic neuromodulation system 5600 comprises a single disposable
catheter 5605 with a mechanically-deployable scaffold 5610 having
two opposing contact points 5612A and 5612B. The scaffold 5610 may
be mechanically expanded and retracted by a mechanical pull wire
(not shown). In one embodiment, the scaffold 5610 comprises a
funnel-shaped basket. An electrode may be positioned at the second
contact point 5612B to deliver energy for the purpose of ablation
and a cooling tip may be positioned at the first contact point
5612A 180 degrees opposed to the second contact point 5612B to
facilitate creation of a cooled tissue zone for the purpose of
preventing or inhibiting lesion circumferentiality. In accordance
with several embodiments, the size of the cooled tissue zone would
differ based upon vessel diameter, but would be sufficient to
prevent or inhibit full circumferentiality of the lesion. In one
embodiment, the cooling tip may be facilitated by continuously
infusing cooled liquid through a lumen of the catheter 5605. The
cooling tip may be directed toward the vessel wall adjacent to the
electrode contact area. In this manner, the tissues adjacent to the
electrode contact point may be cooled before, during, and/or after
the electrode is energized or activated. In embodiments that employ
modalities other than RF, the cooling tip may also be used. In
embodiments that employ cryotherapy (such as cryoablation), warming
elements/fluids may be introduced instead.
[0422] In some embodiments, the cooling tip of the catheter 5605
advantageously creates a cooled zone that is 180 degrees in
opposition to the site of ablation during energy delivery to ensure
that the "tails" of the C-shaped lesions do not touch or overlap,
regardless of vessel diameter. The circumferential extent of the
cooled zone can be variable as long as it is cool enough to prevent
or inhibit lesion formation across the entire vessel circumference
regardless of vessel size. In some embodiments, the cooled zone
prevents at least 10% of the vessel circumference from being
ablated regardless of vessel diameter. In some embodiments, the
cooled zone prevents at least 20% of the vessel circumference from
being ablated regardless of vessel diameter. FIG. 56B schematically
illustrates treatment zones 5625 and cooled zones 5630 for vessels
having diameters of 3 mm, 5 mm and 7 mm.
[0423] FIG. 57 schematically illustrates a metabolic
neuromodulation system configured to provide controlled
circumferentiality of lesions, thereby allowing for creation of two
opposing lesions in the same plane while preventing or reducing the
likelihood of circumferentiality or overlap of the two lesions. The
neuromodulation system may comprise a single disposable catheter
having an energy source 5702 (e.g., electrode) surrounded by
shielding material or a shielding structure 5704 configured to
cause directional energy delivery that creates an asymmetric
lesion. The neuromodulation system may include instructions stored
on a non-transitory computer-readable medium that, upon execution
by a processor or other computing device, cause delivery of an
energy protocol that allows for the creation of two opposing
lesions in the same plane while ensuring that lesion borders do not
touch or overlap across a range of representative vessel inner
diameters (e.g., 3 mm-7 mm). FIG. 57 schematically illustrates
examples of lesions formed for vessels having inner diameters of 3
mm (FIG. 57D), 5 mm (FIG. 57B) and 7 mm (FIG. 57C).
[0424] The embodiments illustrated in FIGS. 56A,B and 57 may allow
for (1) increased lesion-to-length ratio without increase in risk,
(2) a single ablation protocol to be developed for a full range of
vessel diameters that ensures optimal (e.g., 50-80%)
circumferentiality while eliminating or reducing the likelihood of
risk of lesion tail overlap, (3) improved predictability of lesion
circumferentiality regardless of vessel diameter, and (4) patients
with smaller vessel (e.g., common hepatic artery) lengths to be
treatment candidates. Other devices may also be configured to
provide like performance across variable patient anatomy.
[0425] FIG. 58 illustrates an embodiment of an intravascular RF
ablation catheter 5800 configured to prevent or reduce the
likelihood of circumferentiality due to formation of multiple
lesions within a single cross-sectional slice around a vessel wall.
In one embodiment, the RF ablation catheter 5800 may provide
assurance that energy is delivered in a manner that does not
involve heating or ablation of more than 75% of the adventitia in
any cross-sectional slice of the vessel. The RF ablation catheter
5800 comprises an expandable frame or scaffold 5805 configured to
contact the vessel wall at spaced-apart locations around a
circumference of the vessel. The expandable frame or scaffold 5805
comprises two treatment members or loops 5810 spaced 180 degrees
apart from each other having electrodes 5815 positioned at vessel
contact points along the members and two cooling members or loops
5820 spaced 180 degrees apart from each other and spaced 90 degrees
apart from the two treatment members or loops 5810 having the
electrodes 5815. The total number of members or loops of the
expandable frame or scaffold 5805 may vary (e.g., 2, 4, 8) and the
number of treatment members or loops 5810 and the number of cooling
members or loops 5820 may vary. For example, the expandable frame
or scaffold 5805 may comprise three treatment members or loops 5810
and one cooling member or loop 5820. The members or loops may
comprise flexible splines, tines, arms, or the like. The expandable
frame or scaffold may form a basket-like scaffold. The members or
loops may be spaced in a uniform manner or a non-uniform manner.
The treatment members and cooling members may alternate
consecutively or may not alternate consecutively. In some
embodiments, the catheter 5800 comprises one or more expandable
members. The expandable member may be constructed of members that
expand in a basket form. In the expanded form, the members may
contact the vessel wall. The individual members of the basket can
include at least one cooling channel configured to cool the vessel
wall and at least one member with one or more RF electrodes that
transfer RF energy into the vessel wall via contact. Multiple
cooling members or electrode members can be configured to effect
the desired ablation result. In one embodiment, the expandable
member comprises a balloon that is expanded with cooling fluid and
electrodes mounted on the surface of the balloon or an expandable
basket that include RF electrodes mounted thereon. In various
embodiments, the cooling fluid may be contained within the cooling
members or released from the cooling members toward the vessel
wall.
[0426] In accordance with several embodiments, lesions may be
coordinated and positioned to provide continuous oblique
circumferential lesions without creating a circumferential lesion
at any one location or cross-sectional slice. In some embodiments,
both the position and the extent of the lesions are controlled. The
lesions may be placed 180 degrees apart and displaced axially along
the vessel length. In some embodiments, the circumferential and
axial extent of the lesion are controlled so that the margins of
the lesions just intersect at a location 90 degrees on either side
of the energy delivery element (e.g., electrode) positions. In some
embodiments, a reference electrode may be positioned between the
lesions to measure temperature or impedance to detect lesion
intersection. In some embodiments, lesions are spaced between 1-50
mm apart (e.g., 1, 5, 10, 12, 15, 20, 25, 50 mm, and overlapping
ranges thereof). Lesions may be overlapping or non-overlapping. In
one embodiment, multiple foci or ablation sites, which may or may
not overlap, are created to generate lines of thermal injury. The
foci or sites can be spaced at 0.2 mm to 20 mm apart (e.g., 0.2 mm
to 2 mm, 5 mm to 15 mm, 10 mm to 20 mm, 1 mm to 12 mm, or
overlapping ranges thereof). In some embodiments, lesions are
non-circumferential. In some embodiments, lesions are
circumferential, including off-set circumferential, partially
circumferential, and fully circumferential. In various embodiments,
lesions may be spaced between 1 to 15 times the electrode diameter.
For example, for electrodes having diameters of 1 or 2 mm, the
electrodes may be spaced from 1 mm to 30 mm apart (e.g., 1 to 12
mm, 5 to 15 mm, 10 to 20 mm, and overlapping ranges thereof).
Lesion spacing may be adjusted based on vessel diameter. The number
of ablations may also vary based on vessel diameter.
[0427] Because catheter tip temperature and impedance alone may be
poor indicators of tissue temperature or lesion size, tip
temperature and impedance may both be measured during ablation in
order to monitor lesion development and/or to confirm lesion
formation, thereby providing confirmation of denervation of target
nerves.
[0428] Initially, tip temperature increases and impedance
decreases. Tissue conductivity increases with temperature up to a
certain threshold (e.g., approximately 80 degrees Celsius). Above
this threshold temperature, tissue may begin to contract and
desiccate and impedance may start to increase instead of decrease.
The decoupling of temperature and impedance may be used as an
indication of lesion formation to confirm denervation. If impedance
begins to increase without a corresponding decrease in tip
temperature, this may be used as an end point or as confirmation of
lesion formation. The time of decoupling of temperature and
impedance may also be used as feedback to trigger other changes in
an energy delivery protocol, such as decreasing power or increasing
cooling.
[0429] Turning to FIG. 59, a shaft or frame of an RF ablation
catheter may be configured to ensure that a longitudinal axis 5905
of an electrode 5910 is not in the same plane as the vessel
longitudinal axis 5915. For such a configuration, the longest
dimension of the lesion created by the electrode may not be
parallel to the vessel longitudinal axis 5915, as schematically
illustrated in FIG. 59. In one embodiment, in order to orient an
electrode 5910 off the vessel longitudinal axis 5915 for a catheter
having a single distal electrode, a shaft of the catheter may be
configured to form a spiral on the distal end, which may tilt the
electrode 5910 out of the vessel's longitudinal plane.
Alternatively, a pre-shaped shaft can be employed that shifts from
a relatively straight to a non-straight orientation with the
insertion or removal of a mandrel or guidewire. For multiple
electrode catheter approaches, a basket or scaffold comprising a
plurality of electrodes disposed around the basket or scaffold may,
when actuated, be configured to hold the electrodes off axis.
[0430] In some embodiments, complete circumferential ablation of a
vessel may be prevented or inhibited by spacing ablation sites
radially at 90 degree intervals as opposed to at 180 degree
intervals. FIG. 60 schematically illustrates ablation performed at
180 degree intervals and at 90 degree intervals. As shown, even if
the 180 degree intervals are spaced apart axially along the length
of the vessel, the "tails" of the ablation lesions could
potentially overlap on both sides of the vessel (assuming that each
ablation forms a lesion that extends around 180 degrees of the
vessel circumference), thereby forming a complete circumferential
lesion. When 90 degree intervals are used, there may potentially be
overlap between adjacent lesions but the risk of complete vessel
circumferentiality of the overall lesion composed of the multiple
lesions is reduced. A single or multi-point RF ablation catheter
may facilitate radial spacing of ablation sites by approximately 90
degrees and longitudinal spacing of at least one electrode length.
In some embodiments, radial spacing of the ablation sites by 90
degrees causes less than complete circumferential ablation of the
vessel (e.g., 75%-95%, 70%-90%, 65%-80%, 75%-90%, or overlapping
ranges thereof). In some embodiments, treatment sites (e.g.,
ablation sites) may be spaced 120 degrees apart circumferentially
(for example, if the energy delivery device includes three
electrodes).
[0431] In accordance with several embodiments, the systems and
methods described herein advantageously increase the perivascular
ablation size and nerve impact while decreasing vascular wall
injury and adjacent structure involvement. For example, for RF
electrode embodiments, the electrode shape and energy delivery
parameters may be designed to maximize or increase the perivascular
ablation area and nerve impact while minimizing vascular wall
injury and adjacent structure involvement. In various embodiments,
an energy delivery device consisting essentially of a single
electrode is used. In other embodiments, an energy delivery device
consisting essentially of two and only two electrodes is used. In
some embodiments, an energy delivery device consisting essentially
of four and only four electrodes is used. In other embodiments, an
energy delivery device consisting essentially of three and only
three electrodes is used. In yet other embodiments, an energy
delivery device consisting essentially of five and only five
electrodes is used.
[0432] With reference to FIG. 61A and FIG. 61B, ablation patterns
may advantageously increase the overall perivascular ablation
volume while maintaining little to no thermal damage or
endothelialization (e.g., less than 20% mean maximum circumference
of vessel injury, no internal elastic lamina disruption, no
arterial dissection, and/or no clinically significant neointimal
formation, no long-term vascular stenosis, no circumferential
vessel wall injury) to the portions of the vessel wall in contact
with an ablation member (e.g., electrode, transducer). FIG. 61A
illustrates one embodiment of an ablation pattern comprising four
spaced-apart ablation locations 6105A-6105D. The ablation locations
are spaced apart at an equal distance X and each ablation location
is offset by 180 degrees from the next location. In some
embodiments, the spacing between the locations is determined by a
minimum threshold and the spacing does not necessarily have to be
equal (just above the minimum threshold spacing). The minimum
threshold spacing (between center points of lesion zones) may be
between 2 and 8 mm (e.g., between 2 and 4 mm, between 3 and 6 mm,
between 4 and 8 mm, between 3 and 7 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6
mm, 7 mm, 8 mm, overlapping ranges thereof or any value of or
within the ranges). In some embodiments, the minimum threshold
spacing depends on anatomical limitations of target vessel length.
For example, for the common hepatic artery, spacing is 4 mm or 6 mm
in accordance with several embodiments. The spacing described with
respect to FIG. 61A may be used for spacing of electrodes in any of
the embodiments described herein. For devices having deployed
configurations, the spacing may be the spacing when the devices are
in the deployed configuration in contact with a vessel wall.
[0433] FIG. 61B illustrates a schematic representation of the
lesion zones 6110A-D formed by ablation at the four locations shown
in FIG. 61A. As shown, the combination of the spacing and
180-degree offset increases perivascular lesion blending to provide
larger circumferential perivascular injury along the vessel length,
thereby increasing the likelihood of efficacy, while avoiding
circumferential vessel wall injury. Factors of electrode size,
power, duration and level of contact may also contribute to
efficacy. In accordance with several embodiments, the individual
ablation point and subsequent lesion zone is influenced by the
electrode size and shape, the energy algorithm applied by the
ablation system, vessel diameter, vessel wall thickness, and blood
flow rates. The spacing between the ablation points facilitates the
blending or separation of the individual lesion zones in the vessel
wall and the perivascular space. In accordance with several
embodiments, increasing the space between ablation points reduces
(e.g., minimizes) lesion zone blending while decreasing the space
between ablation points increases (e.g., maximizes) lesion zone
blending. When creating a lesion zone for disruption of nerves
surrounding a vessel it is desirous to reduce (e.g., minimize) the
lesion zone within the vessel wall and increase (e.g., maximize)
the lesion zone in the perivascular space. Optimization of lesion
zone blending increases the likelihood of a 360 degree (or near 360
degree) circumferential perivascular lesion zone while reducing the
likelihood of circumferential vessel wall injury along the length
of the treated vessel, thereby avoiding vascular stenosis. The
frequency of 360 degree circumferential perivascular ablation zones
along the length of the vessel can be increased while holding the
vessel wall injury constant by reducing the distance between the
ablation points from 8 mm or more (e.g., 8 mm, 9 mm, 10 mm, 11 mm,
12 mm) to 6 mm or less (e.g., 6 mm, 5 mm, 4 mm, 3 mm, 2 mm) within
a vessel diameter range while holding the electrode diameter and
length (e.g., electrode area of between 3 mm.sup.2 and 16 mm.sup.2
(e.g., between 3 mm.sup.2 and 6 mm.sup.2, between 4 mm.sup.2 and 8
mm.sup.2, between 4 mm.sup.2 and 10 mm.sup.2, between 6 mm.sup.2
and 8 mm.sup.2, between 8 mm.sup.2 and 12 mm.sup.2, between 10
mm.sup.2 and 16 mm.sup.2, 4 mm.sup.2, 6 mm.sup.2, 8 mm.sup.2, 10
mm.sup.2, overlapping ranges thereof or any value of or within the
recited ranges) and energy algorithm constant (e.g., from 500
J/ablation point to 2000 J/ablation point, from 500 J/ablation
point to 1000 J/ablation point, 1000 J/ablation point to 2000
J/ablation point, 500 J/ablation point, 1000 J/ablation point, 1200
J/ablation point, 1600 J/ablation point, 2000 J/ablation point). In
accordance with several embodiments, the pattern (including point
spacing, electrode size, energy algorithm, circumferential offset)
is configured to produce ratios of circumferential perivascular
injury to circumferential vessel wall injury of greater than or
equal to 2:1 (e.g., 5:1, 4:1, 3:1, 2:1). In some embodiments, the
pattern may also include level of contact (such as indentation
depth or contact force). For example, indentation depth may range
from 0-1 mm (e.g., 0.1 mm to 0.3 mm, 0.2 mm to 0.4 mm, 0.3 mm to
0.6 mm, 0.4 mm to 0.8 mm, 0.6 mm to 1 mm, overlapping ranges
thereof or any value of or within the recited ranges). Contact
force may range from 1 to 15 grams of force (gmf) (e.g., between 1
and 5 gmf, between 5 and 10 gmf, between 10 and 15 gmf, overlapping
ranges thereof or any value of or within the recited ranges). In
some embodiments, each ablation point is offset by 180 degrees. In
other embodiments, the circumferential offset is between 90 and 180
degrees (e.g., between 90 and 130 degrees, between 100 and 140
degrees, between 110 and 160 degrees, between 130 and 180 degrees,
overlapping ranges thereof or any value of or within the recited
ranges).
[0434] One embodiment of a treatment configuration in a treatment
vessel, such as the common hepatic artery, is to treat two or more
zones (e.g., two, three, four, five, six, more than six) that are
longitudinally and/or rotationally spaced from each other. In some
instances it may be advantageous to treat two or more zones wherein
adjacent zones are both longitudinally and rotationally spaced from
each other, such as shown in FIG. 61A. Such a series of treatment
zones may be created with single electrode embodiments, by
manipulations of the electrode both longitudinally and
rotationally. In some cases it may be desirable to include two or
more electrodes that tend to align along opposing quadrants (or
sides) of the lumen of treatment vessel. This may be particularly
beneficial if multiple non-overlapping treatment zones, such as
described in FIG. 61A, are desired.
[0435] In various embodiments, the electrode(s) is/are
approximately 0.5 mm to 5 mm in diameter (e.g., 0.5 mm, 1 mm, 1.5
mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm or any diameter
within the recited range). The electrode(s) may have a length of
between 1 mm and 4 mm (e.g., 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4
mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm,
2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1
mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 2.7 mm, 3.8 mm, 3.9 mm,
4.0 mm), between 2.5 mm and 3.0 mm, between 2.6 mm and 2.9 mm,
between 2.7 mm and 3.0 mm, between 3.0 mm and 3.5 mm, between 3.5
mm and 4.0 mm, between 2.0 mm and 2.5 mm, or overlapping ranges
thereof. In some embodiments, the ratio of electrode length to
electrode diameter is 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1,
1.7:1, 1.8:1, 1.9:1, or 2:1. In some embodiments, the electrode(s)
comprise cylindrical (e.g., rounded) or non-cylindrical (e.g.,
curved, slotted) electrodes.
[0436] In one embodiment, an electrode catheter consists
essentially of a single rounded electrode at a distal tip of a
deflectable or steerable catheter shaft. The electrode may be
coupled to a flexible shaft segment that enables, in a deflected
shaft state, for the side of the electrode to generally lay in
parallel with the vessel wall to provide a stable contact area. The
diameter of the electrode may enable a consistent and large contact
area with the vessel wall, thereby minimizing the ability of the
operator to bury the electrode into the vessel wall. The vessel
contact area and the remaining surface area may advantageously
allow for effective energy transmission into the vessel wall while
maintaining a controlled tip temperature with an energy algorithm
that steps energy up to 10 watts and monitors electrode temperature
to modulate energy delivery during the treatment cycle. The energy
delivery parameters may fall within the ranges of those described
herein.
[0437] In accordance with several embodiments, the systems and
methods described herein utilize a single electrode, two electrodes
or four electrodes having a size and shape and energy delivery
parameters that affect on average 5-30% (e.g., 5-10%, 10-15%,
15-20%, 20-25%, 25%-30% or overlapping ranges thereof) of the
vessel wall circumference (e.g., common hepatic artery wall
circumference) and between 40% and 80% (e.g., 40-60%, 45-55%,
50-60%, 60-85%, or overlapping ranges thereof) of perivascular
circumference at depths of about 5 mm, thereby impacting a large
number of nerves per ablation (by achieving larger ablation zones)
while using fewer total ablations within the patient's artery to
achieve a desired treatment effect. Because the length of the
common hepatic artery is only 30 mm on average, embodiments
targeting the common hepatic artery the number of ablations that
can be performed over the length of the common hepatic artery is
constrained. Accordingly, it is advantageous to reduce the number
of ablations and increase the effectiveness of the ablations when
targeting this anatomy while still reducing or limiting damage to
the vessel wall. In accordance with several embodiments, RF
ablation catheters described herein maintain proper contact
conditions to initiate or complete energy cycles required for
successful ablations, thereby reducing the number of ablation
cycles or placement locations despite the constrained vessel
length.
[0438] FIGS. 62A and 62B illustrate an embodiment of a treatment
catheter 6200 and positioning method that incorporates use of
lesion spacing indicators 6202 to aid in the positioning of the
treatment catheter 6200 when it is desired to position the
treatment catheter 6200 at multiple locations to create multiple
treatment zones, for example as shown in FIGS. 61A and 61B. The
lesion spacing indicators and technique described could be
incorporated into any embodiment of neuromodulation device (e.g.,
treatment catheter, ablation catheter or device) described herein,
whereby the neuromodulation device (e.g., treatment catheter) would
be repositioned to create multiple treatment zones 6204. The
treatment catheter 6200 includes multiple electrodes 6205 (in this
case, two electrodes) that, when in the deployed configuration, are
longitudinally spaced by a separation distance of L, and contact
the vessel on opposing sides of the vessel (e.g., offset by about
180 degrees). The treatment catheter 6200 may include two lesion
spacing indicators 6202, and may be secured on the distal end
portion of the treatment catheter 6200 distally of the electrodes
6205. The spacing of the lesion spacing indicators 6202 may be of a
predetermined relationship to the longitudinal spacing (when
deployed) of the electrodes 6205. In this case, the spacing of the
lesion spacing indicators 6202 is twice the length L (or 2L). As
shown, the treatment catheter 6200 includes one electrode on a
deflectable portion and one electrode on a non-deflectable portion;
however, in other embodiments, both electrodes 6205 may be
positioned along a deflectable portion or along a non-deflectable
portion.
[0439] In use, the treatment catheter 6200 can be positioned within
a desired treatment vessel with the aid of fluoroscopic
angiographic imaging. Once positioned at a desired first location
within the vessel (for example as shown in FIG. 62A), the
electrodes 6205 are activated to create a first set of treatment
zones 6204A, such as lesion zones, at contact locations of the
electrodes 6205 with the vessel wall. The treatment catheter 6200
is re-positioned to a second location (in this case withdrawn) by
positioning the distal lesion spacing indicator 6202B where the
proximal lesion spacing indicator 6202A was previously. Once
deployed, the electrodes 6205 are activated a second time to create
a second set of treatment zones 6204B (as shown in FIG. 62B). In
this manner, four relatively equally spaced treatment zones, on
alternating opposing sides of the vessel are created.
[0440] When the treatment catheter is in the first position (e.g.,
the position shown in FIG. 62A), it may also be advantageous if a
corresponding anatomic landmark is noted on the fluoroscopic or
angiographic image (for example, a side branch adjacent the
proximal marker 6202A). If a "roadmap" is created from this first
angiographic image, the treatment catheter 6200 can be repositioned
to the second location with only the use of fluoroscopic imaging
"on top" of the roadmap, without the need of additional contrast
delivery. The radiopaque markers 6202 can also be useful in the
case of digital subtraction angiography. In this embodiment, a
ghost image of the lesion spacing indicators 6202 can be created
when the treatment catheter 6200 is in its first location.
Repositioning to the second location can be accomplished without
need of additional contrast delivery.
[0441] While two lesion spacing indicators, such as radiopaque
marker bands, distal of the electrodes 6205 have been described, it
is contemplated that the lesion spacing indicators could also be
proximal of the electrodes, one of the electrodes 6205 could also
be used as one of the lesion spacing indicators, as long as the
electrode is fluoroscopically visible. Portions of the catheter
shaft that incorporate radio dense materials could also be
used.
[0442] In the above embodiment in which two electrodes when
deployed are in a longitudinally spaced arrangement, but on
opposing sides of the vessel, the lesion indicator spacing is
advantageously twice the electrode spacing. However, in some
embodiments in which the deployed electrodes may be longitudinally
spaced, but on the same side of the vessel, the spacing between the
lesion spacing indicators is advantageously equal to the spacing or
half the spacing between the electrodes. The spacing between the
electrodes may vary depending on vessel diameter. In other
embodiments, the first two lesion zones 6204A are on the same side
of the vessel and the second two lesion zones 6204B are on the
opposite side of the vessel, with the treatment catheter 6200 being
rotated to the opposite side of the vessel and positioned such that
the distal electrode is positioned axially between the first two
lesion zones 6204A, as may be determined by a spacing between and
positioning of the lesion spacing indicators.
[0443] In accordance with several embodiments, controlled electrode
deployment is desired to achieve consistent electrode positioning,
contact force and orientation. Various means for controllably
releasing and recovering multiple elastic or deformable electrode
support members are described herein. In several embodiments, the
means for controllable releasing and recovering electrodes
functions even when an electrode is very close to (e.g., within 5
mm) a distal terminus of a guide catheter. In some embodiments the
orientation of an electrode deployment arm and/or an electrode
deployment sheath may be reversed to permit an electrode to be
positioned proximate to a distal terminus of a guide catheter. In
several embodiments, an actuation coupling element is provided to
actuate the electrode deployment arms or sheath from the distal
direction.
[0444] For example, FIGS. 63A to 63C illustrate various embodiments
of deployment sleeve systems for providing multiple electrodes
deployed laterally along a shaft without increasing profile. One or
more electrodes 6305 may be mounted on elastic flexural elements
that may be deployed to contact a vessel wall. FIGS. 63A-1 and
63A-2 illustrate embodiments of coaxial electrode deployment sleeve
systems 6300. The deployment sleeve system 6300 of FIG. 63A-1
comprises a single inner sleeve 6302 and a coaxial outer sleeve
6304 that are independently adjustable to control electrode
deployment. The first electrode deployment arm is coupled to a
common support element 6308 by a rail member. The second electrode
deployment arm is not surrounded by an inner sleeve and is deployed
by retraction of the outer sleeve 6304. The deployment sleeve
system 6300 of FIG. 63A-2 comprises two inner sleeves 6302 slidably
coupled to the common support element 6308 by rail sections 6306.
The common support element 6308 may be a guide wire. FIG. 63B
illustrates an embodiment of a dovetail electrode deployment sleeve
system 6300'. The deployment sleeve system 6300' comprises two
inner sleeves 6302 that are independently advanceable within the
outer sleeve 6304. The two inner sleeves 6302 are coupled to each
other in a dovetail manner. The two inner sleeves can be translated
with respect to each other to position the electrodes 6305 such
that they are spaced apart axially along the length of the vessel
or such that they are aligned axially along the length of the
vessel but offset by 180 degrees. FIG. 63C illustrates an
embodiment of a side-hole sleeve deployment system 6300''. The
sleeve 6302 may have a plurality of side holes 6312 designed to
allow for deployment and recovery of a plurality of electrodes (as
illustrated) or may have a single side hole for deployment and
recover of a single electrode. For embodiments involving multiple
electrodes or electrode deployment members, the electrodes may be
independently adjustable to provide offset spacing
circumferentially and/or axially. In some embodiments, the
sleeve(s) and/or guide wires may be formed to permit nesting of
electrodes and the electrodes may be slotted to nest over the
sleeve or guide wire. The orientation of the various embodiments
illustrated in FIGS. 63A-63C may be reversed to facilitate
treatment of sites very close to a distal terminus of a guide
catheter.
[0445] In one embodiment, a deployment sleeve is actuated by
hydraulic pressure. For example, the sleeve may comprise a rolling
membrane. An electrode on the hydraulic sleeve may be recovered by
mechanical tension after hydraulic deployment.
[0446] f. Multi-Electrode Devices
[0447] FIGS. 64A to 64K illustrate various embodiments of
multi-electrode energy delivery devices. As illustrated, the energy
delivery devices may consist essentially of two electrodes or four
electrodes. In various embodiments, the electrodes and the energy
delivery parameters are designed such that more than two or more
than four electrodes, respectively are not required to achieve
successful modulation of nerves (e.g., denervation or ablation of
nerves in the perivascular area of the hepatic arteries, such as
the common hepatic artery, the proper hepatic artery, the right
hepatic artery, the left hepatic artery). In accordance with
several embodiments, the energy delivery devices provide uniform
contact characteristics, thereby achieving consistent ablation
performance with maximal contact customization per catheter
placement.
[0448] FIGS. 64A to 64D illustrate undeployed and deployed states
of embodiments of multi-electrode delivery devices. FIGS. 64A-1 and
64A-2 illustrate undeployed and deployed configurations of a distal
portion of a multi-electrode catheter 6400 having two button
electrodes 6405. The button electrodes 6405 may be radially
deployed mechanically or hydraulically from the catheter surface by
expelling the electrode shafts outward as a result of an expansion
member 6410 within the catheter shaft. The expansion member 6410
may be a balloon, an expandable mechanical scaffold or frame or
other expandable member or structure that, upon expansion or other
actuation, expels the electrodes 6405 to a deployed state against
the vessel wall. The expansion member 6410 provides a uniform
outward pressure on the electrodes 6405. The electrodes 6405
comprise a coil spring 6415 or another control element (e.g.,
compression and/or tension member) surrounding the electrode shaft
surface contained within the catheter shaft in the un-deployed
state. The coil springs or other control elements (e.g., force
limiting and/or force restoration structures) may advantageously
limit the maximum outward force an electrode can project and enable
the electrode to return to the un-deployed state once the internal
expansion member is returned to the non-actuated (e.g., unexpanded)
state. The multi-electrode catheter may be an over-the-wire
catheter or a steerable catheter. The multi-electrode catheter 6400
may advantageously provide one or more of the following benefits:
(i) simultaneous and balanced electrode deployment; (ii) reduces
the exposed length of catheter beyond a guide catheter or sheath
tip required for electrode deployment against the vessel wall;
and/or (iii) enables the ability to independently limit the
electrode contact force.
[0449] Some embodiments of multi-electrode delivery devices
comprise pairs of electrode deployment arms placed along a catheter
shaft. The electrodes can be deployed by a number of mechanisms,
such as (1) a retractable sheath which releases the deployment arms
to self-expand into the deployed state, (2) a retractable tip that
mechanically separates and radially expands the deployment arms to
ensure electrode contact with the vessel; and/or (3)
pullwire-activated deployment arms that include structures that
elastically deform into a predetermined shape enabling contact of
the electrodes with the vessel wall.
[0450] FIGS. 64B-1 and 64B-2 illustrate undeployed and deployed
configurations of an embodiment of a multi-electrode catheter 6400
having a retractable sheath 6402 to facilitate deployment of
multiple electrodes 6405. The multiple electrodes 6405 are coupled
to ends of individual deployment arms 6406 that include structures
that elastically deform into a predetermined shape, thereby
enabling contact of the electrodes 6405 with the vessel wall. The
electrode deployment arms 6406 may comprise shape memory material
that automatically transitions to a preformed shape upon retraction
of the retractable sheath 6402. As shown, the multi-electrode
catheter may comprise a core member 6407 having a distal tip sized
to interface with the distal end of the retractable sheath 6402.
The core member 6407 includes a central lumen to facilitate
over-the-wire advancement. In other embodiments, the core member
6407 does not include a central lumen. The retractable sheath 6402
and the core member 6407 may be independently controlled and moved
with respect to each other.
[0451] FIGS. 64C-1 and 64C-2 illustrate undeployed and deployed
configurations of an embodiment of a multi-electrode catheter 6400
having a retractable catheter tip 6403 configured to mechanically
separate and radially expand electrode deployment arms 6406 to
facilitate uniform electrode contact with the vessel wall. Similar
to multi-electrode catheter of FIG. 64B, the multi-electrode
catheter of FIG. 64C comprises a retractable sheath 6402. However,
the electrode deployment arms 6406 in this embodiment are not
automatically deployed upon retraction of the retractable sheath
6402 or actuated by a pullwire. In the illustrated embodiment, the
electrode deployment arms are separated and expanded outward toward
the vessel wall by retraction of the catheter tip 6403 in a
proximal direction. The catheter tip 6403 may be coupled to an
inner member (e.g., wire, tether, shaft) that may be pulled in a
proximal direction. The orientation of the various embodiments
illustrated in FIGS. 64A-64C may be reversed to facilitate
treatment of sites very close to a distal terminus of a guide
catheter.
[0452] FIGS. 64D-1 and 64D-2 illustrate undeployed and deployed
configurations of an embodiment of a multi-electrode catheter 6400
having multiple pullwire-activated electrode deployment arms 6406
that include structures that elastically deform into a
predetermined shape, thereby enabling uniform contact of the
electrodes 6405 with the vessel wall. The electrode deployment arms
6406 comprise biased slotted hypotubes or microtubes. In the
illustrated embodiment, a distal segment of the electrode
deployment arms 6406 have slots or slits configured to cause the
distal end of the electrode deployment arms 6406 to elastically
deform into a predetermined shape. The electrode deployment arms
6406 each comprise a "soft", or flexible, segment 6408 just
proximal of the electrode attachment point designed to enable a
pivot of the electrode such that the side of the electrode is at
least substantially parallel with the vessel wall. In accordance
with several embodiments, the soft segment 6408 may advantageously
limit the maximum force the electrode can exert on the vessel in
the fully deployed state. The electrode deployment arms may be
collectively actuated by a single pullwire 6401 or individually
actuated by separate pullwires 6401.
[0453] FIG. 64E illustrates an embodiment of a multi-electrode
catheter 6400 configured to provide uniform and consistent contact
by the multiple electrodes. The multi-electrode catheter 6400 is an
over-the wire catheter comprising a lever arm 6409 having a central
pivot point 6411 and two electrodes 6405, one electrode positioned
at each end of the lever arm 6409. Torque is applied by any one or
more torque application mechanisms. In various embodiments, the
torque application mechanism may convert linear motion to
rotational motion. Such mechanisms may include but are not limited
to one or more of the following: pulley, rack and pinion, Scotch
Yoke, Crank shaft, ball screw, lead screw, and/or cam follower. In
some embodiments, the linear to rotational mechanism is comprised
of an elongate tube or shaft having a helical groove or slot and a
rotational element providing a pin, the pin being adapted to slide
within the slot or groove. In other embodiments the torque
application mechanism may convert rotational motion in a first
direction into rotational motion in a second direction. Such
mechanisms include but are not limited to one or more of the
following: worm gears, spiral gears, beveled gears and/or a twisted
belt or chain. In some embodiments, the gear is a pin gear. The
central pivot point may advantageously enable electrode deployment
and catheter centering at the deployment site, as well as the
ability to independently limit the electrode contact force with a
single deployment mechanism. The multi-electrode catheter 6400 may
comprise more than one lever arm 6409 in other embodiments.
[0454] FIGS. 64F-1 to 64F-4 illustrate an embodiment of a
neuromodulation device (e.g., treatment catheter) 6400 comprising
two electrodes 6405 which may be actively deployed to create two
longitudinally displaced treatment zones at opposing sides of a
treatment vessel (e.g., a "bowstring" design). In a deployed
configuration, as shown in FIG. 64F-2, the treatment catheter 6400
comprises a deployment segment 6406 including (e.g., carrying) a
first electrode 6405A configured to be brought into contact at a
first location on a first side of a vessel wall. The deployment
segment 6406 also urges the adjacent distal and proximal portions
of the catheter shaft 6416 against the opposite side of the vessel
wall. A second electrode 6405B may be coupled or secured to the
catheter shaft 6416 on the proximal portion 6417, and is therefore
brought into contact against the vessel wall on the opposing
quadrant of the vessel from the first electrode 6405A. The distal
portion 6419 of the catheter shaft 6416 is also urged against this
opposing quadrant which tends to keep the treatment catheter 6400
oriented along the axis of the blood vessel. The deployment may be
controlled by retraction (e.g., by longitudinal actuation) of an
inner tube 6418 relative to the remainder of the catheter shaft
6416. The inner tube 6418 may also serve to provide a lumen for use
with a guide wire.
[0455] The deployment segment 6406 may comprise a ribbon-like cross
section, which may provide structural stability as it is deployed
outwards. As seen in FIG. 64F-3, the elements that make up the
deployment segment 6406 may comprise a ribbon composite including
two laterally-displaced outer structural wires 6422, with inner
sensor and/or power leads 6424 (e.g., bifilar thermocouple such as
a T-type thermocouple comprising copper and constantan leads,
optical fibers, other temperature-measurement device leads and/or
other sensor or power conductor leads) in between. The outer
structural wires 6422 may comprise nitinol, stainless steel or
other metallic, metallic alloy or shape-memory materials. In one
embodiment, the diameter of the outer structural wires 6422 is
0.006 inches; however, other diameters may be used as desired
and/or required (e.g., from 0.0004 inches to 0.0010 inches, from
0.0005 inches to 0.0015 inches, from 0.0008 inches to 0.0012
inches, overlapping ranges thereof or any value of or within the
recited ranges). The inner leads may optionally be encased in an
insulation covering or jacket comprised of one or more polymeric
materials such as polyimide, PTFE, perfluoroalkoxy alkane (PFA),
polyurethane, Nylon and/or the like. Where the deployment segment
6406 connects to the first electrode 6405A (as shown in FIG.
64F-4), the energizing lead (which may be one of the leads for the
thermocouple, if included) is electrically connected to the
electrode 6405A, by suitable connection means, such as by soldering
or welding. In some embodiments, the structural wires 6422 comprise
generally planar structural elements of electrically insulated
metal or metallic alloy (e.g., polyimide laminate, thermoplastic
reflow insulation). In various embodiments, the ribbon composite
structure optionally comprises an outer covering (not shown)
surrounding the outer structural wires and the inner sensor and/or
power wires. The outer covering may comprise polyimide tape,
Pebax.RTM., coextruded polymers (inside hot melt adhesive), and/or
adhesives used to bond everything together.
[0456] The first electrode 6405A may have a generally "horseshoe"
or U-shape, as seen in FIG. 64F-4. The opening allows for the
electrode 6405A to be nested around the inner tube 6418 during
placement of the treatment catheter 6400 within the vasculature,
when the treatment catheter is undeployed (FIG. 64F-1). Upon
deployment, the first electrode 6405A can move laterally away from
the inner tube 6418. In some embodiments, the first electrode 6405A
comprises a keyhole 6426 within which the deployment segment 6406
can securely reside. Such a keyhole 6426 provides good mechanical
connection to the first electrode 6405A. The second electrode 6405A
may have a similar shape as the first electrode 6405B or may have a
cylindrical shape that extends around a full circumference of the
catheter shaft 6416.
[0457] The multi-electrode catheters 6400 of FIGS. 64B to 64E may
advantageously provide one or more of the following benefits: (i)
simultaneous and balanced electrode deployment of an electrode
pair; (ii) centers the catheter during electrode deployment; (iii)
reduces the exposed length of catheter beyond a guide catheter or
sheath tip required for electrode deployment against the vessel
wall; and/or (iv) enables the ability to independently limit the
electrode contact force. The electrode deployment arms 6406 may be
designed to space the electrodes along a single circumferential
cross-section at a single position along the length of the vessel
wall or at different positions along the length of the vessel wall.
The electrodes 6405 may be activated simultaneously or
sequentially.
[0458] FIGS. 64G-1, 64G-2, 64G-3, 64G-4, 64G-5, 64G-6, 64H and 64I
illustrate various embodiments of multi-electrode catheters 6400
having multiple cantilevered tines or electrode deployment arms
6406 configured to provide controlled self-expanding electrode
deployment of multiple electrodes 6405 along the catheter shaft
without increasing profile. The deployment arms 6406 may comprise
free-floating distal ends that do not connect back to the main
catheter shaft (as shown for example in FIGS. 64H and 64I). In some
embodiments, the multi-electrode catheters 6400 comprise closed
configurations of deployment arms in which the deployment arms are
connected to the main shaft at both ends (such as shown in FIGS.
64G and 64J)). The number of deployment arms may vary (for example,
2, 3, 4 or more arms). Each deployment arm may consist of a single
electrode or multiple electrodes positioned along the length of the
deployment arm. For closed configurations, each electrode may be
positioned at a central portion of the length of the deployment arm
(as shown, for example, in FIG. 64G-1) or the electrodes may be
positioned at axially offset positions along the length (as shown,
for example, in FIG. 64G-2) of the deployment arms to facilitate
lesion formation at locations spaced apart along a length of a
vessel. If monopolar, the multiple electrodes may be activated
simultaneously or sequentially. The cantilevered tines may be
deployed from straight axial slots (as shown for example in FIG.
