|Número de publicación||US20070021803 A1|
|Tipo de publicación||Solicitud|
|Número de solicitud||US 11/459,582|
|Fecha de publicación||25 Ene 2007|
|Fecha de presentación||24 Jul 2006|
|Fecha de prioridad||22 Jul 2005|
|También publicado como||US8504147, US8676309, US8989859, US20100010567, US20140012256, US20140200573, US20150216588|
|Número de publicación||11459582, 459582, US 2007/0021803 A1, US 2007/021803 A1, US 20070021803 A1, US 20070021803A1, US 2007021803 A1, US 2007021803A1, US-A1-20070021803, US-A1-2007021803, US2007/0021803A1, US2007/021803A1, US20070021803 A1, US20070021803A1, US2007021803 A1, US2007021803A1|
|Inventores||Mark Deem, Hanson Gifford|
|Cesionario original||The Foundry Inc.|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citada por (88), Clasificaciones (20), Eventos legales (3)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
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.
1. Field of the Invention
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.
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.
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.
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.
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.
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.
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.
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.
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.
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™). 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Examples of arteries that can be used to access particular target nerves of the body regions include:
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
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 (
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.
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:
FIGS. 5A-D—depict various electrode catheter configurations adapted to deliver energy or energy and therapeutic agents to target tissue.
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.
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.
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.
Cranial nerves are mostly associated with motor function, or a combination of motor and sensory functions. As shown in
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.
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.
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.
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).
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 μs) 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).
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.)
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.
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 104 V/cm for a duration of 10 μs to 100 ms may be used to achieve reversible electroporation and in the range of 100 V/cm to 106 V/cm for a duration of 10 μsec to 100 msec to achieve irreversible electroporation or apoptosis. As shown in
Further catheter devices and electrode configurations are shown in
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.
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.
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
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).
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.
Methods of Use.
In yet another embodiment shown in
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
As shown in
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.
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|Clasificación de EE.UU.||607/46, 607/61|
|Clasificación cooperativa||A61B2018/0044, A61B18/1492, A61B18/1477, A61N1/327, A61N1/0492, A61B2018/00613, A61N1/0412, A61N1/36021, A61N1/0551, A61N1/36071, A61N1/36017, A61N1/05, A61N1/0456|
|Clasificación europea||A61N1/36Z, A61N1/36Z3C, A61N1/04E1E, A61N1/36E4|
|19 Sep 2006||AS||Assignment|
Owner name: THE FOUNDRY, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEEM, MARK E.;GIFFORD, HANSON;REEL/FRAME:018275/0239
Effective date: 20060821
|8 Abr 2009||AS||Assignment|
Owner name: THE FOUNDRY, LLC,CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:THE FOUNDRY, INC.;REEL/FRAME:022520/0499
Effective date: 20090402
|26 Abr 2010||AS||Assignment|
Owner name: ARDIAN, INC.,CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:THE FOUNDRY, LLC;REEL/FRAME:024289/0742
Effective date: 20091104
Owner name: ARDIAN, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:THE FOUNDRY, LLC;REEL/FRAME:024289/0742
Effective date: 20091104