Patent Grant
11964150
All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Embodiments of the invention relate generally to apparatuses (e.g., systems and devices) and methods of establishing neuronal stimulation. In particular, described herein are implantable microstimulation (MS) devices for treatment of chronic inflammation adapted for electrically stimulating one or more nerves (e.g., the vagus nerve) to treat chronic inflammation by modulation of the inflammatory response via the nicotinic cholinergic anti-inflammatory (“NCAP”) pathway. These apparatuses may batteryless. Any of the methods and apparatuses described herein may be in particular adapted for stimulation of the vagus nerve below the diaphragm (e.g., sub-diaphragmatic vagus nerve stimulation).
Electrical stimulation of the cholinergic anti-inflammatory pathway (NCAP) by stimulation of the carotid vagus nerve been well described. For example, see U.S. Pat. Nos. 6,838,471, 8,914,114, 9,211,409, 6,610,713, 8,412,338, 8,996,116, 8,612,002, 9,162,064, 8,855,767, 8,886,339, 9,174,041, 8,788,034 and 9,211,410, each of which is herein incorporated by reference in its entirety.
Implantable electrical stimulation devices have been developed for therapeutic treatment of a wide variety of diseases and disorders. For example, implantable cardioverter defibrillators (ICDs) have been used in the treatment of various cardiac conditions. Spinal cord stimulators (SCS), or dorsal column stimulators (DCS), have been used in the treatment of chronic pain disorders including failed back syndrome, complex regional pain syndrome, and peripheral neuropathy. Peripheral nerve stimulation (PNS) systems have been used in the treatment of chronic pain syndromes and other diseases and disorders. Functional electrical stimulation (FES) systems have been used to restore some functionality to otherwise paralyzed extremities in spinal cord injury patients.
Typical implantable electrical stimulation systems may include one or more programmable electrodes on a lead that are connected to an implantable pulse generator (IPG) that contains a power source and stimulation circuitry. However, these systems can be difficult and/or time consuming to implant, as the electrodes and the IPG are usually implanted in separate areas and therefore the lead must be tunneled through body tissue to connect the IPG to the electrodes. Also, leads are susceptible to mechanical damage over time, particularly as they are usually thin and long.
Recently, small implantable neural stimulator technology, i.e. microstimulators, having integral electrodes attached to the body of a stimulator has been developed to address the disadvantages described above. This technology allows the typical IPG, lead and electrodes described above to be replaced with a single integral device. Integration of the lead has several advantages including reduction of surgery time by eliminating, for example, the need for implanting the electrodes and IPG in separate places, the need for a device pocket, the need for tunneling to the electrode site, and requirements for strain relief ties on the lead itself. Reliability may therefore be increased significantly, especially in soft tissue and across joints because active components, such as lead wires, are now part of the rigid structure and are not subject to the mechanical damage due to repeated bending or flexing over time.
There remains a need for a leadless integral device that is stably positioned on the nerve, and can provide for removal and/or replacement of the stimulation device with relative ease.
Charging and/or communication with an implant by electrical induction (e.g., via one or more inductive coils) may be well suited for use with implantable microstimulators, including those adapted for use to treat inflammation. However, induction may be difficult, particularly where the implant is located deep within the body, as may be the case with a sub-diaphragmatic implant, or where the orientation is not known or is difficult to align with. In previous iterations of the recharging portion of the system, the recharger included a coil that could be worn around a patient's neck. In this configuration, the coil is able to generate an electromagnetic field having sufficient strength to penetrate the patient's body and reach the implanted device for recharging the implanted device. While this recharging scheme is effective, it requires the patient to periodically wear a ring around their necks.
Described herein are microstimulators, charging systems, and methods of using them that may address some of the needs identified above.
Although stimulation of the vagus nerve at the upper levels has been well characterized, stimulation of the NCAP pathway at more distal sites, including sub-diaphragmatic sites has not been well characterized, and poses unique problems and opportunities.
For example, stimulation of sub-diaphragmatic sites may provide fewer adverse events and particularly possibly providing fewer undesirable cardiac effects and laryngeal effects. However, sub-diaphragmatic placement has not been characterized, and may be expected to have a lower efficacy. In addition, the NCAP pathways in sub-diaphragmatic regions may be difficult to access and provide stable placement of a microstimulator.
Also described herein are methods an apparatuses that may address the issues raised above.
The present invention relates generally to apparatuses (systems and devices) and methods for treating an inflammatory disease stimulation the NCAP. Any of the methods and apparatuses described herein may be configured for sub-diaphragmatic stimulation. Also described herein are methods of implanting a stimulation apparatus (including sub-diaphragmatic implantation of a stimulation apparatus) for NCAP stimulation, apparatuses for stimulation (including sub-diaphragmatic stimulation apparatuses for sub-diaphragmatic NCAP stimulation), and methods and apparatuses for noninvasively charging a stimulation apparatus, including but not limited to apparatuses and methods for sub-diaphragmatic NCAP stimulation.
Described herein are microstimulators (MSs, also referred to herein as microregulators or MRs) that may be implanted for stimulating a nerve, such as the vagus nerve. Any of these apparatuses may include a coil for receiving (and in some variations transmitting) information and/or for inductively charging the implanted device. The coil may be referred to as an antenna or inductive coil, or inductive coil antenna. In some variations the coil may be wrapped around a housing and/or a core which may be completely or partially ferromagnetic, which may modify (e.g., concentrate, direct) the magnetic field for effective charging and/or communication with a remote charger.
For example, a microstimulator may include: a housing made of a high magnetic permeability material; a coil wrapped around the housing, wherein the housing functions as a magnetic core for the coil; a resonator comprising the coil and a capacitor configured to resonate at a predetermined frequency range; a pair of electrodes disposed on the housing; a battery within the housing; and an electronic assembly within the housing, wherein the electronic assembly comprises power management circuitry configured to receive power from the resonator to charge the battery, and a microcontroller configured to control stimulation of the vagus nerve from the electrodes.
In general, a material having a high magnetic field permeability may include certain iron alloys (ferrites), ferrite-filled polymer, ferrite-embedded polymer, alloys of iron and nickel (e.g., commercially sold as MUMETAL and PERMALLOY) and the like. The high magnetic permeability material may be selected from the group consisting of a ferrite and a Mu-metal.
In any of these variations, the high magnetic permeability material may include one or more slits configured to reduce formation of eddy currents in the high magnetic permeability material.
In any of the variations described herein, the resonator (including the coil and a capacitor) may be configured to resonate at a predetermined frequency range, as described in greater detail herein.
A microstimulator may include: a housing; a pair of electrodes disposed on the housing; a battery within the housing; an electronic assembly disposed on a printed circuit board within the housing; a high magnetic permeability core integrated with the printed circuit board; a coil wrapped around the printed circuit board; and a resonator within the housing, the resonator comprising the coil and a capacitor configured to resonate at a predetermined frequency range; wherein the electronic assembly comprises power management circuitry configured to receive power from the resonator to charge the battery, and a microcontroller configured to control stimulation of the vagus nerve from the electrodes.
In some variations, the high magnetic permeability core may be a rod or a plate.
Any of the microstimulators described herein may include a pair of end caps attached to a first end and a second end of the housing. The end caps may be made of a high magnetic permeability material and the high magnetic permeability core may extend to at least one of the end caps.
A microstimulator may include: a housing; a pair of electrodes disposed on the housing; a battery within the housing, the battery coated (and in some variations covered) with a high magnetic permeability material; a coil wrapped around the battery; a resonator within the housing, the resonator comprising the coil and a capacitor configured to resonate at a predetermined frequency range; and an electronic assembly within the housing; wherein the electronic assembly comprises power management circuitry configured to receive power from the resonator to charge the battery, and a microcontroller configured to control stimulation of the vagus nerve from the electrodes.
A microstimulator may include: a magnetic core having a first end and a second end; a coil wrapped around the magnetic core; a housing, wherein the magnetic core and coil are disposed outside of the housing; a pair of electrodes disposed on the housing; a battery within the housing; a resonator comprising the coil and a capacitor configured to resonate at a predetermined frequency range; and an electronic assembly within the housing; wherein the electronic assembly comprises power management circuitry configured to receive power from the resonator to charge the battery, and a microcontroller configured to control stimulation of the vagus nerve from the electrodes. The first end of the magnetic core may be attached to the housing.
The magnetic core may be configured to be remotely placed away from the housing while remaining in electrical communication with the electronic assembly.
Any of the microstimulators described herein may be adapted for application to a vagus nerve.
The apparatuses (devices and systems) and methods of using them described herein may incorporate some or all of the features of microstimulators (which may also be referred to as microcontrollers), nerve cuffs (“PODs”), chargers, and programmer/controllers described herein may be similar or identical to those described in U.S. patent application Ser. No. 12/874,171, titled “PRESCRIPTION PAD FOR TREATMENT OF INFLAMMATORY DISORDERS”, filed on Sep. 1, 2010, Publication No. US-2011-0054569-A1 and U.S. patent application Ser. No. 12/797,452, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR”, filed on Jun. 9, 2010, now U.S. Pat. No. 8,886,339 and U.S. patent application Ser. No. 14/887,192, titled “NEURAL STIMULATION DEVICES AND SYSTEMS FOR TREATMENT OF CHRONIC INFLAMMATION”, filed on Oct. 19, 2015, Publication No. US-2016-0038745-A1.
The apparatuses (devices and systems) described herein may include chargers that are adapted to direct the magnetic field for communication with an implanted microstimulator. These chargers may include a high magnetic permeability material that shapes the magnetic field. In particular, the charger may be configured as a collar or wearable loop (belt, wristlet, anklet, necklace, etc.) that includes a magnetically permeable material to displace the density of the magnetic field axially “up” or “down” relative to the loop.
For example, a charger for inductively charging a neurostimulator implanted within a portion of the patient's body may include: a coil configured to be disposed around the portion of the patient's body with the implanted neurostimulator; a covering having a tubular shaped disposed over the coil, wherein the covering comprises a high magnetic permeability material that is arranged on an inner surface of the tubular shape but is not on an outer surface; an amplifier configured to drive an electrical current through the coil to generate an electromagnetic field; and a controller configured to modulate the electrical current driven through the coil.
For example, a charger for charging a neurostimulator implanted within a portion of the patient's body may include: a coil configured to be disposed around the portion of the patient's body with the implanted neurostimulator; a covering disposed over the coil, wherein the covering is made at least in part of a high magnetic permeability material, wherein the high magnetic permeability material has a magnetic permeability greater than 10 times the magnetic permeability of vacuum; an amplifier configured to drive an electrical current through the coil to generate an electromagnetic field; and a controller configured to modulate the electrical current driven through the coil.
In general, the high magnetic permeability material may be selected from the group consisting of a ferrite, a ferrite polymer composite, a ferrite filled polymer, a ferrite loaded rubber, and a ferrite tape.
The high magnetic permeability material (HMPM) may be disposed asymmetrically over the coil in order to concentrate and bias the electromagnetic field passing through the coil towards the implanted neurostimulator. For example, the HMPM may form a U-shape over the coil with the mouth of the U-shape (opening) directed axially “up” to direct the field in this direction. The high magnetic permeability material may be disposed on a skin facing side of the covering that is configured to face the patient's skin when the coil is disposed around the portion of the patient's body with the implanted neurostimulator. The high magnetic permeability material may be disposed on a portion of the covering that is configured to face implant when the coil is disposed around the portion of the patient's body with the implanted neurostimulator.
In any of the variations described herein, a high magnetic permeability material may include at least one slit that is configured to reduce formation of eddy currents in the high magnetic permeability material.
Also described herein are testers and chargers. For example, a handheld charger for charging a neurostimulator implanted within a portion of the patient's body may include: a C-shaped ferrite having a first end, a second end, and a gap between the first end and the second end, wherein the gap is adapted to be placed against the patient's skin; a coil wrapped around the ferrite; an amplifier configured to drive an electrical current through the coil to generate an electromagnetic field that extends through the ferrite and the gap; and a controller configured to modulate the electrical current driven through the coil.
Also described herein are methods of charging a microcontroller/microregulator (e.g., neurostimulator) implant as described herein. For example, a method for charging a neurostimulator implanted in a patient's neck may include: positioning a coil of a charger around the patient's neck, the charger having a covering over the coil comprising a high magnetic permeability material disposed on a portion of the covering; positioning the high magnetic permeability material to face towards the implant; passing a current through the coil; and generating an electromagnetic field that is concentrated towards the implanted neurostimulator.
Also described herein are wireless charging or recharging of an implantable neurostimulation device. The implantable neurostimulation device has been implanted about a patient's vagus nerve and is able to provide stimulation to the vagus nerve in a periodic fashion. The components for transferring energy to the implanted neurostimulation device are embedded in a pillow. The pillow recharger allows recharging of the implanted neurostimulation device while the patient sleeps or rests.
The pillow recharger includes at least one transmitter coil that is configured to generate electromagnetic waves. The transmitter coil or coils are configured to generate electromagnetic energy that oscillates within a threshold of the desired resonant frequency such that the transmitter coil(s) are able to transfer energy to the corresponding receiver coils within the implanted neurostimulation device. The power transmitter coil or coils may be in a figure eight configuration where the coils are circular, square, rectangular, and so forth. In some examples, the coil is one contiguous stretch of conductive material, but in others, there may be more than one discrete coil. If the surface of the pillow and the transmitter coil(s) are defined as being in an x/y plane, the current will run in an opposing fashion within the transmitter coil or coils. The electromagnetic field generated by the transmitter coil or coils will generally provide current that traverses up through the x/y plane along a z axis direction and drop down toward the opposing z axis direction through the other transmitter coil.
The pillow recharger may also include a physical backing that is able to support the transmitter coil or coils. The physical backing may also function to provide shielding to the transmitter coils such that nearby metallic objections do not interfere with the electromagnetic field generated. The backing may be made from a material with a high magnetic permeability, such as ferrite, which provides shielding by providing a low-reluctance return path for the magnetic field beneath the pillow. The backing may also be made of a conductive material, which provides shielding by the induction of eddy currents in the backing.