64H) or curved slots (as shown for example in FIG. 64I). As shown,
the multi-electrode catheters 6400 may comprise a central lumen to
facilitate advancement over a guidewire. The multi-electrode
catheters may consist of two electrodes or four electrodes in
various embodiments. The electrodes may be configured to be
deployed at various positions spaced along the length of the vessel
(e.g., 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1 cm, 1.1
cm, 1.2 cm, 1.3 cm, 1.4 cm, 1.5 cm, 1.6 cm, 1.7 cm, 1.8 cm, 1.9 cm,
2 cm, less than 0.4 cm or more than 2 cm apart). The electrodes may
comprise rounded electrodes (e.g., cylindrical, slotted,
half-cylinder, C-shaped, D-shaped electrodes) configured to match
the curvature of the vessel wall to facilitate increased surface
contact with the vessel wall. The electrodes may also comprise
keyhole slots as described above in connection with FIG. 64F-4. The
orientation of the various embodiments illustrated in FIGS. 64G-64I
may be reversed to facilitate treatment of sites very close to a
distal terminus of a guide catheter. The deployment arms or
segments described herein may be pull-actuated or
push-actuated.
[0459] FIG. 64G-2A illustrates an embodiment of a treatment
catheter 6400 having two deployable electrodes 6405 mounted on two
deployment arms or segments 6406 on opposite sides of the treatment
catheter 6400. The distal ends of each deployment segment 6406 may
be secured within the treatment catheter 6406 at the same
longitudinal location. The proximal portions of each deployment
segment 6406 may emanate from the same longitudinal location on the
catheter shaft 6416. The electrodes 6405 may be located
asymmetrically along the deployment segments 6406. For example, a
first electrode may be mounted to its deployment segment 6406 more
distally, while a proximal electrode is mounted more proximally, as
shown in FIG. 64G-2A.
[0460] The deployment segments 6406 may have a uniform cross
section, or may have a non-uniform cross section, as is the case in
FIG. 64G-2A. Each deployment segment 6406 may have a different
bending stiffness that extends distal of the electrode as compared
to proximal of the electrode 6405. In this manner, the deployment
segment 6406 may deploy in an eccentric fashion, as shown in FIG.
64G-2A for example. The different bending stiffness may be
achieved, for example, by reducing the dimension of a portion of
the deployment segment 6406.
[0461] The deployment segments 6406 may be actuated by advancing a
proximal portion of each deployment segment in a distal direction
relative to the catheter shaft 6416. The deployment segments 6406
may be actuated simultaneously or sequentially. As seen in the
cross-sectional view of FIG. 64G-2A (FIG. 64G-2B), the proximal
portions of the deployment segments 6406 may both be coupled or
secured to a longitudinally movable element 6430 (such as a tubular
sleeve) that also includes or contains the electrical lead wires
that connect to the electrodes 6405 via the deployment segments
6406. The treatment catheter 6400 may include a distal extension
6424 as described elsewhere herein to facilitate guidewire
trackability.
[0462] FIGS. 64G-3A to FIGS. 64G-3C illustrate an embodiment of a
deployable multi-electrode treatment catheter 6400. The treatment
catheter 6400 comprises two offset deployment arms or segments
6406, each comprising an electrode 6405 (e.g., a "double bowstring"
design). Each deployment segment 6406 is configured to extend
laterally away from the catheter shaft 6416. The deployment
segments 6406 may be positioned at 180 degrees apart, such that
when they are in contact with the vessel wall they are on generally
opposite sides. Other angular orientations are contemplated, as
well as more than two deployment segments along the length of the
catheter shaft or more than one electrode per deployment
segment.
[0463] As with the embodiment described in connection with FIGS.
64F-1 to 64F-4, the electrodes 6405 of FIGS. 64G-3A to FIG. 64G-3C
may be "horseshoe" or U-shaped such that when in the undeployed
condition (as shown in FIGS. 64G-3B), the electrodes 6405 can nest
around the shaft 6416 of the treatment catheter 6400. Other slotted
or nested shapes or configurations are also contemplated. The
method of deployment of the electrodes 6405 may include a
longitudinally moveable inner tube 6430 relative to the outer tube
of the proximal catheter shaft, as can be seen in the
cross-sectional view of FIG. 64G-3C. Movement (e.g., retraction) of
the inner tube 6430 may retract the distal connections of the
deployment segments 6406, thereby causing the electrodes 6405 to
deploy radially outward. In accordance with several embodiments,
while both electrodes 6405 also move in a retrograde fashion as
they move radially outward, the longitudinal spacing between them
remains relatively constant, advantageously resulting in the
longitudinal spacing being consistent across a wide range of vessel
diameters. The deployment segments 6406 may be of a composite
ribbon-like construction, similar to the construction described in
FIG. 64F-3. In some embodiments, the catheter 6400 comprises a
distal extension 6419 to facilitate trackability.
[0464] In various embodiment, the electrodes 6405 may be supported
between stent-like support structures providing expansion and
stabilization of the electrodes 6405, said support structures being
connected by substantially axial connectors that control the axial
spacing of the electrodes 6405 substantially independent of vessel
diameter. Stent-like support structures may be braid, zig zag,
serpentine, sinusoidal, pinwheels, tessellated or non-tessellated
designs. Supports may be comprised of PEEK fiber, insulated metal
or a combination of the two.
[0465] FIG. 64G-4 illustrates an embodiment of a deflectable
portion of an RF electrode treatment catheter 6400. The deflectable
portion comprises two deployment segments 6406 each comprising an
electrode 6405. The electrodes are positioned so as to be offset
longitudinally and circumferentially (e.g., 180 degrees offset)
when in the deployed configuration as shown. The deployment
segments 6406 are configured to be actuated by a braid guide
assembly 6421 of wires. In one embodiment, a proximal portion of
the braid guide assembly 6421 is coupled to an outer tube 6423 of
the catheter shaft 6416 and a distal portion of the braid guide
assembly 6421 is coupled to an inner tube 6425 within the catheter
shaft 6416, with the inner tube 6425 being moveable with respect to
the outer tube 6423, or vice-versa.
[0466] FIGS. 64G-5 and 64G-6 illustrate embodiments of
multi-electrode catheters 6400 comprising frames or scaffolds 6404
having multiple electrodes 6405 positioned along the length of the
frames or scaffolds 6404. The frame or scaffold 6406 of FIG. 64G-5
comprises a planar frame 6404 having electrodes 6405 aligned along
the same plane but spaced 180 degrees apart from each other and
spaced apart axially along the length of the frame 6404. Only a
portion of the frame 6404 is illustrated. It should be appreciated
that the frame 6404 may include additional electrodes following the
same alternating 180-degree pattern (for example, four total
electrodes). The electrodes 6405 illustrated in FIG. 64G-5 are
monopolar electrodes. In an alternative embodiment, the electrodes
6405 comprise a first electrode (e.g., active electrode) of a
bipolar electrode pair and corresponding second electrodes (e.g.,
return electrodes) may be positioned on the frame 6404 on the strut
opposite the first electrodes. In some embodiments, the frame 6404
can be non-planar (for example, the frame 6404 may have a helical
or spiral configuration. In some embodiments, the frame 6404 can
have a configuration similar to a stent.
[0467] The frame 6404 of FIG. 64G-6 comprises two continuous wires
extending through a lumen of each of the electrodes 6405. The wires
are adapted to cause the electrodes 6405 to contact a vessel wall
at axially spaced-apart locations that are offset circumferentially
by 180 degrees. The portions of the wires between the electrodes
may be sized and shaped so as to deploy outward and to contact the
vessel wall to provide support to maintain contact of the
electrodes 6405 with the vessel wall.
[0468] In some embodiments, the electrodes 6405 of the frames 6404
are offset at other than 180 degrees (for example 120 degrees, 90
degrees). The frames 6404 may comprise shape-memory metallic alloy
material or other self-expandable material adapted to cause the
electrodes 6405 to be placed into effective contact with a vessel
wall inside any vessel having a diameter of between 3 mm and 10 mm
upon exiting a sheath or sleeve and transitioning to a pre-formed
shape. The frames 6404 may also be adapted to be recaptured within
the sheath or sleeve for repositioning at another location in the
vessel or for removal from the body. The strut or cell pattern of
the frames 6404 are provided as examples; the patterns may vary as
desired and/or required. The electrodes 6405 may comprise generally
cylindrical electrodes as shown or non-cylindrical electrodes
(slotted, D-shaped, C-shaped).
[0469] FIGS. 64J and 64K illustrate embodiments of a
multi-electrode catheter 6400 comprising slots 6412 positioned
along the length of the catheter shaft 6413 to permit deformation
of a portion of the catheter shaft 6413 to deploy the multiple
electrodes 6405 in a serpentine fashion at various locations along
the length of a vessel wall. The multi-electrode catheter 6400 may
comprise or consist essentially of two electrodes (as shown in FIG.
64J), three electrodes (as shown in FIG. 64K), four electrodes, six
electrodes, or eight electrodes. In some embodiments, the
electrodes 6405 are configured to be positioned 180 degrees apart
from each other (as shown in FIGS. 64G-1, 64G-2, 64G-3, 64G-4, 64J
and 64K). In various embodiments, the electrodes 6405
advantageously facilitate ablation of only two quadrants of the
vessel wall instead of all four quadrants. If monopolar, the
multiple electrodes may be activated simultaneously or
sequentially. The multi-electrode catheters 6400 of FIGS. 64G to
64K may advantageously provide one or more of the following
benefits: (i) low profile, (ii) large electrode surface and
curvature, (iii) lateral deployment, (iv) low force, (v) controlled
flexibility; and/or (vi) effective denervation of nerves in a
perivascular region while maintaining minimal heating of, or
thermal injury to, the inner vessel wall.
[0470] FIG. 65 illustrates an embodiment of a pivoting electrode
6500 on a distal end of a shaft or electrode deployment arm 6502.
The pivoting electrode 6500 is mounted on a pivot 6504 configured
to facilitate an orientation that is in substantial alignment with
the vessel wall. The pivoting electrode 6500 comprises an elongate
electrode that provides increased surface area compared to a
spherical electrode of comparable thickness. In the illustrated
embodiment, the pivot DD04 comprises a pin. The pin may be
substantially at the center of the electrode 6500. The pivot 6504
may be formed of a highly flexible polymer or gel. In some
embodiments, the pivot 6504 may comprise a fiber or thread. In some
embodiments, the pivot 6504 may comprise a ball and socket
joint.
[0471] The pivoting electrode 6500 may be substantially cylindrical
(e.g., a half cylinder). In one embodiment, the electrode 6500 has
substantially spherical ends. One end and/or a side of the
electrode 6500 may be slotted to permit access to the pivot 6504.
In some embodiments, the electrode 6500 is attached to the shaft
6502 using a saddle, stirrup or clevis arrangement. If a clevis
fastener is used, the clevis may be on the electrode or the
shaft.
[0472] The pivot 6504 may be skew to the central longitudinal axis
of the shaft 6502 to correct for helical deformation of the
deflected catheter shaft. The pivot 6504 may provide a restricted
range of motion. In some embodiments, the pivot 6504 provides
substantially zero moment or torque within its range of motion. In
some embodiments, the pivot 6504 provides a specified moment or
torque within its range of motion. The pivoting electrode 6500 may
be incorporated into any of the electrode-based devices or systems
described herein. The pivoting electrode 6500 may advantageously
provide one or more of the following benefits: (i) uniform
electrode contact in a desired orientation despite possible
deformation of the vessel by a catheter or variations in vascular
anatomy, (ii) increased electrode surface contact, (iii) consistent
lesion size, (iv) reduced superficial vessel wall injury by
reducing electric current and cooling variations, (v) increased
catheter lengths, trackability and steerability; and/or (vi) not
dependent on apposition force to achieve reorientation that may not
be consistent with different vessel geometry.
[0473] g. RF Energy Delivery Parameters
[0474] In some embodiments, an RF energy delivery system delivers
RF energy waves of varying duration. In some embodiments, the RF
energy delivery system varies the amplitude of the RF energy. In
other embodiments, the RF energy delivery system delivers a
plurality of RF wave pulses. For example, the RF energy delivery
system may deliver a sequence of RF pulses. In some embodiments,
the RF energy delivery system varies the frequency of RF energy. In
other embodiments, the RF energy delivery system varies any one or
more parameters of the RF energy, including, but not limited to,
duration, amplitude, frequency, and total number of pulses or pulse
widths. For example, the RF energy delivery system can deliver RF
energy selected to most effectively modulate (e.g., ablate or
otherwise disrupt) sympathetic nerve fibers in the hepatic plexus.
In some embodiments, the frequency of the RF energy is maintained
at a constant or substantially constant level.
[0475] In some embodiments, the frequency of the RF energy is
between about 50 kHz and about 20 MHz, between about 100 kHz and
about 2.5 MHz, between about 400 kHz and about 1 MHz, between about
50 kHz and about 5 MHz, between about 100 kHz and about 10 MHz,
between about 500 kHz and about 15 MHz, less than 50 kHz, greater
than 20 MHz, between about 3 kHz and about 300 GHz, or overlapping
ranges thereof. Non-RF frequencies may also be used. For example,
the frequency can range from about 100 Hz to about 3 kHz. In some
embodiments, the amplitude of the voltage applied is between about
1 volt and 1000 volts, between about 5 volts and about 500 volts,
between about 10 volts and about 200 volts, between about 20 volts
and about 100 volts, between about 1 volt and about 10 volts,
between about 5 volts and about 20 volts, between about 1 volt and
about 50 volts, between about 15 volts and 25 volts, between about
20 volts and about 75 volts, between about 50 volts and about 100
volts, between about 100 volts and about 500 volts, between about
200 volts and about 750 volts, between about 500 volts and about
1000 volts, less than 1 volt, greater than 1000 volts, or
overlapping ranges thereof.
[0476] In some embodiments, the current of the RF energy ranges
from about 0.5 mA to about 500 mA, from about 1 mA to about 100 mA,
from about 10 mA to about 50 mA, from about 50 mA to about 150 mA,
from about 100 mA to about 300 mA, from about 250 mA to about 400
mA, from about 300 to about 500 mA, or overlapping ranges thereof.
The current density of the applied RF energy can have a current
density between about 0.01 mA/cm.sup.2 and about 100 mA/cm.sup.2,
between about 0.1 mA/cm.sup.2 and about 50 mA/cm.sup.2, between
about 0.2 mA/cm.sup.2 and about 10 mA/cm.sup.2, between about 0.3
mA/cm.sup.2 and about 5 mA/cm.sup.2, less than about 0.01
mA/cm.sup.2, greater than about 100 mA/cm.sup.2, or overlapping
ranges thereof. In some embodiments, the power output of the RF
generator ranges between about 0.1 mW and about 100 W, between
about 1 mW and 100 mW, between about 1 W and 10 W, between about 1
W and 15 W, between 5 W and 20 W, between about 10 W and 50 W,
between about 25 W and about 75 W, between about 50 W and about 90
W, between about 75 W and about 100 W, or overlapping ranges
thereof. In some embodiments, the total RF energy dose delivered at
the target location (e.g., at an inner vessel wall, to the media of
the vessel, to the adventitia of the vessel, or to the target
nerves within or adhered to the vessel wall) is between about 100 J
and about 2000 J, between about 150 J and about 500 J, between
about 300 J and about 800 J (including 500 J), between about 500 J
and about 1000 J, between about 800 J and about 1200 J, between
about 1000 J and about 1500 J, and overlapping ranges thereof. In
some embodiments, the impedance ranges from about 10 ohms to about
600 ohms, from about 100 ohms to about 300 ohms, from about 50 ohms
to about 200 ohms, from about 200 ohms to about 500 ohms, from
about 300 ohms to about 600 ohms, and overlapping ranges thereof.
In some embodiments, power is provided between 8 W and 14 W (e.g.,
10 W, 12 W) for between 30 seconds and 3 minutes (e.g., 1 minute,
90 seconds, 2 minutes, 150 seconds) to provide a total energy
delivery of between 240 J and 2520 J (e.g., 1200 J-10 W for 2
minutes, 1500 J-12 W for 2 minutes). Electrode(s) may be coupled
(e.g., via wired or wireless connection) to an energy source (e.g.,
generator) even if the generator is not explicitly shown or
described with each embodiment. The various treatment parameters
listed herein (e.g., power, duration, energy, contact
force/pressure, electrode size, pulsing, resistance, etc.) may be
used for any of the embodiments of devices (e.g., catheters) or
systems described herein.
[0477] In various embodiments, the generator comprises stored
computer-readable instructions that, when executed, provide
specific treatment (e.g., custom energy algorithm) to treat
specific vessels selected by an operator. Accordingly, the
generator facilitates delivery of RF energy having different
treatment parameters using a single RF energy delivery device
configured to provide similar or consistent performance across
varying patient anatomy (e.g., one-size-fits-all). The generator
may comprise safety controls tailored to environment: vessel size,
flow, resistance, and/or other structures. The stored
computer-readable instructions (e.g., software, algorithms) may be
customized to deliver optimized lesion depth and/or may comprise
pre-programmed operator-independent treatment algorithms. In some
embodiments, a pre-programmed treatment course, which may include
one or more parameters (such as power, treatment duration, number
of target locations, spacing of target locations, energy, pulsed or
non-pulsed, etc.) is provided. The pre-programmed treatment course
may be based on vessel dimensions (e.g., diameter, segment length,
wall thickness, age of patient, weight of patient, etc.). In one
embodiment, a preconfigured or predetermined course of
neuromodulation (e.g., ablation) may be performed (e.g.,
automatically or manually) to modulate (e.g., ablate) one or more
nerves. The predetermined treatment course or profile may comprise
a full or partial route of treatment or treatment points. The route
may extend around a partial circumference of a blood vessel (e.g.,
270 degrees, 220 degrees, 180 degrees, 90 degrees, or 60 degrees)
or around the entire circumference.
[0478] For example, in some patients a target modulation (e.g.,
ablation) location (such as the common hepatic artery) may not be
long enough to allow for complete modulation (e.g., ablation) of
target nerves. In some embodiments, it may be desirable to treat
multiple vessels adjacent to or that are portions of the hepatic
artery vasculature (e.g., celiac, splenic, common hepatic, proper
hepatic arteries) using a single energy delivery device. In some
embodiments, an operator may select a vessel to be treated and the
generator may automatically adjust the energy delivery parameters
(e.g., select a pre-determined energy algorithm) based on the
selected vessel. For example, different vessels may have different
flow characteristics and different diameters. Accordingly,
different energy profiles (e.g., varying power and/or time) may be
associated with the different vessels to achieve a desired overall
energy output. In ablation embodiments, the different energy
profiles provide the same volume and/or circumferential arc of
lesion for the various different vessels. The delivery of energy
may be controlled manually or automatically according to a
preconfigured energy profile determined by a controller, processor
or other computing device (e.g., based on execution of instructions
stored in memory) within the generator. For example, if the nominal
vessel diameter (e.g., common hepatic artery) is greater than an
adjacent vessel diameter, the power level and time can be adjusted
lower as there will be a greater area of contact between the vessel
wall and electrode surface. In some embodiments, the allowable
temperature target or limit may be adjusted higher to compensate
for a lower capacity of the blood flow to remove heat from the
electrode. If the adjacent artery is larger, then power may be
increased to modulate (e.g., ablation) a larger area in a single
cycle. In some embodiments, a tendency towards more modulation
(e.g., ablation) sites in the larger adjacent vessel may be
employed.
[0479] The RF energy can be pulsed or continuous. The voltage,
current density, frequencies, treatment duration, power, and/or
other treatment parameters can vary depending on whether continuous
or pulsed signals are used. For example, the voltage or current
amplitudes may be significantly increased for pulsed RF energy. The
duty cycle for the pulsed signals can range from about 0.0001% to
about 100%, from about 0.001% to about 100%, from about 0.01% to
about 100%, from about 0.1% to about 100%, from about 1% to about
10%, from about 5% to about 15%, from about 10% to about 50%, from
about 20% to about 60% from about 25% to about 75%, from about 50%
to about 80%, from about 75% to about 100%, or overlapping ranges
thereof. The pulse durations or widths of the pulses can vary. For
example, in some embodiments, the pulse durations can range from
about 10 microseconds to about 1 millisecond; however, pulse
durations less than 10 microseconds or greater than 1 millisecond
can be used as desired and/or required. In accordance with some
embodiments, the use of pulsed energy may facilitate reduced
temperatures, reduced treatment times, reduced cooling
requirements, and/or increased power levels without risk of
increasing temperature or causing endothelial damage due to
heating. In some embodiments involving use of a catheter having a
balloon, the balloon can be selectively deflated and inflated to
increase lumen wall cooling and enhance the cooling function that
pulsed energy provides.
[0480] In some embodiments, the RF energy is pulsed based, at least
in part, on the sensed tissue impedance or temperature, as shown,
for example, in FIG. 66. For example, RF power can be delivered
until a second temperature reaches a predefined value greater than
a first temperature, at which point RF power may temporarily be
interrupted. Because tissues near the arterial lumen cool faster
than the target tissue (e.g., about 3, 3.5, 4, 4.5, 5 mm from the
arterial lumen), in some embodiments, the temporary interruption
tends to concentrate heat at the location of the target tissue, as
shown in FIG. 55. In several embodiments, a similar result can be
obtained by pulsing RF energy based, at least in part, on tissue
impedance. In one embodiment, each subsequent cooling period (A, B,
C, and then D) is longer than the previous cooling period (which
may unexpectedly be particularly important in the hepatic artery,
where flow rate is lower than other endovascular sites).
Embodiments of this approach are described in U.S. Publ. No.
2010/0125268, which is incorporated by reference herein and may be
used in conjunction with embodiments described herein. In some
embodiments, pulsed energy is used to selectively deliver heat to
nerves in the adventitia of the hepatic artery or other target
vessels.
[0481] In several embodiments, the invention is particularly
beneficial because it is unexpectedly useful for concentrating heat
at the region of peripheral nerves (and particularly beneficial for
treating the peripheral nerves about the hepatic artery). In
several embodiments, substantially all of the target tissue treated
is healthy tissue.
[0482] The treatment time durations can range from 1 second to 1
hour, from 5 seconds to 30 minutes, from 10 seconds to 10 minutes,
from 30 seconds to 30 minutes, from 1 minute to 20 minutes, from 1
minute to 3 minutes, from 2 to four minutes, from 5 minutes to 10
minutes, from 10 minutes to 40 minutes, from 30 seconds to 90
seconds, from 5 seconds to 50 seconds, from 60 seconds to 120
seconds, overlapping ranges thereof, less than 1 second, greater
than 1 hour, about 120 seconds, or overlapping ranges thereof. The
duration may vary depending on various treatment parameters (e.g.,
amplitude, current density, proximity, continuous or pulsed, type
of nerve, size of nerve). In some embodiments, the RF or other
electrical energy is controlled such that delivery of the energy
heats the target nerves or surrounding tissue in the range of about
50 to about 90 degrees Celsius (e.g., 60 to 75 degrees, 50 to 80
degrees, 70 to 90 degrees, 60 to 90 degrees or overlapping ranges
thereof). In some embodiments, the temperature can be less than 50
or greater than 90 degrees Celsius. The electrode tip energy may
range from 37 to 100 degrees Celsius. In some embodiments, RF
ablation thermal lesion sizes range from about 0 to about 3 cm
(e.g., between 1 and 5 mm, between 2 and 4 mm, between 5 and 10 mm,
between 15 and 20 mm, between 20 and 30 mm, overlapping ranges
thereof, about 2 mm, about 3 mm) or within one to ten (e.g., one to
three, two to four, three to five, four to eight, five to ten)
media thickness differences from a vessel lumen (for example,
research has shown that nerves surrounding the common hepatic
artery and other branches of the hepatic artery are generally
within this range). In several embodiments, the media thickness of
the vessel (e.g., hepatic artery) ranges from about 0.1 cm to about
0.25 cm. In some anatomies, at least a substantial portion of nerve
fibers of the hepatic artery branches are localized within 0.5 mm
to 1 mm from the lumen wall such that modulation (e.g.,
denervation) using an endovascular approach is effective with
reduced power or energy dose requirements.
[0483] In some embodiments, an RF ablation catheter is used to
perform RF ablation of sympathetic nerve fibers in the hepatic
plexus at one or more locations. For example, the RF ablation
catheter may perform ablation in a circumferential or radial
pattern to ablate sympathetic nerve fibers in the hepatic plexus at
one or more locations (e.g., one, two, three, four, five, six,
seven, eight, nine, ten, six to eight, four to eight, more than ten
locations). Referring now to FIG. 67, cadaver studies have shown
that the hepatic nerves are generally focused in the region defined
by the midpoint between the origin of the common hepatic artery and
the origin of the gastroduodenal artery, as the nerves tend to
approach the arterial lumen along non-branching regions of the
artery, and diverge from the arterial lumen in regions of
branching. The cadaver studies have also shown that the hepatic
nerves predominantly reside within an annulus defined by the lumen
of the artery and a concentric ring spaced approximately 4 mm from
the arterial lumen. In some embodiments, the number of nerves and
the proximity to the arterial lumen of the nerves increases towards
the common hepatic artery midpoint. In some embodiments, the
sympathetic nerve fibers are advantageously modulated (e.g.,
ablated) at the midpoint between the origin of the common hepatic
artery and the origin of the gastroduodenal artery. In some
embodiments, the sympathetic nerve fibers are modulated (e.g.,
ablated) up to a depth of 4-6 mm, 3-5 mm, 3-6 mm, 2-7 mm) from the
lumen of the hepatic artery. In other embodiments, the sympathetic
nerve fibers in the hepatic plexus are ablated at one or more
points by performing RF ablation at a plurality of points that are
linearly spaced along a vessel length. For example, RF ablation may
be performed at one or more points linearly spaced along a length
of the proper hepatic artery to ablate sympathetic nerve fibers in
the hepatic plexus. In some embodiments, RF ablation is performed
at one or more locations in any pattern to cause ablation of
sympathetic nerve fibers in the hepatic plexus as desired and/or
required (e.g., a spiral pattern or a series of linear patterns
that may or may not intersect). The ablation patterns can comprise
continuous patterns or intermittent patterns. In accordance with
various embodiments, the RF ablation does not cause any lasting
damage to the vascular wall because heat at the wall is dissipated
by flowing blood, by cooling provided external to the body, or by
increased cooling provided by adjacent organs and tissue structures
(e.g., portal vein cooling and/or infusion), thereby creating a
gradient with increasing temperature across the intimal and medial
layers to the adventitia where the nerves travel. The adventitia is
the external layer of the arterial wall, with the media being the
middle layer and the intima being the inner layer. The intima
comprises a layer of endothelial cells supported by a layer of
connective tissue. The media is the thickest of the three vessel
layers and comprises smooth muscle and elastic tissue. The
adventitia comprises fibrous connective tissue.
[0484] h. Modulation and Monitoring of Treatment
[0485] In some embodiments, the energy output from the RF energy
source may be modulated using constant temperature mode. Constant
temperature mode turns the energy source on when a lower
temperature threshold is reached and turns the energy source off
when an upper temperature threshold is reached (similar to a
thermostat). In some embodiments, an ablation catheter system using
constant temperature mode requires feedback, which, in one
embodiment, is provided by a temperature sensor. In some
embodiments, the ablation catheter system comprises a temperature
sensor that communicates with energy source (e.g., RF generator).
In some of these embodiments, the energy source begins to deliver
energy (e.g., turn on) when the temperature sensor registers that
the temperature has dropped below a certain lower threshold level,
and the energy source terminates energy delivery (e.g., turns off)
when the temperature sensor registers that the temperature has
exceeded a predetermined upper threshold level.
[0486] In some embodiments, the energy output from an energy
delivery system may be modulated using a parameter other than
temperature, such as tissue impedance. Tissue impedance may
increase as tissue temperature increases. Impedance mode may be
configured to turn the energy source on when a lower impedance
threshold is reached and turn the energy source off when an upper
impedance threshold is reached (in the same fashion as the constant
temperature mode responds to increases and decreases in
temperature). An energy delivery system using constant impedance
mode may include some form of feedback mechanism, which, in one
embodiment, is provided by an impedance sensor. In some
embodiments, impedance is calculated by measuring voltage and
current and dividing voltage by the current.
[0487] In some embodiments, a catheter-based energy delivery system
comprises a first catheter with a first electrode and a second
catheter with a second electrode. The first catheter is inserted
within a target vessel (e.g., the common hepatic artery) and used
to deliver energy to modulate nerves within the target vessel. The
second catheter may be inserted within an adjacent vessel and the
impedance can be measured between the two electrodes. For example,
if the first catheter is inserted within the hepatic arteries, the
second catheter can be inserted within the bile duct or the portal
vein. In some embodiments, a second electrode is placed on the skin
of the subject and the impedance is measured between the second
electrode and an electrode of the catheter-based energy delivery
system. In some embodiments, the second electrode may be positioned
in other locations that are configured to provide a substantially
accurate measurement of the impedance of the target tissues.
[0488] In some embodiments, the impedance measurement is
communicated to the energy source (e.g., pulse generator). In some
embodiments, the energy source begins to generate a pulse (i.e.,
turns on) when the impedance registers that the impedance has
dropped below a certain lower threshold level, and the energy
source terminates the pulse (i.e., turns off) when the impedance
registers that the impedance has exceeded a predetermined upper
threshold level.
[0489] In some embodiments, the energy output of the energy
delivery system is modulated by time. In such embodiments, the
energy source of the energy delivery system delivers energy for a
predetermined amount of time and then terminates energy delivery
for a predetermined amount of time. The cycle may repeat for a
desired overall duration of treatment. In some embodiments, the
predetermined amount of time for which energy is delivered and the
predetermined amount of time for which energy delivery is
terminated are empirically optimized lengths of time. In accordance
with several embodiments, controlling energy delivery according to
impedance and reducing energy delivery when impedance approaches a
threshold level (or alternatively, modulating energy in time
irrespective of impedance levels) advantageously provides for
thermal energy to be focused at locations peripheral to the vessel
lumen. For example, when the energy pulse is terminated, the vessel
lumen may cool rapidly due to convective heat loss to blood,
thereby protecting the endothelial cells from thermal damage. In
some embodiments, the heat in the peripheral tissues (e.g., where
the targeted nerves are located) dissipates more slowly via thermal
conduction. In some embodiments, successive pulses tend to cause
preferential heating of the peripheral (e.g., nerve) tissue. In
accordance with several embodiments, when the impedance of tissue
rises due to vaporization, electrical conductivity drops
precipitously, thereby effectively preventing or inhibiting further
delivery of energy to target tissues. In some embodiments, by
terminating energy pulses before tissue impedance rises to this
level (e.g., by impedance monitoring or time modulation), this
deleterious effect may be avoided. In accordance with several
embodiments, char formation is a consequence of tissue vaporization
and carbonization, resulting from rapid increases in impedance,
electrical arcing, and thrombus formation. By preventing or
inhibiting impedance rises, charring of tissue may be avoided.
[0490] In some embodiments, total energy delivery is monitored by
calculating the time integral of power output (which may be
previously correlated to ablation characteristics) to track the
progress of the therapy. In some embodiments, the relationship
between temperature, time, and electrical field is monitored to
obtain an estimate of the temperature field within the tissue
surrounding the ablation electrode using the Arrhenius
relationship. In some embodiments, a known thermal input is
provided to the ablation electrode, on demand, in order to provide
known initial conditions for assessing the surrounding tissue
response. In some embodiments, a portion of the ablation region is
temporarily cooled, and the resultant temperature is decreased. For
example, for an endovascular ablation that has been in progress for
a period of time, it may be expected that there is some elevated
temperature distribution within the tissue. If a clinician wants to
assess the progress of the therapy at a given time (e.g., to), the
energy delivery can be interrupted, and cooled saline or gas can be
rapidly circulated through the electrode to achieve a predetermined
electrode temperature within a short period of time (e.g., about 1
second). In some embodiments, the resulting temperature rise (e.g.,
over about 5 seconds) measured at the electrode surface is then a
representation of the total energy of the surrounding tissue. This
process can be repeated through the procedure to track
progress.
[0491] In some embodiments, a parameter, such as temperature,
infrared radiation, or microwave radiation can be monitored to
assess the magnitude of energy delivered to tissue, and thus
estimate the degree of neuromodulation induced. Both the magnitude
of thermal radiation (temperature), infrared radiation, and/or
microwave radiation may be indicative of the amount of energy
contained within a bodily tissue. In some embodiments, the
magnitude is expected to decrease following the completion of the
ablation as the tissue cools back towards body temperature, and the
rate of this decrease, measured at a specific point (e.g., at the
vessel lumen surface) can be used to assess the size of the
ablation (e.g., slower decreases may correspond to larger ablation
sizes). Any of the embodiments described herein may be used
individually or in combination to indicate the actual size of the
tissue lesion zone.
[0492] Electrode tip temperature control is often used as a control
variable and treatment progress indicator for ablation procedures,
particularly endovascular and/or cardiac ablation procedures. One
potential problem with this approach is that although the goal is
to treat tissue at a certain depth into the tissue, the temperature
sensing element (thermocouple or thermistor) is generally only able
to measure the surface temperature of the cardiac or vascular
tissue. Furthermore, due to temperature gradients within the
electrode itself, the temperature sensing element tends to measure
the bulk temperature of the electrode, rather than precisely
measure the surface temperature, which is often strongly influenced
by the degree of convective blood flow about the electrode, which
is typically about 37.degree. C.
[0493] In one embodiment, microwave radiometry is used to measure
tissue temperature at depth instead of at the electrode surface,
such as described in US Publ. No. 2007/0299488 (the entire content
of which is hereby expressly incorporated by reference). In
addition to providing improved feedback on ablation progress and
efficacy, microwave radiometry can also be used to estimate the
stability of the treatment electrode within the target, in
accordance with several embodiments. FIG. 68 illustrates an example
of the effects of using microwave radiometry. FIG. 68 illustrates a
base case with conventional electrode tip temperature measurements.
Because the electrode tip temperature sensor measures the
temperature of a small region of tissue around the electrode, the
thermal mass of this tissue is limited. When the electrode is
moved, the new tissue in contact with the electrode is heated
rapidly, and variations in electrode tip temperature due to motion
of the electrode are not significant, making this parameter
potentially unreliable as an indicator of electrode and/or catheter
motion. In accordance with several embodiments, because microwave
radiometry measures the bulk thermal energy of a region of tissue,
the temperature measurement corresponds to a region of tissue
having a much larger thermal mass. Consequently, in accordance with
several embodiments, temperature measurements using microwave
radiometry will drop more significantly with motion of the
electrode and/or catheter, as illustrated in FIG. 68. This fact can
be used to control energy delivery (for example, an alarm can be
generated when temperature drops below a certain threshold,
indicating excessive catheter motion).
[0494] In several embodiments, by accurately measuring tissue
temperature at depth using microwave radiometry lesion assessment,
treatment efficacy and progress can be estimated more reliably.
Excessive electrode and/or catheter motion can also be detected,
thereby alerting a physician or other clinician to confirm good, or
sufficient, electrode contact angiograpically before proceeding
with the treatment.
[0495] Some strategies for increasing lesion depth during ablation
procedures have focused on actively cooling the surface of the
electrode (e.g., using infused saline, internally circulated and/or
chilled fluid). In some embodiments, electrode cooling allows
deeper lesions to be formed without vaporizing the tissue adjacent
to the electrode. In some applications, when cooling, it is
difficult to have feedback about the peak temperature reached by
the tissues, since the typical practice of placing a thermocouple
within the electrode will measure a temperature that is biased by
the cooling itself, and thus may not be representative of the peak
temperature reached by the more distant tissues.
[0496] One embodiment for measuring the adventitia peak tissue
temperature in an endovascular ablation of the hepatic artery is as
follows. A thermocouple, thermistor or other
temperature-measurement device may be placed at a location within
the hepatic artery and used to measure the wall temperature at a
distance of about 5 mm (as a shortest path) from the surface of the
electrode, for electrode sizes between 1 mm and 2 mm in diameter.
Studies have shown that measuring the wall temperature at such a
distance is a fair approximation of the peak temperature reached
within the adventitia.
[0497] With electrode cooling, the thermocouple within the
electrode measures a temperature that is driven by the cooling
itself, which may be much lower than the temperature reached by
more distal tissues. Thus, for a temperature-controlled ablation,
this measurement may not be useful in indicating the temperature
reached by the adventitia, where the nerves are located. As a
consequence, in one embodiment, the nerves can fail to be ablated
if the heat provided is not sufficient to cause ablation within a
certain time period, or there can be collateral damage if the heat
is excessive. In accordance with several embodiments, a
temperature-controlled neuromodulation (e.g., ablation) is
desirable, as if one controls the electrical output (e.g., voltage,
current, or power), the heat transferred to the tissues depends on
a limited number of variables, such as contact force and impedance,
thereby reducing the variability of the therapeutic effect. The
placement of remote probes placed at discrete locations within the
target tissue to address any shortcomings with cooled electrode
strategies may be undesirable in several embodiments because they
would require transvascular placement, thereby increasing the risk
of the procedure.
[0498] Using a numerical model of hepatic arterial ablation, the
Applicant has demonstrated that measuring the temperature at the
arterial lumen at a shortest-path distance of 5 millimeters from
the surface of the electrode provides a temperature that is
reasonably close to the peak temperature reached at the
media-adventitia interface. For the purposes of this analysis, the
numerical model is based on the following assumptions, reflecting
consolidated physiological knowledge of the hepatic arterial
system: [0499] 1. artery with a diameter of 4 millimeters [0500] 2.
thickness of the media is 2 millimeters [0501] 3. no external blood
cooling (this assumption is appropriate because the electrode
cooling dominates the thermal response near the electrode) [0502]
4. electrode diameter between 1 and 2 millimeters [0503] 5. the
electrode is cooled and its surface is maintained around 37.degree.
C.
[0504] FIGS. 69 and 70 represent isothermal contours after a 3
minute ablation at 25 V. The figures are, respectively, the case of
1 and 2 millimeter diameter electrodes. In FIG. 58, the electrode
is in contact with a right side of the artery, while in FIG. 59,
the electrode is in contact with the bottom of the artery. The dots
within the artery are at a distance of about 5 millimeters from the
surface of the electrode. The dots within the adventitia represent
the maximum temperature reached within the adventitia itself. In
both cases, the pairs of dots belong to the same isothermal
surface, and thus are, with good approximation, at the same
temperature. In some embodiments, as the electrode gets smaller,
the gradient of the temperature increases, and for sizes
significantly smaller than 1 millimeter in diameter and for sizes
significantly larger than 2 millimeters, the distance of 5
millimeter will likely change.
[0505] In several embodiments, the temperature at a distance d
(e.g., 5 millimeters) from the electrode is measured using a
temperature-sensing device 6005 (e.g., thermocouple) branching out
of the catheter 6010, either on the same side of the electrode
6015, or on the opposite side (as shown in FIGS. 71A and 71B,
respectively). The distance d between the electrode 6015 and the
temperature-measurement device 6005 may be other than 5 millimeters
(e.g., 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5.5 mm, 6 mm, 6.5
mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm or any distance
between 2 mm and 10 mm, between 5 mm and 15 mm, between 10 mm and
20 mm or overlapping ranges thereof).
[0506] In various embodiments, the rate change of various treatment
parameters (e.g., impedance, electrode temperature, tissue
temperature, power, current, voltage, time, and/or energy) is
monitored substantially in real time and displayed on a user
interface. Treatment parameter data may be stored on a data store
for later reporting and/or analysis. In some embodiments, an energy
delivery system receives inputs transduced from physiologic signals
such as blood glucose levels, norepinephrine levels, or other
physiological parameters indicative of the status of the progress
of treatment.
[0507] Other methods of observing the tissue ablation zone and the
surrounding anatomy may include prior, concomitant, or subsequent
imaging intravascularly by modalities including but not limited to:
intravascular ultrasound, echo decorrelation, optical coherence
tomography, confocal microscopy, infrared spectroscopy, ultraviolet
spectroscopy, Raman spectroscopy, and microwave thermometry. All
such imaging modalities may advantageously be adapted to the
hepatic artery because of its unique tolerance to low flow. In some
embodiments, ultrasound elastography is advantageously used for
imaging. Ultrasound elastography may show areas of localized tissue
stiffness resulting from the denaturing of collagen proteins during
thermal ablation (ablated regions tend to stiffen compared to the
native tissue); for example, stiff regions may correspond to
ablated regions. Intravascular ultrasound may be used for example,
to detect or monitor the presence and depth of ablation lesions.
For example, if the lesions are in the range of 2 to 6 mm from the
lumen wall, the clinician may be confident that the target nerves
were destroyed as a result of thermal coagulation. Extravascular
ultrasound imaging may also be used.
