NZ625695B2 - Therapeutic neuromodulation of the hepatic system - Google Patents
Therapeutic neuromodulation of the hepatic system Download PDFInfo
- Publication number
- NZ625695B2 NZ625695B2 NZ625695A NZ62569512A NZ625695B2 NZ 625695 B2 NZ625695 B2 NZ 625695B2 NZ 625695 A NZ625695 A NZ 625695A NZ 62569512 A NZ62569512 A NZ 62569512A NZ 625695 B2 NZ625695 B2 NZ 625695B2
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- catheter
- ablation
- energy
- nerves
- hepatic
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Abstract
Disclosed is a system adapted for intravascular hepatic neuromodulation. The system includes an energy source adapted to deliver energy, and an ablation device which is sufficiently flexible so as to facilitate access to and positioning within a hepatic artery in a subject. The ablation device has a proximal end and a distal end, the distal end comprising one or more electrodes or transducers. The system also includes one or more electrically conductive wires connecting the energy source to the one or more electrodes or transducers. The system is adapted to deliver a therapeutically effective amount of energy to disrupt communication along one or more nerves surrounding the hepatic artery. proximal end and a distal end, the distal end comprising one or more electrodes or transducers. The system also includes one or more electrically conductive wires connecting the energy source to the one or more electrodes or transducers. The system is adapted to deliver a therapeutically effective amount of energy to disrupt communication along one or more nerves surrounding the hepatic artery.
Description
THERAPEUTIC NEUROMODULATION OF THE HEPATIC SYSTEM
This application claims priority to U.S. Application No. 61/568,843, filed
December 9, 2011, the entirety of which is hereby incorporated herein by reference herein.
The disclosure relates generally to therapeutic neuromodulation 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
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 kidneys and the liver is a significant
contributor to fasting hyperglycemia. The liver is responsible for approximately 90% of the
excessive glucose production.
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.
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
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.
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, obesity, hyperglycemia, 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. In several embodiments, modulation of nervous tissue that innervates (afferently 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, sympathetic nerve fibers associated with the liver
are selectively disrupted (e.g., ablated, denervated, disabled, severed, blocked, 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
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, 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 to facilitate
treatment or reduction of symptoms associated with 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.
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.
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. 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.
In some embodiments, a minimally invasive surgical technique is used to
deliver the therapeutic neuromodulation system. For example, a catheter system 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 to ablate sympathetic nerve fibers in the celiac ganglion or
celiac plexus. 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, bile ducts, brown adipose tissue,
skeletal muscle), at least some of which may be clinically relevant to diabetes.
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.
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.
In some embodiments, minimally invasive surgical delivery 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.
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. In other embodiments, nerve
fibers are surgically cut (e.g., transected) to disrupt conduction of nerve signals.
In some embodiments, a non-invasive (e.g., transcutaneous) procedure is
used to modulate or disrupt sympathetic nerve fibers. 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.
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 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 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.
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, 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.
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.
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).
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.
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.
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.
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 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
catheter into the incision. In some embodiments, the method comprises advancing the
neuromodulation catheter from the femoral artery through an arterial system to a 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 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 catheter 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.
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 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 hepatic artery. In some embodiments, the RF energy is delivered
extravascularly by the RF ablation catheter.
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.
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.
In accordance with several embodiments, a method of decreasing blood
glucose levels within a subject is provided. The method comprises inserting an RF ablation
catheter 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
energy to thermally inhibit neural communication within sympathetic nerves of a hepatic
plexus surrounding the 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 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 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 10 W (e.g., between about 0.5W 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 10W , or overlapping ranges thereof).
In one embodiment, the RF ablation catheter 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 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 a steerable
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 to about 100 g/mm (e.g., between about
0.1 g/mm and about 10 g/mm ). In some embodiments, the RF ablation catheter comprises
at least one anchoring member configured to maintain contact of the at least one electrode
against the inner wall of the hepatic artery branch.
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.
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 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 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
energy to be emitted from one or more electrodes of the RF ablation 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.
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 a hepatic artery branch. 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 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.
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 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
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. In one embodiment, the at least one electrode comprises a coating having
one or more windows.
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.
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.
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 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 and treatment times.
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.
BRIEF DESCRIPTION OF THE DRAWINGS
illustrates the anatomy of a target treatment location including the
liver and hepatic blood supply, in accordance with an embodiment of the invention.
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.
illustrates a schematic drawing of a common hepatic artery and
nerves of the hepatic plexus.
FIGS. 4A-4C, 5A and 5B, 6 and 7 illustrate embodiments of compression
members configured to facilitate modulation of nerves.
FIGS. 8 and 9 illustrate embodiments of neuromodulation catheters.
FIGS. 10 and 11 illustrate embodiments of electrode catheters.
FIGS. 12A and 12B illustrate embodiments of ablation coils.
FIGS. 13A-13C, 14A and 14B illustrate embodiments of energy delivery
catheters.
illustrates several embodiments of catheter distal tip electrode and
guide wire shapes.
FIGS. 16A and 16B illustrate an embodiment of a windowed ablation
catheter.
illustrates an embodiment of a balloon-based volume ablation
catheter system.
illustrates an embodiment of a microwave-based ablation catheter
system.
illustrates an embodiment of an induction-based ablation catheter
system.
illustrates an embodiment of a steam ablation catheter.
illustrates an embodiment of a hot water balloon ablation catheter.
FIGS. 22A – 22D illustrate geometric models.
DETAILED DESCRIPTION
I. Introduction and Overview
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.
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.
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).
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.
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.
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. 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 may also be performed in
combination.
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.
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. The common hepatic artery 215 gives rise to the gastric and
gastroduodenal arteries. The nerves innervating the liver include 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, 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).
With continued reference to FIGS. 1 and 2, 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 sympathetic nerve signaling in the hepatic plexus 245, blood glucose levels can be
decreased or reduced.
In several embodiments, any of the regions (e.g., nerves) identified in
FIGS. 1 and 2 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. 1 and 2 may be modulated in combination
(simultaneously or sequentially).