The pillow recharger also includes a power generator that is configured to power the at least one power transmitter coil or coils. The power generator may provide an initial signal of alternating current through an initial signal generator for bringing the transmitter coil or coils into an ON state.
The pillow recharger will include circuitry and controls for monitoring and controlling the interactions between the recharging pillow and the wireless energy receiver housed within the implanted neurostimulation device. The controls that allow the user to set the recharging sessions and other recharging parameters may be partially or completely external to the recharging pillow. It is also possible that the controls may also be entirely internal to the recharging pillow and be remotely controllable.
The recharging pillow may also include sensors that alert the user if the recharging pillow is malfunctioning or is operating outside the expected range for transmitting power to the receiving mechanism within the implanted neurotransmitter device. For example, the recharging pillow may include a temperature sensor that alerts the user, through some audio signal, that the surface temperature of the pillow is above a certain value. The recharging pillow may also include pressure and force sensors that will sound if the too much pressure or force is applied to the recharging pillow that may damage the internal circuitry.
In other variations, the recharging pillow may be used to inductively recharge an implanted neurostimulator. The recharging pillow may include a first transmitter coil, where the first transmitter coil is capable of generating electromagnetic waves. The recharging pillow may also include a second transmitter coil that is also able to generate electromagnetic waves. The region defined by the first and the second transmitter coil forms a wireless power transmission region for sending power to the wireless receiver within the implanted neurostimulator. The pillow recharger also includes a power generator that is configured to deliver current through the first transmitter coil in a clockwise direction and the second transmitter coil in a counterclockwise direction causing the first transmitter coil and the second transmitter coil to generate electromagnetic energy that inductively charges the implanted neurostimulator.
The pillow recharger will also include a cushioning, support structure around the transmitter coil regions and related circuitry. The cushioning supportive materials may include any suitable material by itself or in combination. Examples of suitable materials include but are not limited to cotton, polyester, gels, foam, water, liquids, natural materials or synthetic materials, and so forth.
Also described herein are methods of treating an inflammatory disease by sub-diaphragmatic stimulation of the vagus nerve, the method comprising implanting inserting a microstimulator at least partially around a sub-diaphragmatic vagus nerve and applying electrical stimulation from the microstimulator to the sub-diaphragmatic vagus nerve to inhibit inflammation.
Implanting may include positioning a nerve cuff over a sub-diaphragmatic vagus nerve of by longitudinally introducing the nerve cuff on the sub-diaphragmatic vagus nerve. Implanting may include positioning the microstimulator within the nerve cuff in electrical contact with the sub-diaphragmatic vagus nerve. Implanting may include placing a nerve cuff around the sub-diaphragmatic vagus nerve with a microstimulator held therein and sealing the microstimulator within the nerve cuff.
Any of these methods may also include inductively charging the microstimulator from a belt worn around an abdominal region of a patient into which the microstimulator has been implanted.
For example, a method of treating an inflammatory disease by sub-diaphragmatic stimulation of the vagus nerve may include: positioning a nerve cuff over a sub-diaphragmatic vagus nerve of a patient by longitudinally introducing the nerve cuff on the sub-diaphragmatic vagus nerve; positioning a microstimulator within the nerve cuff in electrical contact with the sub-diaphragmatic vagus nerve; sealing the microstimulator within the nerve cuff; applying electrical stimulation from the microstimulator to the sub-diaphragmatic vagus nerve to inhibit inflammation; and inductively charging the microstimulator from a belt worn around an abdominal region of the patient. The pillow-charging apparatuses described herein may be particularly well suited to charging implanted microstimulators that are implanted sub-diaphragmatically. Any of the pillow-charging apparatuses may be configured as mattress or mattress-covering devices that may be positioned at or below the patient's torso level when the patient is recumbent thereon.
Also described herein are batteryless and leadless microregulators for nerve stimulation. For example, a batteryless and leadless microregulator may include: a power receiving coil configured to inductively receive a power signal; a microprocessor powered by the electrical energy received by the power receiving coil; a modulator and a demodulator in electrical communication with the power receiving coil and the microprocessor for receiving and transmitting information from the power signal; at least one pair of electrodes configured to deliver electrical stimulation using the electrical energy received by the power receiving coil; and an overmold forming a nerve channel having a slit that provides access to the nerve channel, wherein the microprocessor is configured to apply energy to the at least one pair of electrodes only when the power signal is being received by the power receiving coil, further wherein the microprocessor and electrodes are not connected to a battery.
The energy applied by device may be conditioned by the microprocessor based on the information transmitted with the inductive power signal, which may be encoded by the power signal and demodulated by the microprocessor. The microprocessor may further condition the transmitted energy by waiting until the power achieves a threshold level (and in some cases, sustains this power level at or above a threshold level for a predetermined amount of time, e.g., 0.1 second, 0.5 seconds, 1 second, 2 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, etc.) before transmitting energy.
The power receiving coil, the microprocessor, the modulator, the demodulator, and at least a portion of the at least one pair of electrodes may be encapsulated by a liquid crystal polymer, wherein the liquid crystal polymer is encapsulated by the polymer or silicon overmold. The liquid crystal polymer may form a plurality of conduction windows on the at least one pair of electrodes that are aligned with the plurality of conduction windows in the silicon overmold. In some variations, the conduction windows are dispersed substantially around the entire circumference of the cuff portion.
Any of these apparatuses (devices, systems, etc.) may also include a non-volatile memory in communication with the microprocessor, wherein the microprocessor is programmed to log dose compliance in the non-volatile memory. Any of these apparatuses may also or alternatively include a plurality of shape memory metal struts configured to bias the cuff portion into the closed configuration. These apparatuses may include a thermal protection circuit with a thermistor in electrical communication with the power receiving coil, the thermal protection circuit configured to provide an open circuit when the thermistor measures a temperature that equals or exceeds a predetermined or set temperature. The predetermined or set temperature may be about 41.5 degrees Celsius. In some variations the thermistor is positioned proximate the power receiving coil. In some variations, the thermistor is positioned proximate one of the electrodes.
Any of these apparatuses may include a ferrite disposed within the power receiving coil.
The electrodes may be made of any appropriate material, including, e.g., made at least in part of platinum or a platinum alloy. The material may be selected and/or arranged to avoid interfering with the inductive powering and/or communication. In some variations the at least one pair of electrodes are made at least in part of a platinum-iridium alloy. The at least one pair of electrodes may be spring cut.
For example, a batteryless and leadless microregulator for nerve stimulation may include: a power receiving coil configured to inductively receive a power signal; a microprocessor powered by the electrical energy received by the power receiving coil; a modulator and a demodulator in electrical communication with the power receiving coil and the microprocessor for receiving and transmitting information from the power signal; at least one pair of electrodes configured to deliver electrical stimulation using the electrical energy received by the power receiving coil; and an overmold that encapsulates the power receiving coil, the microprocessor, the modulator, the demodulator, and at least a portion of the pair of electrodes, the overmold having a nerve channel and a slit that provides access to the nerve channel, wherein the overmold is configured to adopt an open configuration in which the slit is open to expose the at least one pair of electrodes within the nerve channel, and a closed configuration in which the slit is closed, wherein the microprocessor is configured to apply energy to the at least one pair of electrodes only when the power signal is being received by the power receiving coil, further wherein the microprocessor and electrodes are not connected to a battery.
Also described herein are methods of using batteryless and leadless microstimulators. For example, a method for stimulating a nerve may include: inductively applying energy to an implanted leadless and batteryless microregulator using an external inductive coil, the implanted leadless and batteryless microregulator having a nerve channel encircling the nerve and at least a pair of electrodes disposed within the nerve channel; and delivering an electrical stimulation to the nerve from the at least one pair of electrodes while inductively applying energy to the implanted leadless and batteryless microregulator, wherein the implanted leadless and batteryless microregulator is configured to condition the electrical stimulation based at least in part on a signal transmitted with the inductively applied energy.
The electrical stimulation may have an amplitude of up to 3 mA and a duration of up to 30 seconds. The electrical stimulation may be delivered as a plurality of sub-bursts, each sub-burst having a duration of about 1-5 seconds.
The method nerve may be any appropriate never or nerve bundle. For example, the nerve may be the vagus nerve, such as the vagus nerve in a cervical region of the neck. The nerve may be a sub-diaphragmatic portion of the vagus nerve. For example, the nerve may be a peripheral nerve.
Described herein are methods and apparatuses (e.g., devices and systems) for vagus nerve stimulation to treat inflammation. Any of the apparatuses and methods described herein may be used with any vagus nerve stimulation (e.g., with any micro-stimulator), but may be adapted in particular for use in sub-diaphragmatic vagus nerve stimulation. In particular, the methods and apparatuses may be used to stimulate the sub-diaphragmatic vagus nerve to treat inflammation and/or inflammatory disorders such as hay fever, atherosclerosis, arthritis (e.g., rheumatoid, bursitis, gouty arthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, nephritis, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, myocarditis, colitis, etc. The apparatus may be a microstimulator (also referred to herein as a “MS”, “nerve stimulator”, “microcontroller”, “MC” or simply “implant”) that is configured to deliver appropriate electrical stimulation to a nerve. The electrical stimulation can modulate the activity of the nerve and cause a wide variety of effects. For example, electrical stimulation of the vagus nerve can result in a reduction of inflammation through activation of the cholinergic anti-inflammatory pathway. The microstimulator may be applied by itself or within or as part of a nerve cuff (referred to herein as a “protection and orientation device” or POD). The microstimulator (“MR”) or POD or combined MR/POD may be specifically adapted for use in the abdomen and placement sub-diaphragmatically. For example, the apparatus may be tethered or tetherable to prevent migration or “loss” of the apparatus within the abdomen. MS, POD or MS/POD may also be adapted for placement specifically on the sub-diaphragmatic region, including but not limited to the sub-diaphragmatic vagus Nerve.
When configured to sub-diaphragmatic vagus nerve stimulation, the apparatuses described herein may be preferred over carotid vagus nerve application. In such variations, a single implant (e.g., single leadless microstimulator, including those described herein) may be adapted for sub-diaphragmatic implantation. Such implants may be adapted for sub-diaphragmatic implantation by including one or more features including: a location and/or orientation emitter (configured to emit a wireless signal indicating implant location and orientation, particularly of an inductive coil(s) within the implant), multiple inductive coils for communication (including charging), a controller adapted to deliver a large simulation dose (e.g., a single pulse or bursts of pulses having between 6.5 and 20 V for a dose duration of between 0.1 second and 1000 seconds (e.g., between 0.3 s and 500 s, between 0.5 s and 100 s, etc.), followed by a low-power, “off” time during which the implant may not apply stimulation; this off time may be between 1 hour and 48 hours (e.g., between 2 hours and 48 hours, between 3 hours and 48 hours, between 4 hours and 36 hours, greater than 2 hours, greater than 3 hours, greater than 4 hours, etc.). The multiple inductive coils may be arranged as a biaxial or tri-axial array of coils. The coils may be arranged (e.g., wrapped, embedded, etc.) on an outer housing of the microstimulator. As will be described in greater detail below, any of these implants may include a magnetically permeable material. Any of these implants may also communicate with a charger which may be worn (e.g., around the abdomen, as a belt, sash, pant, bandolier, etc.) or configured for lying atop (e.g., pad, such as a mattress, pillow, etc.).
Either or both the implant and the charger may be configured to orient the inductive coils between the two devices. For example, the charger may be configured as a three-axis coil(s) so that a plurality of orientations may be used to charge and/or communication. The charger may actively determine which orientation is optimal based on communication with the implant, and may track and use the determined orientation. For example, concurrent or sequential signals (e.g., power) may be applied from each of a plurality of coils having different orientations, and a load detected from the implant reviewing and/or communicating with the charger may allow the charger to optimize (e.g., orient) the applied power to the coil(s) in the appropriate orientation. Any of the chargers described herein may radially cycle through fields from the inductive coil(s), so that the orientation of the applied field changes. Any of the chargers described herein may be tunable, including those configured as a flexible and/or wearable apparatus (e.g., belt), as the orientation of the apparatus, particularly in sub-diaphragmatic implants, may as this region may be mobile. In general, when performing sub-diaphragmatic stimulation, the applied stimulation may be greater than that previously described for cervical vagal stimulation. Typically between 10% and 150% (or more) greater intensity may be applied when performing sub-diaphragmatic stimulation compared to carotid stimulation. For example electrical stimulation may be applied at greater than 6.5 V (e.g., between 6.5 and 20V), although lower intensities (e.g., between 0.5 V and 6.5 V may be used). Typically the voltage does not need to be adjusted during a treatment course, but may be maximally applied during the entire treatment course.
In general, the methods and apparatuses described herein for sub-diaphragmatic stimulation may be used with (or as part of) a laparoscopic surgical approach to placing MR/POD, e.g., on the posterior sub-diaphragmatic vagus nerve. In some variations the methods and apparatuses may be used as part of a Natural orifice transluminal endoscopic surgery (NOTES) procedure.
Examples of microstimulators and apparatuses for holding them onto the sub-diaphragmatic vagus nerve (e.g., a protection and orientation or “POD” device, also referred to herein as a nerve cuff) for use in sub-diaphragmatic stimulation of the NCAP are described herein as well. The methods and apparatuses described herein that are specific to sub-diaphragmatic NCAP stimulation have, in preliminary work, shown many advantages over traditional cervical Vagal placement. For example, these methods and apparatuses typically have fewer adverse events caused by stimulation. Further, these methods and devices may be less safety and time critical, therefore not requiring emergency shutoff as often or as precisely as cervical vagus stimulation. In addition, fewer cardiac effects have been seen with sub-diaphragmatic placement, and no laryngeal adverse events. Finally, there may be a substantial reduction in undesirable muscle stimulation and resulting pain.