[0508] With respect to constant electrode tip temperature ablations
(e.g., controlling RF generator output power to maintain a constant
electrode tip temperature), in a physiologic situation, the degree
of convective cooling effectively confounds the electrode
temperature measurement--whereas for zero or limited convective
cooling the temperature and time can be used to "set" the lesion
size. In some embodiments, when there is significant convective
cooling, the RF generator may end up outputting too much power to
maintain a tip temperature, resulting in dessication and
vaporization at some depth (>0 mm from the electrode surface)
within the tissue where the maximum temperatures are reached,
thereby limiting ablation size. Electrode tip temperature and
lesion size are related, as shown in FIG. 72, but there is always a
maximum, and particularly, a maximum that shifts towards lower
temperatures with increasing convective cooling. In order to assess
which curve was applicable for a given physiologic boundary
condition (e.g., blood flow velocity), a flow sensor could be added
to the catheter to measure the degree of convective cooling. For a
given convective cooling rate, the relationship between electrode
tip temperature and lesion depth can be established using in vivo
and ex vivo techniques to provide a valid look up table for
specifying and assessing lesion size.
[0509] In one embodiment, electrode tip temperature can be used to
prevent or limit thrombus formation, which can start to occur as a
result of an edge effect as delivered power increases. As one
example, RF power or other energy delivery (such as ultrasound,
light, microwave, etc.) can be terminated as a threshold
temperature (e.g., 75.degree. C., 80.degree. C., 90.degree. C.,
etc.) is reached.
[0510] One method for assessing blood flow rate includes
positioning an electrode within the blood flow stream, preferably
in the center of the vessel (e.g., artery or other lumen). A set
power (e.g., 2-10 W, 5 W) can be delivered for a set period of
time, (e.g., 1-10 seconds, 3 seconds). The corresponding rise in
electrode tip temperature measured during this time period may be
inversely proportional to the blood flow rate in the target vessel
(which is expected to range from 100 to 200 mL/min for the hepatic
artery).
[0511] One embodiment for measuring flow is shown in FIG. 73,
depicting a catheter assembly configured to measure blood flow. In
accordance with several embodiments described herein, catheter
assemblies measure flow without impeding, or with minimal occlusion
of, blood flow in the small lumen of the hepatic artery, thereby
taking advantage of the potentially beneficial cooling action of
the blood. The embodiment shown in FIG. 79 employs the fact that an
RF heat source (e.g., an active electrode) is placed in the blood
flow, which additionally may include a thermocouple or other
temperature-measurement device in the electrode tip. As shown, two
more thermocouples or other temperature-measurement devices may be
added to the catheter, one upstream and one downstream from the
electrode, thereby allowing for the measurement of the heat
transferred by the flow. In one embodiment, measurement of the heat
transferred by the flow is performed using consolidated technology
for thermal mass flow in liquids, such as the LIQUI-FLOW.RTM.
controller (Bronkhorst High-Tech, Amsterdam, Netherlands). As
illustrated in FIG. 79, the two thermocouples may be added to the
catheter assembly at discrete locations, for example one at a
distance (e.g., 3 millimeters) downstream from the electrode, and
one at a distance (e.g., 3 millimeters) upstream from the
electrode. Other distances may be used. In some embodiments, the
thermocouples may be disposed at the end of bending segments in
order to achieve stable and precise positioning of the
thermocouples in the vicinity of the electrode.
[0512] FIG. 74 illustrates the principle of a thermal flow sensor.
In some embodiments, the electrode heats the surrounding tissues
(e.g., blood and arterial wall) through the application of RF
energy. When the arterial flow is zero, the two thermocouples sense
the same temperature, as the heat generated in the tissues is
conducted symmetrically from the electrode in the proximal and
distal directions. When the blood flow is greater than zero,
instead, the temperature profile shifts in the direction of the
flow (to the right in FIG. 80) due to convective heat transfer,
thereby resulting in a difference, AT, between the temperatures
detected by the two thermocouples as a result of the heat
transported by the flowing blood. AT is generally proportional to
the magnitude of the flow rate, in some embodiments. By connecting
the output of the thermocouples to an A/D converter and
microprocessor, the precise flow can be determined from a
previously-determined calibration relating AT to flow rate values
under known, controlled conditions, which can be approximated as a
linear relationship.
[0513] Referring now to FIG. 75, an embodiment of an ablation
control process is provided for achieving successful endovascular
ablation of a common hepatic artery. Once the catheter is
positioned, flow, impedance and electrode temperature can start
being monitored in real time, utilizing any of the various
embodiments previously described herein configured to do so. The
blood flow rate value determines the target power according to the
values previously described herein (see, for example, Table 1). If
the value of the flow rate is below the minimum that is needed for
a safe and successful ablation (e.g., at least 0.01 m/s), the
ablation procedure is immediately terminated.
[0514] During application of RF energy, the change in impedance as
the tissue temperature increases should be close (e.g., within a
30% tolerance range) to the impedance-temperature curve (see, for
example, FIG. 76), where an increase in tissue temperature should
correspond to a slight decrease in impedance. If the impedance
decreases too much (e.g., >30% from the curve described in FIG.
76), the electrode may not be in contact with the arterial wall and
instead may be in substantial direct communication with the blood,
which has a significantly lower resistivity. In this situation, the
catheter is repositioned to ensure good contact with the arterial
wall.
[0515] If the impedance remains higher than expected (e.g., per
FIG. 76), the tissue may need to be heated further by increasing
the RF power level. Alternatively, if the impedance is much higher
than expected (e.g., higher than about 200-300.OMEGA.), this is
likely to indicate formation of thrombus. In such case, the
ablations are immediately aborted, as tissue thrombus causes the
ablation to become unpredictable and unsafe.
[0516] In general, according to the ablation control process in
FIG. 75, the power is increased linearly (e.g., at a rate of 0.5
watts per second) until the target power level is reached. After
increase of power, the power level is kept steady if the flow rate
does not change by more than 20%. If flow rate has changed by more
than 20%, the power is adjusted to the new flow rate, as long as
the flow rate is above 0.01 m/s or some other threshold.
[0517] At any time during the ablation, flow, impedance and
electrode temperature are monitored as real time feedback signals,
and the power is adjusted (or stopped) according to their values.
After 4 minutes, or other suitable time period (e.g., according to
the power and time combinations listed in Table 1), RF energy
delivery is terminated and the ablation is completed.
[0518] In the ablation control process described in FIG. 75, a
power-controlled ablation algorithm may be employed instead of a
temperature-controlled algorithm because the temperature at the
electrode is not always a good indicator of the maximum temperature
reached within the tissue. Since the electrode is in contact with
the blood, its temperature is not expected to rise significantly
beyond 37.degree. C., and may be considerably lower than the
temperature within the tissues. Electrode temperature can be used
to detect complications during RF ablation treatments of the
hepatic artery. For example, if the electrode temperature rises too
much (for example, above 80.degree. C.), this may be a sign that
something unexpected has happened (for instance, a hole has been
formed in the arterial wall and the electrode is inserted directly
in the tissue, or alternatively, thrombus formation). In several
embodiments, electrode temperature monitoring provides an
additional layer of control redundancy to ensure procedure safety,
but it may not be used as a primary feedback variable to control RF
energy.
[0519] FIG. 77A illustrates an embodiment of an energy delivery
algorithm based on blood flow measurement. The energy delivery
algorithm utilizes the blood flow velocity or rate (or
alternatively, generic control variable "X," such as impedance) as
a control variable. In some embodiments, the generator conducts a
checksum before applying RF energy to assess the initial value of
the control variable, for example blood flow rate. Based at least
in part on the value of the measured control variable, the
proportional-integral-derivative (PID) controller gain values may
be adjusted to ensure a stable control feedback loop throughout the
duration of the energy application procedure. RF energy delivery
may then be delivered for a first period in a manner that adjusts
output power to maintain a constant first-derivative of the
electrode tip temperature (or other control variable, for example
impedance) until a set threshold value (e.g., 75.degree. C.) is
reached. RF energy may then be delivered for a second period in a
manner that maintains a constant electrode tip temperature (or
other control variable). The output power or current output (as
shown in the current (i) graph in FIG. 77B) by the generator during
time periods 1 and 2 is also shown in FIGS. 77A and 77B for
illustrative purposes.
[0520] Various embodiments of the RF-based systems and methods
described herein may provide one or more of the following
advantages: (i) reduces the number of ablations required for
effective treatment, (ii) reduces the length of vessel required for
effective treatment with an RF ablation device, (iii) enables
effective electrode cooling in targeted vessel, (iv) provides a
consistent vessel contact area while maintaining ample surface area
for electrode cooling; (v) reduces contact pressure of the
electrode(s) on the vessel wall; and/or (vi) effective denervation
of nerves in a perivascular region while maintaining minimal
heating of, or thermal injury to, the inner vessel wall.
2. Ultrasound
[0521] Ultrasound energy delivery devices may also be used to
reduce the likelihood of forming a complete circumferential lesion
around a target vessel. FIGS. 78A and 78B schematically illustrate
embodiments of components of intravascular ablation catheters
configured to prevent or inhibit vessel circumferentiality during
ablation therapy. FIG. 78A schematically illustrates that an
intravascular ablation catheter may comprise a transducer 7805
configured to radially emit ultrasound energy near the distal tip
of the ablation catheter. The construction of the ablation catheter
may be such that the transducer 7805 is always held off the center
of the vessel, similar to the RF ablation catheter approach
described in connection with FIG. 59. In some embodiments, the
radial emission primarily involves an arc of the vessel wall 7810
and adventitia 7815 (which may be considered an outer layer of the
vessel wall 7810) closest to the transducer 7805. Optimization of
energy level can occur such that the wall opposite of where the
transducer 7805 is located is not involved in the ablation arc. In
some embodiments, the intravascular ablation catheter comprises a
balloon that positions the transducer 7805 off the center axis of
the balloon and vessel. Other embodiments include a concentric
balloon that is smaller than the vessel diameter or a catheter
comprising a deflectable shaft that holds the transducer off axis.
In one embodiment, the catheter comprises a pre-shaped distal shaft
that orients the transducer off axis. For example, the shaft could
be held straight by a guide wire or mandrel and, once removed, the
shaft may deflect off axis. As another example, a removable
pre-shaped mandrel could be utilized.
[0522] FIG. 78B schematically illustrates an embodiment of an
intravascular ablation catheter comprising one or more flat
transducers 7805 configured to emit ultrasound energy near the
distal tip of the catheter. The transducers 7805 may be placed
radially and/or longitudinally along the shaft of the catheter in
manner that ensures the ablation pattern formed by all of the
transducers does not involve more than 75% of the vessel
circumference at any vessel cross-section. FIG. 78B schematically
illustrates energy cones 7820 formed by emission of ultrasound
energy from the two transducers 7805. In various embodiments,
tilted ultrasound transducers may be used to create a narrow
oblique circumferential lesion to prevent or inhibit negative
remodeling from occurring in any one circumferential plane. The
ultrasound energy may be beam-shaped or intensity-modulated to
maintain lesion depth.
[0523] FIG. 79 illustrates a schematic representation of a distal
portion 7900 of an ultrasound energy delivery device (e.g.,
comprising a transducer 7915 and a shaft 7920) positioned within a
blood vessel 7905 (e.g., hepatic artery) at a location
corresponding to an identified location along the blood vessel 7905
in which an adjacent dense structure 7910 (a pancreas in this
figure) is in close proximity. The pancreas in this figure could be
replaced with other dense structures 7910 (e.g., liver, stomach,
small intestine, muscle, and/or connective tissue).
[0524] The neuromodulation may be performed intravascularly or from
a source located external to the subject's skin (e.g.,
noninvasively). The neuromodulation may comprise ablation or
denervation of the nerves (e.g., sympathetic nerves innervating the
liver and/or other organ that may influence glucose production).
The neuromodulation may be accomplished by delivery of acoustic
energy using an ultrasound delivery device (e.g., ultrasound
catheter). In some embodiments, neuromodulation may be adjusted
based on the identified locations of the adjacent structures 7910
or the distances to such adjacent structures 7910. In accordance
with several embodiments, the presence of adjacent structures 7910
may be exploited to identify neuromodulation (e.g., ablation)
targets instead of identifying the adjacent structures 7910 to try
to avoid the adjacent structures 7910. In some embodiments, a
minimum threshold distance is also identified so as to effect
modulation of nerves between the hepatic artery and the adjacent
dense structure 7910 without ablating the tissue of the adjacent
dense structure 7910 itself. For example, a range of acceptable
distances may be between 3 mm and 1 cm, between 2 mm and 5 mm,
between 3 mm and 7 mm, between 4 mm and 8 mm, between 5 mm and 9
mm, or overlapping ranges thereof.
[0525] Several embodiments of ultrasound systems, devices and
methods described herein are particularly advantageous because they
include one, several or all of the following benefits: (i) fewer
treatment locations due to increased efficacy; (ii) ability to
effectively treat a short vessel length such as the common hepatic
artery; (iii) reduction in blood glucose, cholesterol and/or
triglyceride levels, (iv) reduction in lipid and/or norepinephrine
levels in the liver, pancreas, and/or duodenum; (v) confirmation of
treatment efficacy; (vi) higher likelihood of successful
neuromodulation due to modulation of areas of high nerve density;
(vii) increased likelihood of modulation having an effect on
glucose production due to modulation of areas of high nerve density
or concentration; (viii), increased circumferential vessel coverage
with reduced axial vessel length coverage; (ix) increased power
transmission without increasing transducer size (x) reduced overall
power or energy delivery by combining treatment using both
radiofrequency and acoustic (ultrasound) energy and/or (xi)
denervation of multiple organs or tissue structures from a single
location. Several embodiments of the invention are adapted to
accomplish one or more of these benefits. For example, some
embodiments have one or more of the following features: are
constructed to balance steerability with flexibility, have a
particular shape to treat target vessels, have a particular
pattern, frequency or power of ultrasonic emission to treat nerves
while limiting heating of non-target tissue, have a dimension
(e.g., length, diameter, cross-section, etc.) to facilitate
positioning and movement through the target vasculature (which may
be tortuous), have elements to center or stabilize the distal end
portion in a vessel, have elements to adjust or control trajectory
or focus or dispersion of energy delivery, have at least one
ultrasound transducer and at least one electrode so as to deliver
both radiofrequency and acoustic energy; have one or more elements
to provide confirmation or other assessment of lesion formation or
other tissue modulation, have elements or structures to increase
operational efficiency while providing increased surface area for
cooling, and/or have elements, materials or mechanisms to adjust
positioning of the transducers or other energy delivery elements
such that the distal end portion of the medical instrument (e.g.,
catheter) has a reduced-profile configuration during introduction
to the target location and an expanded profile configuration in
which circumferential coverage or treatment surface area is
increased.
[0526] FIG. 80 illustrates an embodiment of an energy delivery
system 8000 that is configured to modulate targeted tissue so as to
treat diabetes or symptoms associated with diabetes (e.g., to
reduce glucose levels, to reduce cholesterol levels, to reduce
lipid levels, to reduce triglyceride levels). As shown, the energy
delivery system 8000 can include a medical instrument 8005
comprising one or more energy delivery members 8010 (for example,
ultrasound transducers, radiofrequency electrodes, microwave
antennas) along a distal end of the medical instrument 8005. The
medical instrument 8005 can be sized, shaped and/or otherwise
configured to be passed intraluminally (for example,
intravascularly) through a subject being treated. In other
embodiments, the medical instrument 8005 is not positioned
intravascularly but is positioned extravascularly via laparoscopic
or open surgical procedures. In various embodiments, the medical
instrument 8005 comprises a catheter, a shaft, a wire, and/or other
elongate instrument. The term "distal end" does not necessarily
mean the distal terminus or distal end. Distal end could mean the
distal terminus or a location spaced from the distal terminus but
generally at a distal end portion of the medical instrument
8005.
[0527] In some embodiments, the medical instrument 8005 is
operatively coupled to one or more devices or components. For
example, as depicted in FIG. 80, the medical instrument 8005 can be
coupled to a delivery module 8015 (such as an energy delivery
module). According to some arrangements, the energy delivery module
8015 includes an energy generation device 8020 that is configured
to selectively energize and/or otherwise activate the energy
delivery member(s) 8010 (for example, ultrasound transducers)
located along the medical instrument 8005. In some embodiments, for
instance, the energy generation device 8020 comprises a generator,
a radiofrequency generator, a microwave energy source, a
laser/light source, another type of energy source or generator,
and/or the like, and combinations thereof. In other embodiments,
energy generation device 8020 is substituted with or used in
addition to a source of fluid, such a cryogenic fluid or other
fluid that modulates temperature, or cooling fluid to cool the
energy delivery members or surrounding tissue or blood.
[0528] With continued reference to the schematic of FIG. 80, the
energy delivery module 8015 can include one or more input/output
devices or components 8025, such as, for example, a touchscreen
device with one or more graphical user interfaces, a screen or
other display, a controller (for example, button, knob, switch,
dial, etc.), keypad, mouse, joystick, trackpad, microphone or other
input device and/or the like. Such devices can permit a physician
or other user to enter information into (for example, toggle
between operational modes by pressing touchscreen GUI inputs or
manipulating physical buttons or switches) and/or receive
information from the energy delivery system 8000. In some
embodiments, the output device 8025 can include a touchscreen or
other display or graphical user interface that displays images or
maps, provides temperature information, tissue contact information,
other measurement information and/or other data or indicators that
can be useful for regulating a particular treatment procedure. The
maps may be dynamically updated in real time or may be static maps.
The maps may indicate desirable areas of modulation (e.g.,
ablation) and/or previous modulation (e.g., ablation) sites.
[0529] According to some embodiments, the energy delivery module
8015 includes a processor 8030 (for example, a processing or
control unit) that is configured to regulate one or more aspects of
the energy delivery system 8000. The processor 8030 may include one
or more specific-purpose microprocessors that comprise hardware
circuitry configured to read computer-executable instructions and
to cause portions of the hardware circuitry to perform operations
specifically defined by the circuitry. The energy delivery module
8015 can also comprise a memory unit or other storage device 8035
(for example, computer readable medium) that can be used to store
operational parameters and/or other data related to the operation
of the energy delivery system 8000. The storage device 8035 may
include nonvolatile and/or volatile memory such as random access
memory ("RAM") for temporary storage of information and a read only
memory ("ROM") for permanent storage of information, which may
store some or all of the computer-executable instructions prior to
being communicated to the processor 8030 for execution, and/or a
mass storage device, such as a hard drive, diskette, CD-ROM drive,
a DVD-ROM drive, or optical media storage device, that may store
the computer-executable instructions for relatively long periods of
time, including, for example, when the computer system is turned
off.
[0530] The modules and sub-modules of the energy delivery system
8000 may be connected using a standard based bus system. In
different embodiments, the standard based bus system could be
Peripheral Component Interconnect ("PCI"), Microchannel, Small
Computer System Interface ("SCSI"), Industrial Standard
Architecture ("ISA") and Extended ISA ("EISA") architectures, for
example. In addition, the functionality provided for in the
components and modules of computing system may be combined into
fewer components and modules or further separated into additional
components and modules.
[0531] The system 8000 may also include one or more multimedia
devices, such as speakers, video cards, graphics accelerators, and
microphones, for example. A skilled artisan would appreciate that,
in light of this disclosure, a system including all hardware
components, such as the processor 8030, I/O device(s) 8025, storage
device(s) 8035 that are necessary to perform the operations
illustrated in this application, is within the scope of the
disclosure.
[0532] With reference to FIG. 80, the energy delivery system 8000
comprises (or is in configured to be placed in fluid communication
with) a cooling system 8040. In some embodiments, as schematically
illustrated in FIG. 80, such a cooling system 8040 is at least
partially separate from the energy delivery module 8015 and/or
other components of the energy delivery system 8000. However, in
other embodiments, the cooling system 8040 is incorporated, at
least partially, into the energy delivery module 8015. The cooling
system 8040 can include one or more pumps or other fluid transfer
devices that are configured to selectively move fluid through one
or more lumens or other passages of the medical instrument 8005.
Such fluid can be used to selectively cool (for example, transfer
heat away from) the energy delivery member(s) 8010 and/or to cool
surrounding tissue or blood during use.
[0533] In one embodiment, the energy delivery system 8000 comprises
an ultrasound energy delivery system, the medical instrument 8005
comprises an ultrasound catheter having one or more ultrasound
transducers located on a distal segment of the catheter shaft and
the energy delivery module 8015 comprises a generator configured to
cause the ultrasound catheter to deliver acoustic energy to heat
tissue sufficient to modulate (e.g., ablate or denervate) nerves
innervating the liver, pancreas, stomach, and/or small
intestine.
[0534] In some embodiments, the ultrasound catheter is
angiographically visible and comprises structures configured to
enable mapping locations. For example, if the ultrasound catheter
comprises flat transducers, the mapping structures may indicate the
plane in which the catheter is rotated. The transducer(s) may
advantageously be configured to generate sound waves to modulate
(e.g., ablate) tissue and to detect returning sound waves to sense
or visualize tissue structures. For example the ultrasound catheter
may be used to identify distances from a hepatic or other artery
wall to an adjacent dense structure (such as the liver, pancreas,
stomach, small intestine). As described above, the ultrasound
catheter may be used to detect areas along a hepatic artery in
which the adjacent dense structures are less than a threshold
distance away from the internal wall of the hepatic artery (e.g.,
less than 5 mm, less than 6 mm, less than 7 mm, less than 4 mm,
less than 3 mm, less than 8 mm, less than 9 mm, less than 10 mm)
indicative of a likely high density distribution of nerves.
[0535] In various embodiments, the ultrasound energy delivery
system is configured to operate in either a sensing (e.g.,
visualization, imaging or diagnostic) mode or a treatment (e.g.,
energy delivery) mode. The generator or other energy source may
comprise a graphical user interface that enables toggling between
the sensing mode and the treatment mode (e.g., by pressing
graphical user interface buttons on a touchscreen display of the
graphical user interface). In one embodiment, distances of the
adjacent dense structures are displayed on the graphical user
interface of the generator. In another embodiment, images of the
adjacent structures are displayed and the distances to the adjacent
structures may be determined from the images. As one example, the
output of the sensing mode may be combined with a digital image of
the subject's anatomy to provide an operator a visual map of
desirable/non-desirable modulation sites along the hepatic artery.
In one embodiment, the map comprises a "topographical" map
indicative of distances to dense structures either qualitatively
(e.g., using colors, highlighting or other visual indicators) or
quantitatively (using numerical measurements). In one embodiment,
the map comprises highlighted areas of close dense structures
longitudinally and/or radially from the hepatic artery.
[0536] A single ultrasound catheter may be configured to both sense
and deliver energy (e.g., ablative energy) utilizing at least one
transducer. The frequencies used to ablate the sympathetic nerves
can vary based on expected attenuation, the containment of the beam
both laterally and axially, treatment depths, type of nerve, mode
of operation (e.g., sensing mode or treatment mode) and/or other
parameters. In some embodiments, the frequencies used range from
about 20 kHz to about 60 MHz, from about 20 kHz to about 20 MHz,
from about 1 MHz to about 15 MHz, from about 20 MHz to about 60
MHz, from about from about 500 kHz to about 10 MHz, from about 1
MHz to about 5 MHz, from about 2 MHz to about 6 MHz, from about 3
MHz to about 8 MHz, less than 20 kHz, greater than 60 MHz or
overlapping ranges thereof. The sensing mode may involve use of
frequencies ranging from 10-60 MHz (e.g., from 10-20 MHz, from
15-30 MHZ, from 10-40 MHz, from 15-50 MHz, from 20-50 MHz, from
30-60 MHz, or overlapping ranges thereof). The treatment mode may
involve use of frequencies ranging from 2-45 MHz (e.g., from 2-10
MHz, from 5-15 MHz, from 5-30 MHz, from 10-40 MHz, from 15-45 MHz,
from 30-45 MHz, from 10-45 MHz, or overlapping ranges thereof).
However, other frequencies can be used without limiting the scope
of the disclosure. In some embodiments, sensing is accomplished
using pulse-echo ultrasound signals. In one embodiment, a sensing
transducer is advantageously provided with a damping layer on the
back surface to provide a narrower pulse width e.g., broad band
sensitivity). In one embodiment, narrow transmitted pulses are
achieved using active damping (e.g., shaped pulses). In some
embodiments, the ultrasound transducer is a ceramic chip, such as
lead zirconate titanate, or PZT. In another embodiment, the sensing
ultrasound transducer is a polymer transducer, such as a
polyvinylidene fluoride ("PVDF") transducer. In various
embodiments, the energy delivery system 8000 may adjust an energy
delivery algorithm or treatment parameters based on results or
feedback acquired while in the sensing mode of operation.
[0537] One or more ultrasound transducers of the ultrasound
catheter may emit focused or non-focused sound waves. The
transducers may be directional or non-directional (e.g.,
omni-directional). The transducers may comprise flat, rectangular
transducers or cylindrical transducers. In various embodiments, one
or more transducers are adapted to deliver acoustic energy to
modulate tissue and one or more transducers are adapted to provide
imaging, visualization or other diagnostic measurements. In some
embodiments, transducer(s) may comprise multiple-element
transducers or other type of transducer adapted to provide both
energy delivery and sensing functions. In embodiments where both
imaging and treatment are performed, the imaging element(s) can be
co-localized with the treatment element(s), or can be located
separately (e.g., in different housings, units, transducers,
etc.).
[0538] Embodiments of ultrasound catheters or systems may comprise
structures for centering the one or more transducers within the
hepatic artery or other vessel for maintaining the transducer(s) at
a minimum distance from the inner wall of the artery or otherwise
not in contact with the wall of the artery. For example, such
structures may include one or more balloons or other expandable and
retractable members, such as wires, ribbons, coils, spiral members
or arms. In several embodiments, the ultrasound catheters or
systems comprise structures to cool the transducer(s) or reduce the
likelihood of overheating. For example, the transducer(s) may be
positioned within balloons having cooling fluid or may comprise
structures to transfer, shunt or dissipate heat from the transducer
surface. In some embodiments, the catheter comprises flow-directing
or diverting structures to increase the velocity of blood over the
transducer(s).
[0539] In accordance with several embodiments, positioning of the
ultrasound transducers is manipulated to control circumferential
distribution of power (e.g., to control a shape of an ablation
lesion) and, optionally, to avoid damage to adjacent dense
structures. The energy delivery system 8000 may comprise a sensing
or visualization apparatus to assess position of the transducer(s)
in the blood vessel (e.g., hepatic artery) and/or an apparatus
adapted to move the transducer within the blood vessel (e.g., to
center the transducer or bias the transducer at a distance away
from a wall of the blood vessel). The sensing or visualization
apparatus and the moving apparatus may be integral components or
members of the ultrasound catheter or may comprise one or more
distinct, separate devices from the ultrasound catheter to be used
in conjunction with the ultrasound catheter.
[0540] In one embodiment, the sensing or visualization apparatus
may comprise angiographic markers that define margins of the blood
vessel. In another embodiment, the apparatus may comprise a dilute
contrast-filled balloon that defines the margins of the blood
vessel. In some embodiments, one or more of the transducers are
radiopaque or the ultrasound catheter comprises separate radiopaque
markers to facilitate assessment of positioning.
[0541] In some embodiments, the distal end portion of the shaft of
the ultrasound catheter may be deflected by pull wire(s), by
rotation and/or translation of a curved stylet, by
inflation/deflation of eccentric balloons, and/or by insertion and
withdrawal of a curved or straight sheath. In accordance with
several embodiments, if the general location of the adjacent
extravascular structure(s) is known, the transducer(s) can be
adjusted accordingly (e.g., anteriorly, posteriorly, superiorly,
inferiorly, etc.). In some embodiments, intravascular imaging
techniques (e.g., optical coherence tomography, intravascular
ultrasound) or extracorporeal noninvasive imaging techniques (e.g.,
MRI, CT) are used to identify locations of the adjacent
extravascular structures. In one embodiment, intravascular imaging
is performed using a transducer adapted (e.g., optimized) for
imaging (e.g., broad band, higher frequency). In one embodiment, a
separate sensing transducer proximate an energy delivery transducer
is used to detect backscatter from therapeutic ultrasound waves.
The largest echoes may generally be from the internal elastic
lamina of the blood vessel. The distance can be accurately measured
by pulse echo or correlation algorithms. Averaging of multiple
signals may achieve accuracy better than the wavelength of the
signal if only a single dominant echo is present.
[0542] In accordance with several embodiments, one or more
transducers of the ultrasound catheter or other medical instrument
is/are specifically configured to deliver ablative energy and to
increase (e.g., maximize) ablation lesion size radially while
reducing (e.g., minimizing) axial ablation length of the
transducer(s) (e.g., for flat transducers). The ultrasound catheter
may comprise a pivotable catheter that pivots the longest dimension
of a flat transducer from a position largely parallel to the vessel
length to a position that is largely parallel to the vessel
circumference.
[0543] FIGS. 81A-81D illustrate embodiments of pivoting ultrasound
energy delivery devices (e.g., comprising one or more energy
delivery members 8110 (for example, ultrasound transducers,
radiofrequency electrodes, microwave antennas)) in various pivot
configurations. FIG. 81A illustrates an embodiment of an ultrasound
catheter in a non-pivot configuration prior to energy delivery. The
ultrasound catheter is inserted into a guide or sheath catheter
with the long dimension of the transducer parallel to the guide,
sheath, and/or vessel wall. The ultrasound catheter is then
configured to deflect a distal segment of the catheter shaft into a
pivoting configuration to orient the longest transducer dimension
radially within the vessel. For example, FIG. 81B illustrates the
ultrasound catheter in an L-shaped pivot configuration and FIG. 810
illustrates the ultrasound catheter in an alternative T-shaped
pivot configuration. In one embodiment, the ultrasound catheter may
be configured to deflect the distal segment of the shaft into a
spiral shape to orient the longest transducer dimension radially
within the vessel, as shown in FIG. 81D.
[0544] Several embodiments of the pivoting catheters are
particularly advantageous for flat directional transducers because
they facilitate insertion of the transducer(s) at a low profile
(e.g., lowest possible profile) and the orientation of the
directional transducer(s) is increased (e.g., maximized) radially,
thereby enabling multiple slices of the circumference to be exposed
to energy delivery while reducing (e.g., minimizing) the length of
vessel involved.
[0545] For ultrasound catheters and systems adapted to deliver
power or energy sufficient to ablate tissue, it is particularly
advantageous to deliver sufficient power to a small perivascular
target volume to create a focal lesion and to deliver power to an
oblong region that is longer in the circumferential direction and
shorter in the axial direction, in accordance with several
embodiments of the invention. Accordingly, embodiments of
ultrasound catheters provide relatively large surface area for
power or energy delivery but provide a reduced profile for
introduction into the blood vessel (e.g., hepatic artery) and
increased flexibility to access target vasculature.
[0546] FIGS. 82A-86 illustrate various embodiments of ultrasound
catheters or systems adapted to provide a reduced insertion and
delivery profile while also providing increased circumferential
vessel coverage. FIG. 82A illustrates an embodiment of a distal
portion of an ultrasound energy delivery device having multiple
pivoting transducers 8210 adapted to rotate between a generally
axial reduced-profile configuration for insertion and a transverse
energy delivery configuration for providing an energy delivery
profile that is longer in the circumferential direction and shorter
in the axial direction. The ultrasound transducers 8210 comprise
flat, rectangular transducers.
[0547] In the reduced profile configuration, the longer dimension
of the transducers 8210 is aligned so as to be in parallel with the
longitudinal axis of the shaft of the catheter. As shown, adjacent
transducers 8210 may be stacked or offset vertically so as to
reduce spacing between the transducers when transitioned to the
energy delivery configuration. The transducers 8210 may each pivot
about a respective central pivot 8220 as shown in FIG. 82A. In
other embodiments, the transducers 8210 may be carried or suspended
by mounting structures or carriers that pivot so as not to obstruct
or interfere with operation (e.g., beam pattern) or efficiency of
the transducers 8210. Also as shown, the transducers 8210 may be
positioned in a recessed portion 8215 of the catheter shaft to
reduce the overall profile.
[0548] In various embodiments, the mechanism to cause the pivoting
or rotation of the transducers comprises one or more control or
actuation wires 8225 (e.g., pull wires and/or push wires) or
elastic self-rotating mechanisms or materials capable of
transitioning between the reduced profile configuration and the
energy delivery configuration. The wires 8225 may interface
directly with the transducers 8210 or with mounting frames or
structures holding the transducers 8210. The transducers 8210 may
comprise an array of two, three, four, five or more
transducers.
[0549] In various embodiments, the transducers 8210 have a width of
0.5-2 mm, a length of between 4-6 mm, a spacing of 2-3 mm in the
energy delivery configuration and a thickness of half a wavelength
using the speed of sound in a piezoelectric crystal. In some
embodiments, the active surface of the transducers 8210 is coated
with a polymeric matching layer of quarter-wavelength thickness. In
some embodiments, the opposite surface of the transducers 8210 is
configured to minimize or reduce acoustic coupling and increase
efficiency of the transducers. For example, an air pocket may be
positioned proximate the opposite surface. When an array of
transducers 8210 is used, the transducers 8210 may be offset in a
manner such that the sound waves constructively interfere with each
other to maximize or increase power transmission.
[0550] FIG. 82B illustrates an alternative embodiment of an
assembly of multiple pivoting transducers 8210 of the ultrasound
energy delivery device of FIG. 82B. As shown, instead of the
transducers 8210 each only rotating about their own individual
pivot, the transducers 8210 may rotate about a uniform central
pivot 8230 through the use of one or more connecting members 8235.
The relative spacing and sizing illustrated in the figures is not
necessarily to scale or accurate. In some embodiments, the
transducers are all the same size and shape and are uniformly
spaced in the energy delivery, or deployed, configuration. In other
embodiments, the transducers may have different sizes and/or shapes
and are not uniformly spaced. The transducers may be mounted on a
suspension apparatus that supports the transducers and provides the
connections and pivots without interfering with the function of the
transducers.
[0551] FIG. 83A illustrates an embodiment of a distal end portion
of an ultrasound energy delivery device including a foldable
flexible circuit substrate 8305 carrying an array of ultrasound
transducers 8310. The flexible circuit substrate 8305 comprises
perforations, slots or holes 8315 that define and control hinging
or folding behavior. In one embodiment, the flexible circuit
substrate 8305 is formed of a thin polyimide or other flexible
polymeric material. In various embodiments, the thickness of the
flexible circuit substrate 8305 ranges from about 0.001 to about
0.003 inches. The transducers 8310 and electrical leads 8325 may be
mounted to the flexible circuit substrate 8305. In one embodiment,
the substrate 8305 is trimmed to facilitate withdrawal. The
flexible circuit 8305 is coupled to the distal end of an elongate
delivery member 8320 (e.g., wire, tube, shaft) and may be
configured to be introduced through a sheath or tube 8330 in a
reduced-profile configuration and then deployed to an energy
delivery configuration. The deployment may be facilitated by one or
more actuation or control wires or as a natural result of the
flexibility of the material of the substrate 8305 and the
perforations or slots 8315 in the substrate 8305. As shown in FIG.
83A, electrical leads 8325 may be coupled to the transducers 8310
to deliver electrical energy from a generator or other energy
source to activate the transducers 8310 to deliver acoustic energy.
Each transducer 8310 may have two separate leads 8325 (one for a
top surface and one for a bottom surface) or there may be two leads
8325 total that branch to connect to each of the transducers
8310.
[0552] In some embodiments, the flexible circuit 8305 is reinforced
with (e.g., affixed to the substrate) metallic, metallic alloy
(e.g., Nitinol), ceramic or polymeric material, elements or
structures to provide stability and strength and/or to provide
further control over deployment and withdrawal and to provide more
precision for a desired energy delivery configuration. In one
embodiment, the flex circuit 8305 is reinforced with nitinol stays
or hinges. In some embodiments, the flexible circuit 8305 is
manufactured by plating the substrate with copper and the copper is
etched using photolithography to create a desired circuit pattern.
In various embodiments, the length of the transducers 8310 is
between about 3 mm and about 10 mm (e.g., 3-6 mm, 4-8 mm, 5-10 mm)
and the width of the transducers 8310 is less than 2 mm.
[0553] FIGS. 83B-1 to 83B-3 illustrate (e.g., via side, top, and
open views) another embodiment of a distal end portion of an
ultrasound energy delivery device comprising a flexible circuit. In
the illustrated embodiment, the flexible circuit substrate 8305 is
integral with (or formed from) the elongate delivery member (e.g.,
shaft or tube made of polyimide or other flexible polymeric
material) thereby providing additional stability and strength at
the proximal end for manipulation (e.g., insertion and withdrawal).
For example, skives or cut-outs 8340 may be formed in the elongate
delivery member at spaced-apart locations and a slit 8345 may also
be formed in the elongate delivery member between the skives 8340.
Similar to FIG. 83A, the ultrasound transducers 8310 may be
arranged on the flexible circuit substrate 8305 in any pattern or
configuration. The flexible circuit substrate 8305 may comprise
one, two, three, four, five or any number of transducers 8310. The
transducers 8310 may be coupled to a generator or other energy
source by electrical leads or wires 8325. In some embodiments, the
leads 8325 travel within a micro-coaxial cable 8335 within the
elongate delivery member 8320. In one embodiment, the micro-coaxial
cable 8335 is formed of a braided polyimide if the leads or wires
8325 comprise high conductance braid wires made of copper, nickel,
nickel plating, gold, silver, tungsten and/or the like. In some
embodiments, the leads or wires 8325 comprise two-sided traces with
vias.
[0554] FIGS. 84A-84E illustrate various configurations of a distal
portion of the ultrasound energy delivery device of FIG. 83A or
FIG. 84B. FIG. 84A illustrates a flat energy delivery
configuration. FIG. 84B illustrates an energy delivery
configuration in which the transducers 8310 are angled toward a
focal point to provide focused energy delivery. FIG. 84C
illustrates a folded configuration for introduction of the flexible
circuit 8305 through a sheath or sleeve 8330 (e.g., guide or
extension catheter). The transducers 8310 may be configured to fold
into a triangle, square or other polygonal shape. In some
embodiments, the folded configuration of FIG. 84C may be used for
larger-width transducers. FIG. 84D illustrates a stacked
configuration for introduction of the flexible circuit 8305 through
a sheath or sleeve 8330. FIG. 84E illustrates an energy delivery
configuration in which the ultrasound transducers 8310 are angled
away from each other so as to disperse the power or energy over a
wider area. For example, the energy may be delivered in de-focused
or unfocused manner in a lateral, circumferential or longitudinal
direction.
[0555] FIG. 85 illustrates an embodiment of a distal portion of an
ultrasound energy delivery device configured to deploy by unrolling
a flexible circuit 8505. In some embodiments, the flexible circuit
8505 comprises a plurality of ultrasound transducers 8510 (e.g.,
array) and the flexible circuit 8505 is configured to transition
between a rolled-up configuration for introduction and a deployed,
unrolled configuration for energy delivery. As shown, the
introductory rolled-up configuration may comprise a spiral or
"jelly roll" configuration. The flexible circuit 8505 may be
unrolled and rolled by torqueing parts of the ultrasound catheter
or other medical instrument in opposite directions or as a result
of self-expanding, shape memory material (e.g., Nitinol). The
flexible circuit 8505 may comprise multiple transducers 8510 spaced
relatively close together. In one embodiment, the transducers 8510
are adapted to deliver energy with a more precise focus (e.g., less
than half-wavelength in the media). In one embodiment, the
transducers 8510 are 0.5 mm wide. The relative spacing illustrated
in the figures is not necessarily to scale or accurate.
[0556] FIG. 86 illustrates another embodiment of a distal portion
of an ultrasound energy delivery device comprising multiple
interlocking mounting elements 8602. In this embodiment, multiple
transducers 8610 are distributed in an axial direction along a
flexible catheter 8605. The transducers 8610 are mounted on
mounting elements 8602 that are shaped and formed to interlock with
each other. Once at the treatment site, the mounting elements 8602
may be cinched or otherwise caused to come together to form a rigid
structure having a predefined shape. The predefined shape may
comprise a flat configuration, a concave configuration or a convex
configuration. The cinching may be effected by one or more pull
and/or push wires extending through the mounting elements. The
orientation between mounting elements 8602 may be defined by the
shape of interlocking edges of the mounting elements. The distal
end of ultrasound energy delivery device may comprise an anchor
(not shown) and a soft, steerable tip 8615.
[0557] Several embodiments of the ultrasound energy delivery
devices comprising flexible circuits are particularly advantageous
because they support the electrodes coupled to the transducers
and/or provide electrical leads to opposing surfaces of the
transducer.
[0558] In accordance with several embodiments, acoustic mirrors
and/or lenses are used to control distribution of acoustic energy
delivered by an ultrasound transducer of the ultrasound catheter in
order to control size and shape of the treatment area (e.g., lesion
zone). For example, acoustic impedance may be analogous to index of
refraction in optics. Sound waves traversing regions of different
acoustic impedance may be refracted and/or reflected. Accordingly,
a tighter focus can be achieved by large planar or cylindrical
transducers.
