U.S. patent application number 11/459582 was filed with the patent office on 2007-01-25 for systems and methods for neuromodulation for treatment of pain and other disorders associated with nerve conduction.
This patent application is currently assigned to The Foundry Inc.. Invention is credited to MARK E. DEEM, Hanson Gifford.
Application Number | 20070021803 11/459582 |
Document ID | / |
Family ID | 37680083 |
Filed Date | 2007-01-25 |
United States Patent
Application |
20070021803 |
Kind Code |
A1 |
DEEM; MARK E. ; et
al. |
January 25, 2007 |
SYSTEMS AND METHODS FOR NEUROMODULATION FOR TREATMENT OF PAIN AND
OTHER DISORDERS ASSOCIATED WITH NERVE CONDUCTION
Abstract
Methods and apparatus are provided for selective destruction or
temporary disruption of nerves and/or conduction pathways in a
mammalian body for the treatment of pain and other disorders.
Apparatus comprises catheters having electrodes for targeting and
affecting nerve tissue at a cellular level to reversible and
irreversible nerve poration and incapacitation.
Inventors: |
DEEM; MARK E.; (Mountain
View, CA) ; Gifford; Hanson; (US) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
The Foundry Inc.
Menlo Park
CA
|
Family ID: |
37680083 |
Appl. No.: |
11/459582 |
Filed: |
July 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60701747 |
Jul 22, 2005 |
|
|
|
Current U.S.
Class: |
607/46 ;
607/61 |
Current CPC
Class: |
A61N 1/36021 20130101;
A61N 1/0492 20130101; A61N 1/327 20130101; A61N 1/36017 20130101;
A61N 1/0456 20130101; A61N 1/0551 20130101; A61B 18/1477 20130101;
A61N 1/0412 20130101; A61N 1/05 20130101; A61N 1/36071
20130101 |
Class at
Publication: |
607/046 ;
607/061 |
International
Class: |
A61N 1/34 20070101
A61N001/34 |
Claims
1. Apparatus for selective denervation of target tissue,
comprising: an electrode support having one or more electrodes
disposed thereon, wherein said electrode(s) are adapted to transmit
an electrical pulse and/or series of electrical pulses; and a pulse
generator operatively connected to the catheter, wherein the
electrodes and generator are configured to deliver cellular
poration energy in the range from 10 V/cm to 10.sup.6 V/cm to
disrupt membranes of target cells to disrupt pain conduction
pathways.
2. The apparatus of claim 1, wherein the support comprises a
catheter which is adapted to be positioned percutaneously in an
artery at a location adjacent to a region of the spine in a human
patient selected from the group consisting of the cervical,
thoracic, sacral and lumbar regions.
3. The apparatus of claim 1, wherein the support comprises a
catheter which is adapted to be positioned percutaneously at a
region of the peripheral nerves in a human patient.
4. The apparatus of claim 1, wherein the support comprises a
catheter which is adapted to be implantable within the body and a
pulse generator adapted to be located outside the human body.
5. The apparatus of claim 1, wherein the support and pulse
generator are implantable within the human body.
6. The apparatus of claim 1, wherein the support comprises a patch
and the one or more electrodes are configured on the patch to be
applied to the skin.
7. The apparatus of claim 6, wherein the one or more electrodes
comprise one or more micro needles.
8. The apparatus of claim 1, wherein the pulse generator and
electrodes are adapted to deliver poration energy at from 10 V/cm
to 10.sup.4 V/cm for durations from 10 .mu.sec to 100 msec to
achieve reversible poration.
9. The apparatus of claim 1, wherein the pulse generator and
electrodes are adapted to deliver poration energy at from 100 V/cm
to 10.sup.6 V/cm for durations from 10 .mu.sec to 100 msec to
achieve irreversible poration.
10. A method for selective denervation of targeted tissue of a
patient, said method comprising delivering energy to target cells
of said target tissue under conditions selected to permeabilize the
cell membrane to disrupt a pain conduction pathway provided by the
cell.
11. A method as in claim 10, wherein the target cells are nerve
cells.
12. A method as in claim 11, wherein the nerve cells are selected
from the group consisting of nerves of the spine, peripheral
nerves, nerves of the head and neck, and the brain stem.
13. A method as in claim 12, wherein the nerve cells are in the
spine.
14. A method as in claim 13, wherein the target spinal nerve cells
are in the region of the sacral plexus.
15. A method as in claim 13, wherein the target spinal nerve cells
comprise those in the stellate ganglion in the region of C6.
16. A method as in claim 12, wherein the target spinal nerve cells
are in the area of T6.
17. A method as in claim 11, wherein the nerve cells are
immediately adjacent to an artery.
18. A method as in claim 17, wherein said energy is delivered from
a catheter positioned in the artery.
19. A method as in claim 10, wherein the energy is electric
delivered in the range from 10 V/cm to 10.sup.6 V/cm for a period
in the range from 10 .mu.sec to 100 msec.
20. A method as in claim 10, wherein the energy is delivered under
conditions which provide a reversible poration.
21. A method as in claim 20, wherein the energy is electrical in
the range from 10 V/cm to 10.sup.4 V/cm.