The methods and apparatuses described herein may also alleviate the requirement for titration of stimulation patterns, due to a large predicted therapy window that may be used with sub-diaphragmatic stimulation of the NCAP pathway. This may also prevent or minimize postoperative pain. Sub-diaphragmatic stimulation may also reduce the risk of hemorrhaging due to insertion of the implant. Finally, the resulting microstimulator devices may be made larger, allowing greater energy storage and requiring less frequent charging.
In practice, the microstimulator for use in sub-diaphragmatic NCAP stimulation may be inserted onto a nerve forming a portion of the NCAP pathway below the diaphragm by any appropriate method. In particular, it may be helpful to connect (and tether) a microstimulator onto the posterior sub-diaphragmatic vagus nerve.
For example, a device such as the ones described below, or adapted from these devices, may be inserted by first creating several small incisions (0.5-1.5 cm) in abdomen and insufflating the abdomen with carbon dioxide gas. Two or more trocars may be inserted for access and/or to illuminate the surgical site. It may be helpful to displace internal organs such as the liver with a retractor to expose the posterior sub-diaphragmatic vagus nerve. Once exposed, the nerve may be separated from the tissue so that a POD may be placed under nerve, e.g., by longitudinally introducing a POD on nerve. Once the POD is applied, the microstimulator (MR) may be introduced into the POD, e.g., by separating the seam of the POD. The MR may then be sealed into the POD. The MR and POD may be any of those shown and described in Part II, below, or adapted specifically for sub-diaphragmatic implantation and operation. For example, the MR/POD may be configured to be tethered or attached within the abdominal cavity to prevent migration that may alter the position and/or orientation of the apparatus. This may be a particularly acute issue for sub-diaphragmatic implantation compared to cervical implantation. For example, a POD and/or MR may include one or more clips, anchors, and/or filaments for anchoring/tethering the device such as a polymer filament holding component, or the like.
In general, the methods and apparatuses described herein may be adapted to address needs specific to the sub-diaphragmatic placement. For example, the nerve, e.g., the posterior sub-diaphragmatic vagus nerve, may be more difficult to access without damage to the nerve or surrounding tissue. Further, when inserting in this region of the body, particularly minimally invasively, the surgical tools and instruments may have a limited range of motion resulting in a loss of dexterity, and the region may allow only poor depth perception. Thus, it may be helpful to use a tool to manipulate the nerve without exerting too much force or trauma to the nerve (as it may be difficult to accurately judge the force exerted on the nerve in this location). Traditional surgical tools, such as a harmonic scalpel, may damage nerve, while blunt instrument that may be used to separate the nerve are known to cause chronic inflammation.
To address the implantation issues, the apparatus may be configured to provide stimulation (test stimulation) during implantation, and provide an alert to the surgeon when the nerve is triggered, indicating that the apparatus is properly positioned on the nerve. Nerve monitoring may also be performed, e.g., monitoring afferent stimulation of the vagus from a more proximal site, etc.
As mentioned above, another challenge to the sub-diaphragmatic implantation and stimulation of the NCAP is that this sub-diaphragmatic location may make it difficult to retain the MR and/or POD both during implantation and after implantation. Further, it may also be difficult for an implanted MR/POD to be located (e.g., for charging, etc.) post-implantation. In essence, the device may be “lost” in abdomen. As mentioned above, in any of these variations the use of POD and/or MR that is attached to tissue that is not in direct contact with the nerve may address the problem of wandering and/or lost implants, by anchoring or tethering the MR/POD in position. For example, a tether (e.g., a polymer filament holding component or device) may be used and/or integrated into the POD. In some variations a clip may be used to hold the device along the POD closing seam and can be pulled off after securing the device with POD. In some variations a tether may be anchored to saddle. This tether may be cut short or off after securing the device with POD, or it may be left in place.
Retrieval and/or repositioning of the apparatus may be enhanced by using a vacuum line that attaches to an end-cap and is removed or removable after securing the device with POD.
A detector may also be used either during or after implantation of the apparatus. For example, an electronic wand/probe may be configured to locates device electronically may be used to confirm the location/position and/or orientation of the apparatus. For example, a detector may include a multi-axis inductor in a sterile plastic shield that radiates power at resonant frequency and monitors the mutual inductance; this may provide feedback from the implant. As the mutual inductance increases, the device may signal to the operator.
Any of these methods may also include a retriever, such as an apparatus including a vacuum line that can be used to retrieve found device or device to be explanted.
When a non-invasive, rechargeable microstimulator is used, as described herein in some variations, the implant may be inductively charged. In contrast to the cervical NCAP stimulation previously described, sub-diaphragmatic NCAP stimulators (MR) may be more difficult to charge based on their position deeper within the body. Thus the charging design for a charger of the implant in the abdomen may require more power and it may be difficult to locate the microregulator (MR) within the abdomen.
For example,
In general, a low-resistance connection is required for each turn at the belt latch, e.g. double or triple connection per turn. Resistances of less than 0.2Ω, Q>200 and P<5 W can be achieved with this design. To account for different waist shapes, a number of sets of tuning capacitors could be available and selected either electronically or manually (e.g. by switch) during an initial fitting session or, if the switching is automatic, whenever the belt is worn.
In
Neurostimulators and PODS
Referring to
In general, a nerve cuff including a cuff 104 body having (or forming) a pouch or pocket 106 for removably receiving an active, implantable stimulation device 108 having one or more integrated, leadless electrodes 110 on a surface of stimulation device 108 proximate nerve 102. As illustrated in
Contacts or electrodes 110 can be positioned directly against nerve 102, as illustrated in
In one embodiment, the pocket 106 for containing the stimulation device 108 is defined by the open space between the nerve 102 and the inner surface of the cuff body 104. Stimulation device 108 can be passively retained within pocket 106 by the cuff body 104, or can be actively retained on cuff body with fastening means, such as, for example, sutures. In other embodiments, pocket 106 can comprise a pouch-like structure attached to cuff body 104 into which stimulation device 108 can be inserted. Stimulation device 108 can be passively retained within a pouch-like pocket by simply inserting the device 108 into the pocket or can be actively retained with fastening means. A pouch-like pocket can be positioned either in the interior or on the exterior of cuff body 104. Pouch-like pocket 106 and/or cuff body 104 can include access openings to allow electrodes to be positioned directly proximate or adjacent to nerve 102.
Cuff body 104 can have a constant thickness or a varying thickness as depicted in
A key obstacle to overcome with implanting stimulation devices proximate nerves or nerve bundles is attaching a rigid structure that makes up the stimulation device along a fragile nerve in soft tissue. In one embodiment of the invention, this issue is resolved by encasing nerve 102 and device 108 in a cuff body 104 that comprises a low durometer material (e.g., Silastic™ or Tecothane™) as described above, that conforms around nerve 102. Further, as illustrated in
Given the design or architecture of cuff body 104, any vertical movement of cuff body 104 on nerve 102 is not critical to electrical performance, but can result in friction between device 108 and nerve 102 that could potentially damage nerve 102. For that reason, device 108 should readily move up and down nerve 102 without significant friction while being sufficiently fixated to nerve 102 so that eventually connective tissue can form and aid in holding device 108 in place. The challenge is stabilizing device 108 so that it can be further biologically stabilized by connective tissue within several weeks.
Nerve cuff 100 should not be rigidly stabilized to surrounding muscle or fascia that will shift relative to the nerve. Therefore, referring to
Several stabilizing mechanisms can be used, including suture tabs and holes, staples, ties, surgical adhesives, bands, hook and loop fasteners, and any of a variety of coupling mechanisms.
Muscle movement against cuff adapter 100 can also transfer undesired stresses on nerve 102. Therefore, in an embodiment of the invention, low friction surfaces and/or hydrophilic coatings can be incorporated on one or more surfaces of cuff body 104 to provide further mechanisms reducing or preventing adjacent tissues from upsetting the stability of nerve cuff 100.
As discussed supra, compression of nerve 102 must be carefully controlled. Excess compression on nerve 102 can lead to devascularization and resulting death of the neural tissue. Compression can be controlled by over-sizing or rightsizing nerve cuff 100, so that when pocket sutures 124 are maximally tightened, the nerve diameter is not reduced less that the measured diameter. Cuffs formed from Silastic™ or Tecothane™ materials are relatively low cost, and therefore several sizes can be provided to the surgeon performing the implantation of nerve cuff 100 to better avoid nerve compression.
Miniature stimulators, such as device, are still large enough to be felt and palpated by patients as are state-of-the-art commercial cuff systems. Referring to
When a nerve does not provide sufficient structural strength to support nerve cuff adapter 100, collateral structures can be included in or on cuff body 104. Because of a high degree of anatomical variance such a scheme must demand the skill of the surgeon to utilize a highly customizable solution.
The exemplary cuff shown in
For Example,
Both nerve cuff variations shown in
As can be seen from
As mentioned briefly above, in some variations of the nerve cuff, the inner surface of the cuff body includes one or more internal contacts configured to couple with the microstimulator held within the pouch, and transmit any applied energy to the nerve (or receive energy from the nerve) positioned within the channel through the nerve cuff. The internal lead may be positioned so that it applies current to the underside (along the bottom region of the channel), or around the sides of the nerve as it sits within the channel. In some variations the internal conductor or lead is configured around the channel so that the nerve may be circumferentially stimulated, optimizing the applied stimulation.
Many of the nerve cuff variations described herein may be opened and positioned around the nerve, for example, by splitting them open along a slit or hinge region. The device may be configured so that they have sufficient resiliency to close themselves, or remain closed if the edges of the slit region are brought together. Thus, the device may have a shape memory property that encourages them to close. In some variations, as already mentioned, it may be useful to hold them closed, at least temporarily, once they have been positioned over a nerve and the microstimulator has been positioned within the pocket. Thus, the device may include one or more closure elements. For example, the device may include a suture hole or passage for suturing the device closed. In some variations the nerve cuff includes a button or other fastener element. In some variations, as illustrated in
Any of the nerve cuffs described herein may also include one or more external leads or contacts facing the outside of the nerve cuff body, which may be used to stimulate tissues outside of the nerve cuff, and not just the nerve within the channel through the cuff.
A nerve may sit within a supported channel through the nerve cuff. As illustrated in
In general, the nerve cuff body may be electrically insulating, preventing leakage of charge from the microstimulator during operation. In some variations the nerve cuff includes shielding or insulation sufficient to electrically insulate the microstimulator within the nerve cuff body. Shielding material may particularly include electrically insulative materials, including polymeric insulators.
It may be shown mathematically using an equivalent circuit of the microstimulator, as shown in
For example, assuming a nerve with a cross section of Narea is surrounded by a column of fluid Farea enclosed by the nerve cuff, where contacts on the inside the microstimulator are spaced Espacing apart (center to center) and have a width Ewidth and circle around the column of fluid and nerve Edegrees, it can be shown that the current will leak out the ends through a distance between the center of the electrode and the end of the nerve cuff that is defined by a distance Dguard.
The electrical model (illustrated in
If the nerve has a tight fit, then all the current passing through Rs would contribute towards stimulation, but only a portion of the current can activate the nerve in the case of a loose fit. Based on this model, it can be shown that (assuming that the nerve and fluid columns form an ellipse defined by the major and minor axis a and b, and the pulse width is short and capacitances are large) just the real impedance and efficiency can be estimated.
The electrode surface area is determined to estimate the complex portion of the impedance: Farea=π*aF*bF and Narea=π*aN*bN.
Assuming the impedance of the cuff contained fluid and nerve has a similar conductance p and electrodes are spaced at Espacing then the real resistance of the conduction volume is: Rworking=Espacing*ρ/Farea, where the wasted resistance that should be maximized is calculated by: Rwasted=2*Dguard*ρ/Farea+Rbulk, where Rbulk is defined as the free field resistance between the two ends of the cuff.
So the efficiency (q) of the real current delivered in the POD is Rwasted (Rworking+Rwasted) and for the case of an undersized nerve assuming the conductivity of tissue and the fluid column is about equivalent then the stimulation efficiency is defined as ηT=η*Narea/Farea.
In operation, any of the devices described herein may be positioned around the nerve, and the microstimulator inserted into the nerve cuff, in any appropriate manner.
In some variations, a sizing tool may be used to measure the vagus (e.g., diameter) to select an appropriate microstimulator and cuff (e.g., small, medium, large). In some variations of the method, as described above, an oversized cuff may be used. The nerve cuff is then placed under the nerve with the opening into the nerve cuff facing the surgeon (
Systems for electrically stimulating one or more nerves to treat chronic inflammation may include an implantable, wireless microstimulator such as those described herein and an external charging device (which may be referred to as a charging wand, charger, or energizer). In some variations the system also includes a controller such as a “prescription pad” that helps control and regulate the dose delivered by the system. The microstimulator may be secured in position using a securing device (which may be referred to as a “POD”) to hold the microstimulator in position around or adjacent to a nerve. These microstimulators are designed and adapted for treatment of chronic inflammation, and may be configured specifically for such use. Thus, an implantable microstimulator may be small, and adapted for the low duty-cycle stimulation to modulate inflammation. For example, the implantable microstimulator may hold a relatively small amount of power over weeks or even months and discharge it at a rate sufficient to modulate the anti-inflammatory pathway without significantly depressing heart rate or triggering any number of unwanted effects from the vagus nerve or other neural connections. Any of the nerves of the inflammatory reflex, including the vagus nerve, may be treated as described herein using the systems described.
For example,
In general, the systems described herein may be configured to apply electrical stimulation at a minimum level necessary to modulate the inflammatory reflex (e.g., modulating cytokine release) characterized by the Chronaxie and rheobase. Chronaxie typically refers to the minimum time over which an electric current double the strength of the rheobase needs to be applied in order to stimulate the neuron. Rheobase is the minimal electrical current of infinite duration that results in an action potential. As used herein, cytokines refer to a category of signaling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communication.