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 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 luminal 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.
As shown in the portion of the common hepatic artery 305 is
roughly cylindrical, with parasympathetic nerves 310 innervating approximately a 180° arc of
the cylinder, and the sympathetic nerves of the hepatic plexus 315 innervating the opposite
approximately 180° 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).
In some embodiments, only selective regions of the adventitial layer of
target vasculature is modulated. In some subjects, parasympathetic and sympathetic nerves
may be distributed distinctly on or in 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 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.
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 and portal
vein (which approaches the hepatic artery as it courses distally towards the liver).
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 is ablated. In some embodiments, it is desirable to ablate in the range
of about 60° to about 240°, about 80° to about 220°, about 100° to about 200°, about 120° to
about 180°, about 140° to about 160°, 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. Such cooling may decrease
collateral injury to the nerve fibers not intended for treatment. In many embodiments,
cooling is not used.
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. An example of a
spiral ablation pattern Z, in accordance with one embodiment, is shown in 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, 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
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) to provide a constant reference
point from which to position an ablation catheter. Alternatively, the catheter could also be
anchored in other branches, either individually or simultaneously, to further improve control.
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.
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.
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.
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. 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. Energy modalities include, but are not limited to, microwave,
radiofrequency (RF) energy, thermal energy, electrical energy, ultrasonic energy, focused
ultrasound such as high-intensity or low-intensity focused ultrasound, laser energy,
phototherapy or photodynamic therapy (e.g., in combination with one or more activation
agents), ionizing energy delivery (such as X-ray, proton beam, gamma rays, electron beams,
and alpha rays), cryoablation, and 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 some embodiments, ionizing energy is delivered to a target region to
prevent regrowth of nerves.
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 the common hepatic artery proximal to the
proper 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 fat tissue (e.g., visceral fat), sympathetic nerve fibers
that innervate the adrenal glands (e.g., the renal plexus or suprarenal plexus), sympathetic
nerve fibers that innervate the gut, stomach or small intestine (e.g., the duodenum),
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 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).
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., GLP-1, GIP, CCK, PYY, 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.”
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, GI 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.
II. Types of Neuromodulation
A. Mechanical Neuromodulation
The selective modulation or disruption of nerve fibers may be performed
through mechanical or physical disruption, such as, but not limited to, cutting, ripping,
tearing, 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.
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.
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
2 2 2
range from about 1 to about 100 g/mm , from about 1 g/mm to about 10 g/mm , from about
2 2 2 2 2
3 g/mm to about 5 g/mm (e.g., 8 g/mm ), from about 5 g/mm to about 20 g/mm , from
2 2 2 2
about 10 g/mm to about 50 g/mm , from about 20 g/mm to about 80 g/mm , from about 50
g/mm to about 100 g/mm , or overlapping ranges thereof. These compressive forces may be
effected by the various embodiments of mechanical neuromodulation devices or members
described herein.
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. illustrates a resting conformation of
the shape memory compression clip 400. 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. 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.
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.
Applying compressive 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.
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 to allow the selective application of electric power to vary the compressive
stresses created by the compression member.
FIGS. 5A and 5B illustrate another embodiment of a compression device.
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.
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.
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.
illustrates the vascular wall clamp 515 in a closed conformation.
In , 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 . shows that the detachable insertion catheter 505 has already been removed.
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.
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 515Bof 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.
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 two the at least one
spear shaped clip engagement mechanism 520 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®.
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 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.
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 with in 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).
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.
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.
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.
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 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).
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.
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.
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 °C, 5 seconds, and
120 psi in one embodiment) may be an effective means to seal vessels such as the hepatic
arteries.
B. Catheter-Based Neuromodulation
In accordance with some embodiments, neuromodulation (e.g., the
disruption of sympathetic nerve fibers) is performed using a minimally invasive catheter
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. As described above, the hepatic plexus surrounds the
proper hepatic artery, where it branches from the common hepatic artery. In some
embodiments, the ablation catheter system is introduced via an incision in the groin to access
the femoral artery. The ablation catheter 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).
In some embodiments, the catheter 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 some embodiments, the catheter system comprises a visualization
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. 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 destruction with the axis of the catheter aligned parallel to the
vessel.
Animal studies have shown that the force of electrode contact against the
vessel wall may be a critical parameter for achieving ablative success in some embodiments.
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 pressure during the length of the treatments.
In some embodiments, the catheter of the 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 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) 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, 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.
In accordance with several embodiments, catheters of the catheter-based
systems described herein have steerable, pre-curved, deflectable 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 pressure with a vascular wall,
and/or help navigate the catheter to the target anatomy. In some embodiments, catheters with
steerable, curvable or articulatable or 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 remains within a
guide 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 various embodiments, 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 numbers. The contact pressures described above may be achieved by
any of the neuromodulation (e.g., ablation) devices and systems described herein.
illustrates an embodiment of a steerable neuromodulation catheter
800 having an articulatable tip. The neuromodulation catheter 800 comprises a catheter body
805, multiple segments 810, multiple corresponding hinges 820, and multiple corresponding
articulation wires 830. In some embodiments, the neuromodulation catheter 800 includes
fewer than six segments, hinges, and/or articulation wires (e.g., two, three, four, or five). In
some embodiments, the neuromodulation catheter 800 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 810 and the hinges 820 are hollow.
Each of the segments 810 is coupled to adjacent segment(s) by one of the
hinges 820. Each of the articulation wires is attached to one of the segments and passes from
the segment to which it is attached through the other segments toward the catheter body 805.
In operation, the articulation wires may be extended or retracted as desired, thereby pivoting
the articulatable tip of the catheter 800.