22. A method as in claim 10, wherein the energy id delivered under
conditions which provide an irreversible poration.
23. A method as in claim 22, wherein the energy is electrical in
the range from 100 V/cm to 10.sup.6 V/cm.
24. A method as in claim 10, wherein the energy comprises
ultrasonic energy.
25. A method as in claim 10, further comprising delivering a nerve
blocking agent under conditions to act together with the energy to
block the pain conduction pathway.
26. A method as in claim 25, wherein the nerve blocking agent is
delivered simultaneously with the energy delivery.
27. A method as in claim 10, wherein the energy is delivered with a
catheter.
28. A method as in claim 27, wherein the catheter is implanted.
29. A method as in claim 27, wherein the catheter is percutaneously
positioned in an artery.
30. A method as in claim 10, wherein the energy is delivered
transcutaneously from a surface of the patient's skin.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application No. 60/701,747 (Attorney docket No. 020979-003500US),
filed on Jul. 22, 2005, the full disclosure of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to methods and apparatus for
the treatment of nerve function, and more particularly, for
selective disruption of conduction pathways in the body for the
treatment of pain and other disorders associated with nerve
conduction in various regions within the body.
[0004] Approximately 50 million Americans suffer with persistent
(chronic) pain. The number of people suffering with chronic pain is
higher than the number suffering from serious or terminal
illnesses. Yet, unlike major illnesses, most chronic pain is
untreated or under-treated. Pain surveys report that 42% of those
experiencing chronic pain have such severe pain that they are
unable to work, and 63% of pain sufferers are unable to engage in
the routine activities of daily life. It has been estimated that
among active workers, the loss of productivity from common pain
syndromes costs over 60 billion dollars annually. In recent years,
consumer advocacy, demographics, and advances in pain control
technology have highlighted the clinical need for solutions and
advanced the practice of pain management to a priority for
healthcare providers.
[0005] Irreversible surgical ablation has been relied upon for the
treatment of chronic pain. Lesions are placed on or in the
peripheral nerves, spinal chord or brain, but such placement can
have side effects such as unintended motor system effects, and
required open, surgical procedures. More recently, reversible
electrical and localized pharmacologic solutions started to be
used.
[0006] Electrical techniques, such as neurostimulation, which
deliver a low voltage electrical stimulation to a targeted
peripheral nerve or spinal chord to essentially block the sensation
of pain as recognized by the brain. First used in the 1960's,
electrical stimulation of the peripheral nerves was shown to mask
pain with a tingling sensation (paresthesia). This mechanism is
part of the "gate control theory of pain" (Melzack and Wall,
Science (1965) 150: 971-979.), proposing that a "gate" exists in
the spinal chord that controls the transmission of pain signals to
the brain. The theory suggests that activation of certain nerve
fibers in the dorsal horn of the spinal chord can "close the gate"
thereby inhibiting or muting the pain signals.
[0007] A variety of different electrical stimulation techniques
have been employed to achieve such blocking of the pain signals,
including Transcutaneous Electrical Nerve Stimulation (TENS) which
provides non-invasive (skin surface) electrical stimulation to the
large mylenated fiber spinal afferents, which functionally blocks
nerve signal transmission to essentially create a "short circuit"
between the nerve fibers and the sensory pathway to the brain. TENS
may be applied to peripheral nerve stimulation, as well as spinal
chord stimulation utilizing electrodes placed at the site of the
targeted nerve.
[0008] In addition, a technique utilizing stronger electrical
stimulation applied to acupuncture needles placed beneath the skin,
referred to as Electroacupuncture or Acupuncture Like
Transcutaneous Nerve Stimulation (ALTENS), has been employed with
the goal of optimizing the release of endorphins and serotonin to
combat pain. Various electrical stimulation devices are described
in U.S. Pat. Nos. 4,573,481, 3,911,930 and 4,141,365, each of which
is hereby incorporated by reference in their entirety.
[0009] The LISS Cranial Stimulator (LCS) and the LISS Body
Stimulator (LBS) which deliver a monopolar current at a frequency
of 15,000 Hz, modulated at 50 ms "on" and 16.7 ms "off" has been
used for pain treatment. (Liss, et al., (1996) Behavioral Science
31: 88-94) U.S. Pat. Nos. 5,983,141 and 6,246,912 to Sluijter
describe the application of an electromagnetic signal to neural
tissue for pain relief through an electrode to alter the function
of the tissue without causing temperatures that are lethal to the
tissue.
[0010] Stimulation of the sensory thalamus and periaqueductal or
periventricular gray in the deep brain has also shown promise in
treating patients that have not been helped by other less invasive
modalities of treatment. In this approach, electrodes are placed in
the targeted regions of the brain under stereotactic guidance.
Stimulation is then applied and when a satisfactory results is
achieved, a signal generator may be implanted for long term use. A
variety of severe side effects can result from this approach
however, including intracerebral hemorrhage and life threatening
infections.