The NCAP Systems described herein are typically intended for the treatment of chronic inflammation through the use of implanted neural stimulation devices (microstimulators) to affect the Neural Stimulation of the Cholinergic Anti-inflammatory Pathway (NCAP) as a potential therapeutic intervention for rheumatologic and other inflammation-mediated diseases and disorders. Neurostimulation of the Cholinergic Anti-inflammatory Pathway (NCAP) has been shown to modulate inflammation. Thus, the treatment and management of symptoms manifested from the onset of disease (e.g., inflammatory disease) is based upon the concept of modulating the Cholinergic Anti-inflammatory Pathway. The NCAP pathway normally maintains precise restraint of the circulating immune cells. As used herein, the CAP is a reflex that utilizes cholinergic nerve signals traveling via the vagus nerve between the brain, chemoreceptors, and the reticuloendothelial system (e.g., spleen, liver). Local release of pro-inflammatory cytokines (e.g., tumor necrosis factor or TNF) from resident immune cells is inhibited by the efferent, or indirectly by afferent vagus nerve signals. NCAP causes important changes in the function and microenvironment of the spleen, liver and other reticuloendothelial organs. Leukocytes which circulate systemically become “educated” as they traverse the liver and spleen are thereby functionally down regulated by the affected environment of the reticuloendothelial system. This effect can potentially occur even in the absence of an inflammatory condition.
Under this model, remote inflammation is then dampened by down-regulated cytokine levels. Stimulation of the vagus nerve with a specific regiment of electrical pulses regulates production of pro-inflammatory cytokines. In-turn, the down regulation of these cytokines may reduce localized inflammation in joints and other organs of patients with autoimmune and inflammatory disorders.
The NCAP System includes a neurostimulator that may trigger the CAP by stimulating the cervical vagus nerve. The NCAP System issues a timed burst of current controlled pulses with sufficient amplitude to trigger the CAP at a particular interval. These two parameters, Dose Amplitude and Dose Interval, may be used by a clinician to adjust the device. For example, the clinician may set the Dose Amplitude by modifying the current level. The Dose Interval may be set by changing the duration between Doses (e.g. 12, 24, 48 hours).
In some variations, dose amplitude may be set to within the Therapy Window. The Therapy window is defined as the lower limit of current necessary to trigger the CAP, and the upper limit is the level at which the Patient feels uncomfortable. The lower limit is called the Threshold (T), and the uncomfortable level is called Upper Comfort Level (UCL).
Dose Amplitude thresholds are nonlinearly dependent upon Current (I), Pulse width (PW), Pulse Frequency (PF), and Burst Duration (BD). Amplitude is primarily set by charge (Q), that is Current (I)×Pulse width (PW). In neurostimulation applications current has the most linear relationship when determining thresholds and working within the therapy window. Therefore, the clinician may modify Dose Amplitude by modifying current. The other parameters are held to experimentally determined defaults. Pulse width is selected to be narrow enough to minimize muscle recruitment and wide enough to be well above the chronaxie of the targeted neurons. Stimulus duration and pulse frequency was determined experimentally in Preclinical work.
Dose Interval may be specific for particular diseases and the intensity of diseases experienced by a patient. Our initial research has indicated that the cervical portion of the vagus nerve may be an ideal anatomic location for delivery of stimulation. The nerve runs through the carotid sheath parallel to the internal jugular vein and carotid artery. At this location, excitation thresholds for the vagus are low, and the nerve is surgically accessible. We have not found any significant difference in biomarker modulation (e.g., modulation of cytokines) between right and left. Even though the right vagus is thought to have lower thresholds than the left in triggering cardiac dysrythmias, the thresholds necessary for NCAP are much lower than those expected to cause such dysrythmias. Therefore a device delivering NCAP can safely be applied to either the right or left vagus.
We have also found, surprisingly, that the Therapy Window is maximized on the cervical vagus through the use of a bipolar cuff electrode design. Key parameters of the cuff may be: spacing and shielding of the contacts. For example, the contact points or bands may be spaced 1-2 diameters of the vagus nerve apart, and it may be helpful to shield current from these contacts from other nearby structures susceptible to inadvertent triggering. The cuff may be further optimized by using bands which are as long and wide as possible to reduce neurostimulator power requirements.
Thus, any variations of the systems described herein (e.g., the NCAP system) may be implemented with a Cuff, Lead and Implantable Pulse Generation (IPG), or a Leadless Cuff. The preferred implementation is a leadless cuff implemented by a microstimulator with integral electrode contacts in intimate contact with the nerve and contained within a Protection and Orientation Device (POD). This is illustrated in
Referring back to
As described in more detail in Ser. No. 12/874,171, titled “PRESCRIPTION PAD FOR TREATMENT OF INFLAMMATORY DISORDERS”, filed on Sep. 1, 2010, Publication No. US-2011-0054569-A1, previously incorporated by reference in its entirety, the Prescription Pad may incorporate workflows in a simplified interface and provide data collection facilities that can be transferred to an external database utilizing commercially robust and compliant methods and procedures. In use, the system may be recommended for use by a clinician after assessing a patient; the clinician may determine that treatment of chronic inflammation is warranted. The clinician may then refer the patient to an interventional doctor to implant the microstimulator. Thereafter then clinician (or another clinician) may monitor the patient and adjust the device via a wireless programmer (e.g. prescription pad). The clinician may be trained in the diagnosis and treatment procedures for autoimmune and inflammatory disorders; the interventional placement of the system may be performed by a surgeon trained in the implantation of active neurostimulation devices, with a sufficient depth of knowledge and experience regarding cervical and vagal anatomy, experienced in performing surgical dissections in and around the carotid sheath.
The system may output signals, including diagnostics, historical treatment schedules, or the like. The clinician may adjust the device during flares and/or during routine visits. Examples of implantation of the microstimulator were provided in Ser. No. 12/874,171, titled “PRESCRIPTION PAD FOR TREATMENT OF INFLAMMATORY DISORDERS”, filed on Sep. 1, 2010, Publication No. US-2011-0054569-A1. For example, the implant may be inserted by making an incision in the skin (e.g., ≈3 cm) along Lange's crease between the Facial Vein and the Omohyoid muscle, reflecting the Sternocleidomastoid and gaining access to the carotid sheath. The IJV may be displaced, and the vagus may be dissected from the carotid wall (≤2 cm). A sizing tool may be used to measure the vagus, and an appropriate Microstimulator and POD Kit (small, medium, large) may be selected. The POD may then be inserted under nerve with the POD opening facing the surgeon, so that the microstimulator can be inserted inside POD so that the microstimulator contacts capture the vagus. The POD may then be sutured shut. In some variations a Surgical Tester may be used to activate the microstimulator and perform system integrity and impedance checks, and shut the microstimulator off, during or after the implantation. In other variations the surgical tester may be unnecessary, as described in greater detail below.
A physician may use the Patient Charger to activate the microstimulator, perform integrity checks, and assure sufficient battery reserve exists. Electrodes may be conditioned with sub-threshold current and impedances may be measured. A Physician may charge the microstimulator. In some variations a separate charger (e.g., an “energizer”) may be used by the patient directly, separate from the controller the physician may use. Alternatively, the patient controller may include controls for operation by a physician; the system may lock out non-physicians (e.g., those not having a key, code, or other security pass) from operating or modifying the controls.
In general, a physician may establish safe dosage levels. The physician may slowly increment current level to establish a maximum limit (Upper Comfort Limit). This current level may be used to set the Dosage Level. The exact procedure may be determined during this clinical phase.
The Physician may also specify dosing parameters that specify dosage levels and dosage intervals. The device may contain several concurrent dosing programs which may be used to acclimate the patient to stimulus, gradually increase dosage until efficacy is achieved, reset tachyphylaxis, or deal with unique patient situations.
In some variations, the Prescription Pad may be configured to handle multiple patients and may index their data by the microstimulator Serial Number. For example, a Prescription Pad may handle up to 100,000 patients and 10,000 records per patient, and may store the data in its local memory and may be backed up on an external database. In some variations, during each charging session, accumulated even log contents will be uploaded to the Patient Charger for later transfer to Prescription Pad. The data may or may not be cleared from the microstimulator. For example,
The microstimulators described herein are configured for implantation and stimulation of the cholinergic anti-inflammatory pathway, and especially the vagus nerve. In particular the microstimulators described herein are configured for implantation in the cervical region of the vagus nerve to provide extremely low duty-cycle stimulation sufficient to modulate inflammation. These microstimulators may be adapted for this purpose by including one or more of the following characteristics, which are described in greater detail herein: the conductive capsule ends of the microstimulator may be routed to separate electrodes; the conductive capsule ends may be made from resistive titanium alloy to reduce magnetic field absorption; the electrodes may be positioned in a polymer saddle; the device includes a suspension (e.g., components may be suspended by metal clips) to safeguard the electronics from mechanical forces and shock; the device may include an H-bridge current source with capacitor isolation on both leads; the device may include a built in temperature sensor that stops energy absorption from any RF source by detuning the resonator; the device may include a built-in overvoltage sensor to stop energy absorption from any RF source by detuning resonator; the system may include DACs that are used to calibrate silicon for battery charging and protection; the system may include DACs that are used to calibrate silicon for precision timing rather than relying on crystal oscillator; the system may include a load stabilizer that maintains constant load so that inductive system can communicate efficiently; the system may include current limiters to prevent a current rush so that the microstimulator will power up smoothly from resonator power source; the system may extract a clock from carrier OR from internal clock; the device may use an ultra-low power accurate RC oscillator that uses stable temperature in body, DAC calibration, and clock adjustment during charging process; the device may use a solid state LIPON battery that allows fast recharge, supports many cycles, cannot explode, and is easy to charge with constant voltage; and the device may include a resonator that uses low frequency material designed not to absorb energy by high frequency sources such as MRI and Diathermy devices.
Many of these improvements permit the device to have an extremely small footprint and power consumption, while still effectively modulating the vagus nerve.
In some variations, including those described above, the microstimulator consists of a ceramic body with hermetically sealed titanium-niobium ends and integral platinum-iridium electrodes attached. The microstimulator may be designed to fit within a POD 2609, as shown in
As mentioned above, some of the device variations described herein may be used with a POD to secure the implant (e.g., the leadless/wireless microstimulator implant) in position within the cervical region of the vagus nerve so that the device may be programmed and recharged by the charger/programmer (e.g., “energizer”). For example,
Microstimulator Parameters
In some variations, the microstimulator may have a bipolar stimulation current source that produce as stimulation dose with the characteristics shown in table 1, below. In some variation, the system may be configured to allow adjustment of the “Advanced Parameters” listed below; in some variations the parameters may be configured so that they are predetermined or pre-set. In some variations, the Advanced Parameters are not adjustable (or shown) to the clinician. All parameters listed in Table 1 are ±5% unless specified otherwise.
The Dosage Interval is defined as the time between Stimulation Doses. In some variations, to support more advanced dosing scenarios, up to four ‘programs’ can run sequentially. Each program has a start date and time and will run until the next program starts. Dosing may be suspended while the Prescription Pad is in Programming Mode. Dosing may typically continue as normal while charging. Programs may be loaded into one of four available slots and can be tested before they start running Low, Typical, and High Dose schedules may be provided. A continuous application schedule may be available by charging every day, or at some other predetermined charging interval. For example, Table 2 illustrates exemplary properties for low, typical and high dose charging intervals:
The system may also be configured to limit the leakage and maximum and minimum charge densities, to protect the patient, as shown in Table 3:
In some variations, the system may also be configured to allow the following functions (listed in Table 4, below):
In some embodiments, a modified nerve cuff and electrode can be secured around the sub-diaphragmatic vagus nerve and the electrical stimulation can be delivered to the vagus nerve. For example, when using the nerve cuffs described herein, the slit on the nerve cuff can be opened to allow access to a channel for receiving the nerve. The nerve can be placed within the channel, and the slit can then be closed to secure the nerve within the channel of the nerve cuff.
A nerve cuff can include an electrode for sensing electrical signals, such as action potentials, to measure nerve activity of the nerve attached to the nerve cuff. Alternatively or additionally, as described above, remote sensors can be placed away from the nerve cuff at remote locations to sense electrical activity in nerves or nerve locations described herein. In some embodiments, the remote locations may be closer to the source of pain, such as near or at the extremities and joints.
Microstimulator Configurations
In order to improve the efficiency of power transfer from the charger to the microstimulator, various modifications can be made to the microstimulator. For example, the size of the receiving antenna within the microstimulator can be increased without increasing the size, and particularly the diameter, of the microstimulator. As described above, the receiving antenna can be made of a receiving coil that is wrapped around a magnetic core, as shown in
For example, in some embodiments, the receiving coil and magnetic core of the antenna can be incorporated into the housing of the microstimulator 103, as illustrated in
Examples of high magnetic permeability materials include ferrites, ferrite polymer composites, ferrite filled polymers, ferrite loaded rubber, and a ferrite tape. Other relatively high magnetic permeability materials that may be used include Mu-metal, iron, steel, and various metal alloys. In some embodiments, the high magnetic permeability materials have a relatively high intrinsic magnetic permeability that is greater than 10, 100, 1000, 10,000, or 100,000 times the magnetic permeability of a vacuum.
In some embodiments, as illustrated in
In other embodiments, as shown in
In some embodiments, as shown in
In some embodiments, the magnetic core has approximately the same diameter as the microstimulator. In other embodiments, the magnetic core can have a cross-section that is smaller than the cross-section of the microstimulator, such as about ¼, ⅓, ½, or ¾ the diameter of the microstimulator. In other embodiments, the magnetic core can have a cross-section that is larger than the diameter of the microstimulator, such as about 1.5, 2, 2.5, or 3 times the diameter of the microstimulator. In some embodiments, the magnetic core can have a cross-section that is similar in size and shape with the cross-section of the microstimulator.
In any of the embodiments disclosed herein, the high magnetic permeability material can have one or more slits to reduce eddy currents. In particular, if a conductive material is used for the high magnetic permeability material. Ferrite is an insulator, however if a conductive material (e.g. mu-metal, steel, amorphous/nanocrystalline magnetic alloy) is used, eddy currents can be reduced by breaking the current path, including introducing a gap or space. Depending on the geometry, this may be achieved by cutting slits, laminating thin layers of material, or using a powdered material in an insulating binder.