[0559] FIGS. 87A-87F illustrate various embodiments of acoustic
mirrors and/or lenses to control distribution of acoustic energy
delivered by an ultrasound transducer. Balloons filled with
different fluids may be used to focus or de-focus the output of the
ultrasound transducer. For example, acoustic mirrors or lenses may
be created by a curved surface of a balloon inflated with a media
having an acoustic impedance different from the surrounding media
(e.g., tissue and/or blood). In accordance with several
embodiments, the use of acoustic mirrors and/or lenses
advantageously provides more energy to a target treatment area
without overheating the transducer or causing cavitation at the
transducer surface.
[0560] FIG. 87A illustrates a cylindrical transducer 8710
positioned on a single balloon 8705 filled with a liquid having an
acoustic impedance different than (e.g., greater than, less than)
the surrounding blood and/or tissue, thereby forming an acoustic
lens. As can be seen, the balloon 8705 causes the path of the
acoustic energy to deviate from the initial trajectory. The
acoustic mirror or lens may comprise a single balloon or a double
balloon (e.g., an inner balloon and an outer balloon). FIG. 87B
illustrates an embodiment comprising a double balloon. The inner
balloon 8705A is filled with a first liquid having a first acoustic
impedance and the outer balloon 8705B is filled with a second
liquid having a second acoustic impedance different than the
acoustic impedance of the first liquid. Either the first liquid or
the second liquid may have an acoustic impedance that is
substantially different than the acoustic impedance of the
surrounding tissue and/or blood. For example, fat, blood and soft
tissues have an acoustic impedance of 1.3-1.7 MRayls. Fluids (e.g.,
liquids) in the balloons (in accordance with several embodiments)
have an acoustic impedance approximately 10% different from tissue
or blood. For example, in some embodiments, the fluids have an
acoustic impedance from 0.7 MRayls to 1.8 MRayls. In some
embodiments, a first balloon comprises a first fluid having a first
acoustic impedance and a second balloon comprises a second fluid
having a second acoustic impedance. The cylindrical transducer 8710
is positioned on the inner balloon 8705A.
[0561] In some embodiments, the outer balloon is filled with air to
form an acoustic mirror (as shown in FIGS. 87C and 87D). FIG. 87C
illustrates a mirror configuration for generating generally
non-columnar trajectories to provide for a wider dispersal and FIG.
87D illustrates a mirror configuration for generating generally
columnar trajectories in which the transducer 8710 is positioned at
the focus of the air-liquid interface. In the embodiment of FIG.
87D, the outer balloon 8705B may be formed with the inner balloon
8705A to create a crescent-shaped or parabolic-shaped cavity and
the transducer 8710 may be positioned at the bottom of the
crescent- or parabolic-shaped cavity.
[0562] FIG. 87E illustrates an embodiment in which a flat,
rectangular ultrasound transducer 8710 is positioned on a
double-balloon configuration, in which the inner balloon 8705A is
filled with a liquid to form an acoustic lens and the outer balloon
8705B is filled with air to form an acoustic mirror. FIG. 87F shows
that the acoustic mirrors may be formed from folding mechanical
structures or plates 8715.
[0563] In various embodiments, the balloons comprise spherical
balloons. The focus of the acoustic lens embodiments may be changed
by changing the shape of the balloon(s) through pressurizing or
stretching the balloon(s) and/or by changing the media or
concentration of the fluid in the balloons. The liquids used may
include concentrated saline, concentrated glucose solution,
glycerol, propylene glycol, ethylene glycol, heavy water (D20),
fluorocarbons (e.g., Freon), mercury, gallium,
perfluorotributylamine, perfluorodecalin, and/or oils. The air may
comprise any gas, such as carbon dioxide.
[0564] In accordance with several embodiments, it may be
particularly advantageous to provide a larger area of treatment
(e.g., larger ablation zones) without increasing the size of the
transducers. For example, a plurality of transducers may be
arranged to acoustically couple with each other such that more
power is transmitted from the active surfaces (e.g., increased
efficiency) and more surface area is available for cooling.
[0565] FIG. 88 illustrates a schematic representation of an
embodiment of a resonant cavity ultrasound transducer 8810 adapted
to provide a larger area of treatment (e.g., larger ablation zone).
The ultrasound transducer 8810 comprises two parallel flat
transducers 8805 spaced apart by a distance d that is a multiple of
the wavelength (d=n.times.A) to achieve resonance and adapted to
radiate in opposite directions. The resonant cavity ultrasound
transducer 8810 comprises a suspension structure, frame or
mechanism (not shown) configured to maintain alignment of the two
transducers or plates 8805 in a parallel orientation. The
suspension structure or mechanism may be slightly compliant so as
to allow for self-adjustment to achieve resonance. All exposed
surfaces of the transducers or plates 8805 are surrounded by
cooling fluid contained within a balloon 8815. The outside surfaces
of the transducers 8805 comprise matching layers and the inside
surfaces do not comprise matching layers so as to provide increased
cooling to the transducers 8805.
[0566] In accordance with several embodiments, embodiments
comprising resonant cavity ultrasound transducers advantageously
provide one or more of the following advantages or benefits:
increased cooling, greater amplitude or power, and ability to move
the transducer(s) closer to the wall (e.g., permits a closer focal
distance).
[0567] In accordance with several embodiments, it may be
advantageous to cool the ultrasound transducer(s) without backside
acoustic coupling (e.g., air gaps) that reduces efficiency. FIG. 89
illustrates an embodiment of an ultrasound transducer 8910
comprising a heat pipe configuration to increase heat transfer. In
one embodiment, a flat heat pipe may be positioned on the back side
of the piezoelectric chip or plate to increase heat transfer
without increasing acoustic coupling. The heat pipe configuration
comprises a hot surface 8902, a cold surface 8903 and a thin gap
8904 filled with a two-phase fluid 8905 between the hot surface
8902 and the cold surface 8903. The two-phase fluid 8905 comprises
liquid and gas. The hot surface 8902 is formed on the back surface
of the piezoelectric plate or chip 8906. The fluids may comprise
water, alcohol, refrigerants (e.g., Freon, R12), propane, nitrous
oxide, etc. The quality (e.g., % liquid) of the two-phase fluid or
mixture varies with temperature. In some embodiments, a quality is
desired that provides sufficient heat transfer to maintain
equilibrium at the operating temperature without damping the
transducer. The fluid 8905 migrates or wicks between the hot and
cold surfaces. The fluid 8905 may be stirred by microstreaming
generated by movement of the piezoelectric plate or chip 8906. In
some embodiments, the liquid phase rarely if ever touches the
surface of the piezoelectric plate or chip 8906. Accordingly, the
effective acoustic impedance is determined by the vapor or gas
phase, which is normally very low so that little acoustic energy is
transmitted out the back side of the transducer.
[0568] The interior cold surface 8903 of the cooling plate may be
textured or patterned materially to control nucleation, growth and
transport of condensate. FIG. 89B illustrates various embodiments
of texture patterns of the ultrasound transducer of FIG. 89. The
patterns may comprise grooves, slots, holes, cross hatches, bumps,
spirals, bumps and holes, and/or the like. In some embodiments, the
pattern comprises printed regions of surface coatings having
different affinity for the condensate or liquid phase. The
piezoelectric back surface (e.g., the hot surface or evaporating
surface 8902) has a low affinity for the liquid phase and the
cooling plate surface (e.g., cold surface 8903) has a high affinity
for the liquid phase. If water is used as the fluid, then the hot
surface 8902 is hydrophobic and the cold surface 8903 is
hydrophilic. The thin gap 8904 may have a thickness that is several
times the wavelength of the piezoelectric plate or chip (the hot
plate 8902). The gap 8904 should allow for sufficient growth of
distinct regions of condensate nucleation and growth as the
piezoelectric chip (e.g., PZT) is heated up. As shown in FIG. 89,
the exterior (back) surface of the cooling plate may comprise
textured structures 8907 (e.g., grooves, fins) to promote heat
transfer. In one embodiment, the cooling plate is larger than the
piezoelectric plate or chip 8906 (e.g., hot plate).
[0569] The ultrasound transducer 8910 comprising the heat pipe may
be fabricated using MEMS technology. In various embodiments, the
piezoelectric chip or plate 8906 is hermetically sealed to the
backing or cooling plate using a glass weld 8908. The cooling plate
or backing may comprise glass, ceramic and/or metal. FIG. 89A
illustrates a close-up view of a portion of the cooling plate or
backing of the ultrasound transducer 8910 of FIG. 89. As shown,
condensate 8915 may be formed on the high-affinity surfaces 8909 of
the cold surface 8903. As the condensate collection approaches the
hot surface 8902, heat is transferred to the condensate collection
or droplets and the droplets evaporate. The cooling plate may
transfer heat to a remote location using fluid, heat pipe or
thermal conduction. In other embodiments, the high-affinity
surfaces may be the lowered regions instead of the raised regions
depending on the material used for the various regions. In one
embodiment, the surface of the cooling plate is physically flat but
is patterned with alternating regions of high-affinity and
low-affinity (e.g., hydrophilic and hydrophobic) materials.
[0570] In accordance with several embodiments, energy delivery
devices (e.g., catheters) are adapted to deliver both ultrasound
and radiofrequency energy to target tissue. For example, the energy
devices or systems may be configured to provide unipolar ultrasound
and radiofrequency energy delivery. FIG. 90 illustrates an
embodiment of an energy delivery system 9000 configured to deliver
ultrasound and radiofrequency energy to target tissue using a
single energy delivery device. The energy delivery system comprises
an energy delivery device 9020 comprising one or more ultrasound
transducers 9010 and one or more electrodes 9025, a ground pad 9030
and a generator 9035. The illustrated embodiment of the energy
delivery device 9020 comprises two ultrasound transducers 9010 and
an electrode 9025 positioned between the ultrasound transducers
9010. The electrode 9025 may be coupled or arranged in series or in
parallel with the transducers 9010. In one embodiment, the one or
more electrodes 9025 comprise one or more exposed transducer
electrodes. In another embodiment, the one or more electrodes 9025
comprise separate, distinct elements from the transducers 9010. The
transducers 9010 may comprises focused ultrasound transducers or
non-focused ultrasound transducers. The generator 9035 may include
the features of the other generators or energy delivery modules
described herein.
[0571] In one embodiment, a wire 9040 connects the generator 9035
to one electrode layer of the ultrasound transducer(s) 9010 and the
electrode 9025 and the circuit is completed by the ground pad 9030,
which is also electrically coupled to the generator 9035.
Radiofrequency energy is delivered by the electrode 9025 through
tissue toward the ground pad 9030. The return path of the
ultrasound drive signal also uses tissue conduction to the ground
pad 9030. Accordingly, the ultrasound and radiofrequency energy may
be delivered in a unipolar fashion through a single wire with the
return provided by the ground pad 9030.
[0572] In some embodiments, radiofrequency energy is delivered for
a period of time before the ultrasound energy is delivered in order
to preheat the tissue to a level just below an ablation threshold
(e.g., within 1-10 degrees Celsius, within 1-5 degrees Celsius) of
the tissue. In one embodiment, the ultrasound energy is then
provided to incrementally heat the tissue sufficient to elevate the
temperature above the ablation threshold of the tissue, thereby
reducing the total amount of power or energy required to ablate the
tissue while still providing focused ablation.
[0573] In some embodiments, a sensing wire 9045 is provided to
measure voltage at the electrode(s) 9025, thereby enabling
measurement of both ultrasound and radiofrequency power delivery.
The sensing wire 9045 may connect directly from the generator 9035
to the electrode 9025. In some embodiments, the sensing wire 9045
is used to measure tissue impedance. The sensing wire 9045 may be
used to adjust the proportion of the electrode to change the
proportion of power or energy delivery. For example, the
measurements obtained using the sensing wire 9045 may adjust the
radiofrequency energy delivery to either deliver more
radiofrequency energy or siphon off radiofrequency energy delivery
delivered to the target tissue. The proportion of radiofrequency
and ultrasound power may be adjusted by varying the frequency with
respect to the resonant frequency of the ultrasound transducer(s)
9010. In some embodiments, the ultrasound transducers 9010 deliver
treatment energy in the range of 1-10 MHz (e.g., 2-5 MHz, 3-8 MHz,
1-4 MHz, 6-10 MHz, or overlapping ranges thereof) and the electrode
9025 delivers energy in the range of 400 kHz to 1 MHz (e.g., 450
kHz to 650 kHz, 600 kHz to 800 kHz, 700 kHz to 1 MHz, or
overlapping ranges thereof).
[0574] In several embodiments, changes in impedance of the
electrode 9025 are used as an indicator of lesion formation and the
impedance measurements may be used to adjust energy delivery. In
some embodiments, the impedance measurements or output indicative
of lesion formation or completion may be output on a display of the
generator 9035. In some embodiments, the electrode 9025 is used
only for sensing and not for energy delivery.
[0575] In accordance with several embodiments, embodiments of
systems configured to deliver both ultrasound and radiofrequency
provide one or more of the following advantages or benefits: (i)
fewer wires in the shaft, (ii) lesion characterization or lesion
formation assessment, (iii) additional heat provided by
radiofrequency energy delivery, (iv) simplified catheter
construction by reducing transmission line requirements, (v) use of
transducers with relatively small surface area (e.g., less than 50
mm.sup.2 for cylindrical transducers and less than 15 mm.sup.2 for
rectangular transducers), (vii) use of tissue conduction to ground
pad as return path for ultrasound drive signal, (v) quick formation
of small, focal lesions with reduced power delivered by ultrasound
transducers and/or (vi) creation of more focal lesions with
increased total energy delivered.
[0576] In some embodiments, the energy delivery system 8000
delivers ultrasonic energy to modulate (e.g., ablate, stimulate)
sympathetic nerve fibers in the hepatic plexus. For example, the
energy delivery system 8000 can employ focused ultrasonic energy
such as high-intensity focused ultrasonic (HIFU) energy or
low-intensity focused ultrasonic (LIFU) energy to ablate
sympathetic nerve fibers. As another example, the energy delivery
system 8000 delivers non-focused, or unfocused, energy. For
example, the ultrasound transducer(s) can deliver ultrasonic energy
to one or more target sites to modulate (e.g., ablate) sympathetic
nerve fibers in the hepatic plexus or other nerves described herein
(e.g., celiac plexus or nerves innervating, surrounding or in
proximity to the liver, pancreas, stomach and/or small intestine).
The acoustic, or ultrasonic, energy can be controlled by dosing,
pulsing, or frequency selection. In some embodiments, HIFU energy
can advantageously be focused at a distant point to reduce
potential disturbance of the tissue of the blood vessel (e.g., the
intima and the media layers) or surrounding tissues. HIFU energy
can advantageously reduce the precision required for positioning of
the ultrasound catheter. The one or more ultrasound transducers can
be refocused during treatment to increase the number of treatment
sites or to adjust the depth of treatment. In some embodiments, the
use of HIFU energy can result in increased concentrations of heat
for a shorter duration and can simultaneously focus energy at
multiple focal points, thereby reducing the total time required to
administer the neuromodulation procedure.
[0577] In some embodiments, the energy delivery system 8000
comprises a focused ultrasound (e.g., HIFU) ablation catheter and
an acoustic frequency generator. The ablation catheter can be
steerable from outside of the subject using a remote mechanism. The
distal end of the ablation catheter can be flexible to allow for
deflection or rotational freedom about an axis of the catheter
shaft to facilitate positioning within a hepatic or other artery.
In some embodiments, the ablation catheter comprises focusing
(e.g., parabolic) mirrors or other reflectors, gas-filled or
liquid-filled balloons, and/or other structural focusing elements
to facilitate delivery of the ultrasonic energy. The one or more
transducers can be cylindrical, rectangular, elliptical, or any
other shape. The ultrasound catheter can comprise sensors and
control circuits to monitor temperature and prevent overheating or
to acquire other data corresponding to the one or more ultrasound
transducers, the vessel wall and/or the blood flowing across the
ultrasound transducer. In some embodiments, the sensors provide
feedback to control delivery of the ultrasonic energy. In some
embodiments, the ultrasound energy is controlled such that delivery
of the ultrasound energy heats the arterial tissue in the range of
about 40 to about 90.degree. C. (e.g., 40.degree. C. to 60.degree.
C., 60.degree. C. to 75.degree. C., 65.degree. C. to 80.degree. C.,
60.degree. C. to 90.degree. C., or overlapping ranges thereof. In
some embodiments, the temperature can be less than 40.degree. C. or
greater than 90.degree. C.
[0578] The average ultrasound intensity for ablation of sympathetic
nerve fibers in the hepatic plexus, celiac plexus or other
sympathetic nerve fibers can range from about 0.1 W/cm.sup.2 to
about 10 kW/cm.sup.2, from about 0.1 W/cm.sup.2 to about 10
W/cm.sup.2, from about 0.5 W/cm.sup.2 to about 5 W/cm.sup.2, from
about 1 W/cm.sup.2 to about 100 W/cm.sup.2, from about 10
W/cm.sup.2 to about 10 kW/cm.sup.2, from about 500 W/cm.sup.2 to
about 5 kW/cm.sup.2, from about 2 W/cm.sup.2 to about 8
kW/cm.sup.2, from about 1 kW/cm.sup.2 to about 10 kW/cm.sup.2, from
about 25 W/cm.sup.2 to about 200 W/cm.sup.2, from about 200
W/cm.sup.2 to about 1 MW/cm.sup.2, less than 0.1 W/cm.sup.2,
greater than 10 kW/cm.sup.2, or overlapping ranges thereof. Average
power levels may range from about 0.1 W to about 1 MW (e.g., from
about 0.1 W to about 1 kW, from about 0.1 W to about 10 W, from
about 0.5 W to about 5 W, from about 1 W to about 100 W, from about
25 W to about 1 MW, depending on the intensity of the ultrasound
energy, pulse duty cycle and/or other parameters). The ultrasound
energy can be continuous or pulsed. The average power levels or
energy density levels used for pulsed ultrasound energy may be
higher than the average power levels used for continuous ultrasound
energy.
[0579] The treatment time for each target site (e.g., ablation
site) can range from about 5 seconds to about 120 seconds, from
about 10 seconds to about 60 seconds, from about 20 seconds to
about 80 seconds, from about 30 seconds to about 90 seconds, less
than 10 seconds, greater than 120 seconds, one minute to fifteen
minutes, ten minutes to one hour, or overlapping ranges thereof. In
accordance with several embodiments, the parameters used are
selected to disable, block, cease or otherwise disrupt conduction
of sympathetic nerves (e.g., of the hepatic plexus) for at least
several months.
[0580] In some embodiments, the ultrasound catheter of the energy
delivery system 8000 has a diameter in the range of about 2-8 Fr,
about 3-7 Fr, about 4-6 Fr (including about 5 Fr), and overlapping
ranges thereof. The catheter (e.g., tube, probe or shaft) may have
a varying diameter along its length such that the distal portion of
the catheter is small enough to fit into progressively smaller
vessels as the catheter is advanced within vasculature. In one
embodiment, the catheter has an outside diameter sized to fit
within the common hepatic artery (which may be as small as about 1
mm in lumenal diameter) or the proper hepatic artery. In some
embodiments, the catheter is at least about 150 cm long, at least
about 140 cm long, at least about 130 cm long, at least about 120
cm long, at least about 110 cm long, at least about 100 cm long, at
least about 75 cm long, or at least about 90 cm long. In some
embodiments the catheter length is sufficient for use with
brachial, radial, or femoral artery vascular access techniques. In
some embodiments, the flexibility of the catheter is sufficient to
navigate tortuous hepatic arterial anatomy having bend radii of
about 10 mm, about 9 mm, about 8 mm, about 7 mm, about 6 mm, about
5 mm, about 4 mm, about 3 mm, about 2 mm, about 1 mm, or about 0.5
mm.
[0581] In accordance with several embodiments, the ultrasound
catheters have actuatable, expandable, steerable, pre-curved,
deflectable and/or flexible distal tip components or distal
segments. The deflectability or flexibility may advantageously
permit accurate positioning of the ultrasound transducers and/or
help navigate the ultrasound catheter to the target anatomy. In
some embodiments, devices (e.g., catheters) with steerable,
curvable or articulatable distal portions provide the ability to
cause articulation, bending, or other deployment of the distal end
(which may contain one or more transducers). In some embodiments,
the ultrasound catheters provide the ability to be delivered over a
guidewire. The ultrasound catheters may be configured to enable
guidewire exchanges by a single operator. In one embodiment, the
ultrasound catheter comprises a lumen that accepts a guidewire
along the majority of the portion of the shaft that is inserted
within the subject. In another embodiment, the guidewire is only
received within a distal-most segment of the shaft of the catheter
(e.g., the distal-most 20 cm or less). In one embodiment, the
guidewire is received by a structure distal of the distal-most
ultrasound transducer. In some embodiments, the ultrasound
catheters are inserted within the vasculature through guide sheaths
or guide extension catheters. In some embodiments, guidewires are
not used.
[0582] In accordance with several embodiments, ultrasound energy
delivery systems may comprise a guide catheter, a guide extension
catheter or support catheter (e.g., a Guidezilla.TM. catheter or
GuideLiner.TM. catheter), a microcatheter, and/or a guidewire, in
addition to an ultrasound catheter. In one embodiment, the guide
catheter is a 7 Fr guide catheter that is configured to engage with
the inner wall of the celiac artery to provide a stable anchoring
and/or reference point. The system may comprise a guidewire (e.g.,
0.014'' guidewire) that may be configured to be delivered through a
lumen of the guide catheter and advanced to a position beyond a
target neuromodulation location within a hepatic artery or other
vessel or organ. The system may also comprise a microcatheter
(e.g., 4 Fr or less) and/or a guide extension catheter (e.g., a 6
Fr guide extension catheter). The guide extension catheter may be
configured to fit and be movable within a lumen of the guide
catheter to provide support at a lower profile (e.g., outer
diameter) than the guide catheter. The microcatheter may be
configured to fit and be movable within a lumen of the guide
extension catheter and extend beyond a distal end of the guide
extension catheter. The microcatheter may facilitate tracking and
advancement of the guide extension catheter over the guidewire. In
some embodiments, the microcatheter comprises a rapid exchange
microcatheter. The guidewire may provide a "rail" to aid catheter
tracking and lessen the risk of vessel damage when advancing a
neuromodulation device.
[0583] In some embodiments, the guide catheter and/or the guide
extension catheter comprises an expandable portion that is
configured to be advanced to a desired location and then expanded
before or during advancement of a neuromodulation device through
the guide extension catheter or the guide catheter. The expandable
portion may enable transitory, or temporary, expansion of vessel
inner diameters. In one embodiment, the expandable portion may be
formed of multiple layers that slide over each other. In one
embodiment, the expandable portion may be formed of a cylinder with
interrupted longitudinal cuts and encapsulated by an elastic layer
that keeps the cuts compressed in an unexpanded state. The
expandable portion may provide stabilization or anchoring.
Stabilization mechanisms (in addition to or instead of the
expandable portion) may be provided at various locations along a
length of the guide catheter and/or the guide extension catheter
(e.g., balloons, ribbons, wires). In some embodiments, portions of
the guide catheter or guide extension catheter may be stiffened
after introduction of the neuromodulation device to provide
stability and maintenance of positioning during neuromodulation
procedures. In some embodiments, the system does not comprise a
guidewire, as the guide extension catheter may obviate the need for
a guidewire.
[0584] In some embodiments, ultrasound energy delivery devices or
systems may deliver energy from outside the body (e.g.,
extracorporeally or transcutaneously), extravascularly but within
the body, or intravascularly. Extracorporeal neuromodulation may
include delivery of ultrasound energy (e.g., high-intensity focused
ultrasound energy or low-intensity ultrasound energy) or other
forms of radiative energy other than microwave (e.g., X-ray or
gamma radiation). In some embodiments the desired, or target,
location is defined by external imaging means. The foci or other
target locations may be determined by any of the image-guidance
techniques described herein. In some embodiments, an internal
catheter or other devices (e.g., sensors, beacons or emitters)
positioned at or in the proximity of the foci or other target
locations may be provided to assist in targeting or defining the
target locations. The target catheter may directly sense the
transmitted energy. In other embodiments, the target catheter may
respond to the transmitted energy by reflecting or retransmitting
energy to an external transducer. The external transducer may be
the transmitting transducer or a second transducer.
[0585] The focus or foci of the ultrasound system may be focused on
one or more nerves innervating a liver, pancreas, duodenum or other
organ (e.g., nerves of the hepatic plexus, celiac plexus, celiac
ganglion). The delivery of energy may be controlled manually or
automatically according preconfigured treatment parameters
determined by a controller, processor or other computing device
(e.g., based on execution of instructions stored in memory).
[0586] In addition to external treatment, several embodiments
disclosed herein (both internal and external treatment) can be used
with imaging (for example, as described elsewhere herein). In some
embodiments of the invention, image guidance is provided by
external ultrasound imaging. External imaging may provide direct
representation of a target device (e.g. catheter) and the
surrounding tissues. External imaging may also be used to measure
the temperature of tissues. Energy delivery may be adjusted or
controlled based on tissue temperature. In some embodiments, the
target catheter may be configured to improve visualization. In some
embodiments, materials, coatings or surface treatments are provided
to increase diffuse reflection of ultrasound waves. In other
embodiments, transducers are provided to detect and/or retransmit
ultrasound energy to an external transducer. In some embodiments,
transducers on the target device (e.g., catheter) transmit or
detect ultrasound waves transmitted to or from reference
transducers. References may be internal or external. The position
of the target device can be reconstructed and compared to reference
images or maps. In other embodiments, the catheter may increase the
intensity of the externally transmitted energy by resonating and
retransmitting energy, or the catheter may transmit energy directly
to augment of modify the intensity of external energy delivery. In
various embodiments, imaging may be provided via an endoscope or
other body-inserted imaging device placed in the stomach,
esophagus, colon or intestine. In some embodiments, the target
device comprises polymer coatings or surface texture that
facilitate scattering. The transducers or transponders may resonate
at a different frequency from an excitation wave.
3. Lasers
[0587] In several embodiments, lasers may be used to modulate
(e.g., ablate) sympathetic nerve activity of the hepatic plexus or
other nerves innervating the liver. Although lasers are not
generally used for arterial nerve ablation in other arteries, the
wall thickness of the hepatic arteries is substantially less than
the thickness of other arterial structures, thereby rendering laser
energy delivery possible. In some embodiments, one or more lasers
are used to ablate nerves located within about 2 mm of the intimal
surface, within about 1.5 mm of the intimal surface, within about 1
mm of the intimal surface, or within about 0.5 mm of the intimal
surface of a hepatic artery. In some embodiments, chromophore
staining of sympathetic fibers is performed to selectively enhance
sympathetic nerve absorption of laser energy. In some embodiments,
balloons are used to stretch the hepatic artery, thereby thinning
the arterial wall and decreasing the depth from the intimal surface
to the sympathetic nerve fibers, and thereby improving the delivery
of the laser energy.
[0588] Other forms of optical or light energy may also be used. The
light source may include an LED light source, an electroluminescent
light source, an incandescent light source, a fluorescent light
source, a gas laser, a chemical laser, a dye laser, a metal-vapor
laser, a solid state laser, a semiconductor laser, a vertical
cavity surface emitting laser, or other light source. The
wavelength of the optical or laser energy may range from about 300
nm to about 2000 nm, from about 500 nm to about 1100 nm, from about
600 nm to about 1000 nm, from about 800 nm to about 1200 nm, from
about 1000 nm to about 1600 nm, or overlapping ranges thereof.
4. Externally-Initiated
[0589] In accordance with various embodiments, energy delivery is
initiated from a source external to the subject (e.g.,
extracorporeal activation). FIG. 91 illustrates an embodiment of a
microwave-based energy delivery system 9100. The microwave-based
energy delivery system 9100 comprises an ablation catheter 9105 and
a microwave generating device 9120. In some embodiments, other
energy sources may also be delivered externally.
[0590] In some embodiments, the ablation catheter 9105 comprises a
high conductivity probe 9110 disposed at its distal end. In
operation, the ablation catheter 9105 may be inserted into a target
vessel and positioned such that the high conductivity probe 9110 is
proximate to the site targeted for ablation. The microwave
generating device 9120 is located outside a subject's body and
positioned such that focused microwaves 9125 are delivered towards
the target vessel and the high conductivity probe 9110. In several
embodiments, when the delivered focused microwaves 9125 contact the
high conductivity probe 9110, they induce eddy currents within the
high conductivity probe 9110, thereby heating the high conductivity
probe 9110. The thermal energy 9115 generated from the heating of
the high conductivity probe can heat the target tissue through
conductive heat transfer. In some embodiments, the thermal energy
9115 generated is sufficient to ablate nerves within or disposed on
the target tissue (e.g., vessel wall). In various embodiments, the
high conductivity probe 9110 has a conductivity greater than 1000
Siemens/meter.
[0591] In several embodiments, a neuromodulation device (e.g.,
catheter) comprises a microwave emitter (e.g., transmission
antenna) configured to radiate microwave energy sufficient to
modulate (e.g., ablate, denervate) nerves (e.g., perivascular
sympathetic nerves) within or surrounding a vessel (e.g., hepatic
artery) or nerves that innervate the liver, pancreas, and/or
duodenum. In some embodiments, the microwave emitter is
electrically coupled to an external microwave energy source via a
conductor (e.g., coaxial cable) that extends along the length of a
shaft of the neuromodulation device. In one embodiment, the
external microwave energy source is coupled to a proximal end of
the neuromodulation device. The microwave emitter may be configured
to produce an omnidirectional electromagnetic field or a more
focused (e.g., unidirectional) electromagnetic field. The
neuromodulation device may comprise temperature, pressure,
impedance or other sensors to facilitate monitoring and control of
the treatment procedures. In various embodiments, the microwave
energy has a frequency of between 300 MHz and 300 GHz (e.g.,
between 900 MHz and 5 GHz, between 500 MHz and 3 GHz, between 1 GHz
and 5 GHz, between 10 GHz and 100 GHz, between 100 GHz and 300 GHz,
and overlapping ranges thereof). In various embodiments, the
average amount of power emitted is between 1 W and 30 W (e.g.,
between 1 W and 5 W, between 4 W and 10 W, between 6 W and 12 W,
between 8 W and 14 W, between 10 W and 20 W, between 15 W and 30 W,
or overlapping ranges thereof). The microwave energy may be
delivered for between 30 seconds and 15 minutes (e.g., between 30
seconds and 2 minutes, between 1 minute and 5 minutes, between 3
minutes and 8 minutes, between 5 minutes and 10 minutes, between 8
minutes and 15 minutes, or overlapping ranges thereof). In some
embodiments, the neuromodulation catheter comprises one, two or
more balloons or other like expandable members. The balloon(s) may
comprise one or more cooling elements or may be configured to be
filled with cooling fluid. In some embodiments, the microwave
emitter is positioned within the balloon.
[0592] FIG. 92 illustrates an embodiment of an induction-based
energy delivery catheter system 9200. In the illustrated
embodiment, the induction-based energy delivery system 9200
comprises a catheter 9205, an induction coil 9210, an external
inductor power circuit 9250, an inductor 9260, a resistor 9270, and
a capacitor 9280. In one embodiment, the induction coil 9210 is
disposed at the distal end of the catheter 9205. In operation, the
induction coil 9210 may act as an inductor to receive energy from
the external inductive power circuit 9250. In some embodiments, the
external inductive power circuit 9250 is positioned such that the
inductor 9260 is adjacent the induction coil 9210 within a
sufficient induction range. In some embodiments, current is
delivered through the external inductive power circuit 9250,
thereby causing current to flow in the induction coil 9210 and
delivering subsequent ablative energy to surrounding tissues. In
one embodiment, an induction coil is used in combination with any
of the windowed catheter devices described herein (such as the
windowed catheter devices described in connection with FIGS. 55A
and 55B). For example, the induction coil may be placed within a
lumen of a catheter or sleeve having one or more windows configured
to permit the selective delivery of energy to the target
tissue.
[0593] In some embodiments, one or more synthetic emboli may be
inserted within a target vessel and implanted or lodged therein (at
least temporarily). The synthetic emboli may advantageously be
sized to match the anatomy of the target vessel (e.g., based on
angiography of the target location and vessel diameter). The
synthetic emboli may be selected based on a measured or estimated
dimension of the target vessel. In one embodiment, an energy
delivery catheter is coupled to the one or more synthetic emboli
inserted within a target vessel to deliver energy. In some
embodiments, energy is delivered transcutaneously to the synthetic
emboli using inductive coupling as described in connection with
FIG. 21, thereby eliminating the need for an energy delivery
catheter. The synthetic emboli may comprise an induction coil and a
plurality of electrodes embedded within an insulating support
structure comprised of high dielectric material. After appropriate
energy has been delivered to modulate nerves associated with the
target vessel, the one or more emboli may be removed.
[0594] In several embodiments of the invention, the energy-based
delivery systems comprise cooling systems that are used to, for
example, reduce thermal damage to regions surrounding the target
area. For example, cooling may lower (or maintain) the temperature
of tissue at below a particular threshold temperature (e.g., at or
between 40 to 50 degrees Celsius), thereby preventing or reducing
cell necrosis. Cooling balloons or other expandable cooling members
are used in some embodiments. In one embodiment, ablation
electrodes are positioned on a balloon, which is expanded using
cooling fluid. In some embodiments, cooling fluid is circulated
through a delivery system (e.g., a catheter system). In some
embodiments, cooling fluid (such as pre-cooled saline) may be
delivered (e.g., ejected) from a catheter device in the treatment
region. In further embodiments, cooling fluid is continuously or
intermittently circulated internally within the catheter device to
cool the endothelial wall in the absence of sufficient blood
flow.
[0595] Extracorporeal neuromodulation may include delivery of
ultrasound energy (e.g., high-intensity focused ultrasound energy
or low-intensity ultrasound energy) or other forms of radiative
energy other than microwave (e.g., X-ray or gamma radiation). In
some embodiments, an ultrasound system is configured to deliver
ultrasound at a frequency between about 200 kHz and about 20 MHz
(e.g., between 200 kHz and 2 MHz, between 400 kHz and 4 MHz,
between 1 MHz and 10 MHz, between 5 MHz and 20 MHz, or overlapping
ranges thereof). The parameters of the ultrasound energy may
include any of the parameters and ranges of parameters described
elsewhere herein. In various embodiments, ultrasound energy may be
directed towards the target tissue by means of a single transducer
or a plurality of transducers, which may or may not be placed in
contact with skin of a patient. The one or more transducers are
configured to focus energy at a desired location. In some
embodiments the desired, or target, location is defined by external
imaging means. The foci or other target locations may be determined
by any of the image-guided techniques described herein. In some
embodiments, an internal catheter or other devices (e.g., sensors,
beacons or emitters) positioned at or in the proximity of the foci
or other target locations may be provided to assist in targeting or
defining the target locations. The target catheter may directly
sense the transmitted energy. In other embodiments, the target
catheter may respond to the transmitted energy by reflecting or
retransmitting energy to an external transducer. The external
transducer may be the transmitting transducer or a second
transducer.
[0596] The focus or foci of the ultrasound system may be focused on
one or more nerves innervating a liver, pancreas, duodenum or other
organ (e.g., nerves of the hepatic plexus, celiac plexus, celiac
ganglion). The delivery of energy may be controlled manually or
automatically according preconfigured treatment parameters
determined by a controller, processor or other computing device
(e.g., based on execution of instructions stored in memory).
[0597] In addition to external treatment, several embodiments
disclosed herein (both internal and external treatment) can be used
with imaging (for example, as described elsewhere herein). In some
embodiments of the invention, image guidance is provided by
external ultrasound imaging. External imaging may provide direct
representation of a target device (e.g., catheter) and the
surrounding tissues. External imaging may also be used to measure
the temperature of tissues. Energy delivery may be adjusted or
controlled based on tissue temperature. In some embodiments, the
target catheter may be configured to improve visualization. In some
embodiments, materials, coatings or surface treatments are provided
to increase diffuse reflection of ultrasound waves. In other
embodiments, transducers are provided to detect and/or retransmit
ultrasound energy to an external transducer. In some embodiments,
transducers on the target device (e.g., catheter) transmit or
detect ultrasound waves transmitted to or from reference
transducers. References may be internal or external. The position
of the target device can be reconstructed and compared to reference
images or maps. In other embodiments, the catheter may increase the
intensity of the externally transmitted energy by resonating and
retransmitting energy, or the catheter may transmit energy directly
to augment of modify the intensity of external energy delivery. In
various embodiments, imaging may be provided via an endoscope or
other body-inserted imaging device placed in the stomach,
esophagus, colon or intestine. In some embodiments, the target
device comprises polymer coatings or surface texture that
facilitate scattering. The transducers or transponders may resonate
at a different frequency from an excitation wave.
[0598] In some embodiments, image guidance is provided by external
magnetic resonance (MR) imaging or X-ray imaging. External imaging
may provide direct representation of the target device (e.g.,
catheter) and surrounding tissues. External imaging may also
measure the temperature of tissues. Energy delivery may be adjusted
or controlled based on tissue temperature. In some embodiments, the
target device may be configured to improve visualization. In some
embodiments, materials, coatings or surface treatments are provided
to alter the relaxation of adjacent tissues in a manner that is
visible in an MR or X-ray image. In some embodiments, antennas or
coils are provided to detect or alter locally emitted energy (e.g.,
RF energy) that is used to reconstruct the image. In some
embodiments, local emissions (such as RF) detected by coils or
antennas on the target device (e.g., catheter) are used to
calculate the position of the device. In some embodiments, T1
agents accelerate relaxation of polarized hydrogen nuclei, which
may appear bright on T1 images, and T2 agents provide magnetic
inhomogeneities that may accelerate T2 relaxation (dephasing),
which may appear as dark areas on images. Imaging effects may be
facilitated by coatings or inherent properties of components (e.g.,
materials such as metal) of a target device to be visualized (e.g.,
catheter).
D. Steam/Hot Water Neuromodulation
[0599] FIG. 93 illustrates an embodiment of a steam ablation
catheter 9300. In the illustrated embodiment, the steam ablation
catheter 9300 comprises a water channel 9305, a steam generating
head 9310, and a steam outlet 9315. In operation, water may be
forced through the water channel 9305 and caused to enter the steam
generating head 9310. In one embodiment, the steam generating head
9310 converts the water into steam, which exits the steam ablation
catheter 9300 through the steam outlet 9315.
[0600] In some embodiments, steam is used to ablate or denervate
the target anatomy (e.g., hepatic arteries and nerves associated
therewith). In accordance with several embodiments, water is forced
through the ablation catheter 9300 and out through the steam
generating head 9310 (which converts the water into steam) and the
steam is directed to an ablation target. The steam ablation
catheter 9300 may comprise one or more window along the length of
the catheter body.
[0601] FIG. 94 illustrates an embodiment of a hot fluid balloon
ablation catheter 9400. In the illustrated embodiment, the hot
fluid balloon ablation catheter 9400 comprises an inflatable
balloon 9405. In some embodiments, the inflatable balloon 9405 is
filled with a temperature variable fluid 9410. In accordance with
several embodiments, hot water is the temperature variable fluid
9410 used to fill the inflatable balloon 9405. The heat generated
from the hot fluid within the inflatable balloon may be sufficient
to ablate or denervate the target anatomy (e.g., hepatic arteries
and nerves associated therewith). In some embodiments, the
inflatable balloon 9405 is inserted to the ablation site and
inflated with scalding or boiling fluid (e.g., water), thereby
heating tissue surrounding the inflatable balloon 9405 sufficient
to ablate or denervate the tissue. In some embodiments, the hot
fluid within the balloon 9405 is within the temperature range of
about 120.degree. F. to about 212.degree. F., from about
140.degree. F. to about 212.degree. F., from about 160.degree. F.
to about 212.degree. F., from about 180.degree. F. to about
212.degree. F., about 200.degree. F. to about 212.degree. F., or
overlapping ranges thereof. In some embodiments, the balloon
ablation catheter 9400 comprises a temperature sensor and fluid
(e.g., water) at different temperatures may be inserted and
withdrawn as treatment dictates. In some embodiments, the
inflatable balloon 9405 is made out of polyurethane or any other
heat-resistant inflatable material.
E. Chemical Neuromodulation
[0602] In some embodiments, drugs are used alone or in combination
with another modality to cause neuromodulation of any of the nerves
described herein. Drugs include, but are not limited to, muscarinic
receptor agonists, anticholinesterase agents, nicotinic receptor
agonists, and nicotine receptor antagonists. Drugs that directly
affect neurotransmission synthesis, degradation, or reuptake are
used in some embodiments.