[0011] Another approach used widely is orally administered opiates
and narcotics, however the systemic effect and addictive nature of
the oral medications make them less likely to provide a long term
solution. Localized drug delivery or intraspinal drug
administration has also shown promise, due to the fact that the
approach requires significantly lower doses of narcotics that are
delivered directly to the targeted region of the spinal chord
either through epidural or intrathecal administration. In these
approaches, percutanoues catheters may be placed at the target
region, and attached to implantable (subcutaneous) reservoirs or
pumps, or external drug pumps. Even though the narcotics are
localized, side effects may still present, including impairment of
motor function, nausea, constipation, ulcers and other side effects
attendant oral narcotic administration.
[0012] Various technologies are currently marketed to treat pain
and other motor dysfunctions. Advanced Neuromodulation Systems
(Plano, Tex.) manufactures an RF transmitter and probe for spinal
chord stimulation as well as an implantable drug delivery system to
relieve chronic pain, the latter being described in U.S. Pat. No.
5,938,690, hereby incorporated by reference in its entirety. Vertis
Neuroscience (Vancouver, Wash.) provides externally placed,
targeted electrode arrays that provide stimulation to the upper and
lower back to provide relief to chronic pain referred to as
Percutaneous Neuromodulation Therapy (PNT.TM.). Synaptic
Corporation (Aurora, Colo.) provides a product for external
stimulation for chronic pain by creating electrical impulses along
specific sensory nerve pathways to inhibit pain signals to the
brain, effect tissue healing, and produce general tissue
anesthesia, as further depicted in U.S. Pat. No. 6,161,044, hereby
incorporated by reference in its entirety. US2004/0186532 describes
an electrode implantable in the brain stem to deliver electrical
stimulation to treat pain.
[0013] Additional implantable systems include, a rechargeable
spinal chord stimulation system that includes an implantable pulse
generator and leads attached to various regions of the spine that
are connected to an external remote control or alternative charging
system. Such systems are available from Advanced Bionics, a
division of Boston Scientific, Natick, Mass. and from Medtronic,
Inc. Minneapolis, Minn. Such systems are described in U.S. Pat. No.
6,847,849. The Medtronic system may also include drug delivery
technology including intrathecal drug delivery.
[0014] Although promising, many of these systems do not provide a
lasting effect, and for some, the therapeutic effect is only felt
while the therapy is being administered. The treatment of
intractable chronic pain remains a challenge.
[0015] In light of the foregoing, it would be desirable to provide
methods and apparatus for treating pain and other disorders
associated with nerve conductivity within the human body. The
methods and apparatus preferably are minimally invasive or
non-invasive, are targeted to specific tissue, such as nerve
tissue, and provide a long therapeutic effect. It would further be
desirable to provide devices and methods that modify nerve function
without necessarily causing permanent physical nerve damage
(neuralgia) that can occur once the treated nerve regenerates. At
least some of these objectives will be met by the inventions
described below.
[0016] All publications and patents or patent applications
mentioned in this specification are herein incorporated by
reference to the same extent as if each individual publication,
patent or patent application was specifically and individually so
incorporated by reference.
BRIEF SUMMARY OF THE INVENTION
[0017] The present invention provides methods and apparatus for
treating pain and other nerve related disorders where the methods
and apparatus are minimally or non-invasive, controlled and
selective, and/or offer a more durable effect.
[0018] Methods and apparatus according to the present invention
treat chronic pain and other neural defects by delivering energy to
disrupt nerve tissue at the cellular level to cause
permeabolization (poration) of the cell membrane to affect the
viability of the nerves at the targeted region. Target nerves
include nerves in the spine, particularly cervical, thoracic,
lumbar and sacral regions of the spine; peripheral nerves; nerves
of the head and neck; and the brain stem. Depending on the
amplitude and duration of the applied field, the "poration" of the
target nerve may be reversible or irreversible, as desired.
Reversible electroporation may be used in conjunction with a nerve
blocking agent, chemical or other therapeutic agent to enhance,
modify or otherwise modulate disruption of the nerves and/or
targeted tissue.
[0019] In one aspect of the present invention methods and apparatus
are provided for treating chronic pain and other neural defects by
delivering an electric, ultrasonic or other energy field generated
by a pulse or pulses of a designated duration and amplitude to
disrupt nerve or other tissue at the cellular level via
permeabolization of the cell or cell membrane.
[0020] In a further aspect of the invention, the energy may be
delivered under conditions selected to cause irreversible cell
damage by the creation of pores in the cell membrane which result
in the death of the cell. Alternatively, the conditions may be
selected to cause reversible or partially reversible cell
damage.
[0021] In another aspect of the invention, intracellular
electromanipulation of the targeted tissue (such as nerve tissue)
using ultrashort electric field pulses leading to apoptosis of the
targeted cell may be desirable.
[0022] A further aspect of the invention is to provide methods and
apparatus for treating chronic pain and other neural defects by
utilizing an electric field to disrupt tissue at the cellular level
via permeabolization of the cell causing reversible electroporation
of the cellular membrane, preferably by delivering an electric
pulse or chain of pulses having a voltage between 40V and
1,000,000V. Such reversible electroporation may be applied in
conjunction with a therapeutic agent such as a nerve blocking
agent, a neurotoxin or neurotoxin fragment, such as the light chain
portion of botulinim toxin serotype A.