Charger
In some embodiments, the magnetic properties of the charger, and in particular, the housing surrounding the charger, may be modified to shape the field emitted by the charger for inductively charging the implant. In general, charging of the implant (e.g., inductively charging) may depend in part on the orientation and positon of the implant relative to the charging field. The methods and apparatuses described herein may improve the relationship between the inductive field and the implant. For example, the charger, which may be a wearable charger such a collar, necklace, or the like, or it may be hand-held charger, may be configured (and/or the charging portion of the implant may be configured) to raise the inductance and thus the quality factor (Q), potentially providing a greater power transfer between the applied charging field and the implant.
For example, the charger housing may include a material having a high magnetic field permeability, such as a ferromagnetic ceramic material (ferrite), ferrite-filled polymer, ferrite-embedded polymer, alloys of iron and nickel (e.g., commercially sold as Mumetal and Permalloy) and the like. These high-magnetic-permeability materials may concentrate and direct the magnetic field up from the charger (when worn on the neck, for example) towards the implant, and may help target the field in the neck and for reception by the implanted microcontroller.
For example, the microcontroller may be implanted so that it is generally oriented up and to the right, as shown in
By steering the field, e.g., up from the collar, the collar may be more comfortably worn around the base of the person's neck. This reduces the importance of placing the charger closer (e.g., directly over and/or adjacent to) the implant, which may be located up to several inches above the base of the neck, as show on in
In some variations, a high magnetic permeability material is included around the transmitting coil of the charger to concentrate and shape or direct the magnetic field through the transmitting coil and towards the receiving coil in the neurostimulator.
Examples of high magnetic permeability materials include ferrites, ferrite polymer composites, ferrite filled polymers, ferrite loaded rubber, and a ferrite tape. Other high magnetic permeability materials that may be used include Mu-metal, iron, steel, and various metal alloys. In some embodiments, the high magnetic permeability materials have a relatively magnetic permeability that is greater than 10, 100, 1000, 10,000 or 100,000 times the magnetic permeability of a vacuum.
In some embodiments as described above, the charger can include a transmitting coil that is worn around the neck in order to charge a neurostimulator that is positioned on the cervical portion of the vagus nerve. If the patient is sitting or standing during the charging process, the charger may end up resting on the lower portion of the neck while the neurostimulator is implanted in a higher portion of the neck. The transmitting coil in the charger can generate an electromagnetic field with field lines that run through the loop. A high magnetic permeability material can be added around the transmitting coil to concentrate and direct the field lines towards the neurostimulator. For example, the high magnetic permeability material can be added to the upper inner surface of covering around the transmitting coil in order to concentrate and direct the field lines upwards and inwards towards a neurostimulator located in the neck and above transmitting coil. In other embodiments, the high magnetic permeability material can be added just to the inner surface of the covering that faces the skin, or the high magnetic permeability material can be incorporated into the entire covering.
For example,
In other embodiments, the implant to be charged may be located in a different position with respect to the charger. For example, the implant may be located within the plane encircled by the transmitting coil of the charger. In this configuration, the high magnetic permeability material may be placed on the inside surface of the covering that faces the skin to concentrate the magnetic field inwards towards the implant. More generally stated, the high magnetic permeability material can be positioned around the transmitting coil partially on one or more sides of the coil. The implant may be above, below, or in line with the transmitting coil.
Thus, the charger may include a high magnetic field material on or within the charging housing, including in particularly on an inner face of all or a portion of the charger (e.g., on the inner, skin-facing surface when worn), on a top portion (e.g., where the top portion is closest to the patient's head when the charger is worn) or alternatively on a bottom portion (opposite the patient's head when the charger is worn). The high magnetic field material form a part of the outer housing of the charger, or it may be applied onto the outer housing. The high magnetic field material may be applied all the way around the charger or just around a portion of the charger.
For example, in some embodiments, the high magnetic permeability material can be integrated directly and permanently into the covering around the transmitting coil. In other embodiments, the high magnetic permeability material can be reversibly attached to the charger. For example, the high magnetic permeability material can be incorporated into an elastic sleeve that can be reversibly disposed over the charger and adjusted such that the high magnetic permeability material is correctly positioned, i.e., facing the implant. In other embodiments, the high magnetic permeability material can have a side covered with an adhesive so that the material can be adhered to the charger. In other embodiments, the high magnetic permeability material can have a latch or clamp or other fastener that can be used to reversibly attach the material to the covering around the transmitting coil.
In some embodiments, the high magnetic permeability material can be disposed around the patient's neck in a separate device, such as a sleeve, liner or collar, and the charger can be placed over the high magnetic permeability material device, as shown in
In some embodiments, where a conductive high-permeability material is used, in order to reduce eddy currents which reduce the efficiency of power transfer, the high magnetic permeability material (and/or in some variations the charger itself) can have one or more gaps or openings (e.g., slits). Alternatively, the high magnetic permeability material can be fabricated in a plurality of strips, slices, particles, grains, or powder that can then be incorporated into the covering or sleeve. Gaps in the high magnetic field material may spread out and/or re-orient the magnetic field over a region.
The systems described above can also be used to charge neurostimulators implanted in other parts of the body, such as the torso or limbs. The size of the charger can be made to fit around the body part, such as the torso, leg, or arm, and a high magnetic permeability material can be added as described herein to increase the efficiency of the power transfer.
Hand Held Charger
In some embodiments, the charger can be a hand held device with a high magnetic permeability material, such as a ferrite core, having a gap 4405 between two ends, as shown in
In general the size of the gap may be one to several time the length of the neurostimulator (e.g., between 0.8× to 3× the length of the neurotransmitter). For example, the size of the gap may be at least the length of the neurostimulator coil. The larger the gap, the longer the range of the charger.
Tester
Also described herein are tester apparatuses (testers) that may be used to monitor/test the implantable microregulator/microstimulator before, during or after implantation.
A surgical tester may be similar to a handheld charger as described above. For example, a charger may consist of a cylindrical ferrite core with copper windings. The core may be one to several times the length of the neurostimulator may be positioned adjacent and parallel to the neurostimulator to interact with the neurostimulator.
A tester apparatus may be used to test the microregulator/microstimulator (MR), as described in
A tester may include a probe (having a head) that is connected, e.g., via a cable, to a processor that controls (via inputs, e.g., user inputs such as buttons, switches, etc.) operation of the apparatus. For example, the tester may include outputs (e.g., LEDs, screen, etc.) showing the output mode(s) of the apparatus. For example, an apparatus may include overall status indicators (OK/error) and one or more indicators specific to the operational status (e.g., impedance—low, med, high, etc.). As shown in
The tester may include a neck that is flexible but may hold its shape (as shown in
Also described herein are non-wearable recharging devices and systems that can be used to wirelessly transmit power to a non-stationary wireless receiver contained within an implantable neurostimulation device. As just described, a recharging system may include a necklace, belt, sash or collar type coil that a patient could wear for recharging the implanted neurostimulation device. Recharging devices may also be configured as pads, mattresses, or the like, so that a patient may reline on them for recharging. For example, any of these devices (shown below as ‘pillow’ devices may be configured as a pad or chair for lying/sitting on. The implantable neurostimulator device may be recharged while the patient is resting or sleeping.
The pillow recharger includes a transmitter that is able to provide a relatively uniform electromagnetic field within a given region such that the receiver module in the implantable neurostimulation device, which may include a receiving antenna made of a coil wrapped around a magnetic core, will be exposed to approximately the same amount of energy regardless of the positioning of the patient's head and neck relative to the recharging pillow. To inductively charge the neurostimulator, the transmitter generates an electromagnetic field with field lines that are approximately parallel with the axis of the coil of the receiving antenna, which allows the field lines to extend through the loops of the coils. In other embodiments, the electromagnetic field may not be relatively uniform.
Turning to
In other non-limiting variations, there may be two separate coils that produce a resultant electromagnetic field that goes up along one direction of the z-axis and then arcs down and goes in the opposite direction of the z-axis and has a horizontal component that extends between the two coils. As described above, this can be achieved by running the current in opposite directions for each coil (clockwise in one coil and counterclockwise in the other coil). In yet other examples, there may be multiple transmitter coils that are able to provide the desired resulting electromagnetic field patterns as described earlier. In some variations, it may also be possible to detect which of these sets of coils is most strongly coupled to the receiving antenna, and run current through only that set of coils.
Finally, while in both
The transmitter coil 4104 may also be supported with a backing or support for maintaining the shape of the transmitter coil. While the backing may be of any suitable material, it may be advantageous to select a material that can aid in maintaining a near uniform field distribution over the transmission coils. Thus, materials like aluminum or any other suitable electromagnetic reflective material or materials may be desirable. The backing may be a solid sheet of material or materials or the backing may include holes or perforations. The spacing of the transmitter loops may be adjusted to achieve nearly uniform field distribution over the figure eight coils. In some examples, the transmitter coil backing may include protrusions or couplers to better maintain the shape of the transmitter coils.
As previously alluded to, the transmitter coil is part of a resonant circuit tuned to a particular frequency or may allow for some tuning to maximize the energy transfer between the external wireless transmitter and the implanted receiver coil. Because the transmitter coil may be affected by its surroundings that in turn may alter its resonant frequency, such as when the implantable receiver coil is moved closer or farther away in proximity, in some instances, shielding using a highly magnetically permeable and/or conductive material may be employed. A shielding material, such as a ferrite sheet, or a sheet made of another high magnetic permeability material, that may be part of a support structure for the transmitter coils may offer greater energy transfer properties in addition to shielding from potentially interruptive materials in the vicinity of the recharging pillow.
The wireless power transmitter 4102 may also include a power generator and related circuitry for providing power to the transmitter coil.
When the implantable neurostimulator requires charging, the included wireless receiver may transmit a signal to the wireless power transmitter that would initiate an initiating signal which turns the power generator on. The power generator now can supply energy (drive signal) to create an alternating magnetic field that oscillates within a threshold of the desired resonant frequency. The resonant frequency may be tuned by adjusting the coil spacing and dimensions. In some variations, tuning may be achieved by adjusting the capacitance in the LC circuit, e.g. by switching in additional capacitance using FETs.
Turning to
Next, there may also be a level of intelligent control based on the position of the wireless receiver module. Because the wireless receiver module (e.g., implant) position does not necessarily remain stationary on the pillow charger during charging, it may be advantageous to be able to determine where the wireless receiver module is in relation to the wireless transmitter. The regions of the wireless transmitter may be delineated into regions, including quadrants, where each region may have a unique identifier (e.g., which corresponds to a specific region of the wireless transmitter when the wireless receiver is above it). When actively charging, the wireless receiver may ascertain a tag associated with the particular wireless transmitter region and adjust the power output such that the energy sent to the wireless receiver remains essentially constant even if the position of the wireless receiver module has changed. In some embodiments, each region may have its own set of transmitter coils that can be separately powered. Any of the various sets of coils may be used to address various angular orientations as well as spatial positions.
A wireless power transmitter may be connected to either an internal or external power supply. The wireless power transmitter may also include a controller for manual control of the recharger. A user will be able to power ON or OFF the pillow charger or select a time period for charging or allow the system to automatically turn on for charging and OFF when done.
The wireless power transmitter may also include sensors or indicators. Sensors and indicators may be of the type that alerts the user as to when charging is required or when charging is complete. Sensors may include temperature sensors that monitor the temperature of the pillow at its surface or near surface. Because the wireless recharging system is incorporated into a pillow, it may be desirable to be able to silence certain indicators so not to disturb the user's sleep. In other instances, certain indicators may not be silenced, such as in the case of a temperature sensor alarm that alerts the user of overheating at the pillow surface.
The wireless power receivers contained within the implantable neurostimulation unit, as the term suggests, receives inductive power from the wireless power transmitter. Going back to
While the transmitter coil and receiver coil alignment as shown in the figures will successful charge for the majority of the various sleep orientations, there may be patient sleep orientations that increases the distance between the wireless transmitter coil and the wireless power receiver (e.g. patient sleeps on their stomach or patient sleeps with an arm under their head). Thus alternatively, it may be useful to have a receiver coil that is able to receive energy transmission even if the orientation of and the distance between the transmission and receiver coils are not optimal. In these variations, the receiver coil may be a multi-axes wireless power receiver coupled to a circuit board, where the circuit board includes circuitry for functional components such as controllers, sensors, logic, and so forth. The multi-axes power receiver may include a support structure onto which the wires may be wrapped along more than one axes to achieve proper resonance matching with the wireless power transmitter. The support structure may be composed of a ferrite sheet or plate of any suitable shape. The support structure may include notches or protrusions for retaining the wrapped wire coils. The wrapped wire coils may also be wrapped around the exterior of the support structure. In some examples, the wires may be wrapped in a combination of directions from top to bottom and side to side, around the support structure, and so forth. The number of turns of the wire for each axes may be variable, such as 10 turns, 20 turns, 30 turns, and so forth. The corresponding antennae outputs may each be connected in parallel, having a value where each coil resonates at the driving frequency of the wireless transmitter, e.g., when the antenna outputs are rectified prior to being connected in parallel. The outputs may also be kept separate.
In some instances, the wireless receiver also includes a capacitor or a battery that will be able to store the power received through the wireless power receiver module 4150.
With the figure eight transmitter coil configuration, in some embodiments, the electro-magnetic field created passes out the top portion of the one of the coil halves of the figure eight and then drops down into the other coil halve of the figure eight.
Because the charger described herein may communicate (e.g., recharge) the implantable neurostimulation device while the patient is lying or sleeping on the charger, it is desirable that the wireless transmitter units (including the coil, supporting circuitry, power supply, and other components) remain at a safe temperature to avoid burning the patient (especially when the patient's senses will be slow to respond to such stimuli due to sleep). In some instances, temperature sensors may be included at various locations at or near the pillow surface to ensure that an upper threshold temperature is never reached. The system may also include a cooling mechanism that is able to bring the temperature of pillow down to a safe level if the temperature sensor detects overheating. (In other variations, a flux concentrator may be incorporated into the receiving coil, such that when the temperature exceeds the Curie temperature for the flux concentrator material, the flux concentrator loses their magnetic properties and thereby de-tunes the resonant inductive coupling of the wireless receiver with the wireless power transmitter.)