In some embodiments, all of the articulation wires 830 are extended and
retracted in combination. In other embodiments, each of the articulation wires 830 is
individually actuatable. In such embodiments, each individual segment 810 could be
individually actuatable by each corresponding articulation wire 830. 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 800 may advantageously
permit improved contact pressure between the distal tip of the steerable catheter 800 and the
vascular wall of the target vessel, thereby improving treatment efficacy.
illustrates an embodiment of a neuromodulation catheter 900 with
a deflectable distal tip. The neuromodulation catheter 900 comprises a guidewire configured
to facilitate steerability. The neuromodulation catheter 900 includes an ablation catheter tip
905, a guidewire housing 910, a guide wire channel 915, and a guidewire 920. In operation,
the guidewire 920 may be extended out through guide wire channel 915 to be used in its
guiding capacity to navigate through vasculature. When it is not desirable to use the
guidewire 920 in its guiding capacity, the guide wire 920 may be retracted into the ablation
catheter tip 905 and then extended into the guide wire housing 910, where it may be stored
until needed or desired.
In some embodiments, the guidewire 920 is plastically deformable with a
permanent bend in the distal tip. In such embodiments, the guidewire 920 may be rotated
within the body of the neuromodulation catheter 900 to plastically deform and be pushed into
the guide wire housing 910, or may be rotated 180 degrees and regain its bent configuration
to exit through the guide wire channel 915. In some embodiments, a thermocouple
temperature sensor may be incorporated into the guide wire 920. In some embodiments, the
guide wire 920 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 and the at least one ablation electrode.
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, such as described above, 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.
C. Energy-Based Neuromodulation
1. Radiofrequency
In some embodiments, a catheter system comprises an ablation device
coupled to a pulse-generating device. For example, the ablation device may be an ablation
catheter. The ablation catheter may have a proximal end and a distal end. In some
embodiments, the distal end of the ablation catheter comprises one or more 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 of the ablation catheter. In some embodiments, the electrodes
comprise one or more bipolar electrode pairs. In some embodiments, the electrodes comprise
one or more active electrodes and one or more return electrodes that cooperate to form
electrode pairs. In some embodiments, one or more electrodes are monopolar electrodes. In
some embodiments, the distal end of the ablation catheter comprises at least one bipolar
electrode pair and at least one monopolar electrode. One or more electrically conductive
wires may connect one or more electrodes located at the distal end of the ablation catheter to
the pulse-generating device. In some embodiments, multiple electrodes can extend from the
ablation catheter on multiple wires to provide multiple energy delivery locations or points
within a vessel (e.g., a hepatic artery).
In some embodiments, the pulse-generating device delivers electrical (e.g.,
radiofrequency (RF)) signals or pulses to the electrodes located at or near the distal end 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 some embodiments,
the electrodes are curved or flat. The electrodes can be dry electrodes or wet electrodes. In
some embodiments, the 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. Variable regions of
flexibility or stiffness are provided in some embodiments.
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.
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.
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.
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).
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, 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.
In some embodiments, the ablation catheter includes electrodes having a
2 2 2
surface area of about 2 to about 5 mm , 5 to about 20 mm , about 7.5 to about 17.5 mm ,
about 10 to about 15 mm , overlapping ranges thereof, less than about 5 mm , greater than
2 2 2
about 20 mm , 4 mm , or about 12.5 mm . In some embodiments, the ablation 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 , about 40 to about 110 mm ,
2 2 2
about 50 to about 100 mm , about 60 to about 90 mm , about 70 to about 80 mm ,
overlapping ranges thereof, less than 5 mm , or greater than 120 mm . 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. Patent 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°C and substantially lower conductivity at
temperatures above 60°C, thereby limiting the effect of energy delivery to tissue above 60°C.
illustrates a self-repairing ablation catheter 1000. The self-
repairing ablation catheter 1000 comprises a catheter body 1005, a needle electrode 1010, and
a vascular wall plug 1015. In one embodiment, the needle electrode 1010 is placed at or near
the distal end of the catheter body 1005 and used to heat tissue (which may result in nerve
ablation). The vascular wall plug 1015 may be placed around the needle electrode 1010 such
that when the needle electrode 1010 is pushed into or through the vascular wall, the vascular
wall plug 1015 is pushed into or through the vascular wall as well. Upon retracting the self-
repairing ablation catheter 1000, the needle electrode 1010 fully retracts in some
embodiments, leaving the vascular wall plug 1015 behind, and thereby plugging or occluding
the hole left by the needle electrode 1010.
In embodiments used to modulate (e.g., ablate) extravascularly, the
vascular wall plug 1015 may comprise a hydrogel jacket or coating disposed on the needle
electrode 1010. In some embodiments, the vascular wall plug 1015 is glued or otherwise
adhered or fixed in a frangible manner at its distal end to the needle electrode 1010, yet may
be sufficiently thin so it does not prevent smooth passage of the needle electrode 1010 as it is
advanced into the perivascular space. In some embodiments, once the proximal end of the
vascular wall plug 1015 passes out of the guiding lumen, it cannot be pulled proximally.
Therefore, upon ablation completion, removal of the needle electrode 1010 from the
perivascular space places the hydrogel jacket in compression in the hole made by the needle
electrode 1010 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 1015 is
be 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.
illustrates an embodiment of a hydrogel-coated electrode catheter
1100. The hydrogel-coated electrode catheter 1100 includes a catheter body 1105, an
ablation electrode 1110, and a hydrogel coating 1115. In one embodiment, the ablation
electrode 1110 is attached to the distal end of the catheter body 1105 and the hydrogel
coating 1115 coats the electrode 1110.
In some embodiments, the hydrogel coating 1115 is a previously-
desiccated hydrogel. Upon insertion into the target anatomy, the hydrogel coating 1115 on
the ablation electrode 1110 may absorb water from the surrounding tissues and blood. Ions
drawn in from the blood (or included a priori in the hydrogel coating 1115) may impart
conductive properties to the hydrogel coating 1115, thereby permitting delivery of energy to
tissue. In accordance with several embodiments, the hydrogel-coated electrode catheter 1100
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.
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 free saline to travel into the vessel interface and
reducing any undesired effects of saline infusion.
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.
A illustrates an embodiment of a single ablation coil 1200 device.
The single ablation coil device 1400 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 1200 into one branch of the fork (e.g., proper
hepatic artery branch) and ablate that branch, then insert the single ablation coil 1200 into the
other branch of the fork (e.g., gastroduodenal artery branch) and ablate that branch.