[0023] In a further aspect of the invention, it may be desirable to
provide methods and devices that selectively disrupt certain cell
types and not others, to provide a therapy that can be applied from
multiple locations within the body.
[0024] In a preferred aspect of the present invention, the target
nerves are frequently located adjacent to arteries which can be
used for percutaneous access to the nerves for example, vascular
catheters having electrodes, ultrasonic transducers, or other
energy sources at their distal ends may be advanced through an
artery to an arterial site adjacent to the target nerve which often
runs directly along the outside of the artery energy can be applied
which denervates the nerve while leaving the arterial wall intact
as the nerve cells are more susceptible to injury. Thus, a single
treatment can damage the adjacent nerve for extended periods of
months or more without damaging the artery used for access.
[0025] Examples of arteries that can be used to access particular
target nerves of the body regions include: TABLE-US-00001 Artery
Nerve Carotid Cranio-facial Vertebral Cranio-facial Radial
Peripheral (Arms and Hands) Femoral Lower limbs, Sciatica, Disc
Pain Popliteal Lower limbs, Sciatica, Disc Pain
[0026] In a specific aspect of the present invention, patients
suffering from refactory angina may be treated by reversible or
irreversible disruption of the stellate ganglion in the neck in the
area of the C6 vertebra (FIG. 1B) and/or of the paravertebral
nerves in the spine in the area of the T6 vertebra (FIG. 1B). The
stellate ganglion and associated nerves can be treated or
denervated by passing a nerve poration catheter into the common,
internal or external arteries, placing the treatment electrode(s)
or other component adjacent the nerve level to be treated, and
delivering energy to cause irreversible poration to the target
nerves. Some nerves may be better accessed via catheter placement
in the vertebral or subclavian arteries. Nerves in the area of T6
can be accessed by placing the treatment catheter in the aorta,
anterior or posterior spinal arteries, radicular arteries,
intercostal arteries, or medullary arteries.
[0027] The examples of arteries accessed and nerves treated to
address various pain syndromes should be considered exemplary in
nature and not limiting. It should be recognized that any syndrome
which is amenable by treatment by denervation will be amenable to
treatment via by the inventive technology.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Further features of the invention, its nature and various
advantages will be more apparent from the accompanying drawings and
the following detailed description, in which:
[0029] FIG. 1A--depicts a Dermatome showing areas of the body
(skin) supplied by corresponding nerve fibers on front of body;
[0030] FIG. 1B--depicts a Dermatome showing areas of the body
(skin) supplied by corresponding nerve fibers on rear of body;
[0031] FIG. 2--depicts a side view of three vertebrae in a
vertebral column showing certain relationships between spinal nerve
roots and vertebrae;
[0032] FIG. 3--depicts a schematic of spinal nerve and
vertebrae.
[0033] FIG. 4--depicts a generator and catheter system capable of
supply pulsed electric fields to effect reversible or irreversible
electroporation in targeted cells.
[0034] FIG. 4A and 4B--depict catheter distal tips of the present
invention in various configurations showing spaced apart
electrodes, including an optional monitoring electrode.
[0035] FIGS. 5A-D--depict various electrode catheter configurations
adapted to deliver energy or energy and therapeutic agents to
target tissue.
[0036] FIG. 6--depicts a fully implantable pulse generator and lead
of the present invention.
[0037] FIG. 7--depicts an implantable receiver and external
transmitter and controller for delivering energy according to the
present invention.
[0038] FIG. 8--depicts a schematic representing placement of the
implantable version of the present invention.
[0039] FIGS. 9A and B--depict an electrode pad for placement on the
skin of a patient, including one or multiple circuits, either
smooth or incorporating microneedles.
[0040] FIG. 10--depicts a method of use of the invention according
to FIGS. 9A and 9B.
[0041] FIG. 11--depicts a method of use of the invention according
to FIG. 6.
[0042] FIG. 12--depicts a method of use of the invention according
to FIGS. 5A-5D.
[0043] FIG. 13--depicts a method of use of the invention according
to FIG. 7.
[0044] FIG. 14--depicts a schematic of a nerve fiber showing the
relative cell size allowing selective cell permeabolization of
nerve cells.
[0045] FIG. 15--depicts a schematic of a target nerve region being
treated by a poration catheter in an adjacent artery.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention is directed to methods and apparatus
for targeting, stimulating, and disrupting nerve tissue, or tissue
adjacent nerve tissue (collectively "target tissue") usually at the
cellular level, in order to selectively denervate or disrupt nerves
and nerve pathways responsible for creating a pain response in a
mammalian body. Target tissue may be treated from one or more
locations either adjacent to or at a distance from target tissue.
The target tissue may include the nerve directly associated with
the pain response and/or conduction pathways contributing directly
or indirectly to the pain response.
[0047] Pain syndromes that may be treated utilizing the present
invention include, neuropathic and nociceptive pain, for example,
musculoskeletal pain (back, neck shoulder), myofascial (muscle)
pain, neuropathic pain (complex regional pain syndrome, central
pain syndrome, neuralgia, neuropathy), headaches, cancer pain,
fibromyalgia, pelvic pain, arachnoiditis, arthritis, facial pain
(TMJ, Temporomandibular disorders (TMD)), sciatica, skin disorders
(burn pain, shingles, herpes, tumors, vasculitis), spacicity,
spinal chord injury or stenosis, sickle cell disease, and pain
associated with vascular disease, both peripheral and cardiac.