Note that the inductive communication between the charger and the implants described herein may refer to both charging of the implant from the energy emitted by the charger and communication of information between the two, including in particular, commands for stimulation protocols from a separate controller (e.g., the “prescription pads” described above, which may be a handheld processor such as a smartphone, pad, wearable, etc.). Information from the implant may also be communicated inductively; a communication signal from the charger to the implant may ride on top of the power signal (e.g., may modulate the power signal) or it may be separate from it.
Another consideration for the chargers described herein may be that the internal wireless transmitter components may be protected from a certain amount of force when the patient places their body (e.g., abdomen, torso, head, etc.) on the recharging pillow. Adequate cushioning in the way of sealed air compartments or cushioning materials (e.g. cotton, polyester fill, foam, gels) may be used to further pad and protect the areas around the wireless transmitter module. It may also be desirable to enclose the wireless transmitter module in a waterproof covering to prevent moisture from reaching the transmitter components.
Overall, the pillow recharger may be configured to feel like a traditional pillow cover, e.g., made of natural and/or synthetic fibers. The pillow recharger may include cushioning fill of either natural or synthetic fibers. Note that any of the “pillow” chargers described herein may be configured for charging an implant implanted sub-diaphragmatically, as mentioned above. Thus, these chargers may be configured as mattresses, pads, backrests, seats, etc. for communicating with the implant. Thus, although referred to as a pillow charger, the charger can take a form other than a pillow for a patient's head, such as a pad that can be placed under any portion of the patient to inductively charge an implant located in various locations of the body.
Batteryless Microstimulators
Any of the microstimulators described herein may be configured as batteryless implants. Such implants may provide VNS (vagal nerve stimulation) only when in the presence of a sufficient inductive filed. Such implantable microstimulators/microregulators (MS/MR) can be used to electrically stimulate a nerve such as the vagus nerve for therapeutic purposes, including for treatment of chronic inflammation, such as rheumatoid arthritis and Crohn's disease, by providing neurostimulation of the cholinergic anti-inflammatory pathway. Sub-diaphragmatic stimulation may be particularly well-suited to the use of a batteryless implant, which may be smaller, and lighter without the battery, however it may pose specific challenges, including matching the orientation and identifying such devices. For any of the apparatuses and method described herein, vagus nerve stimulation can also be used to treat other conditions, such as modulating sirtuins levels as described in U.S. Patent Application Publication No. 2013/0079834 to treat a variety of disease and conditions, or modulating levels of Receptor Activator for Necular Factor kB Ligand (RANKL) and/or osteoprotegerin (OPG) for bone erosion or treatment/prevention of cancer as described in U.S. Patent Application Publication No. 2013/0253413. Treatment of epilepsy, depression, headaches, and other neurological disorders can also be accomplished through vagus nerve stimulation.
Various battery-based MR for electrically stimulating a nerve, such as the vagus nerve, have been previously described in U.S. Pat. Nos. 8,612,002 and 8,886,339, herein incorporated by reference it their entireties, and in the examples provided above. Advantages of a battery based MR include automatic dosing, which leads to increased patient compliance to prescribed treatments and increased ease of use. In addition, a battery based MR can more conveniently automatically provide multiple stimulations per day when compared to a batteryless MR which may need patient action for each stimulation. In addition, a battery based MR can include sensor feedback from a motion sensor or a sensor to measure heart rate for closed loop stimulation as further described in U.S. Provisional Patent Application No. 62/286,957, filed on Jan. 25, 2016, and U.S. Provisional Patent Application No. 62/340,950, filed on May 24, 2016, each of which is herein incorporated by reference in their entireties.
As an alternative to a battery based MR, in some embodiments the MR can be batteryless. Since the MR does not have a battery, another device, such as an energizer, is provided to power the MR. Since the batteryless MR is a passive device until powered by the energizer, a patient reminder feature is preferably provided to the energizer or another device, such as a smart watch or a smartphone that can be worn or carried by the patient.
One advantage of a batteryless MR over a battery based MR is a lower cost. The parts for the batteryless MR can be much lower cost than the parts of a battery based MR, as the battery alone may add substantial cost. Another advantage is that the size of the batteryless MR can be about ⅓ the volume as a battery based MR, which allows the batteryless MR to be applied to many other nerves, particularly smaller nerves. As described below, a mold insert for a silicon overmold can be used to set the size of the nerve channel for the MR. Smaller size also facilitates the use of endoscopic and/or laparoscopic procedures for implantation. In addition, the reduced electrical components and the materials used allow the batteryless MR to be tested under accelerated life tests that can be run at 90 degrees Celsius. The tradeoff is that implant life may be reduced as compared to a hermitic battery based MR, depending on the properties of the materials used to fabricate the batteryless MR. Since an external energizer is used to deliver electrical stimulus through the batteryless MR, it may rely on manual operation rather than autonomous operation, because the batteryless MR may generally not be powered unless in proximity to an external energizer. A separate sensor such as an ECG device may be worn to measure continuously (e.g., even when not in the inductive field), e.g., to measure heart rate variability (HRV) or other parameters, for example.
The PCB 5400 and electrical components 5408 can form one layer and a ferrite layer 5404 can be disposed against and/or attached to the PCB layer. In some embodiments, surface mounted components can be soldered on only one side, such as the top side, using only solder. A coil 5410 for power transmission and communication can be wrapped around the PCB 5400 and ferrite 5404 layers. In some embodiments, the coil is made of gold wire or traces. Addition of the ferrite layer improves the efficiency of power transfer and communication signal strength. In other embodiments, the coil is wrapped around a ferrite core, such as a ferrite rod, which can be separate from the PCB. The use of ferrite may allow low frequency power transfer and communication.
The electrodes 5402, which may be spring cut to aid in deployment, can be attached to and/or in electrical communication with the PCB 5400. The electrodes 5402 can made of a platinum alloy (i.e., platinum-iridium) coated metal (i.e., gold traces) that can be encapsulated or sheathed within a polymer such as liquid crystal polymer (LCP). The LCP can provide the metal tracings that form the electrode with support and structure so that the electrodes can maintain the appropriate shape as defined by, for example, the mandrel. The LCP can be melted at 200° C. to encapsulate the electrodes, conductive traces, the PCB with its associated electronics, the coil, and the ferrite. The ferrite can also be coated with a polymer, such as parylene-C. The polymer coatings and/or sheath 412 provides physical support and protection for the various components and provides electrical insulation to the components and stops or reduces undesired or unintended current between electrical components and to wrong tissues in the patient's body. In addition, the polymer coatings, and particularly the LCP, can be used to embed any toxic materials in the electrical components, thereby preventing or greatly reducing the leaching of toxic materials in the patient.
In some embodiments, the batteryless MR is non-hermetic. In this embodiment, the electrodes are not encapsulated by LCP and are instead encapsulated with a standard polymer sheath.
In order to control delivery of electrical current from the electrodes, selective openings or windows 5414 can be created in the polymer coating or sheath 5412, by overmolding or selective application of the polymer, to expose a portion of the electrode. Each electrode can have one or more openings in the polymer coating to expose the platinum alloy coated metal electrode. In some embodiments, the openings can be up to about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 mm2. The current density of the electrodes through these openings can be up to about 0.25, 0.5, 1.0, 1.5, 2.0 mA/mm2.
In some embodiments, the PCB 5510, electrodes 5502, and cuff portion are formed initially into a flat, planar structure, as shown in
After the PCB is molded around the mandrel, the PCB can be cooled and the mandrel can be removed so that a silicon overmold 5700 can be applied over the LCP coated 5500/5506 PCB 5510 and electronics 5504, as shown in
Similar to
After implantation of the batteryless MR at or around a nerve, such as the vagus nerve, the MR can be operated by applying an RF power signal at the resonant frequency to charge up C4 to a set, desired, or predetermined voltage, such as 10V. In some embodiments, charging is relatively quick and can take about 0.5 seconds, or less than 1, 2, 3, 4, or 5 seconds. An external energizer that can be handheld or worn around the body part of the MR, such as the neck, can be used to generate the RF power signal to power and charge the MR. In some embodiments, the energizer can be a powered coil that can be worn around the body part with the MR such that the coil encircles the MR, and the energizer generates an electromagnetic field that inductively charges the MR. However, since the power requirements of the batteryless MR is generally much less than a battery based MR, a handheld energizer with a pancake coil that can be pressed against the body part with the MR may be used instead of a coil that is worn around the body part with the MR.
After the MR is charged up, the MR-MCU can start delivering the electrical stimulus to the nerve, in the form of a sub-burst for example, and can return an acknowledgement and an impedance measurement to the external energizer. The impedance measurement can be used to determine whether the electrodes are in good contact with the nerve. A higher than normal or expected impedance measurement may indicate poor electrode contact. The MR-MCU can also log the success or failure of delivering the sub-burst and can also transmit this information to the energizer. The MR-MCU can complete at least one 1-3 second stimulus sub-burst using the power stored in the array of capacitors, meaning that even if RF power transmission of the energizer fails, the delivery of the full sub-burst can be completed once the capacitors are sufficiently charged, such as being charged to about 10V. Although a 1-3 second sub-burst is described, longer sub-bursts can also be achieved by increasing the capacity of the capacitors and/or by increasing the number of capacitors in parallel. For example, if C4 (array of capacitors in parallel) is charged up to 10V by the Energizer, the Energizer or the MR-MCU itself can instruct the MR to deliver a second sub-burst immediately after delivering the first sub-burst so that a complete burst formed of back-to-back sub-bursts can be delivered. In some embodiments, more than two sub-bursts can be delivered consecutively by, for example, increasing the energy capacity of C4. After the sub-burst and/or complete burst is delivered, the MR-MCU and/or energizer can log the delivery of the stimulus for patient compliance tracking and monitoring onto non-volatile memory of the MR. In some embodiments, once a sub-burst is initiated, it goes to completion, so a shorter duration sub-burst may be preferred, such as less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds, since a shorter sub-burst allows the stimulation to be stopped more quickly if a problem with stimulation is detected.
L1, CT1 and CT2 form a tank circuit that resonates at about 131 KHz. D5 & D7 prevents the tank from going beyond 16V. C2, D4, & D6 form at voltage doubler and impedance matcher. C9-12 stores enough energy for about 5-30 seconds of electrical stimulation, depending on the stimulation amplitude applied. R6 & R8 scale downs PWRIN voltage to be read by the MCU. Q1A shorts the Tank if the temperature as measured by RT1 exceeds a predetermined or set temperature, such as 41.5 C. C3, R2, R3, D1 & C5 extract the AM modulated carrier to extract incoming data. CMP1 slices the data that feeds into the UART RX line. Q2 receives UART TX line and modulates carrier with return data. U1 regulates PWRIN that ranges from 3.4-16V to 3.3V. DAC2 ramps voltage up to 3.3V and GPOB12 holds high during stimulation to save power and then DAC2 ramps down to 0V. DAC1 drives a voltage to current converter (OPAMP, Q4 & R7) to drive stimulation electrodes where C4 protects against DC and D2 recovers stimulation pulse. ADC1_IN4 measures compliance voltage where impedance can be calculated. The MCU stimulates the patient and communicates with the Energizer only when the Energizer is attached.
In some embodiments, the power transfer and magnetics features or requirements of the MR may include, for example, selecting a shape and size for the magnetic core or ferrite 900, as shown in
In some embodiments, the Energizer or another computing device can communicate directly with the MCU hardware bootloader of the MR. The communications protocol can be RS232: 8 bit and parity NRZ at 2,400-4,800 bps. In some embodiments, the communications reliability can be improved by using inverse IrDA because response telemetry can reduce carrier cutout. Physical security as provided by the loop prevents unauthorized access that can result in overwritten and/or corrupted data, which is recoverable. Because the power signal is used for power transfer and communications, there is a tradeoff between power transfer and communication speed, meaning some power transfer may be sacrificed to increase communication speed. Examples of RS232 and IrDA signals for communication are illustrated in
Implantation
The benefit of removing the sheath and optionally separating the vessel from the nerve is that such separation may allow cleaner, closer and more direct contact of the electrodes with the target nerve, which allows the nerve to be stimulated using a lower level of current and/or voltage. For example, testing has shown that removal of the carotid sheath from the vagus nerve can allow stimulation of the vagus nerve using a 5 to 10 fold lower level of current compared to stimulation through the carotid sheath. For a battery based MR, the reduction in current level and/or voltage level allows the MR to be used longer before recharge for a given battery capacity, and/or allows the MR to use a lower capacity battery which can reduce the size of the MR and reduce manufacturing costs. For a batteryless MR, lower current and/or voltage levels can reduce the number and/or capacity of the capacitors used for delivering the electrical stimulus, which can reduce the material costs and the time needed to charge the capacitors before delivering an on-demand type stimulation. Also, in general, using lower current and/or voltage to stimulate the nerve is generally desirable to reduce tissue damage and inadvertent stimulation of other nerves or tissues within or near the sheath, such as baroreceptors.