[0603] In some embodiments, drugs (either alone or in combination
with energy modalities) can be used for neuromodulation. For
example, a delivery device (e.g., catheter) may have one or more
internal lumens. In some embodiments, one or more internal lumens
are in fluid communication with a proximal opening and with a
distal opening of the delivery catheter. In some embodiments, at
least one distal opening is located at the distal end of the
delivery catheter. In some embodiments, at least one proximal
opening is located at the proximal end of the delivery catheter. In
some embodiments, the at least one proximal opening is in fluid
communication with at least one reservoir.
[0604] In some embodiments, at least one reservoir is a drug
reservoir that holds drugs or therapeutic agents capable of
modulating sympathetic nerve fibers in the hepatic plexus. In some
embodiments, a separate drug reservoir is provided for each drug
used with the delivery catheter system. In other embodiments, at
least one drug reservoir may hold a combination of a plurality of
drugs or therapeutic agents. Any drug that is capable of modulating
nerve signals may be used in accordance with the embodiments
disclosed herein. In some embodiments, neurotoxins (e.g., botulinum
toxins) are delivered to the liver, pancreas, or other surrounding
organs or nerves associated therewith. In some embodiments,
neurotoxins (e.g., botulinum toxins) are not delivered to the
liver, pancreas, or other surrounding organs or nerves associated
therewith.
[0605] In some embodiments, a delivery catheter system includes a
delivery device that delivers one or more drugs to one or more
target sites. For example, the delivery device may be a pump. Any
pump, valve, or other flow regulation member capable of delivering
drugs through a catheter may be used. In some embodiments, the pump
delivers at least one drug from the at least one drug reservoir
through the at least one internal lumen of the catheter delivery
system to the one or more target sites.
[0606] In some embodiments, the pump selects the drug dosage to be
delivered from the reservoir to the target site(s). For example,
the pump can selectively vary the total amount of one or more drugs
delivered as required for neuromodulation. In some embodiments, a
plurality of drugs is delivered substantially simultaneously to the
target site. In other embodiments, a plurality of drugs is
delivered in series. In other embodiments, a plurality of drugs is
delivered substantially simultaneously and at least one other drug
is delivered either before or after the plurality of drugs is
delivered to the target site(s). Drugs or other agents may be used
without delivery catheters in some embodiments. According to
several embodiments, drugs may have an inhibitory or stimulatory
effect.
[0607] In some embodiments, an ablation catheter system uses
chemoablation to ablate nerve fibers (e.g., sympathetic nerve
fibers in the hepatic plexus). For example, the ablation catheter
may have one or more internal lumens. In some embodiments, one or
more internal lumens are in fluid communication with a proximal
opening and with a distal opening. In some embodiments, at least
one distal opening is located in the distal end of an ablation
catheter. In some embodiments, at least one proximal opening is
located in the proximal end of the ablation catheter. In some
embodiments, at least one proximal opening is in fluid
communication with at least one reservoir.
[0608] In some embodiments, at least one reservoir holds and/or
stores one or more chemicals capable of disrupting (e.g., ablating,
desensitizing, destroying) nerve fibers (e.g., sympathetic nerve
fibers in the hepatic plexus). In some embodiments, a separate
reservoir is provided for each chemical used with the ablation
catheter system. In other embodiments, at least one reservoir may
hold any combination of chemicals. Any chemical that is capable of
disrupting nerve signals may be used in accordance with the
embodiments disclosed herein. For example, one or more chemicals or
desiccants used may include phenol or alcohol, guanethidine, acids,
phenol-crotons, zinc sulfate, nanoparticles, radiation sources for
brachytherapy, neurostimulants (e.g., methamphetamine), and/or
oxygen radicals (e.g., peroxide). However, any chemical that is
capable of ablating sympathetic nerve fibers in the hepatic plexus
may be used in accordance with the embodiments disclosed herein. In
some embodiments, chemoablation is carried out using a fluid
delivery needle delivered percutaneously, laparascopically, or via
an intravascular approach.
F. Cryomodulation
[0609] In some embodiments, the invention comprises cryotherapy or
cryomodulation. In one embodiment, the ablation catheter system
uses cryoablation techniques (e.g., cryogenic energy delivery) for
neuromodulation. In one embodiment, cryoablation is used to ablate
sympathetic nerve fibers in the hepatic plexus. For example, the
ablation catheter may have one or more internal lumens. In some
embodiments, one or more internal lumens are in fluid communication
with a proximal opening. In some embodiments, at least one proximal
opening is located in the proximal end of the ablation catheter. In
some embodiments, at least one proximal opening is in fluid
communication with at least one reservoir (e.g., a cryochamber). In
some embodiments, the at least one reservoir holds one or more
coolants including but not limited to liquid nitrogen, CO.sub.2,
argon, or nitrous oxide. The ablation catheter can comprise a feed
line for delivering coolant to a distal tip of the ablation
catheter and a return line for returning spent coolant to the at
least one reservoir. The coolant may reach a temperature
sufficiently low to freeze and ablate sympathetic nerve fibers in
the hepatic plexus. In some embodiments, the coolant can reach a
temperature of less than 75 degrees Celsius below zero, less than
80 degrees Celsius below zero, less than 90 degrees Celsius below
zero, or less than 100 degrees Celsius below zero.
[0610] In some embodiments, the ablation catheter system includes a
delivery device that controls delivery of one or more coolants
through one or more internal lumens to the target site(s). For
example, the delivery device may be a pump. Any pump, valve or
other flow regulation member that is capable of delivering coolants
through a catheter may be used. In some embodiments, the pump
delivers at least one coolant from at least one reservoir, through
at least one proximal opening of the catheter body, through at
least one internal lumen of the catheter body, and to the distal
end of the ablation catheter (e.g., via a feed line or coolant
line).
[0611] In some embodiments, the target nerves may be irreversibly
cooled using an implantable Peltier cooling device. In some
embodiments, an implantable cooling device is configured to be
refilled with an inert gas that is injected at pressure into a
reservoir within the implantable device and then released
selectively in the vicinity of the target nerves, cooling them in
an adiabatic fashion, thereby slowing or terminating nerve
conduction (either temporarily or permanently). In some
embodiments, local injections or infusion of ammonium chloride is
used to induce a cooling reaction sufficient to alter or inhibit
nerve conduction. In some embodiments, delivery of the coolant to
the distal end of the ablation catheter, which may comprise one or
more ablation electrodes or a metal-wrapped cylindrical tip, causes
denervation of sympathetic nerve fibers in the hepatic plexus. For
example, when the ablation catheter is positioned in or near the
proper hepatic artery or the common hepatic artery, the temperature
of the coolant may cause the temperature of the surrounding area to
decrease sufficiently to denervate sympathetic nerve fibers in the
hepatic plexus. In some embodiments, cryoablation is performed
using a cryocatheter. Cryoablation can alternatively be performed
using one or more probes alone or in combination with a
cryocatheter.
[0612] The treatment time for each target ablation site can range
from about 5 seconds to about 100 seconds, 5 minutes to about 30
minutes, from about 10 minutes to about 20 minutes from about 5
minutes to about 15 minutes, from about 10 minutes to about 30
minutes, less than 5 seconds, greater than 30 minutes, or
overlapping ranges thereof. In accordance with several embodiments,
the parameters used are selected to disable, block, cease or
otherwise disrupt conduction of, for example, sympathetic nerves of
the hepatic plexus. The effects on conduction of the nerves may be
permanent or temporary. One, two, three, or more cooling cycles can
be used.
[0613] In some embodiments, any combination of drug delivery,
chemoablation, and/or cryoablation is used for neuromodulation of
any of the nerves described herein, and may be used in combination
with an energy modality. In several embodiments, cooling systems
are provided in conjunction with energy delivery to, for example,
protect tissue adjacent the nerve fibers.
III. Catheter Access and Delivery Systems and Methods
A. Access
[0614] In accordance with some embodiments, neuromodulation (e.g.,
the disruption of sympathetic nerve fibers) is performed using a
minimally invasive system, such as an ablation catheter system. In
some embodiments, an ablation catheter system for ablating nerve
fibers is introduced using an intravascular (e.g., intra-arterial)
approach. In one embodiment, an ablation catheter system is used to
ablate sympathetic nerve fibers in the hepatic plexus and/or nerves
innervating the liver. As described above, the hepatic plexus
surrounds the common hepatic artery or the proper hepatic artery,
where it branches from the common hepatic artery. In some
embodiments, a neuromodulation system (e.g., an ablation catheter
system) is introduced via an incision in the groin to access the
femoral artery. The neuromodulation system may be advanced from the
femoral artery to the proper hepatic artery via the iliac artery,
the abdominal aorta, the celiac artery, and the common hepatic
artery. In other embodiments, any other suitable percutaneous
intravascular incision point or approach is used to introduce the
ablation catheter system into the arterial system (e.g., a radial
approach via a radial artery or a brachial approach via a brachial
artery).
[0615] In some embodiments, the catheter (e.g., hollow, solid,
partially hollow, catheter, probe, shaft or other delivery device
with or without a lumen) may be placed into the target region
substantially close to the target nerve through percutaneous
injection. Using such a percutaneous placement may allow less
destructive, less invasive selective destruction or disruption of
the target nerve, in accordance with some embodiments.
[0616] In some embodiments, the catheter system comprises a
visualization or other diagnostic device substantially close to the
distal end of the catheter. The visualization device may promote
nervous visualization, thereby possibly allowing higher levels of
precision in targeted nervous disruption. In some embodiments, the
catheter system comprises a light source configured to aid in
visualization. In some embodiments, a light source and a
visualization device (such as a camera) are used in tandem to
promote visibility. A diagnostic device may include a
temperature-measurement device (e.g., thermistor, thermocouple,
radiometer), contact sensor(s) or one or more ultrasound
transducers. In some embodiments, the catheter system comprises a
distal opening out of which active elements (such as any camera,
light, drug delivery port, and/or cutting device, etc.) are
advanced. In some embodiments, the catheter system comprises a side
opening out of which the active elements (such as any camera,
light, drug delivery port, and/or cutting device, etc.) may be
advanced, thereby allowing the user to access the vessel wall in
vessels with tortuous curves and thereby allowing nerve treatment
(e.g., destruction) with the axis of the catheter aligned parallel
to the vessel.
[0617] Animal studies have shown that the force of electrode
contact against the vessel wall may be a critical parameter for
achieving ablative success in embodiments of devices incorporating
radiofrequency electrodes to deliver energy. Therefore, ablation
catheter devices may advantageously not only be small enough to
access the target vasculature, but also to incorporate low-profile
features for facilitating sufficient electrode contact force or
pressure during the length of the treatments.
[0618] In some embodiments, the catheter of the neuromodulation
catheter system has a diameter in the range of about 2-8 Fr, about
3-7 Fr, about 4-6 Fr (including about 5 Fr), and overlapping ranges
thereof. The catheter (e.g., tube, probe or shaft) may have a
varying diameter along its length such that the distal portion of
the catheter is small enough to fit into progressively smaller
vessels as the catheter is advanced within vasculature. In one
embodiment, the catheter has an outside diameter sized to fit
within the common hepatic artery (which may be as small as about 1
mm in lumenal diameter) or the proper hepatic artery. In some
embodiments, the catheter is at least about 150 cm long, at least
about 140 cm long, at least about 130 cm long, at least about 120
cm long, at least about 110 cm long, at least about 100 cm long, at
least about 75 cm long, or at least about 90 cm long. In some
embodiments, the flexibility of the catheter is sufficient to
navigate tortuous hepatic arterial anatomy having bend radii of
about 10 mm, about 9 mm, about 8 mm, about 7 mm, about 6 mm, about
5 mm, about 4 mm, about 3 mm, about 2 mm, about 1 mm, or about 0.5
mm.
[0619] In accordance with several embodiments, devices of the
catheter-based systems described herein have actuatable,
expandable, steerable, pre-curved, deflectable and/or flexible
distal tip components or distal segments. The deflectability or
flexibility may advantageously bias an energy applicator against
the arterial wall to ensure effective and/or safe delivery of
therapy, permit accurate positioning of the energy applicator,
maintain contact of an energy delivery element against a vascular
wall, maintain sufficient contact force or pressure with a vascular
wall, and/or help navigate the catheter (e.g., neuromodulation
catheter) to the target anatomy. In some embodiments, devices
(e.g., catheters) with steerable, curvable or articulatable distal
portions provide the ability to cause articulation, bending, or
other deployment of the distal tip (which may contain an ablation
element or energy delivery element) even when a substantial portion
of the catheter (e.g., neuromodulation catheter) remains within a
guide catheter or guide extension catheter. In some embodiments,
the neuromodulation catheters provide the ability to be delivered
over a guidewire, as placing guide catheters may be unwieldy and
time-consuming to navigate. In some embodiments, the
neuromodulation catheters are inserted within the vasculature
through guide sheaths or guide extension catheters. In some
embodiments, guidewires are not used.
[0620] In accordance with several embodiments, catheter-based
systems may comprise a guide catheter, a guide extension catheter
or support catheter (e.g., a Guidezilla.TM. catheter or
GuideLiner.TM. catheter), a microcatheter, and/or a guidewire, in
addition to a neuromodulation catheter. FIG. 95 illustrates an
embodiment of a "telescoping" system 9500 for facilitating delivery
of a low-profile neuromodulation catheter to a hepatic artery
branch. The "telescoping" system 9500 comprises a guide catheter
9505. In one embodiment, the guide catheter 9505 is a 7 Fr guide
catheter that is configured to engage with the inner wall of the
celiac artery to provide a stable anchoring and/or reference point.
The system 9500 further comprises a guidewire 9510 (e.g., 0.014''
guidewire) that may be configured to be delivered through a lumen
of the guide catheter 9505 and advanced to a position beyond a
target neuromodulation location within a hepatic artery or other
vessel or organ. The system 9500 also comprises a microcatheter
9515 (e.g., 4 Fr or less) and a guide extension catheter 9520
(e.g., a 6 Fr guide extension catheter). The guide extension
catheter 9520 may be configured to fit and be movable within a
lumen of the guide catheter 9505 to provide support at a lower
profile (e.g., outer diameter) than the guide catheter 9505. The
microcatheter 9515 may be configured to fit and be movable within a
lumen of the guide extension catheter 9520 and extend beyond a
distal end of the guide extension catheter 9520. The microcatheter
9515 may facilitate tracking and advancement of the guide extension
catheter 9520 over the guidewire 9510. In some embodiments, the
microcatheter 9515 comprises a rapid exchange microcatheter. The
guidewire 9510 may provide a "rail" to aid catheter tracking and
lessen the risk of vessel damage when advancing a neuromodulation
device.
[0621] In some embodiments, the guide catheter 9505 and/or the
guide extension catheter 9520 comprises an expandable portion that
is configured to be advanced to a desired location and then
expanded before or during advancement of a neuromodulation device
through the guide extension catheter 9520 or the guide catheter
9505. The expandable portion may enable transitory, or temporary,
expansion of vessel inner diameters. In one embodiment, the
expandable portion may be formed of multiple layers that slide over
each other. In one embodiment, the expandable portion may be formed
of a cylinder with interrupted longitudinal cuts and encapsulated
by an elastic layer that keeps the cuts compressed in an unexpanded
state. The expandable portion may provide stabilization or
anchoring. Stabilization mechanisms (in addition to or instead of
the expandable portion) may be provided at various locations along
a length of the guide catheter 9505 and/or the guide extension
catheter 9520 (e.g., balloons, ribbons, wires). In some
embodiments, portions of the guide catheter 9505 or guide extension
catheter 9520 may be stiffened after introduction of the
neuromodulation device to provide stability and maintenance of
positioning during neuromodulation procedures. In some embodiments,
the "telescoping" system 9500 does not comprise a guidewire, as the
guide extension catheter 9520 may obviate the need for a guide
wire.
[0622] In some embodiments, the system 9500 may include a flexible
introducer that provides a tapered transition between the guidewire
9510 and the guide catheter 9505 or guide extension catheter 9520,
thereby facilitating access to the tortuous hepatic artery
vasculature. The flexible introducer may replace the microcatheter
9515 and/or guide extension catheter 9520. In some embodiments, the
flexible introducer comprises elastic or shape-memory materials
such as nitinol or low durometer Pebax.RTM.. The flexible
introducer may have a coil cut pattern or a torque converter or
flexure cut pattern (e.g., similar to the cut pattern illustrated
in FIGS. 48A-48C) or a metallic coil may be encapsulated within the
flexible introducer. Portions of the guide catheter 9505, guide
extension catheter 9520 and/or microcatheter 9515 may be
deflectable and/or steerable. The mechanisms for deflection and/or
steering may comprise any of the deflection or steering mechanisms
described herein (e.g., tension wire, hydraulics, magnetism, and/or
the like). In some embodiments, portions of the guide catheter
9505, guide extension catheter 9520 and/or microcatheter 9515 are
plastically deformable and/or shape set to provide deformability
within vasculature, thereby functioning as accessory devices
configured to fit unique and patient-specific anatomy.
[0623] FIG. 96 illustrates an embodiment of use of the system of
FIG. 95 to access a target neuromodulation location within a
hepatic artery. The guide catheter 9505 is advanced to a position
within an abdominal aorta 9501 or at an origin of the celiac artery
9502 off the abdominal aorta 9501. In some embodiments, the
guidewire 9510 and microcatheter 9515 are then advanced to a
position at or adjacent the target neuromodulation location and the
guide extension catheter 9520 is advanced over the microcatheter
9515 to the target neuromodulation location. The guide extension
catheter 9520 may be advanced over either the guidewire 9510 alone
or over the microcatheter 9515 (which in turn is advanced over the
guidewire 9510). FIG. 96 illustrates the system 9500 after the
guidewire 9510 and/or microcatheter 9515 have been removed. FIG. 96
also illustrates an embodiment of a neuromodulation device 9525
advanced to the target neuromodulation location within the hepatic
artery through the guide extension catheter 9520. In some
embodiments, a guidewire 9510 or microcatheter 9515 may not be used
and the guide extension catheter 9520 may be advanced beyond the
target neuromodulation location and the neuromodulation device 9525
advanced to the target neuromodulation location and then the guide
extension catheter 9520 is withdrawn to unsheathe the
neuromodulation device 9525. In accordance with several
embodiments, the guide extension catheter 9520 may facilitate
torqueing of the neuromodulation device 9525 so as to allow for
rotation of the neuromodulation device 9525 to multiple or all
quadrants of the hepatic artery or other target vessel. In some
embodiments, the guide extension catheter 9520 is removed following
the initial "deployment" of the neuromodulation device 9525. Fluid
(e.g., cooling fluid, contrast or selective dye) may be infused
through the guide catheter 9505 or guide extension catheter 9520
during neuromodulation (e.g., ablation.
[0624] In some embodiments, the guide extension catheter 9520, or
other access device within which the neuromodulation device 9525 is
advanced, is configured to maintain a tight clearance between the
inner diameter of the guide extension catheter 9520 or other access
device and the outer diameter of the neuromodulation device 9525.
For example, the inner diameter may have a low friction surface or
coating and/or structures (e.g., raised ribs of a compliant
material such as silicone) that reduce the number of contact points
and provide an inward radial force against the outer surface of the
neuromodulation device that run along the length of the guide
extension catheter 9520 or other access device and are coated with
a low-friction coating, such as a hydrophilic coating. The enhanced
support along the flexible length of the neuromodulation device may
allow the neuromodulation device to be more accurately flexed and
may support increased torque efficiency.
[0625] Movement of the guide catheter 9505 or guide extension
catheter 9520 may disturb the position of the neuromodulation
device. For example, movement of the guide catheter 9505 or guide
extension catheter 9520 may cause an electrode of an RF energy
delivery device delivered through a lumen of the guide catheter
9505 or guide extension catheter 9520 to move due to friction
between the devices. Accordingly, in some embodiments, anchoring
the catheter 9505 or guide extension catheter 9520 may
advantageously minimize or reduce movement artifacts.
[0626] FIGS. 97A and 97B illustrate embodiments of a catheter-based
vascular access system comprising a guide sheath or captive support
sleeve 9721 to provide additional support to the shaft of a
neuromodulation device 9725 (e.g., electrode treatment catheter).
Similar to the systems described above in connection with FIGS. 95
and 96, the system comprises a guide catheter 9705 adapted to be
advanced through the abdominal aorta 9701 to a location where the
celiac artery 9702 branches off from the abdominal aorta 9501
(e.g., an ostium of the celiac artery). The guide sheath or captive
support sleeve 9721 extends out of an open distal end of the guide
catheter 9705. In the illustrated embodiment, the captive support
sleeve 9721 has a length that corresponds to the length of the
celiac artery 9702 from the abdominal aorta 9701 to the junction of
the common hepatic artery 9703 and the splenic artery 9704. FIG.
97A illustrates a neuromodulation device 9725 comprising an
over-the-wire RF energy delivery catheter having two spaced-apart
electrodes positioned along a shaft of the catheter. The two
spaced-apart electrodes are positioned such that at least one of
the electrodes is in contact with an inner wall of the common
hepatic artery 9703 for ablation. The electrodes may both be
positioned in contact with the inner wall. The electrodes may
comprise monopolar electrodes or a pair of bipolar electrodes.
[0627] In accordance with several embodiments, the neuromodulation
device 9725 is positioned with the aid of angiographic and
fluoroscopic visualization. Contrast media may be provided through
the lumen of the guide catheter 9705. Alternatively, contrast media
may be delivered through the guide sheath or captive support sleeve
9721, through which the neuromodulation device 9725 extends. If the
guide sheath 9721 is positioned near the ostium of the common
hepatic artery 9703, visualization may be enhanced as the majority
of contrast would flow through the common hepatic artery instead of
the splenic artery 9704. The guide sheath or captive support sleeve
9721 may also provide enhanced support to the proximal portion of
the neuromodulation device 9725. Alternatively or additionally, the
neuromodulation device 9725 can include an additional lumen for
contrast delivery, whereby the contrast can exit at an outlet 9727
positioned distally of a major side vessel, such as the splenic
artery 9704. FIG. 97B illustrates an embodiment of a
neuromodulation device incorporating a contrast lumen. The outlet
may be located along a portion of the captive support sleeve 9721
or at a location of the neuromodulation device 9725 distal of the
captive support sleeve 9721). Although illustrated and described
herein with respect to positioning within a common hepatic artery,
the neuromodulation device 9725 could alternatively be positioned
in other vessel segments, and catheter delivery could be performed
by placement of a guide catheter at the ostium of any appropriate
vessel.
[0628] FIGS. 98A and 98B illustrate an embodiment of a wedge-type
expanding anchor 9800 that can be used to secure a guide catheter
9505 or guide extension catheter 9520 in place. The anchor 9800 may
be placed on a distal end of a guide catheter to prevent or reduce
the likelihood of movement of the guide catheter or guide extension
catheter (e.g., during treatment or during injection of contrast).
The anchor 9800 comprises two portions 9801A, 9701B that are cut at
a slant and connected by a pull wire 9802 fixed to a joint
positioned on portion 9801B. As the two portions 9801 are drawn
together (e.g., by pulling the pull wire 9802 and pushing the
portion 9801A, the two portions 9801 move sideways and expand into
the vessel wall, thereby providing an anchor for the guide
catheter, guide extension catheter or guide sheath.
[0629] FIGS. 99A and 99B illustrate embodiments of devices (and
methods of using such devices) specifically designed to facilitate
access to tortuous hepatic vasculature. In certain situations, it
may be difficult for a clinician to locate an artery using a
guidewire. In accordance with some embodiments, a balloon catheter
9905 may be used to temporarily block distal portions of arteries.
An electrode catheter or guidewire 9910 having a very loose,
flexible distal portion may be positioned near an origin of a
branch vessel where access is desired. The distal portion of the
electrode catheter or guidewire may comprise an inflatable or
otherwise expandable sail or parachute-like attachment 9915
designed to capture blood flow and drift with the blood flow into a
target branch vessel, thereby facilitating access to the target
branch vessel. FIG. 99A illustrates advancement of the balloon
catheter 9905 and the electrode catheter or guidewire 9910 from a
downstream location with respect to a main vessel 9920 and FIG. 99B
illustrates advancement of the balloon catheter 9905 and the
electrode catheter or guidewire 9910 from an upstream location with
respect to the main vessel 9920. In some embodiments, blood flow
may facilitate stabilization and maintenance of electrode contact
and/or direct the electrode to the wall of the vessel.
[0630] In accordance with several embodiments described herein, the
electrode catheters advantageously facilitate improved
stabilization of the catheter and/or electrode within target
vessels, which can lead to more predictable outcomes and more
effective procedures. For example, the improved stabilization may
prevent or reduce the likelihood of heating, burning or charring of
unwanted portions of tissue or of the blood (which may prevent or
reduce the likelihood of thrombus formation). Embodiments of
catheters described herein may also facilitate access from the
origin of the common hepatic artery.
B. Contact Facilitation
[0631] In one embodiment, a neuromodulation catheter (e.g., hollow,
solid, partially hollow, catheter, probe, shaft or other delivery
device with or without a lumen) is provided that comprises one or
more customizable bending or deflection regions. In one embodiment,
the neuromodulation catheter facilitates adjustment of multiple
articulation or bending regions (collectively or independently). In
one embodiment, a method of using the neuromodulation catheter
comprises performing a computed tomography (CT) scan, digitizing
the CT scan to create a three-dimensional (3D) model of a target
anatomical region, determining the location(s) of major arterial or
other vascular or anatomical bends and bend radii, and adjusting
one or more articulation portions of the catheter to correspond to
(e.g., match or line up with) the location(s) of the major arterial
bends or other vascular or anatomical bends. In some embodiments,
the neuromodulation catheter is configured to have a first bend
corresponding to a first anatomical bend (e.g., first bend in a
first portion of a hepatic artery or branch off of a hepatic
artery) and a second bend corresponding to a second anatomical bend
(e.g., second bend in a second portion of the hepatic artery or
branch off of a hepatic artery). In some embodiments, the
neuromodulation catheter is configured to have three or four bends
corresponding to third and/or fourth anatomical bends. The bends
may be approximately right angle bends or acute bends ranging from
5 degrees to 90 degrees (e.g., 5-10 degrees, 10-20 degrees, 20-40
degrees, 40-60 degrees, 60-90 degrees, and overlapping ranges
thereof). One or more of the bends may be pre-formed and/or one or
more of the bends may be formed by movement during delivery (e.g.,
by expansion, inflation, articulation, actuation, unsheathing).
[0632] In some embodiments, a first bend is located or formed in
the distal 10-40% (e.g., 20%) of the catheter length and a second
bend is located or formed in the distal 1-20% (e.g., 5%) of the
catheter length. The bends may be partially or wholly pre-formed.
In several embodiments, the bends conform to a bend in the vessel
wall such that the outer portion of the catheter optionally
contacts the interior of the vessel wall. In one embodiment, the
catheter bend conforms to the vessel wall but does not touch the
vessel wall (e.g., is substantially parallel to the vessel wall but
is separated by a distance of 0.1 mm-10 mm, or more). In some
embodiments, a first bend is approximately 90.degree. (e.g.,
70-110.degree.) in a first plane, about a radius of approximately
0.5 cm (e.g., 0.3 to 0.7 cm), corresponding to the takeoff of the
celiac axis from the aorta. In some embodiments, a second bend is
approximately 90.degree. (e.g., 70-110.degree.) in a second plane,
about a radius of approximately 0.4 cm (e.g., 0.2 to 0.5 cm), the
second plane being substantially orthogonal to the first plane, and
corresponding to the bifurcation of the common hepatic and splenic
arteries. In some embodiments, a third bend is approximately
90.degree. (e.g., 70-110.degree.) in a third plane, about a radius
of approximately 0.3 cm (0.2 to 0.4 cm), the third plane being
substantially orthogonal to the first and second planes,
corresponding to the bend in the common hepatic artery. The bends
may be achieved by any of the means described herein, including,
but not limited to, hydraulic, pneumatic, pull-wire, resilient
deformation, magnetic, and electromagnetic means. In yet another
embodiment, a plurality of bends are configured to bias an
electrode or other treatment member against the arterial wall,
thereby generating an electrode contact force, and further yet
provide a defined reaction force to balance the electrode contact
force, as illustrated, for example, in FIG. 100. In one embodiment,
the catheter comprises one or more spring-like or coil-like members
to facilitate electrode contact force.
[0633] In various embodiments in which contact is desired and/or
required, the contact force exerted on the vessel wall to maintain
sufficient contact pressure is between about 1 g to about 500 g,
from about 20 g to about 200 g, from about 10 g to about 100 g,
from about 50 g to about 150 g, from about 100 g to about 300 g,
from about 200 g to about 400 g, from about 300 g to about 500 g,
or overlapping ranges thereof. In some embodiments, the same ranges
may be used but expressed as g/mm.sup.2 pressure numbers. The
contact forces/pressures described above may be achieved by any of
the neuromodulation (e.g., ablation) devices and systems described
herein.
[0634] In accordance with several embodiments, the contact force of
an RF electrode or other treatment member against the hepatic
arterial wall is a key variable determining ablative success. In
various embodiments, devices providing tangential electrode contact
through bending regions having bend radii of approximately 0.5 cm
(e.g., 0.2 cm-0.8 cm) are provided. In other embodiments, devices
having means to exert a controllable reaction force to the
electrode contact force are provided. In some embodiment, suction
is provided to ensure reliable contact between the electrode(s) or
other treatment members and the vessel wall (e.g., hepatic arterial
wall).
[0635] In some embodiments, a portion of an electrode of an RF
energy delivery device is comprised of a deformable membrane, with
fluid perfused through this region. In one embodiment, the fluid is
coolant fluid circulated within the catheter or delivered to the
arterial lumen to cool the electrode. An external controller can be
configured to maintain a constant flow rate of the coolant, and the
resulting driving pressure required to do so may be directly
correlated with the contact pressure along the deformable region of
the electrode.
[0636] Referring now to FIG. 101, an embodiment of a catheter
distal tip design is illustrated having a radiopaque marker
disposed within a distal lumen of the catheter and attached to the
electrode at one end and an extensible spring anchored at a
proximal region of the catheter. The catheter in region A, the
flexible region, is configured to be substantially radiopaque,
whereas the catheter in region B is configured to be
non-radiopaque. Upon contact of the electrode against the arterial
wall, which causes deflection of the catheter in region A, the
radiopaque marker is urged distally into the radiopaque region A,
thereby decreasing the visible length, d, of the radiopaque marker,
and thereby providing a visual indicator of the electrode contact
force, visible during angiography or other imaging modalities. In
some embodiments, the visible length, d, may be indirectly related
to the electrode contact force.
[0637] FIG. 102 illustrates an embodiment of a steerable
neuromodulation catheter 10200 having an articulatable tip. The
neuromodulation catheter 10200 comprises a catheter body 10205,
multiple segments 10210, multiple corresponding hinges 10220, and
multiple corresponding articulation members (e.g., wires) 10230. In
some embodiments, the neuromodulation catheter 10200 includes fewer
than six segments, hinges, and/or articulation wires (e.g., two,
three, four, or five). In some embodiments, the neuromodulation
catheter 10200 includes more than six segments, hinges, and/or
articulation wires (e.g., seven, eight, nine, ten, eleven to
twenty, or more than twenty). In one embodiment, the segments 10210
and the hinges 10220 are hollow.
[0638] Each of the segments 10210 is coupled to adjacent segment(s)
by one of the hinges 10220. Each of the articulation wires is
attached to at least one of the segments and passes from the
segment to which it is attached through the other segments toward
the catheter body 10205. In operation, the articulation members
(e.g., wires) may be extended or retracted as desired, thereby
pivoting the articulatable tip of the catheter 10200. In one
embodiment, the steerable neuromodulation catheter comprises an
"inchworm" end.
[0639] In some embodiments, all of the articulation wires 10230 are
extended and retracted in combination. In other embodiments, each
of the articulation wires 10230 is individually actuatable. In such
embodiments, each individual segment 10210 could be individually
actuatable by each corresponding articulation wire 10230. For
example, even when the third segment, the fourth segment, the fifth
segment, and the sixth segment are constrained within a guide
catheter, the first segment and the second segment may be
articulated by extending or retracting the first articulation wire
and/or the second articulation wire, respectively, with sufficient
force. The steerable catheter 10200 may advantageously permit
improved contact pressure between the distal tip of the steerable
catheter 10200 and the vascular wall of the target vessel, thereby
improving treatment efficacy. In various embodiments, a first
portion of segments 10210 is actuated to have a first bend shape
configured to conform to a first anatomical bend (e.g., a first
bend of a hepatic artery branch or portion) and a second portion of
segments 10210 is actuated to have a second bend shape configured
to conform to a second anatomical bend (e.g., a second bend of a
hepatic artery branch or portion). The first portion of segments
10210 and second portion of segments 10210 may be actuated by
movement of one or more articulation wires 10230 (if multiple,
collectively or independently). In one embodiment, the steerable
catheter 10200 substantially locks in a shaped configuration
matching the shape of the hepatic artery or other artery or vessel,
providing improved stability.
[0640] FIG. 103 illustrates an embodiment of a neuromodulation
catheter 10300 with a deflectable distal tip. The neuromodulation
catheter 10300 comprises a guidewire configured to facilitate
steerability. The neuromodulation catheter 10300 includes an
ablation catheter tip 10305, a guidewire housing 10310, a guide
wire channel 10315, and a guidewire 10320. In operation, the
guidewire 10320 may be extended out through guide wire channel
10315 to be used in its guiding capacity to navigate through
vasculature. When it is not desirable to use the guidewire 10320 in
its guiding capacity, the guide wire 10320 may be retracted into
the ablation catheter tip 10305 and then extended into the guide
wire housing 10310, where it may be stored until needed or desired.
In one embodiment, the steerable neuromodulation catheter comprises
an "inchworm" end.
[0641] In some embodiments, the guidewire 10320 is plastically
deformable with a permanent bend in the distal tip. In such
embodiments, the guidewire 10320 may be rotated within the body of
the neuromodulation catheter 10300 to plastically deform and be
pushed into the guide wire housing 10310, or may be rotated 180
degrees and regain its bent configuration to exit through the guide
wire channel 10315. In some embodiments, a thermocouple (e.g., type
T thermocouple) temperature sensor may be incorporated into the
guidewire 10320. The thermocouple may be used to assess thermal
loss delivered to target tissue compared to thermal loss convected
away by blood. In some embodiments, the guidewire 10320 is used to
deliver ablative energy (such as RF energy) to at least one
electrode. In one embodiment, delivery of the ablative energy is
facilitated by disposing a conductive gel between the guidewire
10320 and the at least one ablation electrode. In various
embodiments, the deflectable distal tip comprises two deflectable,
steerable and/or actuatable portions, with a first portion
configured to have a first bend shape to conform to a first
anatomical bend (e.g., a first bend of a hepatic artery branch) and
a second portion configured to have a second bend shape to conform
to a second anatomical bend (e.g., a second bend of a hepatic
artery branch). In one embodiment, the neuromodulation catheter
10300 comprises one or more pre-bent or pre-curved portions. The
pre-bent or pre-curved portions may conform to particular
anatomical bend shapes (e.g., within the hepatic arteries or
neighboring branches upstream or downstream of the hepatic
arteries).
[0642] As shown in FIGS. 111, 112A and 113A, the common hepatic
artery and celiac trunk can be very tortuous (e.g., can have
multiple bends). In some embodiments, accessing this anatomy is
performed using a highly flexible catheter or other instrument with
sufficiently strong column strength. In some embodiments, the
neuromodulation (e.g., ablation) catheters described herein having
a single electrode are configured to make contact with multiple
points around the circumference of the target vessel, and have
excellent torque transfer through the catheter shaft. In some
embodiments, the catheters are flexible enough to navigate a
tortuous anatomy without kinking or reduce the likelihood of
kinking. Kinking can occur because the cross section of the shaft
becomes oval as it is bent. For example, after a critical bend
radius is reached, the oval may collapse and a kink may be created.
In accordance with several embodiments, the catheters described
herein prevent, or reduce the likelihood of, "ovalization" while
enabling material on the inner and outer arcs to compress and
stretch, respectively.
[0643] With a single electrode or limited number of electrodes on
an ablation device, rotation of the electrodes and multiple
ablation doses may be required to create circumferential or
increased volume of ablation of the nerves surrounding a vessel
(e.g., perivascular space). In the case of denervating the common
hepatic artery (CHA), unique vessel tortuosity (multiple acute
turns) can make torque transfer more difficult. When a torque is
applied at the proximal end of a catheter shaft the torque may
first be translated into a distal rotational displacement until the
shaft contacts the length of the vessel wall. After the shaft is
supported, the torque applied at the proximal end may then cause a
rotation of the distal end of the shaft, but may "flip" or
otherwise result in uncontrolled rotation of the distal
electrode.
[0644] Referring now to FIGS. 104A and 104B, an embodiment of a
catheter system configured to support the catheter shaft within the
vessel lumen, thereby reducing the translation of the shaft into
the vessel wall. The illustrated embodiment may advantageously
improve torque efficiency by reducing losses along the length of
the arterial lumen and allow the proximally applied torque to
result in controlled rotation of a distal electrode at a distal end
of the catheter shaft. As illustrated in FIG. 104A, a guide
catheter 10405 with a lumen that is just larger than the outer
diameter of the ablation device 10406 is able to support itself
against a section of the vessel wall by means of a support
structure 10408. In one embodiment, the support structure 10408 is
comprised of multiple wires or ribbons that are pushed out of a
plurality of lumens disposed along a length of the guide catheter
and exposed to the arterial or other vessel lumen near (e.g.,
within 1 cm of, within 2 cm of, within 3 cm of) the distal end of
the guide catheter. The wires or ribbons, disposed within the
lumens and controlled at the proximal end of the guide catheter
10405, expand outward until they contact the vessel wall. In some
embodiment, the wires or ribbons exert a force against the vessel
wall at multiple points, thereby providing a reaction force to
restrict lateral movement of the guide catheter when the ablation
device 10406 is rotated within the guide catheter 10405. The inner
lumen of the guide catheter 10405 and outer surface of the ablation
device 10406 (e.g., electrode/catheter) can be comprised of
materials or coatings having low coefficients of friction (e.g.,
polytetrafluoroethylene or hydrophilic coatings) in order to
further reduce the rotational friction between the two devices.
[0645] In one embodiment, a plurality of support structures could
be used to place the guide catheter 10405 in contact with the
vessel wall. Some examples include pressurized support balloons
(such as shown in FIG. 104B) that may allow for perfusion,
self-expanding stent structures, and basket sections of the guide
catheter polymer tube that can be compressed and expanded radially
or otherwise deployed.
[0646] In one embodiment, illustrated in FIG. 105, an inner support
member 10504 (e.g., a guidewire) is configured to hold the ablation
device. For example, loops 10501 and 10502 can be welded or
otherwise fixed or coupled to the inner support member to hold the
ablation device. The ablation device may then be passed through the
loops and wrapped in a spiral around the inner support member
between the loops. When a torque is applied (in one direction) to
the ablation device, the ablation device can take up the slack
between the inner support member and then transfer the torque to
the distal end, "winding" the distal end of the ablation device in
one rotational direction. If the torque is applied in the opposite
direction, the ablation device wants to "unwind." In one
embodiment, this torque improvement mechanism advantageously allows
for improved torque efficiency in one direction. In one embodiment,
a pull force can be applied to a proximal end of the ablation
device, either alone, or in combination with the torque.
[0647] In one embodiment, illustrated in FIG. 106, the guide
catheter is comprised of an expandable balloon 10520 having an
internal catheter-receiving lumen 10522 and an external, arterial
contacting surface 10524, with an external lumen extending between
the internal lumen 10522 and the external surface 10524. The
internal lumen 10522 and external lumen are connected by a
plurality of struts 10526 running along a portion of, or
substantially the entire, length of an inflatable guide region of
the guide catheter. Upon insertion at the target anatomy (e.g., the
celiac axis), the balloon chambers defined by the struts are
inflated to maintain the position of the guide catheter and improve
navigation and torque response of the ablation catheter inserted
within the internal lumen 10522 of the guide catheter.
[0648] Referring now to FIG. 107, an embodiment of a control
mechanism configured to provide precise control of an electrode or
other treatment element at the distal end of a catheter by
controlling the distal end of the catheter directly is provided. As
shown in FIG. 107, the direct control maybe accomplished by
applying torque/rotation to a control wire disposed within the
catheter shaft and anchored to a distal location of the catheter,
such as near the electrode region. In accordance with several
embodiments, the challenges associated with torqueing a catheter
disposed in tortuous anatomy may altogether be avoided or
reduced.
[0649] FIG. 108 illustrates one embodiment of a distal portion of a
catheter that combines the benefits of a coil 10805 (e.g., kink
prevention or inhibition) and a solid rod 10810 (improved torque
transfer for a given diameter constraint). The catheter comprises a
hose having a coiled and ribbed polymer inner layer (for example,
polyimide) and a braided outer layer (for example, Pebax.RTM.) that
is disposed about the inner layer. The inner layer prevents, or
reduces the likelihood of, "ovalization" while the outer layer
provides improved column strength and torque transfer properties.