B illustrates a forked ablation coil device 1250. The forked
ablation coil device1250 comprises two ablation coils, a first ablation coil 1255 and a second
ablation coil 1260. In accordance with several embodiments, the forked ablation coil device
1250 allows an entire vascular fork to be ablated simultaneously. In operation, the forked
ablation coil device 1250 may be inserted to the target vasculature by overlapping the first
ablation coil 1255 and the second ablation coil 1260 (effectively creating a single double
helix coil). Once the target fork is reached, the first ablation coil 1255 and the second
ablation coil 1260 may be separated and the first ablation coil 1255 inserted into a first
branch of the target fork and the second ablation coil 1260 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.
In some embodiments, the coiled electrodes (e.g., ablation coil device
1200 or forked ablation coil device 1250) 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.
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.
FIGS. 13A-13C illustrate embodiments of balloon ablation catheters.
A illustrates an embodiment of a single balloon ablation catheter 1300, B
illustrates an embodiment of a forked double balloon ablation catheter 1325, and C
illustrates an embodiment of a forked balloon ablation catheter 1375.
The single balloon ablation catheter 1300 of A comprises an
electrode balloon 1305 having at least one electrode 1310 (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. 13A – 13C
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 1300 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). To ablate a vascular fork, it may be necessary to insert the single balloon ablation
catheter 1300 into one branch of the fork and ablate that branch, then retract the single
balloon ablation catheter 1300 from that branch and insert the single balloon ablation catheter
1300 into the other branch of the fork and ablate that branch.
The forked two balloon ablation catheter 1325 of B includes a first
electrode balloon 1330 and a second electrode balloon 1335. The first electrode balloon
1330 includes at least a first electrode 1340, and the second electrode balloon 1330 includes
at least a second electrode 1345. In several embodiments, the forked two balloon ablation
catheter 1325 allows an entire vascular fork (e.g., all branches) to be ablated simultaneously.
In operation, the forked two balloon ablation catheter 1325 is inserted into the vasculature
and advanced to the target fork. Once the target fork is reached, the left electrode balloon
1330 and the right electrode balloon 1335 may be inflated and the left electrode balloon 1330
inserted into the left branch of the target fork and the right electrode balloon 1335 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 pulse generator. 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. 13C, energy could be directed between electrode 1390A and electrode
1390B in order to create a focused lesion within the vessel wall, or between electrode 1390C
and 1390D to focus energy delivery at the vessel bifurcation.
The forked balloon ablation catheter 1375 of C includes a single
balloon which has a left fork 1380 and a right fork 1385 with at least one balloon electrode
1390. In some embodiments the forked balloon ablation catheter 1375 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 1375 operates in the same manner as the
forked double balloon ablation catheter 1325; 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 1375 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 1375 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.
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), 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.).
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 various vessel portions.
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.
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 and such that
the heat created thermally ablates the region (e.g., vessel wall surface) proximate to the at
least one high permittivity 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.
In some embodiments, lower power and longer timed ablations may be
used for ablation procedures involving occlusion within the hepatic arteries than in other
arteries. Such treatment may be uniquely possible because of the liver’s dual source blood
supply (as described above). Balloon ablation of the 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
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°C to about 80°C, about 40°C to about 70°C,
or about 50°C to about 60°C. In one embodiment, temperatures greater than 45°C and less
than 60°C are used.
In some embodiments, the arterial lumen may be 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 (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 arterial 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).
Balloon ablation catheter systems may be advantageous for denervating
nerves surrounding the hepatic artery branches may be advantageous in that the 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.
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°C and about 10°C. In some embodiments, 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.
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. 14A and 14B illustrate an embodiment of a low-profile ablation catheter 1400 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 1400 comprises an inner electrode member 1410 and an outer sheath 1415. The
inner electrode member 1410 may comprise a reversibly deflectable, pre-shaped cylindrical
shaft comprising resilient (e.g., shape memory) material and at least one electrode 1420. In
one embodiment, the outer sheath 1415 comprises a guide catheter having a lumen. The
inner electrode member 1410 may be configured to be delivered within the lumen of the outer
sheath 1415 and to be translatable relative to the outer sheath 1415 such that the inner
electrode member 1410 may be advanced out of a distal end of the outer sheath 1415 and
retracted back in. In one embodiment, the inner electrode member 1410 assumes a generally
deflected (e.g., off-axis) configuration when advanced out of the distal end of the outer sheath
1415, as shown in B. In this unconstrained state, the distal end of the inner electrode
member 1410 deviates from a longitudinal axis defined by the proximal portion of the
electrode. When the inner electrode member 1410 is retracted within the outer sheath 1415,
the inner electrode member 1410 is resiliently deformed to assume a substantially straight
shape defined by the substantially straight shape of the lumen of the outer sheath 1415, as
shown in A. In some embodiments, when the inner electrode member 1410 is
advanced out of the distal end of the outer sheath 1415, the distal end portion of the inner
electrode member 1410 deflects to contact a vessel wall (e.g., arterial wall). The shape of the
distal end of the inner electrode member 1410 in the unconstrained state may be pre-formed
to ensure contact with the vessel wall.
In some embodiments, the outer sheath 1415 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 1410 comprises a shaft formed, at least partly, of
memory material such as a nickel titanium alloy material. The inner electrode member 1410
may have an outer cross-sectional dimension that is substantially equal to the outside
diameter of the outer sheath 1415 or may have an outer cross-sectional dimension that is
smaller or larger than the outside diameter of the outer sheath 1415. In some embodiments,
when the inner electrode member 1410 is slid out of the outer sheath 1415 past a pre-formed
step 1425 at or near its distal end, the step 1425 at or near the distal end places the surface of
the distal end of the inner electrode member 1410 away from the natural axis of the outer
sheath 1415. In some embodiments, the step 1425 near the distal end of the inner electrode
member 1410 places the surface of the inner electrode member 1410 between about the same
plane as the outer surface of the outer sheath 1415 and about double the diameter from the
center of the outer sheath 1415 to the outer surface of the outer sheath 1415.