The batteryless MR can be implanted to the target nerve using various surgical procedures, including minimally invasive procedures such as a laparoscopic procedure as shown in
For example, the batteryless MR 1300 can be delivered using a laparoscopic delivery tube 1302 with an optional removable sheath 1304, which can be used to prop open the cuff portion of the MR. The batteryless MR 1300 can be loaded within the distal end of the laparoscopic delivery tube 1302 at a temperature below body temperature, such as at ambient temperature (i.e., about 23 degrees C.) or colder. At this temperature, the Nitinol struts 1306 within the cuff portion of the MR 1300, as also shown in
Although the laparoscopic procedures described herein can also be adapted and used for cervical placement of the MR on, for example, the cervical portion of the vagus nerve, the laparoscopic procedures are particularly suited for placement of the MR in the thorax and other areas below the neck. For example, the laparoscopic procedure can be used for placement of the MR on the sub-diaphragmatic portion of the vagus nerve. Sub-diaphragmatic placement on the vagus nerve in contrast to cervical vagal placement may result in fewer side effects such as avoiding laryngeal adverse events (change or loss of voice) and avoiding changes to the heart rate and other changes to the cardiovascular system because the stimulation site is downstream of the portion of the vagus nerve that innervates the heart. In addition, a laparoscopic procedure in the thorax, which is typically covered by clothing, avoids creating a scar on a highly visible area such as the neck. Other advantages of a laparoscopic procedure include the ability to perform the procedure in an outpatient surgery and reduced costs as compared to traditional hospital based surgery where the patient remains for one or more days and/or nights. Furthermore, sub-diaphragmatic placement may result in less undesirable muscle stimulation and the resulting pain. The laparoscopic procedure, which may be adapted for use with a MR with a battery, is particularly suited for delivering the smaller batteryless MR, which may also lack a hermetic seal that may limit the operation lifetime of the MR to about 5 to 10 years. A batteryless MR implanted within the thorax can be used with a chest strap type energizer that can be adapted from the energizer worn around the neck as previously described in U.S. Pat. Nos. 8,612,002 and 8,886,339. The chest strap energizer can have a power source and a coil that extends through the strap to encircle the patient's chest when worn. Any of the chargers described herein may be used with these devices. For example, as shown in
After the implantation site has been prepared, by for example dissecting the nerve from the sheath and blood vessels, a trocar 1614 or catheter or other access device, which can have a lumen for receiving the insertion tool 1600, can be inserted into the patient and advanced near the target site using conventional techniques. The trocar 1614, catheter, or other access device may have already been inserted into the patient during the preparation of the implantation site, in which case the preexisting access device can be used instead. As shown in
To hold the MR in place while the insertion tool is extracted, a MR stabilizing device can be advanced to the MR to abut against the proximal end of the MR and/or to grasp a portion of the MR as the MR receiving portion of the insertion tool is retracted in a proximal direction. In some embodiments, the MR stabilizing device may be advanced over the shaft of the insertion tool and/or may be integrated into the insertion tool as a component that can be advanced and retracted relative to the shaft of the insertion tool. In some embodiments, the MR stabilizing device can have a distal end that is arched with a U-shaped cross-sectional profile that is similar in shape with the MR receiving portion, except that the U-shaped cross-sectional profile of the distal end of the MR stabilizing device can be slightly larger than the size of the MR receiving portion of the insertion tool so that the MR receiving portion can be retracted within or through the U-shaped portion of the MR stabilizing device while the MR stabilizing device abuts against the MR.
Alternatively, the MR stabilizing device can be positioned to abut against the MR during loading of the MR onto the insertion tool. The insertion tool and the MR stabilizing device can both be inserted through the access device, such as the trocar illustrated herein, and advanced to and positioned over the nerve as described herein. To deploy the MR, the MR receiving portion of the insertion tool can be retracted while the MR stabilizing device is held in place.
In some embodiments, the MR stabilizing device can have a different shaped cross-section, such as rectangular, square, or curved, that can be aligned and/or abutted against a portion of the MR, such as the portion with the PCB and electronic components.
As shown in
When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.
Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”.
Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.
In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and/or steps may alternatively be exclusive, and may be expressed as “consisting of” or alternatively “consisting essentially of” the various components, steps, sub-components or sub-steps.
As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.
The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.
This patent application is a continuation of U.S. patent application Ser. No. 16/356,906, titled “BATTERYLESS IMPLANTABLE MICROSTIMULATORS,” filed Mar. 18, 2019, now U.S. Patent Application Publication No. 2019/0275328, which claims priority as a continuation-in-part to U.S. patent application Ser. No. 15/411,936, titled “IMPLANTABLE MICROSTIMULATORS AND INDUCTIVE CHARGING SYSTEMS,” filed on Jan. 20, 2017, now U.S. Pat. No. 10,314,501, which claims priority to U.S. Provisional Patent Application No. 62/281,029, titled “SUB-DIAPHRAGMATIC STIMULATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY,” filed on Jan. 20, 2016; U.S. Provisional Patent Application No. 62/286,940, titled “PILLOW CHARGER FOR IMPLANTABLE NEURAL STIMULATION DEVICES,” filed on Jan. 25, 2016; U.S. Provisional Patent Application No. 62/286,943, titled “NEURAL STIMULATION DEVICES AND SYSTEMS,” filed on Jan. 25, 2016; and U.S. Provisional Patent Application No. 62/286,945, titled “INDUCTIVE CHARGERS FOR NEURAL STIMULATION DEVICES,” filed on Jan. 25, 2016. Each of these patent applications is herein incorporated by reference in its entirety. This application may also be related to one or more of: U.S. patent application Ser. No. 14/887,192, titled “NEURAL STIMULATION DEVICES AND SYSTEMS FOR TREATMENT OF CHRONIC INFLAMMATION”, filed on Oct. 19, 2015, Publication No. US-2016-0038745-A1 and Patent Cooperation Treaty (PCT) Application No. PCT/US2016/032169, titled “EXTERNAL PROGRAMMER”, filed on May 12, 2016, Publication No. WO2016/183353. Each of these patent applications is herein incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2164121 | Pescador | Jun 1939 | A |
| 3363623 | Atwell | Jan 1968 | A |
| 3631534 | Hirota et al. | Dec 1971 | A |
| 4073296 | McCall | Feb 1978 | A |
| 4098277 | Mendell | Jul 1978 | A |
| 4305402 | Katims | Dec 1981 | A |
| 4503863 | Katims | Mar 1985 | A |
| 4573481 | Bullara | Mar 1986 | A |
| 4590946 | Loeb | May 1986 | A |
| 4632095 | Libin | Dec 1986 | A |
| 4649936 | Ungar et al. | Mar 1987 | A |
| 4702254 | Zabara | Oct 1987 | A |
| 4840793 | Todd, III et al. | Jun 1989 | A |
| 4867164 | Zabara | Sep 1989 | A |
| 4929734 | Coughenour et al. | May 1990 | A |
| 4930516 | Alfano et al. | Jun 1990 | A |
| 4935234 | Todd, III et al. | Jun 1990 | A |
| 4979511 | Terry, Jr. | Dec 1990 | A |
| 4991578 | Cohen | Feb 1991 | A |
| 5019648 | Schlossman et al. | May 1991 | A |
| 5025807 | Zabara | Jun 1991 | A |
| 5038781 | Lynch | Aug 1991 | A |
| 5049659 | Cantor et al. | Sep 1991 | A |
| 5073560 | Wu et al. | Dec 1991 | A |
| 5106853 | Showell et al. | Apr 1992 | A |
| 5111815 | Mower | May 1992 | A |
| 5154172 | Terry, Jr. et al. | Oct 1992 | A |
| 5175166 | Dunbar et al. | Dec 1992 | A |
| 5179950 | Stanislaw | Jan 1993 | A |
| 5186170 | Varrichio et al. | Feb 1993 | A |
| 5188104 | Wernicke et al. | Feb 1993 | A |
| 5203326 | Collins | Apr 1993 | A |
| 5205285 | Baker, Jr. | Apr 1993 | A |
| 5215086 | Terry, Jr. et al. | Jun 1993 | A |
| 5215089 | Baker, Jr. | Jun 1993 | A |
| 5222494 | Baker, Jr. | Jun 1993 | A |
| 5231988 | Wernicke et al. | Aug 1993 | A |
| 5235980 | Varrichio et al. | Aug 1993 | A |
| 5237991 | Baker et al. | Aug 1993 | A |
| 5251634 | Weinberg | Oct 1993 | A |
| 5263480 | Wernicke et al. | Nov 1993 | A |
| 5269303 | Wernicke et al. | Dec 1993 | A |
| 5299569 | Wernicke et al. | Apr 1994 | A |
| 5304206 | Baker, Jr. et al. | Apr 1994 | A |
| 5330507 | Schwartz | Jul 1994 | A |
| 5330515 | Rutecki et al. | Jul 1994 | A |
| 5335657 | Terry, Jr. et al. | Aug 1994 | A |
| 5344438 | Testerman et al. | Sep 1994 | A |
| 5351394 | Weinberg | Oct 1994 | A |
| 5403845 | Dunbar et al. | Apr 1995 | A |
| 5458625 | Kendall | Oct 1995 | A |
| 5472841 | Jayasena et al. | Dec 1995 | A |
| 5487756 | Kallesoe et al. | Jan 1996 | A |
| 5496938 | Gold et al. | Mar 1996 | A |
| 5503978 | Schneider et al. | Apr 1996 | A |
| 5531778 | Maschino et al. | Jul 1996 | A |
| 5540730 | Terry, Jr. et al. | Jul 1996 | A |
| 5540734 | Zabara | Jul 1996 | A |
| 5567588 | Gold et al. | Oct 1996 | A |
| 5567724 | Kelleher et al. | Oct 1996 | A |
| 5571150 | Wernicke et al. | Nov 1996 | A |
| 5580737 | Polisky et al. | Dec 1996 | A |
| 5582981 | Toole et al. | Dec 1996 | A |
| 5604231 | Smith et al. | Feb 1997 | A |
| 5607459 | Paul et al. | Mar 1997 | A |
| 5611350 | John | Mar 1997 | A |
| 5618818 | Ojo et al. | Apr 1997 | A |
| 5629285 | Black et al. | May 1997 | A |
| 5637459 | Burke et al. | Jun 1997 | A |
| 5651378 | Matheny et al. | Jul 1997 | A |
| 5654151 | Allen et al. | Aug 1997 | A |
| 5683867 | Biesecker et al. | Nov 1997 | A |
| 5690681 | Geddes et al. | Nov 1997 | A |
| 5700282 | Zabara | Dec 1997 | A |
| 5705337 | Gold et al. | Jan 1998 | A |
| 5707400 | Terry, Jr. et al. | Jan 1998 | A |
| 5709853 | Iino et al. | Jan 1998 | A |
| 5712375 | Jensen et al. | Jan 1998 | A |
| 5718912 | Thompson et al. | Feb 1998 | A |
| 5726017 | Lochrie et al. | Mar 1998 | A |
| 5726179 | Messer, Jr. et al. | Mar 1998 | A |
| 5727556 | Weth et al. | Mar 1998 | A |
| 5733255 | Dinh et al. | Mar 1998 | A |
| 5741802 | Kem et al. | Apr 1998 | A |
| 5773598 | Burke et al. | Jun 1998 | A |
| 5786462 | Schneider et al. | Jul 1998 | A |
| 5788656 | Mino | Aug 1998 | A |
| 5792210 | Wamubu et al. | Aug 1998 | A |
| 5824027 | Hoffer et al. | Oct 1998 | A |
| 5853005 | Scanlon | Dec 1998 | A |
| 5854289 | Bianchi et al. | Dec 1998 | A |