In one embodiment, the inner layer comprises a coil (without the
ribbed polymer) and the outer layer comprises a round or flat
braid.
[0650] FIGS. 109A and 109B illustrate an embodiment of a hypotube
having a cut pattern that advantageously provides bending
flexibility, column strength, and torqueability. Material may be
removed around the circumference of a tube so that only a
"peninsula" of material connects one ring or portion of material to
another, thereby allowing the rings of material to bend towards
each other and move into the empty space. Alternating the position
of the rings by 90 degrees or about 90 degrees can enable the ring
portions to bend in multiple directions. The cut pattern may be
formed by laser or mechanical cutting means. In accordance with
several embodiments, the hypotube or shaft of the catheter
comprises a substantially non-electrically conductive reinforced
shaft in order to provide improved dielectric strength and reduced
electrical shaft capacitance, thereby improving electrical safety.
In some embodiments, the effective shaft capacitance as described
in iec60601-2-2-R12 is less than 2 pF/cm of shaft length. In other
embodiments, the requirements of IEC60601-2-2-R12 can be met with
an over-the-wire catheter having a diameter of less than 5 Fr. The
shaft may be formed of a first material selected from a list
comprising Polyimide, polyester, polyether block amide,
polyurethane, Nylon, polyethylene, Pebax.RTM., grilamid,
thermoplastic elastomers and copolymers and a second reinforcing
material such as polyether ether ketone (PEEK), liquid crystal
polymer (LCP), Vectran.RTM., Spectra.RTM., Dyneema.RTM.,
Kevler.RTM. or polyimide material. The reinforcement material may
comprise a round or flat braid. In some embodiments the reinforcing
material is a coil. In other embodiments, the reinforcing material
is a braid. In some embodiments, the hypotube or shaft is lined
with polyimide, PTFE or Polyimide/PTFE composite. In some
embodiments, the hypotube or shaft comprises a Pebax.RTM. outer
layer.
[0651] Torqueability can be especially advantageous in branches of
the hepatic artery or surrounding arteries, where the small size of
the arterial lumen may not permit passage of a multi-tip electrode
catheter. In accordance with several embodiments, it is
particularly advantageous to have fine control of the rotation of
an electrode (e.g., to adjust the position of the electrode in
subsequent ablations or other procedural actions to cover the area
in the proximity of the efferent nerves). One embodiment of a
catheter for improving user control of electrode positioning is
schematically shown in FIG. 110. As shown, a small-diameter shaft
of the catheter may be connected to a larger-diameter cylindrical
shaft, thereby providing a physician or other clinician with a
larger control surface for adjustment. In one embodiment, the
control surface could comprise the ring gear of a planetary gear
system, with the catheter shaft forming the sun gear and the ratio
of the rotation of the control surface to the rotation of the
catheter being determined by the planetary gears. In one
embodiment, the ratio is <1:1 (e.g., 1:10, 1:9, 1:8, 1:7, 1:6,
1:5, 1:4, 1:3, 1:2).
[0652] Referring now to FIG. 111, the tortuous anatomy of the
hepatic artery and surrounding arteries may provide challenges for
access and catheter contact (in embodiments where contact with the
arterial wall facilitates modulation of nerves, such as RF catheter
ablation with one or more electrodes). For example, FIG. 26
illustrates an electrode catheter within a tortuous artery. As
shown in FIG. 111A, a straight line formed between an electrode and
a distal articulation link of the catheter may be indicative of
poor arterial wall contact, whereas a curved line between the
electrode and the distal articulation link (as shown in FIG. 111B)
may indicate that the electrode is cantilevered against the
arterial wall (which may be indicative of sufficient arterial wall
contact).
[0653] FIGS. 112A and 112B illustrate an embodiment of a catheter
system configured to provide improved wall contact and catheter
stabilization within tortuous vasculature (e.g., tortuous
vasculature of the common hepatic artery). The catheter system
comprises a guide catheter 11205 and an expandable element catheter
11210 (e.g., balloon catheter). In the illustrated embodiment, the
expandable element catheter 11210 comprises a balloon catheter
having a balloon positioned at a distal end of the balloon
catheter. The balloon catheter may be inserted within the common
hepatic artery in a deflated state (as shown in FIG. 112A) and then
inflated to an expanded state (as shown in FIG. 112B). In some
embodiments, expansion of the expandable element 11215 (e.g.,
inflation of a balloon) straightens out a tortuous vessel (e.g.,
hepatic artery portion) to facilitate wall contact of one or more
electrodes or other treatment members (e.g., transducers, microwave
emitters) disposed in or on the expandable element. If multiple
electrodes or other treatment members are used, the multiple
members may be spaced at various positions along the length and/or
circumference of the expandable element, thereby facilitating
treatment at multiple locations (simultaneously or separately). The
expanded state may also result in improved catheter stabilization,
thereby improving efficiency of the treatment procedure and
reducing treatment times.
[0654] The expandable element may be self-expandable, mechanically
expandable, or pneumatically expandable (e.g., inflatable). In one
embodiment, the expandable element comprises shape memory material
(e.g., a self-expandable stent-like element). In one embodiment,
the catheter system comprises a passive segmented catheter (e.g.,
shapelock assembly of one or more nested links) that guides the
catheter into and through a tortuous vessel in a flexible state and
then transitions to a rigid, shape-locked state. In one embodiment,
the catheter enters the tortuous vessel in a curved state and then
straightens out the vessel to cause the vessel to form a
substantially straight cylindrical shape.
[0655] Respiration can cause movement of vessels being targeted for
nerve modulation. For example, respiration can cause movement by as
much as 2-5 cm in the area of the common hepatic artery, which may
result in undesirable motion of a neuromodulation catheter or a
treatment element (e.g., electrode, transducer or emitter) disposed
thereon. The motion caused by respiration may adversely affect
continuous and sufficient wall contact of a treatment element
(e.g., electrode or transducer) against a vessel wall, and in
several embodiments described herein, the adverse effect is reduced
or removed.
[0656] FIG. 113 illustrates an embodiment of a temporary frame or
scaffold 11300 configured to provide vessel stabilization and to
provide landmarks for positioning treatment elements (e.g.,
ablation electrodes) of a neuromodulation device or system. The
frame 11300 may advantageously stabilize a vessel (e.g., hepatic
artery) that has been deformed under forces exerted by a catheter
and/or stretched or deflected with respiration. In some
embodiments, the frame 11300 provides access to the vascular wall
at desired treatment (e.g., ablation) sites. The frame 11300 may
stabilize both the general vascular geometry as well as the local
wall position. In accordance with several embodiments, the frame
11300 is deployed and retrieved during the procedure.
[0657] In the illustrated embodiment, the frame 11300 is a
hexagonal wire mesh. The frame 11300 may be fabricated as a slotted
tube or a woven wire. The frame 11300 may be constructed of polymer
or metal. Metallic materials may include Nitinol, stainless steel,
MP35N alloy, elgiloy alloy, and/or the like. The metal may be
insulated with a polymer or an oxide layer. Polymeric materials may
include polyurethane, parylene, fluorocarbon,
polytetrafluoroethylene (PTFE), fluorinated ethylene propylene
(FEP), perfluoroalkoxy alkane (PFA), thermoplastic elastomers,
nylon, Hytrel.RTM., Pebax.RTM., Arnitel.RTM., and/or the like.
Frame elements may be wrapped, folded, or bent to provide desired
mechanical properties. Frame elements may be joined or coupled with
solder, braze, adhesive, and/or the like. The frame mesh may be a
single continuous element or segmented into separate elements. The
frame 11300 may be rigid or flexible. The frame 11300 may comprise
any polygonal mesh structure. In other embodiments, the frame 11300
may be a braid, coil, weave or other intertwined configuration
formed of metal or polymeric wire or filaments.
[0658] In some embodiments, the frame 11300 may comprise radiopaque
elements or radiopaque material to provide visualization. The frame
11300 may provide radiographic landmarks to aid in positioning
ablation electrodes or other treatment elements of an energy
delivery device to be inserted through the frame 11300. The
radiographic landmarks may include radiopaque markers. In some
embodiments, the radiographic landmarks may be based on the
structure and visibility of the frame 11300 itself. The entire
frame 11300 may be radiopaque or certain portions or elements may
be radiopaque.
[0659] In several embodiments, the frame 11300 provides for
mechanical orientation and positioning of treatment elements (e.g.,
electrodes). For example, interaction between the frame 11300 and
an electrode assembly may provide tactile feedback or direct
positioning of the electrode(s) with respect to the frame 11300.
When used in conjunction with electrode catheters, the frame 11300
may also provide for electrical position sensing to aid electrode
placement. Electrical position sensing may be accomplished by
providing a sensing element on the electrode shaft that detects
proximity to a corresponding element on the frame 11300 or
vice-versa. The sensing element may detect proximity using
continuity, resistance, conductivity, magnetoresistance (e.g.,
GMR), Hall Effect, capacitance, magnetism, light, reflectance,
absorbance, refraction, diffraction, sound, acoustic reflection,
and/or the like. A separate electrode catheter (not shown) may be
advanced within the frame 11300 and manipulated such that the
electrode(s) are delivered through openings in the wire mesh of the
frame 11300 to contact the vessel wall. The frame 11300 may
advantageously stabilize the vessel wall in the region of a target
ablation site by placing the vessel wall under slight tension,
thereby limiting or reducing the deformation of the vessel wall by
the contact forces imposed by the electrode(s). In some cases,
these contact forces might otherwise increase the contact area
between the electrode and vessel wall and restrict blood flow near
the electrode, which may impair cooling and increase vessel injury.
In some embodiments, a neuromodulation device may itself comprise a
frame instead of the frame being a separate device. The frame 11300
may comprise one or more monopolar electrodes or bipolar electrode
pairs for delivering RF energy to the vessel wall.
[0660] The hepatic arteries move due to the tidal breathing motions
of the hemidiaphragm and the motion of the diaphragm. The vertical
motion of the hepatic arteries generally matches that of the right
or left hemidiaphragm. In one embodiment, the mean horizontal
movement can be up to 1.90 mm. During a porcine study of hepatic
arterial ablation, it was observed that the position of a catheter
tip post-ablation was consistently up to 1 cm from the initial
target location, increasing the variability of the resulting lesion
and, correspondingly, the consistency with which hepatic arterial
denervation was achieved. In various embodiments, methods and
systems aimed at reducing catheter tip and/or electrode motion
during the procedure are provided, as breathing suspension may not
be feasible for the duration of the procedures (e.g., ablations)
required to achieve hepatic denervation or other nerve
modulation.
[0661] In various embodiments, undesired motion of neuromodulation
catheters (e.g., ablation catheters) can be reduced by
substantially reducing the friction between the neuromodulation
catheter and the guide catheter within which the neuromodulation
catheter is inserted. The reduction of friction can be achieved,
for example, by means of a hydrophobic (e.g., fluorine-based)
lubricant or coating. In some embodiments, the force and/or
displacement translation from the proximal end of the catheter
(e.g., in contact with an introducer sheath) and the distal end of
the catheter (e.g., electrode) can be reduced to address the motion
of the catheter. In some embodiments, the friction near the
catheter's distal end (e.g., electrode) and the target tissue can
be increased to address the motion of the catheter.
[0662] FIGS. 114A and 114B illustrate an embodiment of catheter
configured to address the effects of respiratory motion on the
hepatic arteries. FIG. 114A illustrates the catheter during an
inhalation and FIG. 114B illustrates the catheter during an
exhalation. The catheter comprises a disconnection or a flexible
and/or passive segment. In some embodiments, the flexible and/or
passive segment is positioned at an origin of the common hepatic
artery (as shown in FIG. 114A and FIG. 114B).
[0663] FIG. 115 illustrates an embodiment of a catheter system
configured to address motion of the target vessels by reducing the
force and/or displacement translation from the proximal end of the
catheter and the distal end of the catheter. In methods of using
the catheter of FIG. 115, slack can be placed in the catheter
system between an access site and a distal end of the catheter
(e.g., electrode). In one embodiment, the slack formation is
accomplished by fixing the distal end of the catheter and then
pushing the flexible catheter forward a few centimeters so
additional material lies between the distal end of the catheter and
the access site. In one embodiment, any movement of the distal end
relative to the access site straightens out the slack in the
catheter instead of applying a translational force to the distal
end and/or access site.
[0664] In some embodiments, the catheter could also be designed to
selectively create or allow slack between the distal end and
proximal end of the catheter. One embodiment of a catheter with a
distal segment and a proximal segment is shown in FIGS. 116A and
116B. In one embodiment, a tension wire or tether 11605 runs from
the distal segment to the proximal segment. When placed in tension,
this wire or tether 11605 can pull the distal segment towards the
proximal segment. A mechanical interface 11610 (e.g., a tapered end
of the proximal section and a flared end of the distal section),
can align the two segments and prevent or inhibit the distal
segment from sliding over the proximal segment. During access and
navigation of the catheter, the tension wire or tether 11605 can be
placed in tension; however, during treatment (e.g., ablation
dosage), the tension can be released and the wire or tether 11605
can act as the tether connecting the two segments. The mechanical
interface 11610 may be formed by any corresponding mechanical
structures (e.g., notch/protrusion, latches) or adhesive
structures.
[0665] In accordance with some embodiments, flexibility of the
catheter allows slack to be added to the system, but also decreases
push-efficiency and reduces the catheter's ability to access the
hepatic arteries. In some embodiments, a mechanism for switching
between a flexible and a stiff configuration is advantageously
provided. One embodiment of such a switching mechanism involves
moving a stiff member 11705 axially into or out of a nominally
flexible catheter shaft 11710, thereby defining a selectably stiff
region, as illustrated in FIG. 117. For example, the stiff member
could comprise a removable guidewire.
[0666] In one embodiment, the switching mechanism involves
combining two coaxial members having a flexible region and a
singular bending plane, e.g., rotatable members that are flexible
in a singular direction, as illustrated in FIG. 118. When the
flexible directions of the two rotatable members are aligned, the
catheter portion is flexible, and when the rotatable members are
rotated relative to each other substantially along their
longitudinal axes such that their flexible directions are out of
alignment, the catheter portion is stiff or substantially
rigid.
[0667] Through various studies of the common hepatic artery
anatomy, there seems to be greater variation in motion as one
proceeds distally down the length of the common hepatic artery,
which makes sense physiologically, since more distal points are
closer to the diaphragm, which is causing such variation. In some
embodiments, catheter stiffness may be varied along its length to
compensate for the variation in anticipated motion of the target
vessel (e.g., common hepatic artery) due to respiratory motion. One
or more portions of the catheter length configured to be positioned
in portions of the vessel likely to experience greater movement due
to respiration may be constructed to have greater axial compliance,
thereby allowing the portion of the catheter to move and stretch
with the vessel. In one embodiment, the catheter may have an axial
stiffness gradient along the length of the catheter by using alloys
that allow for change in stiffness with relative composition of
different metals. In one embodiment, the same material (e.g.,
metal) is used but the thickness of the catheter wall is tapered
along its length. In one embodiment, material composition or amount
may be changed at discrete locations or "links" along the length of
the catheter. In some embodiments, the stiffness of a catheter
configured to access and target the common hepatic artery decreases
along the length of the catheter from proximal to distal at the
portion of the catheter configured to be positioned within the
common hepatic artery. In one embodiment, the catheter comprises
multiple electrodes positioned at different points along the length
of the catheter, and thus at different points of catheter
stiffness. The more distal electrodes could track with greater
respiratory movement than the more proximal electrodes. Keeping the
position of the electrodes stationary may allow for a more
consistent spacing between ablations, potentially allowing patients
with shorter vessels to achieve more ablations.
[0668] In some embodiments, energy delivery may be gated based on
respiration using temperature or impedance measurements due to the
asymmetric motion of an energy delivery element during a
respiratory cycle. The energy delivery element may remain
relatively stationary for about two-thirds of the respiratory cycle
(expiration) and during this time period the tissue being treated
may increase in temperature. When the energy delivery element is in
motion during the other third of the respiratory cycle
(inspiration), the tissue may cool down. The changes in temperature
may be monitored and used to gate the delivery of energy so that
energy is only delivered when the energy delivery element is
stationary (e.g., during expiration) or power may be increased
during the stationary period to maintain a desired average power
level (e.g., 10 Watts). Because tissue impedance varies with
temperature, impedance measurements could be monitored (either
alternatively or in combination with temperature) and used to start
and stop the energy delivery. In situations where variation in
temperature and/or impedance measurements is not detected, power
may be delivered at a constant rate.
[0669] In such embodiments in which power output is synchronized
with respiration, the ramp of the energy source may be adjusted to
achieve an almost instantaneous climb of power. The adjustment may
be performed by modifying a ramping algorithm of the energy source.
In some embodiments, the energy source may be programmed to ramp up
from a power output below 1 W to a peak power output in less than
half a second. In accordance with several embodiments,
synchronization of power output with respiration takes advantage of
the time frame when blood flow in the vessel (e.g., common hepatic
artery) is at a maximum, thereby providing enhanced cooling to the
energy delivery element and vessel wall, which may reduce charring,
notching and vessel spasm.
C. Contact Assessment
[0670] In some embodiments, feedback and/or evaluative measures are
provided for assessing the quality and/or magnitude of wall
contact. For example, fluoroscopic imaging (e.g., angiography) can
be used to assess the magnitude of lumen indentation caused by the
contact of an electrode against a vessel (e.g., arterial) wall. The
indentation size may be directly correlated to the contact force.
Additionally, because there is a significant difference between
blood and arterial resistivity and permittivity, the electrode
impedance can be used as an indicator of contact force, with
increased impedance generally correlated with improved contact.
Prior to initiating an ablation, a test current can be applied by a
generator to measure the impedance of the tissue immediately
surrounding the electrode. Complex impedance can be obtained based
on electromagnetic property measurements obtained using a single
main electrode (monopolar), a split electrode (bipolar), one or
more coils (e.g., loops or solenoids), one or more giant magneto
resistance devices or other sensors positioned on the
neuromodulation device or on separate adjunctive sensors. The
complex impedance can be determined based on current, voltage,
resistance and/or power measurements available from the generator.
The contact sensing methods may use existing frequency content of
an energy delivery signal (e.g., ablation signal) provided by the
generator. The treatment electrode(s) may be used to perform
contact sensing or adjunctive sensors or electrodes may be used. In
some embodiments, the frequency used for contact sensing may range
from 500 kHz to 10 MHz, which may be within or above the treatment
frequency range. In other embodiments, the frequency used for
contact sensing may range from 500 kHz to 100 MHz In one
embodiment, the sensing frequency is different from the ablation
frequency. In some embodiments, loss tangent, magnetic
permeability, action potentials and/or components of complex
impedance (e.g., resistance and reactance or magnitude and phase
angle) are calculated and used to determine contact level. Contact
sensing may also be determined based on thermal response using one
or more temperature sensors positioned along the neuromodulation
device or on standalone device(s). For example, an impulse or step
response can be measured to facilitate contact assessment. In some
embodiments, affirmative contact is not required because contact is
guaranteed by a particular design of an intravascular
neuromodulation device.
[0671] In various embodiments, two electrode elements are provided
in close proximity to each other, separated by an adhesive or
insulation layer. The at least two electrode elements may be
connected in parallel for therapeutic power delivery in a unipolar
mode, where the current return path is provided either by a ground
pad, indifferent electrode or other return electrode remote from
the treatment site. The at least two electrode elements can be
excited in a differential or bipolar mode to provide sensing
information related to the composition of tissue proximate the
electrode elements. In some embodiments, the sensing information
(signal) is used to assess the degree of contact between the
electrode assembly and the vessel wall. In other embodiments, the
sensing signal is used to assess the change in temperature of the
tissue proximate the electrode assembly. In still other
embodiments, the sensing signal is used to assess the distance
between the electrode assembly and a tissue or structure.
[0672] In some embodiments, at least two electrode elements are
created by splitting a larger electrode into sections of conductive
material separated by thermally and/or electrically insulating
material. In one embodiment, the larger electrode is substantially
cylindrical. In another embodiment, the electrode is substantially
spherical. In yet another embodiment, the electrode is comprised of
separate cylindrical or spherical elements positioned adjacent to
each other. In one embodiment, a first electrode element is
positioned between a second and third electrode element. The second
and third electrode elements may be connected in parallel. In
various embodiments, the electrode elements are distributed
coaxially along a shaft of a catheter. In some embodiments, the
electrode elements are distributed longitudinally or
circumferentially on a shaft of a catheter. In some embodiments, a
first electrode element may be substantially contained within a
second electrode element.
[0673] FIGS. 119A-119D illustrate embodiments of an electrode
configuration or assembly adapted to provide power delivery for
treatment (e.g., ablation or other neuromodulation) and tissue
contact sensing comprising two coaxial electrodes. In the
illustrated embodiment, a first electrode element 11905A is
substantially contained within a second electrode element 11905B in
a concentric manner. FIG. 119A is a top view, FIG. 119B is a
cross-sectional side view and FIG. 119C is a cross-sectional
isometric view of one embodiment of an electrode assembly
configured for providing power delivery and tissue contact sensing.
FIG. 119D is a top view of a second embodiment of an electrode
assembly configured for providing power delivery and tissue contact
sensing. In the illustrated embodiments, a first electrode element
11905A forms a circular aperture in a wall of a second electrode
element 11905B such that the first electrode element is
concentrically positioned within the second electrode element. In
some embodiments, at least one of the electrode elements 11905 is
configured to be placed near or in contact with the area or region
where the electrode assembly contacts the vessel wall. The first
electrode element 11905A may be substantially circular or
spherical, polygonal, disk shaped or other regular geometric form.
The electrode elements 11905 are separated by an electrically
and/or thermally insulating material 11910. In some embodiments,
the electrically and/or thermally insulating material 11910 may be
formed from adhesives, polymers or ceramics selected from a group
including, without limitation, delrin, epoxy, nylon, polyurethane,
alumina, aluminum oxide, macor, polyethylene, cyano acrylate,
acetal, PTFE, PFA, FEP and PEEK. In some embodiments, the shaft
provides electrical and/or thermal isolation.
[0674] FIGS. 119A-1190 illustrate two connecting wires 11915
connecting to the electrode elements 11905. FIG. 119C illustrates
that the covering of one of the connecting wires 11915 (e.g., a
copper wire) may include a slot 11916 such that a connection may be
formed with the first electrode element 11905A and the second
electrode element 11905B using a single connecting wire. In some
embodiments, ablation current and sensing current can be
apportioned among the electrode elements by providing separate
connecting wires 11915 for each element, as shown for example in
the embodiment illustrated in FIG. 119D. Filtering, modulation and
multiplexing methods can be used to distribute power to the various
connecting wires 11915. In one embodiment, the connecting wires
11915 in electrical contact with an electrode element form a
thermocouple or other temperature measuring apparatus. In another
embodiment, the connecting wire(s) 11915 to an electrode element is
a single conductor. A non-limiting example of such connecting wire
arrangement is to provide a thermocouple lead (e.g., 40 gauge
T-type thermocouple lead) to the smaller of the electrode elements
11905A near the vessel wall contact area of the electrode assembly
and a single power lead (e.g., 40 Gauge copper wire) to the
surrounding electrode element 11905B. In some embodiments, ablative
power (e.g., 5 W-20 W, 5 W-15 W, 8 W-12 W, 10 W-20 W) at a
frequency between 400 kHz-650 kHz (e.g., 400 kHz, 450 kHz, 500 KHz,
550 kHz, 600 kHz, 650 kHz) may be delivered to the larger or both
of the electrode elements in a unipolar mode (e.g., common mode
signals delivered to both electrode elements with return signals
going to a ground pad or indifferent electrode), while sensing
signals (e.g., 1-20 mA (such as 10 mA) of current at 1 MHz to 100
MHz (e.g., 1 MHz to 10 MHz, 5 MHz to 15 MHz, 10 MHz, 15 MHz to 50
MHz, 30 MHz to 60 MHz, 50 MHZ to 100 MHz) may be delivered between
the two electrode elements in a bipolar mode. Other power levels,
current levels or frequencies may be used as desired and/or
required. In accordance with several embodiments, the frequencies
for sensing are outside the range of the frequencies used for
ablative power. The complex impedance, phase, loss tangent,
reactance and resistance of the sensing current can be analyzed at
high sensitivity for the adjacent tissue. Sensing current may be
provided at multiple frequencies and impedance can be compared or
combined into a composite parameter describing the tissue contact.
Sensing current may be analyzed in the time domain or the frequency
domain. The sensing waveform may be swept, narrow band broad band,
pulsed, square wave, chirp, frequency modulated, multitonal, or
other suitable waveforms. A sensing system may comprise an external
driver and generator to separate the frequencies of the sensing
signals between the two electrodes. The sensing system may comprise
common mode choke(s), high pass, low pass and/or band pass filters
or other filtering circuitry. The sensing system may comprise a
processing device adapted to determine whether a sufficient amount
of contact exists or to determine a quantitative level of tissue
contact based on tissue contact measurements received from the
electrode assembly. The processing device may generate an output
indicative of contact or the level of tissue contact for display or
other output to a user. The tissue contact measurements may
comprise bipolar contact impedance measurements or temperature
measurements. The contact sensing features and embodiments
described in connection with FIGS. 119A-119D may be incorporated
into any of the neuromodulation devices (e.g., treatment catheters,
ablation catheters or other devices) described herein.
[0675] In some embodiments, a temperature sensing device may be
provided within a first electrode element in a manner to provide
high thermal response and high sensitivity to the surrounding
tissue. Temperature sensors may be comprised of thermocouples,
resistance temperature detectors (RTDs), thermistors, fluoroptic
temperature sensors, Fabry-Perot temperature sensors or other
suitable sensors. In one embodiment, power delivered in a unipolar
mode through at least one electrode element causes modest, benign,
local heating of the tissue proximate the temperature sensor. The
rate or magnitude of temperature change as measured by the sensor
reflects the degree of contact with tissue or blood. Small contact
area and low thermal mass and insulation from non-sensing surfaces
increase responsiveness and sensitivity. In one non limiting
example, a 40 Gauge type T thermocouple lead is connected to the
smaller of the electrode elements 11905A near the vessel wall
contact area of the electrode and a single 40 Gauge copper wire is
connected to the surrounding electrode element 11905B. Other types
or sizes of temperature-measurement devices or wires may be used as
desired and/or required. In one embodiment, 1 W of power is
delivered in a unipolar or bipolar mode through the electrode
elements. The magnitude or rate of temperature rise or decay is
taken as an indication of vessel wall contact. Other power levels
may be used as desired and/or required.
[0676] In some embodiments, fiberoptic sensors may be configured
proximate an electrode to measure reflected light from blood or
tissue at or near the contact area of the electrode. A non-limiting
example of a fiberoptic sensor is as follows: Blood is known to
contain a high concentration of hemoglobin. Hemoglobin may exist as
oxyhemoglobin or deoxyhemoglobin, oxyhemoglobin being generally
more prevalent in the arterial system. Both of these compounds and
blood as a whole have well characterized absorption and scattering
spectra. The absorption and scattering spectra of arterial vessel
walls are also well described, although some variability exists due
to various diseases of the vessel wall such as atherosclerosis. As
optical characteristics of blood are more consistent, an algorithm
compares the measured intensity of reflected light to provide a
measure of deviation from the expected values for blood. High
deviation is associated with vessel wall contact whereas low
deviation is associated with blood contact. Red and green
wavelengths may be selected for comparison due to the
characteristic red color of blood.
[0677] FIGS. 120A and 120B illustrate an embodiment of a
neuromodulation device comprising an optical sensor 12000 for
tissue contact sensing. The optical sensor 12000 may be
incorporated into any of the neuromodulation devices (e.g.,
treatment catheters, ablation catheters or other devices described
herein). The optical sensor 12000 may comprise at least one
illumination fiber 12002 and at least one sensing fiber 12004 along
or in a catheter or elongated body 12005 of the neuromodulation
device that terminate in the electrode 12006. The electrode 12006
may be constructed to have an optical window or side port 12008
near the contact area of the electrode 12006 and vessel wall. The
optical fibers 12002, 12004 may be cut at an angle (e.g., 45 degree
angle) and the distal tips may be coated with a reflective material
(e.g., mirrored coating) to direct both incident and reflected
light laterally towards the vessel wall and perpendicular to the
fibers 12002, 12004. The optical window 12008, together with the
cut ends of the fibers 12002, 12004 may be encapsulated with
optical adhesive (e.g., epoxy) having a refractive index similar to
the fibers 12002, 12004 in order to improve transmission of
incident and reflected light into the tissue. The optical adhesive
is not shown in FIG. 120A because it would obscure the view of the
optical fibers 12002, 12004. If the optical adhesive has the same
index of refraction as the optical fibers 12002, 12004, the light
will reflect off of the coating and travel across the boundary
between the fibers and the optical adhesive as though it wasn't
there. One example is "optical epoxy" or "optical adhesive." In
various embodiments, the coating comprises a very thin coating of
metal (such as nickel, silver, aluminum and/or the like).
[0678] An optical sensing control and/or detection unit external to
the body may provide illumination and detection at at least one
wavelength. Illumination may be broad band or white light or may be
at a single or finite number of wavelengths. Illumination sources
may include lasers, light emitting diodes (LEDs), superluminescent
diodes, laser diodes, halogen or xenon bulbs or other suitable
sources. Detectors may include narrow band or broad band detectors,
with or without optical filters. FIG. 120B shows that a
thermocouple lead 12009 may run along the catheter (for example in
between the optical fibers 12002, 12004). The thermocouple lead may
be coupled to the electrode 12006 or may rest within the optical
window 12008 of the electrode 12006 (not shown in FIG. 120B).
[0679] Other embodiments may employ other types of optical
detection including fluorescence, spectroscopy, ultraviolet/visible
reflectance spectroscopy, Raman spectroscopy, backscatter analysis
or other methods. Separation of the illumination and sensing fibers
may advantageously provide measurement of the different degrees of
specular and diffuse reflection from the vessel compared to
blood.
[0680] In some embodiments, a pressure, force or contact sensor is
incorporated directly onto or adjacent the catheter tip, such as
the FlexiForce.RTM. Force Sensor (Tekscan Inc., South Boston,
Mass.). In some embodiments, the contact force may be displayed on
a display of a neuromodulation system (e.g., RF energy delivery)
system. In some embodiments, an alert or warning may be provided
audibly or visually when the contact force goes above or below a
threshold range. Contact of the energy delivery member (e.g.,
electrode) may be adjusted (manually or automatically) based on
feedback (e.g., measurements) received from the sensor. For
example, FIG. 121 illustrates an embodiment of a system 12100
comprising a controller 12105 (e.g., generator) positioned outside
of a subject's body that is communicatively coupled (via wired or
wireless connection) to an energy delivery device 12110. The energy
delivery device 12110 includes an energy delivery element 12115
(e.g., electrode) at a distal tip of the energy delivery device
12110 and a force sensor 12120 adjacent the energy delivery element
12115 to sense force exerted by the energy delivery element 12115
on a vessel wall. In the illustrated embodiment, the distal end
portion of the energy delivery device 12110 is deflectable via a
deflection or actuation wire 12125. A tension force of the wire
12125 may be adjusted based on feedback received from the sensor
12120 in order to maintain a preferred contact force (even during
respiration and/or blood flow cycles). The adjustment of the
tension force of the wire 12125 may be performed automatically by
one or more computing or processing devices of the controller 12105
or manually by an operator. The maintained contact force may
advantageously facilitate consistent lesion creation for ablative
energy delivery embodiments. The force sensor may also provide
real-time feedback of lesion creation due to heat changes resulting
from tissue stiffness. The controller 12105 may include a display
(e.g., a graphical user interface on a monitor or screen) to
display the contact force or temperatures or may cause the contact
force or temperature measurements to be displayed on a separate
display device. In some embodiments, ultrasound modalities are used
to perform contact sensing. For example, ultrasound elastography or
ultrasound imaging (e.g., A-mode, B-mode, 3D, Doppler, or
interference pattern imaging) may be used to provide an indication
of contact state or other contact assessment between a treatment
element of a neuromodulation device (e.g., ablation catheter) and
target tissue (e.g., vessel wall). Acoustic sensors (such as
piezoelectric, capacitive, passive low frequency, mechanical or
phased array, beam pattern, IVUS, TEE, TTE, HIFU, fuel gauge,
actuators) may be used to provide contact assessment. In some
embodiments, optical sensors or sensing methods are used to provide
contact assessment. Mechanical devices and methods may also be used
to evaluate, for example, elasticity, plasticity, complex impedance
(storage modulus/loss modulus), dynamic mechanical analysis
(DMA/DMTA), high frequency/low frequency, chirp, or force. Force
may be measured by a strain gauge, spring, capacitive sensor, piezo
sensor, or displacement transducer.
[0681] In various embodiments, contact is required to be above a
threshold level prior to initiation of energy delivery. In some
embodiments, contact level is continuously monitored during
treatment. If the contact level falls below or rises above a
threshold level, the controller 12105 may generate an alert to
cause a user to terminate the treatment procedure or adjust
treatment parameters or the controller 12105 may automatically
terminate the treatment procedure or adjust treatment parameters.
The controller 12105 may be located within a power or energy source
(e.g., a generator) or may be a separate component within a sensing
unit or control unit.
IV. Image Guidance, Mapping and Selective Positioning
A. Image Guidance
[0682] Image guidance techniques may be used in accordance with
several of the embodiments disclosed herein. For example, a
visualization element (e.g., a fiber optic scope) may be provided
in combination with a catheter-based energy or fluid delivery
system to aid in delivery and alignment of a neuromodulation
catheter. In other embodiments, fluoroscopic, ultrasound, Doppler
or other imaging is used to aid in delivery and alignment of the
neuromodulation catheter. In some embodiments, radiopaque markers
are located at the distal end of the neuromodulation catheter or at
one or more locations along the length of the neuromodulation
catheter. For example, for catheters having electrodes, at least
one of the electrodes may comprise a radiopaque material. In one
embodiment, a proximal radiopaque marker is positioned so as to
identify sufficient extension beyond a distal end of the guide
catheter. In one embodiment, a distal radiopaque marker indicates
registration of axial catheter position with respect to an
anatomical landmark (for example, distal bifurcation between the
common hepatic artery and the splenic artery or between the hepatic
artery proper and the gastroduodenal artery. Computed tomography
(CT), fluorescence, radiographic, thermography, Doppler, optical
coherence tomography (OCT), intravascular ultrasound (IVUS), and/or
magnetic resonance (MR) imaging systems, with or without contrast
agents or molecular imaging agents, can also be used to provide
image guidance of a neuromodulation catheter system. In some
embodiments, the neuromodulation catheter comprises one or more
lumens for insertion of imaging, visualization, light delivery,
aspiration or other devices.
[0683] In accordance with some embodiments, image or visualization
techniques and systems are used to provide confirmation of
disruption (e.g., ablation, destruction, severance, denervation) of
the nerve fibers being targeted. In some embodiments, the
neuromodulation catheter comprises one or more sensors (e.g.,
sensor electrodes) that are used to provide confirmation of
disruption (e.g., ablation, destruction, severance, denervation) of
communication of the nerve fibers being targeted. Sensors may
include but are not limited to: imaging sensors, temperature
sensors, impedance sensors, optical sensors, electromagnetic
sensors, force sensors, pressure sensors, blood sensors or other
sensors configured to measure other treatment or tissue parameters.
Treatment or patient parameters may be monitored based on signals
received from one or more sensors. The sensors may provide
information regarding patient or treatment parameters (such as
tissue temperature, treatment element temperature, tissue
impedance, blood temperature, blood pressure, contact pressure,
blood flow levels, blood sugar levels, triglyceride levels, insulin
levels, glucagon levels, norepinephrine levels, lipid levels,
gastrointestinal hormone levels, or combinations of two, three or
more of any of the foregoing parameters.
B. Mapping
[0684] In some embodiments, the sympathetic and parasympathetic
nerves are mapped prior to modulation. In some embodiments, a
sensor catheter is inserted within the lumen of the vessel near a
target modulation area. The sensor catheter may comprise one sensor
member or a plurality of sensors distributed along the length of
the catheter body. After the sensor catheter is in place, either
the sympathetic nerves or the parasympathetic nerves may be
stimulated. In some embodiments, the sensor catheter is configured
to detect electrical activity. In some embodiments, when the
sympathetic nerves are artificially stimulated and parasympathetic
nerves are left static, the sensor catheter detects increased
electrical activity and the data obtained from the sensor catheter
is used to map the sympathetic nervous geometry. In some
embodiments, when the parasympathetic nerves are artificially
stimulated and sympathetic nerves are left static, the sensor
catheter detects increased electrical activity and the data
obtained from the sensor catheter is used to map the
parasympathetic nervous geometry. In some embodiments, mapping the
nervous geometry using nervous stimulation and the sensor catheter
advantageously facilitates improved or more informed selection of
the target area to modulate, leaving select nerves viable while
selectively ablating and disrupting others. As an example of one
embodiment, to selectively ablate sympathetic nerves, the
sympathetic nerves may be artificially stimulated while a sensor
catheter, already inserted, detects and maps areas of increased
electrical activity. To disrupt the sympathetic nerves, only the
areas registering increased electrical activity may need to be
ablated.
[0685] In one embodiment, a method of targeting sympathetic nerve
fibers involves the use of electrophysiology mapping tools. While
applying central or peripheral nervous signals intended to increase
sympathetic activity (e.g., by administering noradrenaline or
electrical stimulation), a sensing catheter may be used to map the
geometry of the target vessel (e.g., hepatic artery) and highlight
areas of increased electrical activity. An ablation catheter may
then be introduced and activated to ablate the mapped areas of
increased electrical activity, as the areas of increased electrical
activity are likely to be innervated predominantly by sympathetic
nerve fibers. In some embodiments, nerve injury monitoring (NIM)
methods and devices are used to provide feedback regarding device
proximity to sympathetic nerves located perivascularly. In one
embodiment, a NIM electrode is connected laparascopically or
thorascopically to sympathetic ganglia.
C. Selective Positioning
[0686] In some embodiments, to selectively target the sympathetic
nerves, local conductivity may be monitored around the perimeter of
the hepatic artery. Locations corresponding to maximum impedance
are likely to correspond to the location of the sympathetic nerve
fibers, as they are furthest away from the bile duct and portal
vein, which course posterior to the hepatic artery and which are
highly conductive compared to other tissue surrounding the portal
triad. In some methods, to selectively disrupt sympathetic nerves,
locations with increased impedance are selectively modulated (e.g.,
ablated). In some embodiments, one or more return electrodes are
placed in the portal vein and/or bile duct to enhance the impedance
effects observed in sympathetic nervous tissues. In some
embodiments, return electrodes are placed on areas of the skin
perfused with large veins and having decreased fat and/or
non-vascular tissues (such as the neck or wrist, etc.). The
resistance between the portal vein and other veins may be very low
because of the increased electrical conductivity of blood relative
to other tissues. Therefore, the impedance effects may be enhanced
because comparatively small changes in resistance between various
positions on the hepatic artery and the portal vein are likely to
have a relatively large impact on the overall resistance
registered.
[0687] In some embodiments, impedance and/or temperature may be
measured with a reference transducer placed near the midpoint
between adjacent lesions in order to help form continuous lesions
with minimal overlap. In some embodiments, impedance is measured
with reference to a ground electrode or a local bipolar reference
electrode. Impedance changes as the lesion approaches the reference
electrode. As one example, if two lesions are placed 5-10 mm apart
axially and/or circumferentially along a vessel, a reference
transducer may be positioned along a shaft of an ablation catheter
at position corresponding to the desired extent of the lesion
(e.g., approximately 2.5 mm-5 mm). The reference transducer may be
configured to be placed in contact with the vessel wall. In some
embodiments, impedance is measured at a different frequency than
the ablation frequency. The reference transducer may be filtered to
selectively measure the reference signal. In some embodiments, the
reference transducer has high input impedance to avoid distorting
the ablation field. In other embodiments, the reference transducer
is gated so that impedance measurements are interleaved with an
ablation signal.
[0688] In some embodiments, the sympathetic nerves are targeted
locationally. It may be observed in some subjects that sympathetic
nerve fibers tend to run along a significant length of the proper
hepatic artery while the parasympathetic nerve fibers tend to join
towards the distal extent of the proper hepatic artery. In some
embodiments, sympathetic nerves are targeted by ablating the proper
hepatic artery towards its proximal extent (e.g., generally
half-way between the first branch of the celiac artery and the
first branch of the common hepatic artery or about one centimeter,
about two centimeters, about three centimeters, about four
centimeters, or about five centimeters beyond the proper hepatic
artery branch). Locational targeting may be advantageous because it
can avoid damage to critical structures such as the bile duct and
portal vein, which generally approach the hepatic artery as it
courses distally towards the liver.