In some embodiments, the magnitude of the off-axis deflection created in
the step 1425 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 1410 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 1410 is
rotated within the catheter body
In some embodiments, the at least one electrode 1420 of the inner
electrode member 1410 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 1410 to create a catheter with any desired properties.
In some embodiments, the shaft of the inner electrode member 1410
comprises an insulation member to prevent heat transfer away from or electrically insulate
portions of the inner electrode member 1410. 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 1410. 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 1410
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 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 1420 comprises
a spherical electrode. In one embodiment, the distal end of the inner electrode shaft
comprises a series of electrodes.
In some embodiments, the low-profile ablation catheter 1400 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 1410 is configured to be deployed
out of the radial window or slot. In one embodiment, the lumen of the ablation catheter 1400
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.
In accordance with several embodiments, the low-profile ablation catheter
1400 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 1410 of the low-profile ablation catheter 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 1400 advantageously
facilitates solid and continuous contact with the vessel wall, thereby allowing for
substantially constant voltage to maintain a desired electrode tip temperature.
illustrates various embodiments of distal tip electrode and guide
wire shapes 1500. The distal tip electrode and guide wire shapes 1500 may include an “L”
shaped tip 1505, a “J” shaped tip 1510, a “shepherds crook”-shaped tip 1515, a “hook”
shaped tip 1520, a “line” shaped tip 1525, a “key” shaped tip 1530, a “circle” shaped tip
1535, a “square hook” shaped tip 1540, or a “step” shaped hook 1545. A spiral-shaped tip
(such as shown in A) 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 1535
but with the “circle”- or “lasso”-shaped tip portion being oriented substantially perpendicular
to the straight line portion. The various shapes illustrated in may advantageously be
selected from and used in conjunction with the low-profile ablation catheter 1400 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 1500 shown in may comprise a plurality of electrodes arranged in
different patterns.
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. 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 (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.
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 Φ between lines
drawn between two of the radiopaque markers can be designed such that F' = f(Φ(F)). A
clinician may then adjust the force on the proximal end of the electrode to achieve the desired
contact force.
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.
FIGS. 16A and 16B illustrate an embodiment of a windowed ablation
catheter 1600. The windowed ablation catheter 1600 comprises a catheter body 1605, an
inner sleeve 1610 having a first window 1620 and at least one ablation electrode 1630 and an
outer sleeve 1615 having a second window 1625. A shows a view of the distal end
of the windowed ablation catheter 1600 and B shows a detailed cut-away view of the
distal end of the windowed ablation catheter 1600.
In some embodiments, the ablation electrode 1630 is disposed within a
lumen of the inner sleeve 1610. The inner sleeve 1610 is rotatably received within the outer
sleeve 1615 such that the outer sleeve 1615 is rotatable about the inner sleeve 1610. Energy
can be delivered by the catheter by aligning the second window 1625 of the outer sleeve 1615
with the first window 1620 of the inner sleeve 1610 by rotating the inner sleeve 1610 with
respect to the outer sleeve 1615, or vice-versa. In one embodiment, the inner sleeve 1610
comprises a dielectric covering to provide insulation. .
In some embodiments, when the first window 1620 of the inner sleeve
1610 and the second window 1625 of the outer sleeve 1615 overlap, the ablating electrode
1630 is exposed to the outside of the outer sleeve 1615 (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 1620 and the second window 1625 overlap, or are at least partially
aligned. The degree of overlap may be controlled by the rotation or translation of the inner
sleeve 1610 relative to the outer sleeve 1615. In one embodiment, the catheter is inserted by
a user, the inner sleeve 1610 is turned based on user control, and the outer sleeve 1615 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.
In some embodiments, the inner sleeve 1610 comprises multiple openings
spaced along the length of the inner sleeve 1610 at different locations. For example, the
inner sleeve 1610 may have openings spaced linearly along the axis of the inner sleeve 1610
and openings rotated about the axis of the inner sleeve 1610. In one embodiment, the
openings of the inner sleeve 1610 define a spiral pattern. As shown in B, the external
surface of the inner sleeve 1610 and the internal surface of the outer sleeve 1615 may be
threaded such that the inner sleeve 1610 is translated with respect to the outer sleeve 1615 by
rotation of the outer sleeve 1615 relative to the inner sleeve 1610. In some embodiments,
relative rotation of the outer sleeve 1615 with respect to the inner sleeve 1610 serves to both
translate and rotate window 1625 of the outer sleeve 1615, sequentially exposing vascular
tissue to the ablation electrode 1635 through each of the openings of the inner sleeve 1610.
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 1610, and rotating the outer sleeve 1615 with respect to
the inner sleeve 1610, substantially any pattern of ablation along a helical path may be
created.
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.
is an embodiment of a balloon-based volume ablation system
1700, 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 1700
comprises a plurality of occlusive balloons 1725, a plurality of balloon guide wires 1730, a
catheter 1750, and an electrode 1740. also illustrates the abdominal aorta 1705, the
celiac artery 1706, the common hepatic artery 1707, the splenic artery 1708, the proper
hepatic artery 1709, the right hepatic artery 1710, and the left hepatic artery 1711 as an
example of a target treatment site. In operation, the balloon-based volume ablation system
1700 may be inserted to the target treatment site through the abdominal aorta 1705 and into
the celiac artery 1706. Individual occlusive balloons 1725 may then be advanced into
subsequent vessels, such as the splenic artery 1708, the right hepatic artery 1710 and the left
hepatic artery 1711. When the appropriate occlusive balloons 1725 have been placed such
that they define the desired volume of vasculature to be ablated, the occlusive balloons 1725
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 1740 is activated to
deliver electrical energy to heat the entire target volume simultaneously. The electrode 1740
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 1725 may be deflated and the entire balloon-based volume ablation system
1700 may be retracted.
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 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.
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 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 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.
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.
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.
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 1MHz, between about 50kHz and about 5 MHz, between about 100 kHz and about
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
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.