[0048] The body's nervous system consists of the central nervous
system (brain), spinal chord nerves and the peripheral nervous
system (sensory nerve fibers and motor nerve fibers outside of the
brain and spinal chord). The system includes nerves (bundles of
axons enclosed in connective tissue) and can be characterized as
sensory/afferent, motor/efferent, or a combination of both sensory
and motor fibers. The spinal nerves include fused nerve roots, for
example, the dorsal root nerves are associated with sensory
functions, and the ventral root nerves are associated with motor
functions. Peripheral nerves may be cranial (arising from the
brain), or spinal (arising from the spinal column), and are usually
associated with sensations or motor functions in the hands, arms,
legs or feet.
[0049] Cranial nerves are mostly associated with motor function, or
a combination of motor and sensory functions. As shown in FIG. 2,
the spinal nerves consist of 31 pairs of nerves organized into
various regions along the spine the cervical (C), thoracic (T),
lumbar (L), and sacral (S). The spinal nerves are further organized
into nerve networks or nerve plexus including C1-C4 (cervical
plexus), C5-C8 and T1 (brachial plexus), L1-14 (lumbar plexus), and
L4-S4 (sacral plexus). The relationship between the spinal nerve
and the muscle (myotome) and between spinal nerve and skin
(dermatome) are depicted in FIGS. 1A and 1B, showing the nerves
associated with the particular region of the body. In treating pain
or other disorders associated with nerve conduction in the body,
devices can target a relatively localized region of the spinal
column depending on the type of pain or motor function and location
of pain or motor function (dermatome or myotome) to be treated.
[0050] Devices of the present invention may be directed to
"targeted regions" such as cervical, thoracic, lumbar and sacral
regions of the spine, peripheral nerves, nerves of the head and
neck, brain stem, and deep brain. Some particular examples include,
spinal chord modulation for chronic pain (for example application
of energy of the present invention to the region of the spine at
L1-L5 to treat lower limb and/or back pain), peripheral nerve
modulation for chronic pain (for example the radial or ulnar nerve
to treat hand or finger pain or dysesthesias.), and sacral nerve
modulation to treat pelvic pain. In some instances, the devices and
methods of the present invention may also be employed to treat
certain motor dysfunctions; for example, spinal chord nerve
modulation to treat peripheral vascular disease (PVD), deep brain
nerve modulation for tremor, Parkinsons, depression, obsessive
compulsive disorder, motor dysfunction, and brain injury, and vagus
nerve modulation for treatment of epilepsy, or obesity.
[0051] High Voltage Pulsed Electric Fields. To achieve the goals of
the present invention, it may be desirable to employ methods and
apparatus for achieving nerve modulation and/or denervation
utilizing pulsed electric fields and/or electroporation applied
directly to the targeted region or in proximity to the targeted
region to produce the desired denervation or nerve disruption. For
purposes of this disclosure, the term "electroporation" can
encompass the use of pulsed electric fields (PEFs), nanosecond
pulsed electric fields (nsPEFs), ionophoreseis, electrophoresis,
electropermeabilization, sonoporation and/or combinations thereof,
permanent or temporary, reversible or irreversible, with or without
the use of adjuctive agents, without necessitating the presence of
a thermal effect. Similarly, the term "electrode" used herein,
encompasses the use of various types of energy producing devices,
including antennas (microwave transmitters) and ultrasonic
elements. In practice, sonoporation, cell membrane manipulation by
application of ultrasonic energy, may have advantages in performing
the therapeutic treatment of the present invention due to its
ability to manipulate the membrane without producing as much heat
at the treatment site as other energy modalities that have been
used, and its ability to focus at a specific treatment site.
[0052] The methods and apparatus of the present invention can
employ reversible electroporationof the type used in medicine and
biology to transfer chemicals, drugs, genes and other molecules
into targeted cells for a variety of purposes such as
electrochemotherapy, gene transfer, transdermal drug delivery,
vaccines, and the like. Irreversible electroporation may also be
employed as used for cell separation in debacterilization of water
and food, stem cell enrichment and cancer cell purging (U.S. Pat.
No. 6,043,066 to Mangano), directed ablation of neoplastic prostate
tissues (US2003/0060856 to Chornenky), treatment of restenosis in
body vessels (US2001/0044596 to Jaafar), selective irreversible
electroporation of fat cells (US 2004/0019371 to Jaafar) and
ablation of tumors (Davalos, et al. Annals of Biomedical
Engineering 33: 223-321. The entire contents of each of these
references are expressly incorporated herein by reference.
[0053] Energy fields applied in ultrashort pulses, or nanosecond
pulsed electric fields (nsPEFs) may also be used to porate target
nerve and other cells in accordance with the present invention.