[0689] FIG. 122 illustrates a schematic representation of organs
adjacent to the liver (e.g., gall bladder, pancreas, stomach). In
accordance with several embodiments of the invention, the catheters
and procedures described herein may prevent or reduce the
likelihood of collateral damage to organs or tissue surrounding the
liver (e.g., bile duct, portal vein, pancreas, stomach) during
neuromodulation (e.g., RF electrode ablation) of the nerves within
or surrounding the hepatic arteries. In various embodiments, the
catheters and methods of use described herein can prevent or reduce
the likelihood of biliary stenosis, portal vein thrombosis, or
pancreatitis. In some embodiments, energy is directed away from the
bile duct, portal vein, pancreas, and/or other organs or tissues
using bipolar energy delivery devices and methods. In some
embodiments, bipolar devices and methods limits the impact of
adjacent structures (e.g., bile duct and portal vein) on an
ablation region and prevents or inhibits energy from tracking
towards the adjacent structures.
[0690] In one embodiment, biliary protectant (e.g., a
nonconductive, insulating substance) is injected percutaneously
into the gall bladder or via endoscopic retrograde
cholangiopancreatography (ERCP). In one embodiment, a cooled
solution is injected into the biliary tree by the same means. In
one embodiment, an insulating "ring" around the artery is injected,
similar to hydrodissection but with a non-conductive biocompatible
substance (e.g., a polyethylene glycol (PEG) hydrogel).
[0691] One method of decreasing likelihood of collateral damage to
the gall bladder or other organs in the proximity of the hepatic
arteries is to administer a bile acid inhibitor drug to a patient
systemically before the neuromodulation procedure or to request
that the patient not eat a fatty meal before the procedure in order
to minimize or otherwise reduce bile secretion. Other precautionary
steps could involve inducing vomiting to drain bile or
administering ethanol to the patient prior to the procedure in
order to cause "fatty" live protection and/or less conductivity. In
one embodiment, protection of the stomach against possible
collateral damage may be facilitated by having the patient swallow
air or inflating the stomach to provide an air barrier to
conduction in the stomach. For protection of the gall bladder, an
intra-arterial catheter (e.g., having one or more magnetic
portions) can be inserted within a hepatic artery or adjacent
artery to "pull" the hepatic artery away from the gall bladder.
External magnets may also be used to "pull" the hepatic artery away
from the gall bladder.
[0692] In some embodiments, neuromodulation location is selected by
relation to the vasculature's known branching structure (e.g.,
directly after a given branch). In some embodiments,
neuromodulation location is selected by measurement (e.g.,
insertion of a certain number of centimeters into the target
vessel). Because the relevant nervous and vessel anatomy is highly
variable in humans, it may be more effective in some instances to
select neuromodulation location based on a position relative to the
branching anatomy, rather than based on a distance along the
hepatic artery. In some subjects, nerve fiber density is
qualitatively increased at branching locations.
D. Angiography
[0693] In some embodiments, a method for targeting sympathetic
nerve fibers comprises assessing the geometry of arterial
structures distal of the celiac axis using angiography. In one
embodiment, the method comprises characterizing the geometry into
any number of common variations and then selecting neuromodulation
(e.g., ablation) locations based on the expected course of the
parasympathetic nerve fibers for a given arterial variation.
Because arterial length measurements can vary from subject to
subject, in some embodiments, this method for targeting sympathetic
nerve fibers is performed independent of arterial length
measurements. The method may be used for example, when it is
desired to denervate or ablate a region adjacent and proximal to
the bifurcation of the common hepatic artery into the
gastroduodenal and proper hepatic arteries.
E. Physiologic Monitoring
[0694] In the absence of nerve identification under direct
observation, nerves can be identified based on their physiologic
function. In some embodiments, mapping and subsequent modulation is
performed using glucose and norepinephrine ("NE") levels. In some
embodiments, glucose and NE levels respond with fast time
constants. Accordingly, a clinician may stimulate specific areas
(e.g., in different directions or circumferential clock positions
or longitudinal positions) in a target artery or other vessel,
monitor the physiologic response, and then modulate (e.g., ablate)
only in the locations that exhibited the undesired physiologic
response. Sympathetic nerves tend to run towards the anterior
portion of the hepatic artery, while the parasympathetic nerves
tend to run towards the posterior portion of the hepatic artery.
Therefore, one may choose a location not only anterior, but also
(using the aforementioned glucose and NE level measurements) a
specific location in the anterior region that demonstrated the
strongest physiologic response to stimulation (e.g., increase in
glucose levels due to sympathetic stimulation). In some
embodiments, stimulation with 0.1 s-on, 4.9 s-off, 14 Hz, 0.3 ms, 4
mA pulsed RF energy is a sympathetic activator and stimulation with
2 s-on, 3 s-off, 40 Hz, 0.3 ms, 4 mA pulsed RF energy is a
parasympathetic activator. However, other parameters of RF energy
or other energy types may be used.
[0695] In some embodiments, using electrical and/or positional
selectivity, a clinician could apply a stimulation pulse or signal
and monitor a physiologic response. Some physiologic responses that
may indicate efficacy of treatment include, but are not limited to,
the following: blood glucose levels, blood and/or tissue NE levels,
vascular muscle tone, blood insulin levels, blood glucagon levels,
blood C peptide levels, blood pressure (systolic, diastolic,
average), and heart rate. In some cases, blood glucose and tissue
NE levels may be the most accurate and readily measured parameters.
The physiologic responses may be monitored or assessed by arterial
or venous blood draws, nerve conduction studies, oral or rectal
temperature readings, or percutaneous or surgical biopsy. In some
embodiments, transjugular liver biopsies are taken after each
incremental ablation to measure the resultant reduction in tissue
NE levels and treatment may be titrated or adjusted based on the
measured levels. For example, in order to measure tissue NE levels
in the liver, a biopsy catheter may be inserted by a TIPS approach
or other jugular access to capture a sample of liver parenchyma. In
some embodiments, the vein wall of the portal vein may safely be
violated to obtain the biopsy, as the vein is surrounded by the
liver parenchyma, thereby preventing or inhibiting blood loss.
[0696] In various embodiments, a signal or response detected by a
circuit comprised of sensing electrodes or other diagnostic members
on both sides of the ablation or denervation site could be (1)
impedance (e.g., a change in dynamic resistance or conductance of
the circuit created) and/or (2) action potentials (e.g., the
circuit could be probed with a brief voltage impulse and then
electrical response monitored, since nerve fibers conduct
physiologically using such action potentials). In some embodiments,
physiologic responses are monitored, leading to several
possibilities depending on the organ and physiology interrogated.
Examples of physiologic responses include the following: (1)
Liver/glucose: since stimulation of the hepatic sympathetic nerves
increases net hepatic glucose production and thus systemic glucose
levels, a lesser increase in blood glucose levels may be observed
after denervation or ablation; (2) pancreas/insulin-glucagon: since
stimulation of the pancreatic sympathetic nerves could increase
insulin secretion and decrease glucagon secretion, both of these
hormone levels could be measured pre and post denervation; and (3)
duodenum-stomach/motility: since stimulation of the
gastrointestinal (GI) sympathetics may lead to decreased motility,
direct observation of motility or via a number of motility tests
could be measured pre and post denervation or ablation. The systems
and methods described above may be universally applicable to
intravascular denervation regardless of the end organ (e.g., may
apply to any organ innervated by nerves around an artery). The
measurements (whether electrical or physiologic or other type) may
be conducted serially during an ablation procedure, or chronically
(e.g., at some period of time after the procedure), to assess
success of denervation.
[0697] In embodiments involving liver, or hepatic, denervation,
confirmation of denervation may be assessed by tissue
norepinephrine levels. For example, the tissue norepinephrine
levels may be reduced by more than 90%. In some embodiments
involving hepatic denervation by ablating the common hepatic artery
or other adjacent vessels, there may be a corresponding
"dose-response" in the pancreas and duodenum. In other words, in
some embodiments, the pancreas and/or duodenum may be sufficiently
denervated (e.g., >90%) in addition to the liver being
denervated, by ablating the common hepatic artery and/or
surrounding vessels as described herein. Accordingly, physiologic
assessments (e.g., established clinical tests or measurements) of
the pancreas or duodenum that suggest impact of denervation may be
used to confirm success of liver denervation. In some embodiments,
ablations could be continued until an intended or expected clinical
change is detected.
[0698] Clinical measurements for measuring pancreatic response
affected by denervation may include oral glucose challenges and
subsequent insulin response. Denervation of the pancreas in theory
should lead to greater insulin secretion, and evidence of this has
been observed in dog studies. Thus, multiple oral glucose
challenges could be given, and blood insulin levels measured, and
if the insulin levels increased, denervation success could be
inferred. Clinical measurements for measuring pancreatic response
may also include spot insulin measurements without glucose
challenge. In some embodiments, glucagon measurements, which is a
hormone secreted from the pancreas that may be affected by
denervation) may be taken to confirm denervation of the liver.
[0699] Clinical measurements for measuring duodenal response may
include GI motility testing, since with sympathetic denervation of
the duodenum, there may be increased duodenal motility and
decreased transit time. Several clinically validated tests exist to
measure motility changes, including nuclear medicine tests looking
at transit of radioactive food ingested, and C-acetate breath
testing. In some embodiments, an endoscopy could be performed and
the duodenum visualized directly to look at signs of motility
changes.
[0700] In some embodiments, system-wide responses (due to
possibility that afferent neural connections could be disrupted by
ablating the common hepatic artery) may be measured to facilitate
confirmation of liver denervation upon ablation of the common
hepatic artery. Sympathetic outflow to other organs may be reduced
via a reflex path from the liver to the brain to other organs.
Parameters that could be affected and measured include, but are not
limited to, blood pressure, heart rate and muscle sympathetic nerve
activity (MSNA).
F. Sympathetic Tone Measurement
[0701] The rate at which sympathetic neurons fire under normal
conditions is called the sympathetic tone. Likewise, the rate at
which parasympathetic neurons fire under normal conditions is
called the parasympathetic tone. Changes in the firing of the
neurons, for example due to ablation or stimulation of one or more
neurons, can result in changes to the tone. Tone can be measured,
detected, or monitored before, during, and/or after treatment to
provide information about the procedure. For example, a monitored
change in sympathetic tone or physiological responses (e.g., as a
way to measure tone) during or after a procedure can provide
real-time verification about the efficacy of a sympathetic neuron
denervation procedure. For another example, sympathetic tone can be
measured before a procedure for patient screening, identifying
regional locations for treatment, and the like. The measurement may
be global or regional.
[0702] In some embodiments, tone can be measured using an
intravascular device. For example, noradrenaline (NA) plasma
concentration can be measured in an artery and/or a vein.
Noradrenaline spillover can be measured throughout the vasculature,
including as examples the heart (cardiac NA spillover), forearm
(forearm NA spillover), kidney (renal NA spillover), liver (hepatic
NA spillover), skeletal muscle vasculature, and the like. For
another example, microneurography, for example, measuring MSNA, can
be used to measure activity in superficial nerves. Other blood
components can also be measured, for example but not limited to
norepinephrine (NE). Certain blood components may be measured for
the total body and/or proximate to a known or believed origination
location. For example, NE may be measured proximate to a specific
organ such as the lungs, which are believed to originate about 40%
of NE. A measurement may be characterized by the value at a
substantially steady-state condition, for example a change less
than about 25%, less than about 10%, less than about 5%, etc. over
a certain amount of time such as about 30 minutes, about 15
minutes, about 5 minutes, etc. Measurement in body lumens other
than blood vessels is also possible. For example, urinary
cathecholamines can be indicative of sympathetic tone. Body lumens
in which measurement may occur include, for example, arteries,
veins, chambers, arterioles, venules, ducts or tracts (e.g.,
urinary, gastrointestinal), pockets, tubules, and the like.
[0703] In an embodiment, a catheter is placed in a body lumen and
navigated proximate to an organ. A probe may be deployed into the
wall of the lumen, for example at a certain depth and/or angle. The
position of the probe may be stabilized, for example by an anchor,
barb, balloon, expandable cage or portion thereof, combinations
thereof, and the like. The probe may receive electrophysiological
signals that can be recorded, for example to generate a metric
characteristic of sympathetic tone. Background signals or noise may
be removed, for example, by deploying a probe to measure
electrophysiological signals away from the organ. The probe may
measure one or more of: blood or other fluid analyte level, blood
or other fluid flow, blood or other fluid flow differential, blood
oxygen saturation, blood perfusion, blood pressure, central
sympathetic drive, an electroacoustic event, an electromyographic
signal, evoked potential, a local field potential, a
mechanomyographic signal, MSNA, nerve traffic, remote stimulation
of nervous activity, temperature, tissue tone, vasodilation, vessel
wall stiffness, water concentration, combinations thereof, and the
like. A plurality of probes may be used to measure multiple signals
or other properties, the same signal at different places in the
body, and combinations thereof.
[0704] In an embodiment, a first catheter is placed in an artery
proximate to an organ such as a liver and a second catheter is
placed in a vein proximate to the organ. The first catheter
comprises a first sensor configured to detect a blood component
(e.g., NA, NE, and/or the like). The second catheter comprises a
second sensor configured to detect the same blood component (e.g.,
NA, NE, and/or the like). At least one of the first catheter and
the second catheter comprises a flowmeter configured to measure
blood flowrate. Blood component spillover (e.g., in ng/min), which
may be indicative of sympathetic tone, can be measured by
multiplying a flowrate (e.g., in ml/min) by the difference in the
concentration (e.g., in ng/mL) of the blood component in the artery
and in the vein. In some embodiments, the first catheter and the
second catheter may be placed in the same vessel, for example
upstream and downstream of the organ.
[0705] In some embodiments, tone can be measured using a
noninvasive device or a device external to the body. A non-invasive
tool may be easier and/or more accurate than existing
microneurographs such as for MSNA or an intravascular device. A
change in sympathetic tone may be characterized by a change in
resting heart rate, as acute modifications in sympathetic tone are
paralleled by consensual heart rate changes. Heart rate may be
measured using a blood pressure cuff, optical monitor, EKG, smart
phone, smart watch, etc.
[0706] Spectral analysis of heart rate variability (HRV) can be
used to assess changes in sympathetic tone. For example, an EKG can
be used to measure spectral power or intensity at various
frequencies. An HRV spectrum can be aggregated into three main
frequency bands: a high frequency band (about 0.15 Hz to about 0.4
Hz), corresponding to a parasympathetic component, a low frequency
band (about 0.04 Hz to about 0.15 Hz), corresponding to both
sympathetic and parasympathetic components, and a very low
frequency band (about 0.0033 Hz to about 0.04 Hz), which may
reflect the influence of several physiological mechanisms including
vasomotor tone. The resulting spectral power or intensity can be
plotted against frequency. Peaks at certain frequencies can be
indicative of sympathetic nerve activity such that changes to peaks
can indicate changes in sympathetic nerve activity. In addition or
alternatively, changes to the total spectral power, measured as the
area under the spectral plot or a portion thereof (e.g., high
frequency only, low frequency only, high frequency and low
frequency only, etc.), can be indicative of sympathetic nerve
activity such that changes to total spectral power can indicate
changes in sympathetic nerve activity.
[0707] Measurement values of sympathetic tone, for example a static
number obtained in a screening phase, may be indicative of a
suitable subject for denervation or stimulation. Changes in
measurement values of sympathetic tone, for example up or down
depending on the measurement type and procedure, may be indicative
of success of a procedure that should result in a change to
sympathetic tone such as denervation or stimulation. If the
expected result was not achieved, the procedure may be repeated or
modified for example adjusting position, power, energy type,
etc.
G. Fluoroscopy
[0708] In some embodiments, ablation is performed using an ablation
catheter with radiopaque indicators capable of indicating proper
position when viewed using fluoroscopic imaging. Due to the
two-dimensional nature of fluoroscopic imaging, device position can
only be determined along a single plane, providing a rectangular
cross-section view of the target vasculature. In order to overcome
the difficulty of determining device position along a vessel
circumference without repositioning the fluoroscopic imaging
system, rotational positioning indicators that are visible using
fluoroscopic imaging may advantageously be incorporated on an
endovascular ablation device to indicate the circumferential
position of ablation components (e.g., electrodes) relative to the
vessel anatomy.
[0709] In one embodiment, an ablation catheter having an ablation
electrode comprises three radiopaque indicators positioned along
the longitudinal axis of the ablation catheter. In one embodiment,
the first radiopaque indicator is positioned substantially adjacent
to the electrode on the device axis; the second radiopaque
indicator is positioned proximal to the electrode on the device
axis; and the third radiopaque indicator is positioned off the
device axis. In one embodiment, the third radiopaque indicator is
positioned between the first and second radiopaque indicators. In
embodiments with three radiopaque indicators, the ablation
electrode is configured to contact the vessel wall through
deflection from the central axis of the catheter. In one
embodiment, alignment of the first and second radiopaque indicators
means that the ablation electrode is located in a position spaced
from, and directly perpendicular to, the imaging plane (e.g.,
either anteriorly or posteriorly assuming a coronal imaging plane).
In one embodiment, the position of the third radiopaque indicator
indicates the anterior-posterior orientation. For example, position
of the third radiopaque indicator above, on, or below the line
formed between the first and second radiopaque indicators may
provide the remaining information necessary to allow the user to
infer the position of the ablation catheter.
H. Neural Targeting
[0710] In accordance with several embodiments, methods of specific
neural chemical targeting for labeling and destruction are
provided. Nerves within or surrounding the hepatic arteries may be
closer to the arterial lumen than for the renal artery. In some
instances, the nerves converge towards the arterial lumen at a
midpoint of a common hepatic artery segment and diverge thereafter.
Nerves innervating the common hepatic artery may be predominantly
sympathetic efferent nerves. As shown in FIG. 56, the nerves
innervating the common hepatic artery may be embedded mostly in fat
tissue
[0711] In some embodiments, a method of targeting nerves comprises
injecting a drug specific to efferent fibers (e.g., a TH inhibitor
that spares afferent nerves while destroying efferent). In some
embodiments, a chemical solution (e.g., potassium hydroxide) is
used to dissolve nerves while leaving fat intact. In one
embodiment, fat-specific dissolving drugs are injected to
skeletonize nerves, thereby bringing the nerves even closer to the
arterial lumen or vascular wall.
[0712] In some embodiments, the nerves are targeted mechanically
instead of chemically (e.g., by taking advantage of different
stiffness properties of nerves versus soft fat. Vibrational energy
(e.g., sound, ultrasound) may be used, for example to target
nerves. In one embodiment, fluorescent markers are injected in
specific lobes of the liver to determine where they innervate
around the hepatic artery. In one embodiment, a midpoint specific
ablation pattern is used to ablate the common hepatic artery.
I. Lesion Monitoring
[0713] In accordance with several embodiments, monitoring lesion
growth during ablation can provide a method to produce consistent
lesions. In addition, overtreatment can be avoided knowing lesion
size and severity during ablation. In some embodiments, echo
decorrelation of ultrasound images may be used to map tissue
changes during ablation. Echo decorrelation is performed by
measuring changes in the local ultrasound signal frame to frame.
Degradations in the signal are recorded to produce a cumulative
decorrelation map. These resulting images can visualize tissue
changes due to injury severity. In some embodiments, an
intravascular ultrasound probe is positioned at the site of
ablation. In other embodiments, the intravascular ultrasound probe
is positioned in a parallel vein or artery or other structure. Echo
decorrelation can be performed in real time to monitor the growth
of one or more ablation lesions formed in the wall (e.g., intima,
media and/or adventitia) of the vessel. In some embodiments, echo
decorrelation uses thresholds defined from in vitro empirical
tissue ablation data to visualize one or more growing lesions. The
monitoring may advantageously be used to stop ablative energy
delivery (e.g., from an electrode or ultrasound transducer) when
the lesion has reached a sufficient size or if the lesion severity
approaches unsafe levels.
[0714] As mentioned above, diagnostic probes may be inserted within
structures adjacent to the common hepatic artery to be used as a
monitoring site to detect formation of ablation lesions or other
penetration of ablation. For example, the stomach and duodenum may
be accessed via an endoscopic approach using probes placed at the
time of the procedure. Diagnostic devices may be inserted into the
portal vein through a percutaneous approach directly from outside
the abdomen or through venous access crossing the liver tissue from
the vena cava. Diagnostic devices may be inserted into the bile
duct, which may be accessed, for example, percutaneously from
outside the abdomen. Diagnostic devices may be inserted into the
inferior vena cava through standard venous approaches. In some
embodiments, diagnostic elements are placed external to the patient
on the skin of the abdomen. The various diagnostic devices (e.g.,
probes) may measure temperature using thermocouples, thermistors,
microwave detection, volumetric heat mapping, or mechanical changes
in tissue (e.g., using ultrasound or optical coherence tomography
(OCT) probes). In accordance with several embodiments, the
diagnostic devices (e.g., probes) inserted into the adjacent
structures may advantageously give the operator confidence that
energy was actually delivered to the intended sites (thus
suggesting efficacy) and provide assurance that adjacent sensitive
structures that were not intended to be ablated (such as the bile
duct) were not impacted (thus ensuring safety).
J. Nerve Conduction Monitoring
[0715] Various systems and methods are provided herein to provide
the ability to detect (acutely and/or chronically) whether nerves
have been ablated or denervated and the neural connections to the
end-organ (e.g., liver, pancreas, duodenum, etc.) thus disrupted.
In accordance with several embodiments, it may be desirable to
detect in real-time the actual energy being delivered. Since nerves
carry electrical signals, and denervated or ablated nerves can no
longer carry these signals, it may be possible to measure
conduction along the length of the nerve fibers. In some
embodiments, a binary signal (e.g., on/off) or a quantitative
signal correlating with degree of nerve disruption could be
determined. In some embodiments, expected physiological responses
(e.g., glucose changes, insulin or glucagon changes, GI motility,
etc.) to stimulation of the target nerves (e.g., nerves surrounding
the hepatic arteries) may be monitored directly after a denervation
or nerve ablation procedure to determine whether or not the
expected physiological responses occur, thereby leading to the
possibility of a real-time intra-procedural diagnostic. In some
embodiments, real-time feedback during the ablation procedure may
facilitate delivery of only enough energy (or formation of only
enough lesions) as needed for successful denervation, thereby
opening up a wider population to the procedure due to anatomic
constraints (e.g., vessel length, tortuosity, etc.) that may limit
the number of possible ablations and/or reducing the likelihood of
any safety effects (e.g., vascular or adjacent structure injury)
due to excessive energy delivery.
[0716] In accordance with several embodiments, the catheter used
for energy delivery (e.g., ablation) comprises sensing electrodes
proximal and/or distal to the site of ablation. The sensing
electrodes may be configured to be placed in contact with a vessel
wall in order to detect conduction in the targeted nerve fibers
(e.g., nerve fibers in the adventitia surrounding a common hepatic
artery). Any of the structures and features described herein for
facilitating contact of electrodes with vessel walls may be used.
For example, a balloon ablation catheter may comprise ablation
electrodes in the middle of the balloon and sensing electrodes on
the same balloon proximal and distal of the ablation electrodes. In
some embodiments, the same electrodes are configured to provide
ablation and sensing functions. In some embodiments, a balloon
ablation catheter may comprise multiple balloons, with sensing
balloons (e.g., balloons with sensing electrodes) on either side of
an ablation balloon (or balloon with ablation electrodes).
[0717] Similar technologies could be employed on a separate
catheter from the ablation catheter, and a diagnostic procedure
could be performed with the separate sensing catheter immediately
after or within a certain time (e.g., 5 minutes, 10 minutes, 15
minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes) following
the ablation or on some other diagnostic or treatment session in
the future. In some embodiments, non-catheter-based diagnostic
systems and methods are used. For example, the proximal and distal
sensing electrodes may be positioned on cuffs, needles, patches,
and/or the like. Access could be percutaneous, placed on the skin
outside of the body, placed in adjacent structures (e.g., portal
vein, bile duct, inferior vena cava), or placed in organ tissue
(e.g., liver tissue) itself. In accordance with several
embodiments, the methods advantageously involve monitoring at the
physiology that is being targeted (e.g., neural electrical
conduction), which provides the most direct measurement
conceivable.
V. Alternative Delivery Methods
A. Intravascular
[0718] In addition to being delivered intravascularly through an
artery, the neuromodulation systems described herein (e.g.,
ablation catheter systems and other access/delivery systems) can be
delivered intravascularly through the venous system. For example,
an ablation catheter system may be delivered through the portal
vein. In other embodiments, an ablation catheter system is
delivered intravascularly through the inferior vena cava. Any other
intravascular delivery method or approach may be used to deliver
neuromodulation systems, e.g., for modulation of sympathetic nerve
fibers in the hepatic plexus.
B. Transluminal, Laparoscopic, Percutaneous or Open Surgical
[0719] In some embodiments, the neuromodulation systems (e.g.,
catheter and other access/delivery systems) are delivered
transluminally to modulate nerve fibers. For example, catheter
systems may be delivered transluminally through the stomach. In
other embodiments, the catheter systems are delivered
transluminally through the duodenum, or transluminally through the
biliary tree via endoscopic retrograde cholangiopancreatography
(ERCP). Any other transluminal or laparoscopic delivery method may
be used to deliver the catheter systems according to embodiments
described herein.
[0720] In some embodiments, the catheter systems are delivered
percutaneously to the biliary tree to ablate sympathetic nerve
fibers in the hepatic plexus. Any other minimally invasive delivery
method may be used to deliver neuromodulation systems for
modulation or disruption of sympathetic nerve fibers in the hepatic
plexus as desired and/or required.
[0721] In some embodiments, an open surgical procedure is used to
modulate sympathetic nerve fibers in the hepatic plexus. Any open
surgical procedure may be used to access the hepatic plexus. In
conjunction with an open surgical procedure, any of the modalities
described herein for neuromodulation may be used. For example, RF
ablation, ultrasound ablation, HIFU ablation, ablation via drug
delivery, chemoablation, cryoablation, ionizing energy delivery
(such as X-ray, proton beam, gamma rays, electron beams, and alpha
rays) or any combination thereof may be used with an open surgical
procedure. In one embodiment, nerve fibers (e.g., in or around the
hepatic plexus) are surgically cut in conjunction with an open
surgical procedure in order to disrupt sympathetic signaling, e.g.,
in the hepatic plexus.
C. Non-Invasive
[0722] In some embodiments, a non-invasive procedure or approach is
used to ablate sympathetic nerve fibers in the hepatic plexus
and/or other nerve fibers. In some embodiments, any of the
modalities described herein, including, but not limited, to
ultrasonic energy, HIFU energy, electrical energy, magnetic energy,
light/radiation energy or any other modality that can effect
non-invasive ablation of nerve fibers, are used in conjunction with
a non-invasive (e.g., transcutaneous) procedure to ablate
sympathetic nerve fibers in the hepatic plexus and/or other nerve
fibers.
D. Robotic/Automated Treatment
[0723] The hepatic or other arteries may lend themselves to robotic
or automated treatments based on a predetermined or preselected
treatment. The automated treatment may minimize or reduce trauma
and risk of deviation from protocol. The preselected treatment may
incorporate treatment parameters (e.g., target locations, spacing
between treatment locations, duration, frequency, etc.).
[0724] In an embodiment, an automated system may be used for
automated treatment of a nerve. The automated system may include
memory that includes a recipe or protocol. The memory may include a
plurality of recipes (e.g., different body parts to be treated,
different treatments of such body parts) that may be selected by an
input device. The recipe can include information about, for
example, how to navigate to the body part and what type of energy
(e.g., energy modality, power level, treatment duration, continuous
versus intermittent) to apply to effect certain treatment.
[0725] The system may include memory that includes information, for
example related to the patient, the components of the system, the
user, environmental factors, etc. The system may use the
information to modify the recipe before, during, and/or after a
procedure.
[0726] A computing device such as a laptop or tablet may include
the memory, input device, a display device, communications devices,
and the like to operate as a control center for the procedure. For
example, a procedure may start by selecting via an input device of
the control center a recipe (e.g., hepatic denervation) and a
patient from menus displayed by the control center. The control
center may visibly and/or audibly provide instructions for initial
setup of the procedure after which the procedure is substantially
automated, or the procedure may begin immediately or soon after
menu selection.
[0727] The system may include a steerable component such as a
guidewire or a guide catheter. The steerable component may be
inserted into the vasculature distant to the nerve to be treated,
for example in a femoral or radial artery. A portion of the
steerable component inside the body may include a monitoring device
such as IVUS, RFID, etc. to monitor position of the catheter. The
control center may receive information from the monitoring device
via wired and/or wireless communication. Alternatively or
additionally, a portion of the steerable component inside the body
may include a radiopaque element (e.g., marker band) and/or other
means for monitoring the position of the steerable component
external to the body.
[0728] Outside of the body, the steerable component may be engaged
with an advancement mechanism. For example, one or more motors may
advance, retract, and/or rotate the steerable component in response
to instructions from the control center. A curvature of at least
part of the steerable component may be modified to provide
navigability through vasculature. IVUS may be used to monitor the
surroundings of the steerable component. The advancement mechanism
may advance the steerable component through the vasculature to a
body part as indicated in the recipe. For example, the steerable
component may be longitudinally distally advanced until the
steerable component reaches a branch vessel, for example indicated
by a dark, non-walled spot on an IVUS output that can be detected
by the control center. Based on the recipe, which may include a map
of the vasculature or a turning guide (e.g., straight after first
branch, left into second branch, right into third branch, or the
like), the steerable component can be advanced into the branch
vessel (e.g., by modifying curvature of the steerable component) or
continue advancing in the original vessel. If the steerable
component is a guidewire, a catheter may be advanced over the
guidewire. If the steerable component is a guide catheter, a
catheter may be advanced in the guide catheter, or the guide
catheter itself may include a treatment tool such as an energy
emitter. In a partially automated system, a user may advance a
steerable component to a location at or proximate to the body part,
and the system can be automated thereafter.
[0729] Once the treatment tool is in a position, the recipe may
call for an initial diagnosis, for example of a bodily parameter.
The bodily parameter may be used as a baseline to evaluate the
treatment and/or as a variable to adjust a treatment parameter. The
treatment tool can be automatically positioned, for example via
longitudinal advancement and/or retraction, rotation, and/or
biasing to a side (e.g., via shape-memory wire, balloon, anchor,
and/or the like), to modulate a nerve. The recipe may call for
denervation or stimulation and may adjust energy application
parameters (e.g., frequency, time, cooling, focus, etc.)
accordingly. The treatment tool may be moved to a plurality of
sites, for example advancing a known or calculated distance in a
particular direction. The recipe may call for an ongoing diagnosis,
for example of the same or a different bodily parameter, during the
treatment. The bodily parameter may be used to adjust a treatment
parameter and/or repeat a treatment mid-procedure. The recipe may
call for a final or post-procedure diagnosis, for example of the
same or a different bodily parameter. The bodily parameter may be
used to confirm completion of the procedure. The bodily parameter
may be used to adjust a treatment parameter and/or repeat a
treatment after the initial completion of the procedure.
[0730] A user of the system may be standing by in case
non-automated action may be needed. Action may be indicated by the
system itself, for example via a warning on a control center.
VI. Stimulation
[0731] According to some embodiments, neuromodulation is
accomplished by stimulating nerves and/or increasing
neurotransmission. Stimulation, in one embodiment, may result in
nerve blocking. In other embodiments, stimulation enhances nerve
activity (e.g., conduction of signals).
[0732] In accordance with some embodiments, therapeutic modulation
of nerve fibers is carried out by neurostimulation of autonomic
(e.g., sympathetic or parasympathetic) nerve fibers.
Neurostimulation can be provided by any of the devices or systems
described above (e.g., ablation catheter or delivery catheter
systems) and using any of the approaches described above (e.g.,
intravascular, laparoscopic, percutaneous, non-invasive, open
surgical). In some embodiments, neurostimulation is provided using
a temporary catheter or probe. In other embodiments,
neurostimulation is provided using an implantable device. For
example, an electrical neurostimulator can be implanted to
stimulate parasympathetic nerve fibers that innervate the liver,
which could advantageously result in a reduction in blood glucose
levels by counteracting the effects of the sympathetic nerves.
[0733] In some embodiments, the implantable neurostimulator
includes an implantable pulse generator. In some embodiments, the
implantable pulse generator comprises an internal power source. For
example, the internal power source may include one or more
batteries. In one embodiment, the internal power source is placed
in a subcutaneous location separate from the implantable pulse
generator (e.g., for easy access for battery replacement). In other
embodiments, the implantable pulse generator comprises an external
power source. For example, the implantable pulse generator may be
powered via an RF link. In other embodiments, the implantable pulse
generator is powered via a direct electrical link. Any other
internal or external power source may be used to power the
implantable pulse generator in accordance with the embodiments
disclosed herein.
[0734] In some embodiments, the implantable pulse generator is
electrically connected to one or more wires or leads. The one or
more wires or leads may be electrically connected to one or more
electrodes. In some embodiments, one or more electrodes are
bipolar. In other embodiments, one or more electrodes are
monopolar. In some embodiments, there is at least one bipolar
electrode pair and at least one monopolar electrode. In some
embodiments, one or more electrodes are nerve cuff electrodes. In
other embodiments, one or more electrodes are conductive
anchors.
[0735] In some embodiments, one or more electrodes are placed on or
near parasympathetic nerve fibers that innervate the liver. In some
embodiments, the implantable pulse generator delivers an electrical
signal to one or more electrodes. In some embodiments, the
implantable pulse generator delivers an electrical signal to one or
more electrodes that generates a sufficient electric field to
stimulate parasympathetic nerve fibers that innervate the liver.
For example, the electric field generated may stimulate
parasympathetic nerve fibers that innervate the liver by altering
the membrane potential of those nerve fibers in order to generate
an action potential.
[0736] In some embodiments, the implantable pulse generator
recruits an increased number of parasympathetic nerve fibers that
innervate the liver by varying the electrical signal delivered to
the electrodes. For example, the implantable pulse generator may
deliver a pulse of varying duration. In some embodiments, the
implantable pulse generator varies the amplitude of the pulse. In
other embodiments, the implantable pulse generator delivers a
plurality of pulses. For example, the implantable pulse generator
may deliver a sequence of pulses. In some embodiments, the
implantable pulse generator varies the frequency of pulses. In
other embodiments, the implantable pulse generator varies any one
or more parameters of a pulse including, but not limited to,
duration, amplitude, frequency, and total number of pulses.
[0737] In some embodiments, an implantable neurostimulator
chemically stimulates parasympathetic nerve fibers that innervate
the liver. For example, the chemical neurostimulator may be an
implantable pump. In some embodiments, the implantable pump
delivers chemicals from an implanted reservoir. For example, the
implantable pump may deliver chemicals, drugs, or therapeutic
agents to stimulate parasympathetic nerve fibers that innervate the
liver.
[0738] In some embodiments, the implantable neurostimulator uses
any combination of electrical stimulation, chemical stimulation, or
any other method to stimulate parasympathetic nerve fibers that
innervate the liver.
[0739] In some embodiments, non-invasive neurostimulation is used
to stimulate parasympathetic nerve fibers that innervate the liver.
For example, transcutaneous electrical stimulation may be used to
stimulate parasympathetic nerve fibers that innervate the liver. In
other embodiments, any method of non-invasive neurostimulation is
used to stimulate parasympathetic nerve fibers that innervate the
liver.
[0740] In accordance with the embodiments disclosed herein,
parasympathetic nerve fibers other than those that innervate the
liver are stimulated to treat diabetes, hypertension and/or other
conditions, diseases, disorders, or symptoms related to metabolic
conditions. For example, parasympathetic nerve fibers that
innervate the pancreas, parasympathetic nerve fibers that innervate
the adrenal glands, parasympathetic nerve fibers that innervate the
small intestine, parasympathetic nerves that innervate the stomach,
parasympathetic nerve fibers that innervate the kidneys (e.g., the
renal plexus) or any combination of parasympathetic nerve fibers
thereof may be stimulated in accordance with the embodiments herein
disclosed. Any autonomic nerve fibers can be therapeutically
modulated (e.g., disrupted or stimulated) using the devices,
systems, and methods described herein to treat any of the
conditions, diseases, disorders, or symptoms described herein
(e.g., diabetes or diabetes-related conditions). In some
embodiments, visceral fat tissue of the liver or other surrounding
organs is stimulated. In some embodiments, intrahepatic stimulation
or stimulation to the outer surface of the liver is provided. In
some embodiments, stimulation (e.g., electrical stimulation) is not
provided to the outer surface of the liver or within the liver
(e.g., to the liver parenchyma), is not provided to the vagal or
vagus nerves, is not provided to the hepatic portal vein, and/or is
not provided to the bile ducts.
[0741] Stimulation may be performed endovascularly or
extravascularly. In one embodiment, a stimulation lead is
positioned intravascularly in the hepatic arterial tree adjacent
parasympathetic nerves. The main hepatic branch of the
parasympathetic nerves may be stimulated by targeting a location in
proximity to the proper hepatic artery or multiple hepatic branches
tracking the left and right hepatic artery branches and
subdivisions. In one embodiment, the stimulation lead is positioned
within a portion of the hepatoesophageal artery and activated to
stimulate parasympathetic nerves surrounding the hepatoesophageal
artery, as both vagal branches travel along the hepatoesophageal
artery.
[0742] In one embodiment, the stimulation lead is positioned in the
portal vein and activated to stimulate nerve fibers surrounding the
portal vein, which may have afferent parasympathetic properties. In
one embodiment, the stimulation lead is positioned across the
hepatic parenchyma from a central venous approach (e.g., via a
TIPS-like procedure) or positioned by arterial access through the
hepatic artery and then into the portal vein. In one embodiment,
the portal vein is accessed extravascularly through a percutaneous
approach. The stimulation lead may be longitudinally placed in the
portal vein or wrapped around the portal vein like a cuff.
Extravascular stimulation of the portal vein may be performed by
placing the stimulation lead directly on the parasympathetic fibers
adhered to or within the exterior vessel wall. In various
embodiments, the stimulation lead is placed percutaneously under
fluoroscopy guidance, using a TIPS-like approach through the wall
of the portal vein, by crossing the arterial wall, or by accessing
the biliary tree.
[0743] In some embodiments, the stimulation lead is stimulated
continuously or chronically to influence resting hepatic glucose
product and glucose uptake. In various embodiments, stimulation is
performed when the subject is in a fasting or a fed state,
depending on a subject's glucose excursion profile. In some
embodiments, stimulation may be programmed to occur automatically
at different times (e.g., periodically or based on feedback). For
example, a sensory lead may be positioned in the stomach or other
location to detect food ingestion and trigger stimulation upon
detection. In some embodiments, the stimulation is controlled or
programmed by the subject or remotely by a clinician over a
network.
[0744] In some embodiments, stimulation with 0.1 s-on, 4.9 s-off,
14 Hz, 0.3 ms, 4 mA pulsed RF energy is used for sympathetic nerve
stimulation and stimulation with 2 s-on, 3 s-off, 40 Hz, 0.3 ms, 4
mA pulsed RF energy is used for parasympathetic activation.
However, other parameters of RF energy or other energy types may be
used.
[0745] Parasympathetic stimulation may also cause afferent effects
along the vagus nerve, in addition to efferent effects to the liver
resulting in changes in hepatic glucose production and uptake. The
afferent effects may cause other efferent neurally mediated changes
in metabolic state, including, but not limited to one or more of
the following: an improvement of beta cell function in the
pancreas, increased muscle glucose uptake, changes in gastric or
duodenal motility, changes in secretion or important gastric and
duodenal hormones (e.g., an increase in ghrelin in the stomach to
signal satiety, and/or an increase in glucagon-like peptide-1
(GLP-1) from the duodenum to increase insulin sensitivity).
VII. Examples
[0746] Examples provided below are intended to be non-limiting
embodiments of the invention.
A. Example 1
[0747] Nine dogs were put on a high fat, high fructose diet for
four weeks, thereby rendering the dogs insulin resistant. As
controls, a 0.9 g/kg oral gavage polycose dose was administered
prior to initiation of the diet and at four weeks after initiation
of the diet after an overnight fast and oral glucose tolerance
tests were performed at various time intervals to track glucose
levels. The common hepatic arteries of six dogs were then
surgically denervated, and three dogs underwent a sham operation.
Another 0.9 g/kg oral gave polycose dose was administered after an
overnight fast about two to three weeks following hepatic
denervation. Oral glucose tolerance tests were performed at various
time intervals after administration of the polycose. FIG. 123A-1
illustrates a graph of the average venous plasma glucose over time
for the six denervated dogs reported by the three oral glucose
tolerance tests (OGTTs). The curve with data points represented by
open circles represents the average of glucose measurements from
the OGTT testing of the six dogs prior to high fat, high fructose
diet feeding, and the curve with the data points represented by
gray circles represents the average of the glucose measurements
from the OGTT testing of the six dogs after the four weeks of high
fat, high fructose diet before hepatic denervation. The oral gavage
polycose doses were administered at time zero (as shown in FIG.