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
2 2 2 2
mA/cm and about 100 mA/cm , between about 0.1 mA/cm and about 50 mA/cm , between
2 2 2 2
about 0.2 mA/cm and about 10 mA/cm , between about 0.3 mA/cm and about 5 mA/cm ,
less than about 0.01 mA/cm , greater than about 100 mA/cm , 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 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, between about 500 J and about 1000
J, between about 800 J and about 1200 J, between about 1000J 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.
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.
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, 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 braches 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.
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). 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.
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.
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.
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.
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.
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 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 impedance rises, charring of tissue may be avoided.
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., t ), 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.
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.
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.
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, 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.
2. Ultrasound
In some embodiments, an energy delivery system delivers ultrasonic
energy to modulate (e.g., ablate, stimulate) sympathetic nerve fibers in the hepatic plexus.
For example, the energy delivery system 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. In some embodiments, the energy delivery system
includes an ablation catheter connected to one or more ultrasound transducers. For example,
the ultrasound transducer(s) can deliver ultrasonic energy to one or more ablation sites to
ablate sympathetic nerve fibers in the hepatic plexus. The 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 ablation 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.
In some embodiments, the energy delivery system 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. For
example, the one or more ultrasound transducers, which may be single element or multiple
element transducers, against the intima of the artery or spaced at a distance from the intimal
layer. 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 ablation 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°C (e.g., 40°C to 60°C, 60°C to 75°C, 65°C to 80°C, 60°C to
90°C, or overlapping ranges thereof. In some embodiments, the temperature can be less than
40°C or greater than 90°C.
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, and/or other parameters. In some embodiments, the frequencies used
range from about 20 kHz to about 20 MHz, 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 20 MHz or overlapping ranges thereof.
However, other frequencies can be used without limiting the scope of the disclosure. In some
embodiments, the HIFU catheter can also transmit frequencies that can be used for imaging
purposes or for confirmation of successful ablation or denervation purposes. In some
embodiments, the HIFU catheter delivers energy having parameters such that cavitation does
not occur. 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 1 W/cm
2 2 2 2
to about 10 kW/ cm , from about 500 W/ cm to about 5 kW/cm , from about 2 W/cm to
2 2 2 2
about 8 kW/cm , from about 1 kW/ cm to about 10 kW/cm , from about 25 W/cm to about
2 2 2 2
200 W/cm , from about 200 W/cm to about 1 MW/cm , less than 1 W/cm , greater than 10
kW/cm , or overlapping ranges thereof. Power levels may range from about 25 W/cm to
about 1 MW/cm (depending on the intensity of the ultrasound energy and/or other
parameters). The ultrasound energy can be continuous or pulsed. The power levels or energy
density levels used for pulsed ultrasound energy may be higher than the power levels used for
continuous ultrasound energy.
The treatment time for each target 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 of
the hepatic plexus for at least several months while creating minimal damage of the arterial
walls or surrounding tissues or organs.
3. Lasers
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.
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
In accordance with various embodiments, energy delivery is initiated from
a source external to the subject (e.g., extracorporeal activation). FIG 18 illustrates an
embodiment of a microwave-based energy delivery system 1800. The microwave-based
energy delivery system 1800 comprises an ablation catheter 1805 and a microwave
generating device 1820. In some embodiments, other energy sources may also be delivered
externally.
In some embodiments, the ablation catheter 1805 comprises a high
conductivity probe 1810 disposed at its distal end. In operation, the ablation catheter 1805
may be inserted into a target vessel and positioned such that the high conductivity probe 1810
is proximate to the site targeted for ablation. The microwave generating device 1820 is
located outside a subject’s body and positioned such that focused microwaves 1825 are
delivered towards the target vessel and the high conductivity probe 1810. In several
embodiments, when the delivered focused microwaves 1825 contact the high conductivity
probe 1810, they induce eddy currents within the high conductivity probe 1810, thereby
heating the high conductivity probe 1810. The thermal energy 1815 generated from the
heating of the high conductivity probe can heat the target tissue through conductive heat
transfer. In some embodiments, the thermal energy 1815 generated is sufficient to ablate
nerves within or disposed on the target tissue (e.g., vessel wall). In various embodiments, the
high conductivity probe 1810 has a conductivity greater than 10^3 Siemens/meter.
illustrates an embodiment of an induction-based energy delivery
catheter system 1900. In the illustrated embodiment, the induction-based energy delivery
system 1900 comprises a catheter 1905, an induction coil 1910, an external inductor power
circuit 1950, an inductor 1960, a resistor 1970, and a capacitor 1980. In one embodiment, the
induction coil 1910 is disposed at the distal end of the catheter 1905. In operation, the
induction coil 1910 may act as an inductor to receive energy from the external inductive
power circuit 1950. In some embodiments, the external inductive power circuit 1950 is
positioned such that the inductor 1960 is adjacent the induction coil 1910 within a sufficient
induction range. In some embodiments, current is delivered through the external inductive
power circuit 1950, thereby causing current to flow in the induction coil 1910 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. 16A and 16B). 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.
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 , 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.
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.
D. Steam/Hot Water Neuromodulation
illustrates an embodiment of a steam ablation catheter 2000. In
the illustrated embodiment, the steam ablation catheter 2000 comprises a water channel 2005,
a steam generating head 2010, and a steam outlet 2015. In operation, water may be forced
through the water channel 2005 and caused to enter the steam generating head 2010. In one
embodiment, the steam generating head 2010 converts the water into steam, which exits the
steam ablation catheter 2000 through the steam outlet 2015.