Ultrashort pulse lengths are directed at target subcellular
structures without permanently disrupting the outer membrane. An
example of this technology is described by Schoenbach et al. (2001)
J. Bioelectromagnetics 22: 440-448, and in U.S. Pat. No. 6,326,177,
the contents of which is expressly herein incorporated by
reference. The short pulses target the intracellular apparatus, and
although the cell membrane may exhibit an electroporative effect,
such effect is reversible and does not lead to permanent membrane
disruption. Following application of nanosecond pulses, apoptosis
is induced in the intracellular contents, affecting the cell's
viability (for example limiting the ability to reproduce).
[0054] In a specific embodiment of the present invention,
electroporation may be achieved by energizing an electrode or
series of electrodes to produce an electric field. Such a field can
be generated in a bipolar or monopolar electrode configuration.
When applied to cells, depending on the duration and strength of
the applied pulses, this field operates to increase the
permeabolization of the cell membrane and either (1) reversibly
open the cell membrane for a short period of time by causing pores
to form in the cell lipid bilayer allowing entry of various
therapeutic elements or molecules, after which, when energy
application ceases, the pores spontaneously close without killing
the cell, or (2) irreversibly opening or porating the cell membrane
causing cell instability resulting in cell death utilizing higher
intensity (longer or higher energy) pulses, or (3) applying energy
in nanosecond pulses resulting in disruption of the intracellular
matrix leading to apoptosis and cell death, without causing
irreversible poration of the cellular membrane. As characterized by
Weaver (1993), Journal of Cellular Biochemistry 51: 426-435,
short(1-100 .mu.s) and longer (1-10 ms) pulses have induced
electroporation in a variety of cell types. In a single cell model,
most cells will exhibit electroporation in the range of 1-1.5 V
applied across the cell (membrane potential).
[0055] Certain factors determine how a delivered electric field
will affect a targeted cell, including cell size, cell shape, cell
orientation with respect to the applied electric field, cell
temperature, distance between cells (cell-cell separation), cell
type, tissue heterogeneity, properties of the cellular membrane and
the like. Larger cells may be more vulnerable to injury. For
example, skeletal muscle cells have been shown to be more
susceptible to electrical injury than nearby connective tissue
cells (Gaylor et al. (1988) J. Theor. Biol. 133: 223-237). In
addition, how cells are oriented within the applied field can make
them more susceptible to injury, for example, when the major axis
of nonspherical cells is oriented along the electric field, it is
more susceptible to rupture (Lee et al. (1987) Plastic and
Reconstructive Surgery ______: 672-679.)
[0056] Various waveforms or shapes of pulses may be applied to
achieve electroporation, including sinusoidal AC pulses, DC pulses,
square wave pulses, exponentially decaying waveforms or other pulse
shapes such as combined AC/DC pulses, or DC shifted RF signals such
as those described in Chang, (1989) Biophysical Journal October 56:
641-652, depending on the pulse generator used or the effect
desired. The parameters of applied energy may be varied, including
all or some of the following: waveform shape, amplitude, pulse
duration, interval between pulses, number of pulses, combination of
waveforms and the like.
[0057] Catheter Devices. FIGS. 4 and 4A-4B depict a system 10
comprising an electroporation catheter 12 for selective
denervation/disruption of nerve tissue. For purposes of this
specification, the term "catheter" may be used to refer to an
elongate element, hollow or solid, flexible or rigid and capable of
percutaneous introduction to a body (either by itself, or through a
separately created incision or puncture), such as a sheath, a
trocar, a needle, a lead. In certain configurations of the present
invention, voltages may be applied via the electroporation catheter
12 to induce irreversible electroporation, without requiring the
use of any other agents to achieve the desired cell destruction
and/or denervation. It is a further advantage of this type of
energy that any thermal effect may be minimized thereby preventing
or minimizing collateral damage to tissues near the target tissues,
or the type of physical damage to the nerves themselves that can
lead to permanent neuralgia when the nerve fibers generate A
further advantage of this type of energy is that the
electroporation or electropermeabilization effect is largely
cell-size specific. That is, larger cells will be porated (either
reversibly or irreversibly) at lower energy levels than smaller
cells. This will allow the denervation effect to be directed at the
relatively large nerve cells while sparing smaller adjacent cell
types. In addition, the electric field may be controlled by the
size and relative positioning of the electrodes on the treatment
device or patient.
[0058] The electroporation catheter system 10 further comprises a
pulse generator 14 such as those generators available from
Cytopulse Sciences, Inc. (Columbia, Md.); Bio-Rad, Inc. (Hercules,
Calif.) (the Gene Pulser Xcell); and IGEA (Carpi, Italy). The pulse
generator is electrically connected to the catheter 12 which has a
proximal end 20 and a distal end 22 and is adapted for either
surface placement (cutaneous) or minimally invasive insertion into
the desired region of the body as described herein. The generator
14 may be modified to produce a higher voltage, increased pulse
capacity or other modifications to induce irreversible
electroporation. The catheter 12 further comprises an
electroporation element at the distal end thereof comprising a
first electrode 30 and a second axially spaced-apart electrode 32
operatively connected to the pulse generator through cables 34 for
delivering the desired number, duration, amplitude and frequency of
pulses to affect the targeted nerve tissue. The energy delivery
parameters can be modified either by the system or the user,
depending on the location of the catheter within the body (e.g.,
the nature of the intervening tissues or structures) and whether a
reversible or irreversible cell poration is desired. For example
energy in the range of 10 V/cm to 10.sup.4 V/cm for a duration of
10 .mu.s to 100 ms may be used to achieve reversible
electroporation and in the range of 100 V/cm to 10.sup.6 V/cm for a
duration of 10 .mu.sec to 100 msec to achieve irreversible
electroporation or apoptosis. As shown in FIG. 4A, electrodes 30
and 32 may be axially aligned on one side of catheter 12 to produce
an electric field concentrated in a lateral direction from the
catheter body. Using ring electrodes 30 and 32 as shown in FIG. 4B,
creates a more uniform electric field about the shaft of the
catheter 12. Additional monitoring electrode(s), may be located on
the catheter 12.