123A-2). The curve with the data points represented as black
circles represents the average of the glucose measurements from the
OGTT testing of the same six dogs seventeen days after hepatic
denervation. As can be seen in FIG. 123A, the glucose values after
hepatic denervation peaked at lower glucose concentrations and
dropped much more rapidly than the glucose values prior to hepatic
denervation, and the areas under the curve of the OGTTs improved by
approximately 50% back to normal, chow fed levels. Interestingly,
insulin levels during the OGTT actually increased after
denervation, suggesting a beneficial effect on beta cell function.
FIG. 123B illustrates a graph of the three sham operated dogs at
the same time points, showing an increase over time of glucose area
under the curve. The sham operated dogs also had no increase in
insulin levels. In accordance with several embodiments, the results
of the study provide strong evidence of the efficacy of hepatic
denervation for controlling blood glucose levels. In some
embodiments, insulin levels may remain constant or not increase or
decrease by more than 5%.
B. Example 2
[0748] FIG. 124 illustrates the net hepatic glucose balance
obtained during a hyperglycemic-hyperinsulinemic clamp study. The
data represented with diamond indicators (HDN) represents the
average net hepatic glucose levels of the same 6 dogs from Example
1 four weeks after denervation. The data represented with triangle
indicators (HF/HF) represents the average net hepatic glucose
levels of 5 dogs that were fed a high fat, high fructose diet. The
data represented with the square indicators (Control) represents
the average net hepatic glucose levels of 5 dogs fed a normal diet.
The data shows that toward the end of the curves, hepatic
denervation can restore net hepatic glucose balance to about 50%
back to baseline, which suggests insulin resistance in the liver in
the HF/HF dog model is largely corrected by hepatic denervation,
and which indicates that hepatic denervation has an effect on
hepatic glucose uptake and/or hepatic glucose production, in
accordance with embodiments of the invention.
C. Example 3
[0749] A hepatic artery was harvested from a porcine liver as far
proximal as the common hepatic artery and as far distal as the
bifurcation of the left hepatic artery and the right hepatic
artery. The arterial plexus was sandwiched between two sections of
liver parenchyma (a "bed" and a "roof"), and placed in a stainless
steel tray to serve as a return electrode. A total of 3 arteries
were ablated using a RADIONICS RFG-3C RF generator using a
NiTi/dilator sheath, having an exposed surface of approximately
1/16'' to 3/32'' in length. RF energy was applied for 117 seconds
in each case, with the generator power setting at 4 (generally
delivering 2-3 W into 55-270.OMEGA.). For the first 2 sample
arteries, a K-type thermocouple was used to monitor extravascular
temperatures, which reached 50-63.degree. C. The first ablation was
performed in the left hepatic artery, the second ablation was
performed in the right hepatic artery, and the third ablation was
performed in the proper hepatic artery. For the first ablation in
the left hepatic artery having a lumen diameter of 1.15 mm, two
ablation zone measurements were obtained (0.57 mm and 0.14 mm). A
roughly 3 mm coagulation zone was measured. The electrode exposure
distance was 3/32''. For the second ablation in the right hepatic
artery, an electrode exposure distance of 1/16'' was used. The
generator impeded out due to high current density and no ablation
lesion was observed. For the third ablation of the proper hepatic
artery having a lumen diameter of 2 mm and using an electrode
exposure distance was 3/32'', three ablation zone widths of 0.52
mm, 0.38 mm and 0.43 mm were measured. The measured ablation zone
widths support the fact that nerves surrounding the proper hepatic
artery (which may be tightly adhered to or within the arterial
wall) can be denervated using an intravascular approach.
Histological measurements of porcine hepatic artery segments have
indicated that hepatic artery nerves are within 1-10 medial
thicknesses (approximately 1-3 mm) from the lumen surface, thereby
providing support for modulation (e.g., denervation, ablation,
blocking conduction of, or disruption) of nerves innervating
branches of the hepatic artery endovascularly using low-power RF
energy (e.g., less than 10 W and/or less than 1 kJ) or other energy
modalities. Nerves innervating the renal artery are generally
within the 4-6 mm range from the lumen of the renal artery.
D. Example 4
[0750] An acute animal lab was performed on a common hepatic artery
and a proper hepatic artery of a porcine model. The common hepatic
artery was ablated 7 times and the proper hepatic artery was
ablated 3 times. According to one embodiment of the invention,
temperature-control algorithms (e.g., adjusting power manually to
achieve a desired temperature) were implemented at temperatures
ranging from 50.degree. C. to 80.degree. C. and for total ablation
times ranging from 2 to 4 minutes. According to one embodiment of
the invention, the electrode exposure distance for all of the
ablations was 3/32''. Across all ablations the ablation parameters
generally ranges as follows, according to various embodiments of
the invention: resistance ranged from about 0.1 ohms to about 869
ohms (generally about 100 ohms to about 300 ohms), power output
ranged from about 0.1 W to about 100 W (generally about 1 Watt to
about 10 Watts), generator voltage generally ranged from about 0.1
V to about 50 V, current generally ranged from about 0.01 A to
about 0.5 A, and electrode tip temperature generally ranged from
about 37.degree. C. to about 99.degree. C. (generally +/-5.degree.
C. from the target temperature of each ablation). Energy was
titrated on the basis of temperature and time up to approximately 1
kJ or more in many ablations. Notching was observed under
fluoroscopy in locations corresponding to completed ablations,
which may be a positive indicator of ablative success, as the
thermal damage caused arterial spasm.
[0751] It was observed that, although separation of ablation
regions by 1 cm (in accordance with one embodiment) was attempted,
the ablation catheter skipped distally during the ablation
procedure, which is believed to have occurred due to the movement
of the diaphragm during the ablation procedure, thereby causing
movement of the anatomy and hepatic arterial vasculature
surrounding the liver (which may be a unique challenge for the
liver anatomy).
[0752] Unlike previous targets for endovascular ablation (e.g.,
renal arteries, which course generally straight toward the
kidneys), the hepatic arterial vasculature is highly variable and
tortuous. It was observed during the study that catheters having a
singular articulated shape may not be able to provide adequate and
consistent electrode contact force to achieve ablative success. For
example, in several ablation attempts using an existing
commercially-available RF ablation catheter, with energy delivered
according to a manually-implemented constant-temperature algorithm,
the power level was relatively high with low variability in voltage
output required to maintain the target temperature. This data is
generally indicative of poor vessel wall contact, as the electrode
is exposed to higher levels of cooling from the blood (thereby
requiring higher power output to maintain a particular target
temperature). Additionally, tissue resistivity is a function of
temperature. Although the tissue within the vessel wall is
spatially fixed, there is constant mass flux of "refreshed" blood
tissue in contact with the electrode at physiologic temperatures.
Consequently, in one embodiment, when the electrode is
substantially in contact with "refreshed" blood at physiologic
temperatures, the electrode "sees" substantially constant
impedance. Due to the correlation between impedance and voltage
(e.g., P=V.sup.2/R), the substantially constant impedance is
reflected in a substantially constant (less variable) voltage input
required to maintain a target electrode tip temperature. Therefore,
particular embodiments (such as those described, for example, in
FIGS. 29 and 30) advantageously enable adequate electrode contact
in any degree of hepatic artery tortuosity that may be encountered
clinically.
[0753] In a follow-up hepatic artery denervation procedure, it was
demonstrated that the ability to reduce liver norepinephrine levels
by ablating using a monopolar catheter, the results of which are
shown in FIG. 125. Compared to historical liver norepinephrine
drops observed in dogs following surgical hepatic arterial
denervation, the endovascular ablation denervation procedure was
estimated to be 72-95% effective at destroying sympathetic
communication with the liver.
E. Example 5
[0754] A numerical model representing the hepatic artery and
surrounding structures was constructed in COMSOL Multiphysics 4.3.
using anatomical, thermal, and electrical tissue properties.
Thermal and electrical properties are a function of temperature.
Electrical conductivity (sigma, or .sigma.) generally varies
according to the equation .sigma.=.sigma..sub.0
e.sup.0.015(T-T.sup.0.sup.), where .sigma..sub.0 is the electrical
conductivity measured at physiologic temperatures (T.sub.0) and T
is temperature. With reference to FIGS. 126A-126D, model geometry
was assessed and included regions representing the hepatic artery
lumen, bile duct 12605, and portal vein 12610. The bile 12605 duct
and portal vein 12610 were modeled as grounded structures,
highlighting the effect of these structures on current flow. By
calculating liver blood flow and the relative contributions from
the hepatic artery and portal vein 12610, we determined the flow in
the hepatic artery was significantly lower than flow rates in other
arteries (e.g., renal arteries). In one embodiment, the estimated
flow rate was 139.5 mL/min. for the hepatic artery. Using the model
described above, independent solutions were first obtained for
monopolar and bipolar electrode configuration. A geometric model
corresponding to the common hepatic artery was created and a
time-dependent solution was calculated in COMSOL using the
[0755] bioheat equation,
.rho. b c pb .differential. T .differential. t = .gradient. ( k
.gradient. T t ) + .rho. b uc pb ( T B - T ) + q m ,
##EQU00001##
which, in one embodiment, relates the temperature at any point in
the model as a function of the temperature gradient in the tissue,
blood perfusion, blood temperature entering the geometric region of
interest, and the heat generated (q.sub.m) as a function of RF
energy deposition.
[0756] FIGS. 126A and 126B illustrate a geometric model of RF
energy deposition in the common hepatic artery using a single
electrode, with the conductivity of the bile duct 12605 and the
portal vein 12610 grounded (FIG. 126A) and accounted for (FIG.
126B). As shown in FIG. 126B, biliary and portal vein conductivity
can influence where ablation energy travels when a single electrode
12615 is used. FIGS. 126C and 126D illustrate a geometric model of
RF energy deposition in the common hepatic artery for a bipolar
electrode configuration 12615, with the conductivity of the bile
duct 12605 and the portal vein 12610 grounded (FIG. 126C) and
accounted for (FIG. 126D).
[0757] In accordance with an embodiment of the invention, the shape
of the electric field and resulting thermal ablation 12620 was
significantly affected in the monopolar ablation model due to
biliary and portal vein conductivity (as shown in FIGS. 126A and
126B). Minimal effects due to biliary and portal vein conductivity
(e.g., shaping effects) were observed in the shape of the electric
field and resulting thermal ablation 12620 for the bipolar ablation
model (shown in FIGS. 126C and 126D). FIGS. 126A and 126B were
obtained when the pair of bipolar electrodes were modeled,
according to one embodiment, as disposed at a location that is
substantially tangent to the inner lumen of the artery, with each
individual electrode having an arc length of 20 degrees and with an
inter-electrode spacing of 10 degrees. In one embodiment, the edges
of the electrodes have radii sufficient to reduce current
concentrations (less than 0.001''). In several embodiments, the
bipolar configuration advantageously provides effective ablation
(e.g., thermal ablation of the hepatic artery) without significant
effect on shaping of the ablation zone, despite the effects of
biliary and portal vein conductivity due to proximity of the bile
duct and portal vein to the common hepatic artery.
F. Example 6
[0758] Independent modeling solutions were obtained for an ablation
with convective cooling (e.g., provided by blood flow alone) and
for an ablation incorporating active cooling (e.g., 7.degree. C.
coolant) using the same bipolar configuration model described above
in Example 5. The models showed significantly decreased
temperatures at the location corresponding to the lumen
(endothelial) interface. Higher power (45% higher power) was
delivered to the active cooling model. Even with higher power
delivered (e.g., 45% higher power) to the active cooling model, the
endothelial region of the common hepatic artery remained cool
(e.g., less than hyperthermic temperatures up to 1 mm from the
lumen). The effective shaping of the thermal ablation zone was also
directed into a more linear shape directed radially in the active
cooling model. It was observed, that, in accordance with several
embodiments, as cooling power is increased and RF power is
increased, the linear shaping effect was magnified, thereby
rendering the ablation zone capable of being directed or
"programmed" (e.g., toward a more targeted location).
G. Example 7
[0759] Using a COMSOL model similar to the one described previously
in connection with FIGS. 126A and 126B, the cooling effect of blood
flow is observed to play a major role in the success of an ablation
procedure, as the cooling effect allows the ablation procedure to
achieve greater depth without vaporizing any tissue. The literature
reports a considerable variation of the flow rate in the common
hepatic artery. Moreover, a sudden constriction of the artery may
occur during the procedure, which could considerably change the
outcome of the ablation. In the following example, the importance
of knowing the blood flow rates in the hepatic artery in real time
is quantitatively shown. To do so, results that link the ablation
parameters (e.g., maximum temperature reached within the tissue and
temperature at 6 millimeters from the lumen) with the flow rates in
the common hepatic artery are presented, in accordance with an
embodiment of the invention. Measuring the flow rates in real time
allows for adjustment of the power during the ablation.
[0760] In accordance with several embodiments, one criterion for
the definition of a successful ("effective") ablation is one where
the maximum temperature reached anywhere in the tissue is less than
98.degree. C. at any time during the application of energy to the
tissue. This temperature threshold can advantageously avoid tissue
vaporization, which may cause collateral damage, as well as
increase the tissue impedance, thereby potentially causing the
lesion size to become unpredictable. Moreover, for the ablation to
be successful in accordance with several embodiments, a temperature
of at least 50.degree. C. at a distance of 6 millimeters from the
lumen, and for a period of at least 2 minutes must be achieved.
These parameters may provide increased confidence in cellular death
at the location of the majority of the nerves around the hepatic
artery (e.g., at a distance of about 4 mm from the arterial
lumen).
[0761] In accordance with several embodiments, a successful
ablation of hepatic nerves is defined as one having a depth of 6
mm, even though the nerves are predominantly located 4 mm from the
lumen, because the lesion (in some embodiments) has a conical or
frustoconical shape. If we were to take the maximum at exactly 4
mm, the diameter of the lesion at such depth may be very small. By
considering the maximum temperature at 6 mm, it can be assured that
at 4 mm such temperature is reached for a relatively wide area (as
shown in FIG. 127).
[0762] Data from simulations allows one to estimate what the power
should be, in order to have a desired lesion size of 4 mm in depth,
for a given value of flow rate. In accordance with several
embodiments, there are two main strategies to achieve a lesion: 1)
maximum power-minimum time, and 2) minimum power-maximum time. The
first strategy pushes the temperature near the maximum that the
tissues can reach without being vaporized, thereby minimizing the
total time of ablation. With the second strategy, the temperature
at the edge of the lesion is maintained relatively low, but the
ablation takes a long time for the cumulative effect of the heat to
cause tissue death (according to the Arrhenius equation). Since one
of the problems during ablation of the common hepatic artery is
movement due to breathing, employing the first strategy (maximum
power and minimum time) may be advantageous, as it is reasonable to
want to minimize or otherwise reduce the risk of electrode
movements. In addition, clinicians generally prefer a shorter
procedure time in order to reduce patient risk.
[0763] In some embodiments, energy or power delivery may be gated
based on respiration using temperature or impedance measurements
due to the asymmetric motion of the electrode during a respiratory
cycle. The electrode may remain relatively stationary for about
two-thirds of the respiratory cycle (expiration) and during this
time period the tissue in contact with the electrode increases in
temperature. When the electrode is in motion during the other third
of the respiratory cycle (inspiration), the tissue may cool down.
The changes in temperature may be monitored and used to gate the
delivery of RF energy to the electrode so that energy is only
delivered when the electrode is stationary (e.g., during
expiration) or power is increased during this period to maintain a
desired average power level (e.g., 10 Watts). Because tissue
impedance varies with temperature, impedance measurements could be
monitored (either alternatively or in combination with temperature)
and used to start and stop the energy delivery. In situations where
variation in temperature and/or impedance measurements is not
detected, power may be delivered at a constant rate.
[0764] In such embodiments in which power output is synchronized
with respiration, the ramp of the RF generator may be adjusted to
achieve an almost instantaneous climb of power. The adjustment may
be performed by modifying a ramping algorithm of the generator. In
some embodiments, the generator may be programmed to ramp up from a
power output below 1 W to a peak power output in less than half a
second. In accordance with several embodiments, synchronization of
power output with respiration takes advantage of the time frame
when blood flow in the vessel (e.g., common hepatic artery) is at a
maximum, thereby providing enhanced cooling to the electrode and
vessel wall, which may reduce charring, notching and vessel
spasm.
[0765] FIG. 128 represents the maximum power that can be applied
without resulting in vaporization as a function of arterial flow
rate. The curve is generated based on the assumption of a 4 to 5
minute ablation, with a 2 millimeter diameter electrode. In several
embodiments, to avoid vaporization temperature is maintained below
about 97.degree. C. and the lesion temperature is maintained at a
minimum temperature of 47.degree. C. for at least two minutes. In
certain cases, tissue death may also be caused with a temperature
of about 60.degree. C. for a few seconds. In accordance with
several embodiments, temperatures significantly higher than
50.degree. C. cannot be reached throughout the lesion without
causing tissue vaporization.
[0766] As shown in FIG. 128, as the flow rate increases, the
maximum power increases rapidly for very low levels of flow rate
and plateaus at a flow rate of about 0.6 m/s. The plateau is based
at least in part on the fact that cooling capability of the blood
reaches a saturation point. Thus, even for higher levels of flow
rate, the power cannot be increased. Typical flow rates in the
hepatic artery are generally no higher than 0.5 m/s. The flow rate
value can easily be lowered unpredictably during an ablation (for
example, if the catheter obstructs some of the blood flow).
[0767] This means that in reality, hepatic arterial ablation is
conducted based on the conditions represented by the left part of
the curve in FIG. 128. In this area of the curve, the maximum power
varies considerably with small variations of the flow rate. In
several embodiments, monitoring the flow is vital to avoid
excessive or insufficient power, both of which may cause the
ablation to be unsuccessful.
[0768] The curve linking maximum power and flow rate can be
approximated (for example, as shown in FIG. 129) with a non-linear
least-square curve fitting having the following formula:
Power=K.sub.1-K.sub.2e.sup.(-K.sup.3.sup.*FlowRate), where
K.sub.1=11.27, K.sub.2=10.28 and K.sub.3=151.59
[0769] The table below shows the variation in temperature, for some
embodiments, for different durations of RF power applications, both
at the peak temperature (typically at about 1 mm from the surface
of the electrode) and at about 6 millimeters from the arterial
lumen. In some embodiments, the variation of temperature between
120 and 300 seconds is minimal, however, since the temperature at
the edge of the lesion is relatively low (slightly less than
50.degree. C.), an ablation lasting at least 240 seconds in order
to cause tissue death may be used, in accordance with several
embodiments.
TABLE-US-00001 TABLE 1 Acceptable power and time combinations for
degrees of hepatic artery blood flow various Peak Temperature Temp.
at 6 mm from the lumen Time(s) [deg C.] [deg C.] Flow Rate--0 (free
convection); Power = 0.99059 120 93.888 39.61 180 96.021 40.35 240
97.065 40.77 300 97.612 40.94 Flow Rate = 0.1 m/s; Power = 11.08679
W 120 96.111 47.29 180 96.963 48.67 240 97.279 49.01 300 97.428
49.49 Flow Rate = 0.3 m/s; Power = 11.32912 W 120 95.831 47.14 180
96.718 47.98 240 97.09 49.28 300 97.291 49.66 Flow Rate = 0.5 m/s;
Power = 11.40233 W 120 95.858 47.33 180 96.711 48.74 240 97.052
49.2 300 97.23 49.67 Flow Rate = 0.7 m/s; Power = 11.45126 W 120
95.955 47.2 180 96.838 48.63 240 97.2 49.35 300 97.386 49.6
[0770] From the non-limiting simulations described above, the
minimum flow rate that allows a 4 mm deep lesion (e.g., using the
criteria of no vaporization and a minimum temperature of about
50.degree. C. at a location 6 mm from the vessel lumen) and avoids
vaporization is about 0.01 m/s. Therefore, it may be advantageous
to measure flow in the hepatic artery before the procedure to
ensure flow is adequate before initiating treatment. Below such a
flow rate, other forms of cooling may need to be added, such as
internal electrode cooling or irrigation of the artery.
H. Example 8
[0771] The hepatic artery has an average estimated diameter of 4 mm
in adult humans. In an endovascular ablation, this diameter
restricts the size of the electrode(s) that can be used. A study
was performed to investigate the optimal size of the electrode to
reach a lesion approximately 4 mm deep within the adventitia of the
hepatic artery.
[0772] In accordance with embodiments of the invention, the models
assume an ablation performed in a monopolar setting, with an active
spherical electrode of respectively 1, 2, and 3 millimeters
diameter. The models also assume that the electrode is externally
cooled by a blood flow having a speed of 0.1 m/s, that the media
has a thickness of 2 millimeters, and that 25 V are applied with
minimal contact force, for 3 minutes, in one embodiment. FIG. 130
shows the trend of the temperature changes with electrode size.
[0773] In several embodiments, there are two factors influencing
the lesion size, when electrode size changes. The first factor is
the electric field lines, which tend to become denser in the region
adjacent to the electrode, which may cause a higher temperature
near a smaller electrode and a more rapid decrease with distance
from the electrode. If this effect was dominating, as the electrode
size grows, the temperature would decrease for a given power
level.
[0774] The second factor is the cooling action of the blood flow.
In some embodiments, the electrode diameter is comparable in size
with the artery diameter, and thus a bigger electrode blocks or
occludes some of the blood flow, thereby causing an increase in
temperature as the electrode size increases.
[0775] In the case of the common hepatic artery, the second factor
may slightly dominate the first factor: there may be a slight
increase in temperature as the electrode size increases.
[0776] The study was limited to electrodes of 3 millimeters in
diameter. The diameter was selected based on the diameter of the
hepatic artery to avoid complete occlusion. In various embodiments,
the electrode diameter is selected so as to prevent or inhibit
complete occlusion by the electrode itself and/or to reduce peak
temperature and thereby prevent or inhibit against obtaining the
reaching of the vaporization point.
[0777] In accordance with several embodiments, systems and methods
described herein control neuromodulation (e.g., nerve destruction)
over a wide range of anatomical and physiologic conditions (e.g.,
arterial lumen diameter, blood flow velocity, tissue composition,
etc.), which impacts lesion geometry. In accordance with several
embodiments, for hepatic artery denervation, it is particularly
advantageous to define an energy delivery strategy that is
insensitive (e.g., robust) to initial and boundary conditions
(e.g., blood flow velocity, arterial lumen diameter, breathing
motion). This may be particularly true for hepatic denervation,
where anatomy and physiology can vary more significantly than in
the renal artery, both patient-to-patient and intraoperatively. For
example, the hepatic artery can move up to 5 cm during each
ventilated breathing cycle, leading to variations in electrode
position and arterial blood flow. It has been observed that only
about 60-75% of patients present with normal hepatic arterial
anatomy, and pathology studies in human cadavers have indicated
that tissue composition (especially the degree of visceral fat in
the hepatic arterial region) can vary significantly between
subjects.
[0778] In several embodiments, means for assessing the progress of
an endovascular ablation procedure are provided. Ablations
controlled using electrode tip temperature control can vary based
on the amount of convective cooling in the treatment region--for
high cooling environments, more energy may be delivered to the
target tissue, resulting in larger lesions, and for low cooling
environments, less energy may be delivered to the target tissue,
resulting in smaller lesions. In various embodiments, it may be
desirable to employ open-loop energy control as a primary control
method, including the appropriate safety-monitoring features and
temperature, impedance, or other feedback control schemes as
secondary control means. The open-loop control algorithm, by virtue
of being developed on the basis of historical in vitro and in vivo
studies (e.g., using data mining techniques), can ensure a safe and
effective starting point for the treatment that can then be
adjusted on the basis of feedback signals.
[0779] In one embodiment, a specific power and temperature control
algorithm is described that safely, quickly, and reliably achieves
hepatic denervation. Based on in vitro and/or in vivo testing, the
temperature response of the target tissue to known levels of
constant RF power applications is characterized. Energy may then
first be delivered at a maximum initial power for a first set time
period, followed by a second set time period where power is
decremented by a set amount, and so on, until a steady-state tissue
temperature is achieved at a given steady-state power. Using the
known relationship between impedance and temperature, any marked
increases in tissue impedance can be used to decrease applied power
or terminate energy delivery in order to prevent or inhibit
unpredictable, highly non-linear results. In several embodiments,
the power can be applied such that a defined drop in impedance is
achieved and maintained throughout the duration of the
procedure.
[0780] In some embodiments, electrode tip temperature measurements
are employed as a power shut-off limit and/or used to provide
estimates of blood flow velocity, adjusting target power and
impedance levels accordingly.
[0781] An idealized tissue response to a range of RF power levels
(1 W-5 W) at a given point location is shown in FIG. 131. For some
period of time, t<t.sub.ss, the temperature increases linearly
as a function of time, with dT/dt defined by the delivered power.
In biological tissues, heat losses due to conduction to surrounding
tissues, blood flow, and perfusion causes tissue temperatures to
generally approach steady-values over time. Ideally, one would
simply increase power in order to achieve higher steady-state
temperatures faster. However, because biological tissues have
temperature-dependent properties that are highly non-linear at
temperatures near vaporization temperatures (e.g.,
.about.100.degree. C.), the temperature progression and resulting
lesion size is highly variable and unpredictable (see, for example,
FIG. 134).
[0782] In accordance with several embodiments, a decremented power
delivery algorithm (shown, for example, in FIG. 135) is provided to
maximize or otherwise increase steady-state temperatures and
increase the speed at which they are reached. In cycle 0 (n=0), a
maximum power P.sub.max is applied for a time period t.sub.1, where
P.sub.max is the maximum power that can be delivered in a
controllable time period without causing tissue vaporization and ti
is the maximum time for which P.sub.max can be delivered without
causing vaporization. In cycle 1 (n=1), corresponding to t=ti, the
applied power is decremented to P.sub.max-.DELTA.P and applied for
a period t.sub.2, corresponding to the maximum time for which
P.sub.max-.DELTA.P can be delivered without causing vaporization.
This decrement algorithm may continue for n cycles, where the
delivered power in each cycle n is P.sub.max-n.DELTA.P, and the
power application time t.sub.n corresponds to the maximum time for
which P.sub.max-n.DELTA.P can be delivered without causing
vaporization.
[0783] P.sub.max, .DELTA.P and can be determined empirically using
suitable in vitro and in vivo models and data reported in the
literature, with statistical methods employed to choose levels for
these parameters that will generally ensure tissue vaporization is
avoided (e.g., 99% reliability, 95% confidence lower-bound values
for P.sub.max, .DELTA.P and t.sub.1, . . . , t.sub.n to avoid
vaporization.)
[0784] .DELTA.P might vary in subsequent cycles and is described
here as a single variable for brevity (it may be two, three, four
or more variables). In some embodiments, .DELTA.P decreases (and
t.sub.n increases) with each subsequent cycle as the steady-state
power is approached asymptotically. The algorithm described in FIG.
136 has the effect of delivering the maximum sustainable heating
power to tissue without causing vaporization or inducing
unpredictable, non-linear tissue responses, in one embodiment.
[0785] While, in some embodiments, the open-loop approach provides
a good empirical approach based on historically obtained data, it
may not account for the anatomic and physiologic variations
encountered clinically. Some degree of feedback control may be
desired to tailor the core or primary energy deliver algorithm
described above to each unique clinical situation. For example, in
high cooling environments, less energy may be delivered to the
target tissue (since more of the energy is carried away through
convection), and alternatively, in low cooling environments, more
energy may be delivered to the target tissue. Due to variations in
tissue composition, some tissue might reach vaporization or
dessicate faster than other tissues, leading to non-linear
effects.
[0786] Because impedance is generally related to temperature (as
shown, for example, in FIG. 134), impedance can be used as a proxy
for the bulk temperature of the tissue surrounding the electrode. A
characteristic drop, .DELTA.z.sub.1 in impedance (shown in FIG.
133) during the initial heating period may be indicative of
effective heating, whereas impedance increases .DELTA.z.sub.n after
this initial period may be indicative of non-linear effects and
vaporization. In some embodiments, non-linear effects and
vaporization are avoided.
[0787] An embodiment of an algorithm for overlaying impedance-based
feedback control with the open-loop power control algorithm is
illustrated in FIG. 134. In some embodiments, the effect of this
algorithm is generally to shift P.sub.max (the curve represented in
FIG. 132) upwards in order to achieve the desired drop in impedance
in the first cycle. In subsequent cycles, power may be decremented
after the prescribed time period (t.sub.n) defined by the open loop
algorithm is reached or until a threshold impedance rise
(.DELTA.z.sub.n) is detected, after which power may further be
decremented to avoid vaporization. In some embodiments, RF power
delivery is interrupted or otherwise terminated upon detection of a
threshold impedance rise.
[0788] .DELTA.z.sub.1 can be variably defined as a target impedance
relative to a reference impedance value (e.g., for a target
impedance of 150.OMEGA. and initial impedance of 210.OMEGA.,
.DELTA.z.sub.1=60.OMEGA.), or alternatively, can be strictly
defined relative to the impedance measured at the beginning of
energy delivery to tissue (e.g., a fixed value of
.DELTA.z.sub.1=50.OMEGA. from the impedance measurement at the
start of a treatment or procedure). Similarly, .DELTA.z.sub.n can
be defined as an absolute value or can be scaled relative to the
target impedance value (e.g., 10% deviation from the target
impedance value).
[0789] In order to improve the fidelity of the impedance
measurement in some embodiments, it may be desirable to implement a
filtering or averaging calculation (e.g., a windowed average or
other filter) in order to avoid noise in the impedance measurement
triggering false positive control signals.
[0790] RF generator designs commonly calculate power and impedance
by measuring voltage and current (P=VI, and V/I=R). Due to
reactance in the system, this measurement can be erroneous, leading
to inadequate treatment (e.g., ablation) of the nerves surrounding
the hepatic artery or other target artery, vessel or tissue.
[0791] Reactance, a result of capacitance and inductance in the RF
circuit can lead to a phase shift (as illustrated in FIG. 136),
where the voltage and/or current in the target tissue is offset
from the voltage and/or current measured by the RF generator. When
the measured and actual voltage and current are different, the
progress of the therapy is unknown and can lead to unpredictable
results, since power and impedance are used as control variables
for a wide range of energy control algorithms. Measured power and
impedance can often differ by as much as 10% from the actual
values.
[0792] Inductance is generally a result of the tortuosity of the
electrode lead, and for ablation procedures, is generally ignored.
In biological tissue, capacitance may be a result of capacitive
coupling between the electrode shaft (alternatively, the "electrode
leads") and the tissue across the insulating dielectric generally
disposed about the non-therapeutic portions of the electrode shaft
or electrode leads. Ions in the tissue move in response to changes
in the electrode polarity, but the capacitance leads to discrete
delays in the flow of ions relative to the driving voltage of the
RF generator, manifested as a phase shift. At the tissue level,
capacitance may arise due to the variable composition of
tissue--for example, lipids, fats, and other non-conducting tissues
disposed in the hilus sheath surrounding the hepatic artery can
lead to local capacitance causing discrete delays in the flow of
ions through the tissue, which may also contribute to the phase
shift. In one embodiment, the phase shift may be accounted for by
employing a bi-linear transform such as the bi-linear transform
described in U.S. Publ. No. 2012/0095461 (e.g., paragraphs [0050]
through [0089]), which is incorporated by reference herein. By
accurately accounting for phase and magnitude changes at the load,
power and impedance can be measured more accurately, leading to
more efficacious treatment, e.g., ablation, of the nerves
surrounding the hepatic artery.
[0793] Referring now again to FIG. 135, not shown is the ability to
monitor tip temperature throughout the treatment. The tip
temperature measurement can also be used as a feedback signal, for
example, to terminate RF power delivery once a threshold
temperature is reached. In some embodiments, leveraging the fact
that at a given power level, the tip temperature is a function of
blood flow velocity, P.sub.max can similarly be adjusted up or down
to increase (e.g., maximize) effective energy delivery on the basis
of the available convective cooling power, which effectively
converts the electrode into a hot wire anemometer flow sensor.
[0794] The ability to monitor impedance changes for monopolar
configurations has not been previously appreciated, and for
endovascular ablation, it was generally believed that impedance
control algorithms were only useful for bipolar electrode
configurations. Because the region of tissue heated in a bipolar
configuration is confined to a relatively limited region, the
impedance of the system is generally regarded as the impedance of
the heated region. However, the impedance of the heated region can
be determined for monopolar configurations as well. Although the
resistance pathway through biological tissue is generally regarded
as a bulk property, it can be resolved into three components for a
monopolar configuration, with representative values for each
component highlighted in FIG. 137:
[0795] 1) The resistance of the blood (R.sub.blood)
[0796] 2) The "background" or "remote" resistance of the bulk
tissue (R.sub.remote)
[0797] 3) The resistance of the tissue in the vicinity of the
monopolar electrode (the target tissue), R.sub.tissue.
[0798] In some embodiments, by subtracting out the components of
impedance contributed by the background tissue and blood, a more
sensitive impedance measurement treated tissue region can be
obtained, thereby improving the accuracy and applicability of
impedance control in a monopolar configuration. By subtracting the
power deposited in non-target tissues, a more reliable estimate of
the energy delivered to the target tissue can be obtained.
[0799] As illustrated in FIG. 138, measurable changes in tissue
impedance have been demonstrated during hepatic arterial ablation
by subtracting out the largely "DC" components of resistance and
focusing on the variable component driven by the local tissue
response.
[0800] In accordance with several embodiments, the treatment
control approaches described above unexpectedly provide the
effective "decoupling" of the electrode tip temperature measurement
from variations in blood flow. Using electrode tip temperature
control algorithms, output power may be adjusted to maintain a
generally constant electrode tip temperature. Power may then become
a de facto measurement of convective cooling due to blood flow, but
a lagging indicator as it is the controlled output. By implementing
the power control algorithm described above, the electrode tip
temperature sensor may be "freed" to perform other functions, such
as 1) providing a safety signal to shut-off power in the event
excessive temperatures are reached, to avoid thrombus or eschar
formation or 2) the steady-state temperature reached for a given
power application can be used as a leading indicator of blood flow,
which can also be used to generally increase or decrease the
overall level of power delivered to the tissue (e.g., increase or
decrease P.sub.max).
[0801] While the devices, systems and methods described herein have
primarily addressed the treatment of diabetes (e.g., diabetes
mellitus), other conditions, diseases, disorders, or syndromes can
be treated using the devices, systems and methods described herein,
including but not limited to ventricular tachycardia, atrial
fibrillation or atrial flutter, inflammatory diseases, endocrine
diseases, hepatitis, pancreatitis, gastric ulcers, gastric motility
disorders, irritable bowel syndrome, autoimmune disorders (such as
Crohn's disease), obesity, Tay-Sachs disease, Wilson's disease,
NASH, NAFLD, leukodystrophy, polycystic ovary syndrome, gestational
diabetes, diabetes insipidus, thyroid disease, and other metabolic
disorders, diseases, or conditions.
[0802] In some embodiments, the system comprises one or more of the
following: means for tissue modulation (e.g., an ablation or other
type of modulation catheter or delivery device), means for energy
delivery (e.g., generator or other energy generation module), means
for deploying energy delivery members or other treatment elements
(e.g., pull wire, preformed shape memory material, retractable
sheaths, expansion members), etc.
[0803] In some embodiments, the system comprises various features
that are present as single features (as opposed to multiple
features). For example, in one embodiment, the system includes a
single ablation catheter with a single energy delivery member
(e.g., radiofrequency electrode). A single thermocouple (or other
means for measuring temperature) may also be included. Multiple
features or components are provided in alternate embodiments.
[0804] The various illustrative logical blocks, modules, and
circuits described in connection with the embodiments disclosed
herein (e.g., generators) can be implemented or performed with a
general purpose processor, a digital signal processor (DSP), an
application specific integrated circuit (ASIC), a field
programmable gate array (FPGA) or other programmable logic device,
discrete gate or transistor logic, discrete hardware components, or
any combination thereof designed to perform the functions described
herein. A general purpose processor can be a microprocessor, but in
the alternative, the processor can be any conventional processor,
controller, microcontroller, or state machine. A processor can also
be implemented as a combination of computing devices, e.g., a
combination of a DSP and a microprocessor, a plurality of
microprocessors, one or more microprocessors in conjunction with a
DSP core, or any other such configuration.
[0805] The blocks of the methods and algorithms described in
connection with the embodiments disclosed herein can be embodied
directly in hardware, in a software module executed by a processor,
or in a combination of the two. The modules described herein may
comprise structural hardware elements and/or non-structural
software elements stored in memory (for example, algorithms or
machine-readable instructions executable by processing or computing
devices). Memory or computer-readable storage media can include RAM
memory, flash memory, ROM memory, EPROM memory, EEPROM memory,
registers, a hard disk, a removable disk, a CD-ROM, or any other
form of computer-readable storage medium known in the art. Any
methods described herein may be embodied in, and partially or fully
automated via, software code modules stored in a memory and
executed by one or more processors or other computing devices. The
methods may be executed on the computing devices in response to
execution of software instructions or other executable
machine-readable code read from a tangible computer readable
medium. A tangible computer readable medium is a data storage
device that can store data that is readable by a computer system.
Examples of computer readable mediums include read-only memory (for
example, EEPROM), random-access memory, other volatile or
non-volatile memory devices, CD-ROMs, magnetic tape, flash drives,
and optical data storage devices. A storage medium may
advantageously be coupled to a processor such that the processor
can read information from, and write information to, the storage
medium. In the alternative, the storage medium can be integral to
the processor.
[0806] For example, hardware for performing selected tasks
according to embodiments of the invention could be implemented as a
chip or a circuit. As software, selected tasks according to
embodiments of the invention could be implemented as an algorithm
or a plurality of machine-readable instructions being executed by a
computer using any suitable operating system. In one embodiment, a
network (wired or wireless) connection is provided. A display
and/or a user input device (such as a keyboard, mouse, touchscreen,
user-actuatable inputs, trackpad) may optionally be provided.
[0807] Although certain embodiments and examples have been
described herein, aspects of the methods and devices shown and
described in the present disclosure may be differently combined
and/or modified to form still further embodiments. Additionally,
the methods described herein may be practiced using any device
suitable for performing the recited steps. Some embodiments have
been described in connection with the accompanying drawings.
However, it should be understood that the figures are not drawn to
scale. Distances, angles, etc. are merely illustrative and do not
necessarily bear an exact relationship to actual dimensions and
layout of the devices illustrated. Components can be added,
removed, and/or rearranged. Further, the disclosure (including the
figures) herein of any particular feature, aspect, method,
property, characteristic, quality, attribute, element, or the like
in connection with various embodiments can be used in all other
embodiments set forth herein. For example, features described in
one figure may be used in conjunction with embodiments illustrated
in other figures. Embodiments embodied or carried out in a manner
may achieve one advantage or group of advantages as taught herein
without necessarily achieving other advantages. The headings used
herein are merely provided to enhance readability and are not
intended to limit the scope of the embodiments disclosed in a
particular section to the features or elements disclosed in that
section.
[0808] While embodiments are susceptible to various modifications,
and alternative forms, specific examples thereof have been shown in
the drawings and are herein described in detail. It should be
understood, however, that the embodiments are not to be limited to
the particular forms or methods disclosed, but to the contrary, the
embodiments are to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the various
embodiments described and the appended claims. Any methods
disclosed herein need not be performed in the order recited. The
methods disclosed herein include certain actions taken by a
practitioner; however, they can also include any third-party
instruction of those actions, either expressly or by implication.
For example, actions such as "delivering a neuromodulation catheter
within a hepatic artery" include "instructing the delivery of a
neuromodulation catheter within a hepatic artery."
[0809] Various embodiments of the invention have been presented in
a range format. It should be understood that the description in
range format is merely for convenience and brevity and should not
be construed as an inflexible limitation on the scope of the
invention. The ranges disclosed herein encompass any and all
overlap, sub-ranges, and combinations thereof, as well as
individual numerical values within that range. For example,
description of a range such as from about 5 to about 30 minutes
should be considered to have specifically disclosed subranges such
as from 5 to 10 degrees, from 10 to 20 minutes, from 5 to 25
minutes, from 15 to 30 minutes etc., as well as individual numbers
within that range, for example, 5, 10, 15, 20, 25, 12, 15.5 and any
whole and partial increments therebetween. Language such as "up
to," "at least," "greater than," "less than," "between," and the
like includes the number recited. Numbers preceded by a term such
as "about" or "approximately" include the recited numbers (for
example, "about 3 mm" includes "3 mm"). The terms "approximately",
"about", and "substantially" as used herein represent an amount
close to the stated amount that still performs a desired function
or achieves a desired result.
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