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 2000 and out through the steam
generating head 2010 (which converts the water into steam) and the steam is directed to an
ablation target. The steam ablation catheter 2000 may comprise one or more window along
the length of the catheter body.
illustrates an embodiment of a hot fluid balloon ablation catheter
2100. In the illustrated embodiment, the hot fluid balloon ablation catheter 2100 comprises
an inflatable balloon 2105. In some embodiments, the inflatable balloon 2105 is filled with a
temperature variable fluid 2110. In accordance with several embodiments, hot water is the
temperature variable fluid 2110 used to fill the inflatable balloon 2105. 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 2105 is inserted to the ablation site and inflated with
scalding or boiling fluid (e.g., water), thereby heating tissue surrounding the inflatable
balloon 2105 sufficient to ablate or denervate the tissue. In some embodiments, the hot fluid
within the balloon 2105 is within the temperature range of about 120°F to about 212°F, from
about 140°F to about 212°F, from about 160°F to about 212°F, from about 180°F to about
212°F, about 200°F to about 212°F, or overlapping ranges thereof. In some embodiments,
the balloon ablation catheter 2100 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 2105 is made out of polyurethane or any other heat-
resistant inflatable material.
E. Chemical Neuromodulation
In some embodiments, drugs are used alone or in combination with
another modality to cause neuromodulation. 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.
In some embodiments, drugs (either alone or in combination with energy
modalities) can be used for neuromodulation. For example, a delivery 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.
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.
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.
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.
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.
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, 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
In some embodiments, the invention comprises cryotherapy or
cryomodulation. In one embodiment, the ablation catheter system uses cryoablation
techniques 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. 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.
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).
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.
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
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.
In some embodiments, any combination of drug delivery, chemoablation,
and/or cryoablation is used for neuromodulation, 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. IMAGE GUIDANCE, MAPPING AND SELECTIVE POSITIONING
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. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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
blood loss.
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.
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.
IV. ALTERNATIVE CATHETER DELIVERY METHODS
In addition to being delivered intravascularly through an artery, the
neuromodulation systems described herein (e.g., ablation catheter 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.
In some embodiments, the neuromodulation systems (e.g., catheter
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.
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.
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.
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.
V. STIMULATION
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).
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.
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.
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.
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.
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.
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.
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.
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.
In accordance with the embodiments disclosed herein, parasympathetic
nerve fibers other than those that innervate the liver are stimulated to treat diabetes 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.
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.
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.
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.
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.
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).
VI. EXAMPLES
Examples provided below are intended to be non-limiting embodiments of
the invention.
A. Example 1
Three dogs were put on a high fat, high fructose diet for four weeks,
thereby rendering the dogs insulin resistant. As a control, a 0.9 g/kg oral gavage polycose
dose was administered at four weeks after initiation of the high-fat, high fructose 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 the three dogs were then surgically
denervated. 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. Table 1 below
illustrates a graph of the average venous plasma glucose over time for the three dogs reported
by the two oral glucose tolerance tests (OGTTs). The curve with the data points represented
by black circles represents the average of the glucose measurements from the OGTT testing
of the three dogs after the four weeks of high fat, high fructose diet before hepatic
denervation. The oral gavage polycose doses were administered at time zero shown in Table
1. The curve with the data points represented as white circles represents the average of the
glucose measurements from the OGTT testing of the same three dogs two to three weeks
after hepatic denervation. As can be seen in Table 1, the glucose values after hepatic
denervation peaked at lower glucose concentrations and dropped much more rapidly than the
glucose values prior to hepatic denervation. In accordance with several embodiments, the
results of the study provide strong evidence of the efficacy of hepatic denervation for
controlling blood glucose levels.
TABLE 1
B. Example 2
Table 2 illustrates the net hepatic glucose balanced obtained during a hyperglycemic-
hyperinsulinemic clamp study. The data represented with circle indicators (HDN) represents
the average net hepatic glucose levels of the same 3 dogs from Example 1 four weeks after
denervation. The data represented with square 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 triangle indicators (Chow) 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 restores net hepatic glucose balance to about 60% 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.
TABLE 2
C. Example 3
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 Ω). For the first 2 sample arteries, a K-type
thermocouple was used to monitor extravascular temperatures, which reached 50-63 °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 0.14mm). 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
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°C to 80°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°C to about 99°C (generally +/-
°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.
It was observed that, although separation of ablation regions by 1 cm 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).
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 /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 14 and 15 advantageously enable adequate electrode contact
in any degree of hepatic artery tortuosity that may be encountered clinically.
E. Example 5
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 ) generally varies according to the equation
, where is the electrical conductivity measured at physiologic
temperatures (T ) and T is temperature. With reference to FIGS. 22A-22D, model geometry
was assessed and included regions representing the hepatic artery lumen, bile duct 2205, and
portal vein 2210. The bile 2205 duct and portal vein 2210 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 2210, 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 bioheat equation, ,
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 ) as a function of RF energy
deposition.
FIGS. 22A and 22B illustrate a geometric model of RF energy deposition
in the common hepatic artery using a single electrode, with the conductivity of the bile duct
2205 and the portal vein 2210 grounded (A) and accounted for (B). As shown
in B, biliary and portal vein conductivity can influence where ablation energy travels
when a single electrode 2215 is used. FIGS. 22C and 22D illustrate a geometric model of RF
energy deposition in the common hepatic artery for a bipolar electrode configuration 2215,
with the conductivity of the bile duct 2205 and the portal vein 2210 grounded (C) and
accounted for (D).
The shape of the electric field and resulting thermal ablation 2220 was
significantly affected in the monopolar ablation model due to biliary and portal vein
conductivity (as shown in FIGS. 22A and 22B). 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 2220 for the bipolar ablation model (shown in FIGS. 22C and
22D). FIGS. 22A and 22B 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
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°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).
In some embodiments, the neuromodulation catheter (e.g., ablation
catheter) designs described herein (e.g., the balloon catheters of FIGS. 13A-13C)
advantageously provide effective modulation of nerves innervating branches of the hepatic
artery 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.
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.
Although several embodiments and examples are disclosed herein, the
present application extends beyond the specifically disclosed embodiments to other
alternative embodiments and/or uses of the inventions and modifications and equivalents
thereof. It is also contemplated that various combinations or subcombinations of the specific
features and aspects of the embodiments may be made and still fall within the scope of the
inventions. Accordingly, it should be understood that various features and aspects of the
disclosed embodiments can be combine with or substituted for one another in order to form
varying modes of the disclosed inventions. Thus, it is intended that the scope of the present
inventions herein disclosed should not be limited by the particular disclosed embodiments
described above.