[0059] Further catheter devices and electrode configurations are
shown in FIGS. 5A-5D. FIG. 5A depicts an elongate catheter 50
having a first electrode 52 and second electrode 54 near its distal
tip. A monitoring or stimulation electrode 56 is disposed in the
vicinity of the porating electrodes 52 and 54 for monitoring or
localizing the treatment area. In some embodiments, the monitoring
or stimulating function may be performed by one or more of the
treatment electrodes. The catheter 50 may have an optional sharp
tip 58 (shown in broken line) to facilitate percutaneous
introduction. Electrodes 52, 54 and 56 are shown as axially aligned
on one side of the catheter 50 but could also have ring or other
structures.
[0060] FIG. 5B illustrates a steerable catheter 60 adapted to bend
or articulate at a region 62 near its distal end. Active electrodes
64 and 66 are disposed adjacent to or within the articulated region
62 and a monitoring or stimulation electrode 68 is optionally
disposed proximally of the active electrodes. Such steering ability
enables the operator to introduce the device into tight or tortuous
spaces so that optimal placement of the device may be achieved.
[0061] FIG. 5C depicts a catheter 70 that includes an injection
element 72 to allow for the injection of a therapeutic agent
before, during or after the application of the pulsed energy or
electroporation from active electrodes 74 and 76 and monitoring or
stimulating electrode 78. The injection element may be a needle as
shown in FIG. 5C, an infusion port, or other infusion means. Such a
therapeutic agent may be, for example, lidocaine, botulinum toxin
(either full or in fragment as detailed copending application No.
11/______ (Attorney Docket No. 020979-003410US, filed on Jul. 21,
2006, the full disclosure of which has been incorporated herein by
reference), capsaicin or a variety of nerve blocking agents. The
use of the devices and methods of the present invention can
increase the effectivity and provide for alternative means of
delivery for botulinum toxin to treat pain by inhibiting the
release of the neurotransmitter responsible for the transmission of
pain, such as various neuropathic diseases and disorders as
described in U.S. Pat. Nos. 6,113,915, 6,333,037, 6,372,226,
6,841,156, 6,896,886 and 6,869,610 to Aoki, the contents of which
are expressly incorporated herein by reference in their entirety.
Further, to aid the electroporation process, it may be advantageous
to heat the targeted cells or surrounding tissue by either applying
thermal energy directly to the region, or directing a heated fluid,
such as saline to the region through the injection element.
[0062] FIG. 5D depicts a catheter 80 having deployable electrode
elements 82 and 84 that are adapted to extend laterally from the
main catheter body, and in some cases, penetrate the surrounding
tissue prior to application of energy. In doing so the depth and
direction of the energy field created by the electroporative
process, may be further controlled. As with the previous
embodiments, a stimulating or monitoring electrode 86 may
optionally be provided proximally of the active electrodes.
[0063] In certain configurations it may be advantageous to use the
poration catheters and methods of the present invention in
conjunction with a nerve blocking agent, neurotoxin, neurotoxin
fragment or other therapeutic agents according to methods and
devices described in co-pending patent application no 11/______
(Attorney Docket No. 020979-003410US), filed on Jul. 21, 2006, the
full disclosure of which has been incorporated by reference in its
entirety. In this instance, the voltage applied to the electrode
elements would preferably be in the range applicable to create a
reversible electroporation of the nerve or tissue cells, thereby
porating the cell to allowing the therapeutic agent to be delivered
to achieve the desired effect, but not destroying the cell or
otherwise irreversibly damaging the targeted tissue or nerve
structures.
[0064] Any of the foregoing systems may include electrodes or other
monitoring systems either located on the treatment catheter, or
external to the patient, to determine the degree of treatment to
the region, including, thermocouple, ultrasound transducers,
fiberoptics, sensing or stimulating electrodes. Further, it may be
desirable to incorporate multiple pairs of electrodes that may be
activated in pairs, in groups, or in a sequential manner in order
to maximize the desired shape of the lesion while minimizing the
field strength requirements. Also, the devices of the present
invention may be used in conjunction with more traditional
neuromodulation techniques, such as TENS, to mediate pain
attributable to the treatment (the presence of which may depend on
the level of voltage applied) or neuromuscular response to the
applied electric field as further noted in published U.S.
application No. 2003/0149451, hereby incorporated by reference in
its entirety.
[0065] Implantable Devices. A fully implantable spinal cord
modulation system 100 includes an implantable pulse generator 102
which incorporates a power supply or battery as depicted in FIG. 6.