Claims (33)
1. A system adapted for intravascular hepatic neuromodulation, the system comprising: an energy source adapted to deliver energy; an ablation device which is sufficiently flexible so as to facilitate access to and positioning within a hepatic artery in a subject, the ablation device having a proximal end and a distal end, the distal end comprising one or more electrodes or transducers; and one or more electrically conductive wires connecting the energy source to the one or more electrodes or transducers, wherein the system is adapted to deliver a therapeutically effective amount of energy to disrupt communication along one or more nerves surrounding the hepatic artery.
2. The system of Claim 1, wherein the ablation device is a steerable catheter.
3. The system of Claim 1 or 2, wherein the ablation device comprises an electrode.
4. The system of any one of Claims 1 to 3, wherein the ablation device comprises multiple electrodes.
5. The system of Claim 1 or 2, wherein the ablation device comprises one or more ultrasound transducers.
6. The system of Claim 1 or 2, wherein the energy is within a frequency range of 50 kHz and 20 MHz and is adapted to heat the one or more nerves or surrounding tissue in the range of 60 to 90 degrees Celsius.
7. The system of any one of Claims 1 to 6, further comprising one or more sensors used to provide confirmation of disruption of neural communication.
8. The system of any one of Claims 1 to 7, further comprising a guide catheter, and wherein the ablation device is adapted to be delivered through the guide catheter.
9. An intravascular hepatic neuromodulation system, the system comprising: an ablation source adapted to provide energy or fluid sufficient to ablate one or more nerves innervating the liver; an intravascular ablation device which is sufficiently flexible so as to facilitate access to and positioning within a hepatic artery in a subject, the ablation catheter having a proximal end and a distal end, wherein the system is adapted to disrupt neural communication along the one or more nerves.
10. The system of Claim 9, wherein the distal end of the ablation device is deflectable.
11. The system of Claim 9 or 10, wherein the ablation device comprises at least one of shape memory material and one or more pull wires adapted to cause deflection of the distal end of the ablation catheter.
12. The system of any one of Claims 9 to 11, further comprising a guide catheter, wherein the ablation device is translatable relative to the guide catheter and adapted to be advanced out of a distal end of the guide catheter.
13. The system of any one of Claims 9 to 12, wherein the one or more nerves are sympathetic nerves of a hepatic plexus.
14. The system of any one of Claims 9 to 13, wherein the ablation source comprises a pulse-generating device configured to deliver a therapeutically effective amount of energy to denervate the one or more nerves.
15. The system of Claim 14, wherein the energy is within a frequency range of 50 kHz and 20 MHz, and wherein the energy is adapted to heat the one or more sympathetic nerves to at temperature of up to 90 degrees Celsius and sufficient to cause ablation of the one or more sympathetic nerves.
16. The system of any one of Claims 9 to 15, further comprising one or more sensors used to provide confirmation of disruption of neural communication.
17. The system of any one of Claims 14 or 15, wherein the pulse-generating device is a radiofrequency generator.
18. The system of any one of Claims 9 to 17, wherein the ablation device comprises one or more electrodes adapted to be positioned in contact with a wall of the hepatic artery, and wherein the ablation device is adapted to maintain contact with the wall.
19. The system of Claim 18, wherein the one or more electrodes comprise a bipolar electrode pair.
20. The system of any one of Claims 9 to 16, wherein the ablation device comprises one or more ultrasound transducers.
21. The system of any one of Claims 9 to 12, wherein the ablation source comprises a fluid reservoir comprising one of more of: a drug, a chemical agent, steam, hot water, and a coolant.
22. The system of Claim 18 or 19, wherein the ablation device comprises an expandable structure adapted to cause the one or more electrodes to contact an inner wall of the hepatic artery,
23. The system of Claim 22, wherein the expandable structure comprises one or more of: a balloon, coils, springs, prongs, tines, scaffolds, wires, or stents.
24. An apparatus adapted for intravascular hepatic neuromodulation, the apparatus comprising: a catheter which is sufficiently flexible so as to facilitate access to and positioning within a hepatic artery, the catheter comprising a proximal end and a distal end; wherein the distal end of the catheter comprises at least one electrode adapted to be positioned into contact with an inner wall of the hepatic artery upon deflection of the distal end, wherein the at least one electrode is adapted to deliver energy sufficient to achieve hepatic neuromodulation.
25. The apparatus of Claim 24, wherein the catheter comprises a structure configured to facilitate contact of the at least one electrode with the inner wall of the hepatic artery.
26. The apparatus of Claim 24 or 25, wherein the at least one electrode comprises a bipolar electrode pair.
27. The apparatus of Claim 24 or 25, wherein the at least one electrode comprises a monopolar electrode.
28. The apparatus of any one of Claims 24 or 27, wherein the energy is sufficient to heat the one or more sympathetic nerves to a temperature of up to 90 degrees Celsius and sufficient to cause ablation of the one or more sympathetic nerves.
29. The apparatus of any one of Claims 24 to 28, wherein the energy is radiofrequency energy delivered at a frequency in the range of 50 kHz to 5 MHz and with an energy level between 100 J and 2000 J.
30. The system of Claim 1, wherein the one or more nerves surrounding the hepatic artery comprise sympathetic nerves of the hepatic plexus.
31. The system of Claim 1 or 9, wherein the one or more nerves comprise nerves innervating the pancreas.
32. The system of Claim 1 or 9, wherein the one or more nerves comprise nerves innervating the small intestine.
33. The system of Claim 1 or 9, wherein the one or more nerves comprise nerves innervating the pylorus.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161568843P | 2011-12-09 | 2011-12-09 | |
US61/568,843 | 2011-12-09 | ||
PCT/US2012/068630 WO2013086461A1 (en) | 2011-12-09 | 2012-12-07 | Therapeutic neuromodulation of the hepatic system |
Publications (2)
Publication Number | Publication Date |
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NZ625695A NZ625695A (en) | 2015-10-30 |
NZ625695B2 true NZ625695B2 (en) | 2016-02-02 |
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