The system 100 connects to an implantable lead 104 which includes
electrodes 106 and 108. As shown in FIG. 7, a partially implantable
system 120 includes a transmitter 122, and a receiver 124 that
relies upon radio frequency to transmit the energy to the lead or
electrode. In this system the antenna and transmitter are carried
outside the body, while the receiver connected to the lead 126 with
electrodes 128 and 130) is implanted inside the body. FIG. 8 shows
the placement of the fully implantable pulse generator 100 device
in the region of the sacral plexus of a patient which has been
implanted according to the steps set forth in U.S. Pat. No.
6,847,849, previously incorporated by reference herein.
Implantation of the partially implantable system 120 could be
achieved in the identical manner.
[0066] Cutaneous or Subcutaneous Devices. For some conditions, it
may be desirable to apply the poration energy from the surface of
the skin (transcutaneously), or from just below the skin
(subcutaneously). FIG. 9A depicts a dermal patch 150 having an
electrode pair 152 and 154 for delivery of therapeutic energy of
the present invention to the targeted region. Alternatively, the
pad may include one electrode, while the other (a ground) may be
positioned elsewhere on the patient's skin (not shown). Depending
on the type of voltage applied and condition to be treated, it may
be desirable to have multiple electrode pairs on the surface of the
patch or pad, and in some cases as shown in FIG. 9B, such
electrodes may be in the form of microneedles 160 that puncture the
skin some distance to deliver the therapeutic energy of the present
invention subcutaneously. The patch or pad carrying the electrodes
should be flexible and conformable and may be formed of a polymer
such as silicone, urethane, nylon, polyethylene or other
thermoplastic elastomers, or could be substantially rigid and
formed of a rigid polymer (such as PEEK or polysulfone)or insulated
stainless steel, nickel titanium alloy, or other metal. As noted
above, various monitoring devices and methods may be employed to
track the progress of the therapy. Similarly, algorithms to
activate pairs of electrodes or regions of the pad or patch may be
employed to enhance the therapeutic effect while reducing the
overall power requirements.
[0067] Intraluminal Devices. It may further be advantageous to
position poration catheters through vessels in the body,
particularly arteries to treat adjacent nerves, to direct poration
energy to various regions to effect pain reduction. Such
intraluminal catheters are described in published U.S. applications
2001/0044596 to Jaafar and 2002/0198512 to Seward, hereby
incorporated by reference in their entirety, could be used for such
energy delivery.
[0068] Methods of Use. FIG. 10 illustrates a method for nerve
poration by applying energy to the surface of the skin S via the
electrode patch 150. FIG. 11 depicts the implantation of electrode
lead 104 or 126 that is then operatively connected to the
implantable generator and described herein. FIG. 12 shows
percutaneous nerve poration catheter 12 implanted in a region
within the spine. In FIGS. 11 and 12, the active tip region of the
catheter or lead is shown placed alongside the nerve region NR to
be treated, but in fact may be positioned within the nerve sheath,
or along the spine (SP), or within the muscular layer (MP).
[0069] In yet another embodiment shown in FIG. 13, a receiver 200
may be placed at the target location (here alongside the nerve
region NR in the spine SP), while a transmitter 202 is placed
outside or on the skin of the patient. Once in place adjacent the
nerve region NR to be treated, a pulse generator in the transmitter
202 may be activated, causing an electric field to be generated in
the target area. Prior to activation of therapeutic voltages, once
the catheter(s) have been appropriately positioned, stimulation
using one or more electrodes may be used to elicit a nerve
response. By observing the nerve reflex, a target treatment
location can be confirmed, and then application of poration energy
is employed to eliminate or disrupt the nerve and associated pain
response, thereby selectively denervating the conduction pathways
for the particular type of pain to be treated.
[0070] In operation, effects of poration on nerve tissue may be
selective due to the cellular structure and orientation of the
nerve cells. For example as shown in FIG. 14, targeted nerve cells
may be preferentially affected due to size, sparing smaller or
cross-oriented muscle tissue. As shown, the energy may selectively
rupture the nerve cells 220 at ends 222 while the energy dissipates
over the main body of the cells.
[0071] As shown in FIG. 15, poration catheter 12 can be introduced
into a lumen of artery A to a location immediately adjacent to a
nerve region NR to be treated. The catheter 12 will typically be
introduced over a guidewire GW under fluoroscopic guidance using
well-known intravascular intervention methods and protocols. Once
in place, electroporation or other poration energy can be applied
across the arterial wall toward the nerve region NR to denervate
the nerve as described previously. As the nerve cells will
typically be more susceptible to energy induced damage, the desired
temporary or permanent denervation can usually be achieved with
minimum or no damage to the artery. The catheter 12 can be removed
after the treatment session is completed. The treatment can be
repeated months or years later if and when nerve function
returns.
[0072] Although various illustrative embodiments of the present
invention are described above, it will be evident to one skilled in
the art that various changes and modifications may be made without
departing from the scope of the invention. It will also be apparent
that various changes and modifications may be made herein without
departing from the invention. The appended claims are intended to
cover all such changes and modifications that fall within the true
spirit and scope of the invention.
* * * * *