| 5902814 | Gordon et al. | May 1999 | A |
| 5913876 | Taylor et al. | Jun 1999 | A |
| 5916239 | Geddes et al. | Jun 1999 | A |
| 5919216 | Houben et al. | Jul 1999 | A |
| 5928272 | Adkins et al. | Jul 1999 | A |
| 5964794 | Bolz et al. | Oct 1999 | A |
| 5977144 | Meyer et al. | Nov 1999 | A |
| 5994330 | El Khoury | Nov 1999 | A |
| 6002964 | Feler et al. | Dec 1999 | A |
| 6006134 | Hill et al. | Dec 1999 | A |
| 6017891 | Eibl et al. | Jan 2000 | A |
| 6028186 | Tasset et al. | Feb 2000 | A |
| 6051017 | Loeb et al. | Apr 2000 | A |
| 6083696 | Biesecker et al. | Jul 2000 | A |
| 6083905 | Voorberg et al. | Jul 2000 | A |
| 6096728 | Collins et al. | Aug 2000 | A |
| 6104956 | Naritoku et al. | Aug 2000 | A |
| 6110900 | Gold et al. | Aug 2000 | A |
| 6110914 | Phillips et al. | Aug 2000 | A |
| 6117837 | Tracey et al. | Sep 2000 | A |
| 6124449 | Gold et al. | Sep 2000 | A |
| 6127119 | Stephens et al. | Oct 2000 | A |
| 6140490 | Biesecker et al. | Oct 2000 | A |
| 6141590 | Renirie et al. | Oct 2000 | A |
| 6147204 | Gold et al. | Nov 2000 | A |
| 6159145 | Satoh | Dec 2000 | A |
| 6164284 | Schulman et al. | Dec 2000 | A |
| 6166048 | Bencherif | Dec 2000 | A |
| 6168778 | Janjic et al. | Jan 2001 | B1 |
| 6171795 | Korman et al. | Jan 2001 | B1 |
| 6205359 | Boveja | Mar 2001 | B1 |
| 6208894 | Schulman et al. | Mar 2001 | B1 |
| 6208902 | Boveja | Mar 2001 | B1 |
| 6210321 | Di Mino et al. | Apr 2001 | B1 |
| 6224862 | Turecek et al. | May 2001 | B1 |
| 6233488 | Hess | May 2001 | B1 |
| 6266564 | Hill et al. | Jul 2001 | B1 |
| 6269270 | Boveja | Jul 2001 | B1 |
| 6304775 | Iasemidis et al. | Oct 2001 | B1 |
| 6308104 | Taylor et al. | Oct 2001 | B1 |
| 6337997 | Rise | Jan 2002 | B1 |
| 6339725 | Naritoku et al. | Jan 2002 | B1 |
| 6341236 | Osorio et al. | Jan 2002 | B1 |
| 6356787 | Rezai et al. | Mar 2002 | B1 |
| 6356788 | Boveja | Mar 2002 | B2 |
| 6381499 | Taylor et al. | Apr 2002 | B1 |
| 6405732 | Edwards et al. | Jun 2002 | B1 |
| 6407095 | Lochead et al. | Jun 2002 | B1 |
| 6428484 | Battmer et al. | Aug 2002 | B1 |
| 6429217 | Puskas | Aug 2002 | B1 |
| 6447443 | Keogh et al. | Sep 2002 | B1 |
| 6449507 | Hill et al. | Sep 2002 | B1 |
| 6473644 | Terry, Jr. et al. | Oct 2002 | B1 |
| 6479523 | Puskas | Nov 2002 | B1 |
| 6487446 | Hill et al. | Nov 2002 | B1 |
| 6511500 | Rahme | Jan 2003 | B1 |
| 6528529 | Brann et al. | Mar 2003 | B1 |
| 6532388 | Hill et al. | Mar 2003 | B1 |
| 6542774 | Hill et al. | Apr 2003 | B2 |
| 6556868 | Naritoku et al. | Apr 2003 | B2 |
| 6564102 | Boveja | May 2003 | B1 |
| 6587719 | Barrett et al. | Jul 2003 | B1 |
| 6587727 | Osorio et al. | Jul 2003 | B2 |
| 6600956 | Maschino et al. | Jul 2003 | B2 |
| 6602891 | Messer et al. | Aug 2003 | B2 |
| 6609025 | Barrett et al. | Aug 2003 | B2 |
| 6610713 | Tracey | Aug 2003 | B2 |
| 6611715 | Boveja | Aug 2003 | B1 |
| 6615081 | Boveja | Sep 2003 | B1 |
| 6615085 | Boveja | Sep 2003 | B1 |
| 6622038 | Barrett et al. | Sep 2003 | B2 |
| 6622041 | Terry, Jr. et al. | Sep 2003 | B2 |
| 6622047 | Barrett et al. | Sep 2003 | B2 |
| 6628987 | Hill et al. | Sep 2003 | B1 |
| 6633779 | Schuler et al. | Oct 2003 | B1 |
| 6656960 | Puskas | Dec 2003 | B2 |
| 6668191 | Boveja | Dec 2003 | B1 |
| 6671556 | Osorio et al. | Dec 2003 | B2 |
| 6684105 | Cohen et al. | Jan 2004 | B2 |
| 6690973 | Hill et al. | Feb 2004 | B2 |
| 6718208 | Hill et al. | Apr 2004 | B2 |
| 6721603 | Zabara et al. | Apr 2004 | B2 |
| 6735471 | Hill et al. | May 2004 | B2 |
| 6735474 | Loeb et al. | May 2004 | B1 |
| 6735475 | Whitehurst et al. | May 2004 | B1 |
| 6760626 | Boveja | Jul 2004 | B1 |
| 6762032 | Nelson et al. | Jul 2004 | B1 |
| 6778854 | Puskas | Aug 2004 | B2 |
| 6804558 | Haller et al. | Oct 2004 | B2 |
| RE38654 | Hill et al. | Nov 2004 | E |
| 6826428 | Chen et al. | Nov 2004 | B1 |
| 6832114 | Whitehurst et al. | Dec 2004 | B1 |
| 6838471 | Tracey | Jan 2005 | B2 |
| RE38705 | Hill et al. | Feb 2005 | E |
| 6879859 | Boveja | Apr 2005 | B1 |
| 6885888 | Rezai | Apr 2005 | B2 |
| 6901294 | Whitehurst et al. | May 2005 | B1 |
| 6904318 | Hill et al. | Jun 2005 | B2 |
| 6920357 | Osorio et al. | Jul 2005 | B2 |
| 6928320 | King | Aug 2005 | B2 |
| 6934583 | Weinberg et al. | Aug 2005 | B2 |
| 6937903 | Schuler et al. | Aug 2005 | B2 |
| 6961618 | Osorio et al. | Nov 2005 | B2 |
| 6978787 | Broniatowski | Dec 2005 | B1 |
| 7011638 | Schuler et al. | Mar 2006 | B2 |
| 7054686 | MacDonald | May 2006 | B2 |
| 7054692 | Whitehurst et al. | May 2006 | B1 |
| 7058447 | Hill et al. | Jun 2006 | B2 |
| 7062320 | Ehlinger, Jr. | Jun 2006 | B2 |
| 7069082 | Lindenthaler | Jun 2006 | B2 |
| 7072720 | Puskas | Jul 2006 | B2 |
| 7076307 | Boveja et al. | Jul 2006 | B2 |
| 7142910 | Puskas | Nov 2006 | B2 |
| 7142917 | Fukui | Nov 2006 | B2 |
| 7149574 | Yun et al. | Dec 2006 | B2 |
| 7155279 | Whitehurst et al. | Dec 2006 | B2 |
| 7155284 | Whitehurst et al. | Dec 2006 | B1 |
| 7167750 | Knudson et al. | Jan 2007 | B2 |
| 7167751 | Whitehurst et al. | Jan 2007 | B1 |
| 7174218 | Kuzma | Feb 2007 | B1 |
| 7184828 | Hill et al. | Feb 2007 | B2 |
| 7184829 | Hill et al. | Feb 2007 | B2 |
| 7191012 | Boveja et al. | Mar 2007 | B2 |
| 7204815 | Connor | Apr 2007 | B2 |
| 7209787 | DiLorenzo | Apr 2007 | B2 |
| 7225019 | Jahns et al. | May 2007 | B2 |
| 7228167 | Kara et al. | Jun 2007 | B2 |
| 7238715 | Tracey et al. | Jul 2007 | B2 |
| 7242984 | DiLorenzo | Jul 2007 | B2 |
| 7269457 | Shafer et al. | Sep 2007 | B2 |
| 7345178 | Nunes et al. | Mar 2008 | B2 |
| 7373204 | Gelfand et al. | May 2008 | B2 |
| 7389145 | Kilgore et al. | Jun 2008 | B2 |
| 7454245 | Armstrong et al. | Nov 2008 | B2 |
| 7467016 | Colborn | Dec 2008 | B2 |
| 7544497 | Sinclair et al. | Jun 2009 | B2 |
| 7561918 | Armstrong et al. | Jul 2009 | B2 |
| 7634315 | Cholette | Dec 2009 | B2 |
| 7711432 | Thimineur et al. | May 2010 | B2 |
| 7729760 | Patel et al. | Jun 2010 | B2 |
| 7751891 | Armstrong et al. | Jul 2010 | B2 |
| 7776326 | Milbrandt et al. | Aug 2010 | B2 |
| 7797058 | Mrva et al. | Sep 2010 | B2 |
| 7819883 | Westlund et al. | Oct 2010 | B2 |
| 7822486 | Foster et al. | Oct 2010 | B2 |
| 7829556 | Bemis et al. | Nov 2010 | B2 |
| 7869869 | Farazi | Jan 2011 | B1 |
| 7869885 | Begnaud et al. | Jan 2011 | B2 |
| 7937145 | Dobak | May 2011 | B2 |
| 7962220 | Kolafa et al. | Jun 2011 | B2 |
| 7974701 | Armstrong | Jul 2011 | B2 |
| 7974707 | Inman | Jul 2011 | B2 |
| 7996088 | Marrosu et al. | Aug 2011 | B2 |
| 7996092 | Mrva et al. | Aug 2011 | B2 |
| 8019419 | Panescu et al. | Sep 2011 | B1 |
| 8060208 | Kilgore et al. | Nov 2011 | B2 |
| 8103349 | Donders et al. | Jan 2012 | B2 |
| 8165668 | Dacey, Jr. et al. | Apr 2012 | B2 |
| 8180446 | Dacey, Jr. et al. | May 2012 | B2 |
| 8180447 | Dacey et al. | May 2012 | B2 |
| 8195287 | Dacey, Jr. et al. | Jun 2012 | B2 |
| 8214056 | Hoffer et al. | Jul 2012 | B2 |
| 8233982 | Libbus | Jul 2012 | B2 |
| 8391970 | Tracey et al. | Mar 2013 | B2 |
| 8412338 | Faltys | Apr 2013 | B2 |
| 8504161 | Kornet et al. | Aug 2013 | B1 |
| 8571654 | Libbus et al. | Oct 2013 | B2 |
| 8577458 | Libbus et al. | Nov 2013 | B1 |
| 8600505 | Libbus et al. | Dec 2013 | B2 |
| 8612002 | Faltys et al. | Dec 2013 | B2 |
| 8630709 | Libbus et al. | Jan 2014 | B2 |
| 8688212 | Libbus et al. | Apr 2014 | B2 |
| 8700150 | Libbus et al. | Apr 2014 | B2 |
| 8729129 | Tracey et al. | May 2014 | B2 |
| 8788034 | Levine et al. | Jul 2014 | B2 |
| 8843210 | Simon et al. | Sep 2014 | B2 |
| 8855767 | Faltys et al. | Oct 2014 | B2 |
| 8886339 | Faltys et al. | Nov 2014 | B2 |
| 8914114 | Tracey et al. | Dec 2014 | B2 |
| 8918178 | Simon et al. | Dec 2014 | B2 |
| 8918191 | Libbus et al. | Dec 2014 | B2 |
| 8923964 | Libbus et al. | Dec 2014 | B2 |
| 8983628 | Simon et al. | Mar 2015 | B2 |
| 8983629 | Simon et al. | Mar 2015 | B2 |
| 8996116 | Faltys et al. | Mar 2015 | B2 |
| 9114262 | Libbus et al. | Aug 2015 | B2 |
| 9162064 | Faltys et al. | Oct 2015 | B2 |
| 9174041 | Faltys et al. | Nov 2015 | B2 |
| 9211409 | Tracey et al. | Dec 2015 | B2 |
| 9211410 | Levine et al. | Dec 2015 | B2 |
| 9254383 | Simon et al. | Feb 2016 | B2 |
| 9272143 | Libbus et al. | Mar 2016 | B2 |
| 9358381 | Simon et al. | Jun 2016 | B2 |
| 9399134 | Simon et al. | Jul 2016 | B2 |
| 9403001 | Simon et al. | Aug 2016 | B2 |
| 9409024 | KenKnight et al. | Aug 2016 | B2 |
| 9415224 | Libbus et al. | Aug 2016 | B2 |
| 9452290 | Libbus et al. | Sep 2016 | B2 |
| 9504832 | Libbus et al. | Nov 2016 | B2 |
| 9511228 | Amurthur et al. | Dec 2016 | B2 |
| 9533153 | Libbus et al. | Jan 2017 | B2 |
| 9572983 | Levine et al. | Feb 2017 | B2 |
| 9662490 | Tracey et al. | May 2017 | B2 |
| 9700716 | Faltys et al. | Jul 2017 | B2 |
| 9833621 | Levine | Dec 2017 | B2 |
| 9849286 | Levine et al. | Dec 2017 | B2 |
| 9987492 | Tracey et al. | Jun 2018 | B2 |
| 9993651 | Faltys et al. | Jun 2018 | B2 |
| 10166395 | Tracey et al. | Jan 2019 | B2 |
| 10220203 | Faltys et al. | Mar 2019 | B2 |
| 10449358 | Levine et al. | Oct 2019 | B2 |
| 10561846 | Tracey et al. | Feb 2020 | B2 |
| 10583304 | Faltys et al. | Mar 2020 | B2 |
| 10596367 | Faltys et al. | Mar 2020 | B2 |
| 10695569 | Levine et al. | Jun 2020 | B2 |
| 10716936 | Faltys et al. | Jul 2020 | B2 |
| 10912712 | Tracey et al. | Feb 2021 | B2 |
| 11051744 | Levine et al. | Jul 2021 | B2 |
| 11110287 | Faltys et al. | Sep 2021 | B2 |
| 11173307 | Levine et al. | Nov 2021 | B2 |
| 11207518 | Huston et al. | Dec 2021 | B2 |
| 11260229 | Manogue | Mar 2022 | B2 |
| 11278718 | Faltys et al. | Mar 2022 | B2 |
| 11311725 | Levine et al. | Apr 2022 | B2 |
| 11344724 | Huston et al. | May 2022 | B2 |
| 11383091 | Faltys et al. | Jul 2022 | B2 |
| 11406833 | Faltys et al. | Aug 2022 | B2 |
| 11471681 | Zitnik et al. | Oct 2022 | B2 |
| 20010002441 | Boveja | May 2001 | A1 |
| 20010034542 | Mann | Oct 2001 | A1 |
| 20020026141 | Houben et al. | Feb 2002 | A1 |
| 20020040035 | Myers et al. | Apr 2002 | A1 |
| 20020077675 | Greenstein | Jun 2002 | A1 |
| 20020086871 | O'Neill et al. | Jul 2002 | A1 |
| 20020095139 | Keogh et al. | Jul 2002 | A1 |
| 20020099417 | Naritoku et al. | Jul 2002 | A1 |
| 20020138075 | Edwards et al. | Sep 2002 | A1 |
| 20020138109 | Keogh et al. | Sep 2002 | A1 |
| 20020193859 | Schulman et al. | Dec 2002 | A1 |
| 20020198570 | Puskas | Dec 2002 | A1 |
| 20030018367 | DiLorenzo | Jan 2003 | A1 |
| 20030032852 | Perreault et al. | Feb 2003 | A1 |
| 20030045909 | Gross et al. | Mar 2003 | A1 |
| 20030088301 | King | May 2003 | A1 |
| 20030191404 | Klein | Oct 2003 | A1 |
| 20030194752 | Anderson et al. | Oct 2003 | A1 |
| 20030195578 | Perron et al. | Oct 2003 | A1 |
| 20030212440 | Boveja | Nov 2003 | A1 |
| 20030229380 | Adams et al. | Dec 2003 | A1 |
| 20030236557 | Whitehurst et al. | Dec 2003 | A1 |
| 20030236558 | Whitehurst et al. | Dec 2003 | A1 |
| 20040002546 | Altschuler | Jan 2004 | A1 |
| 20040015202 | Chandler et al. | Jan 2004 | A1 |
| 20040015204 | Whitehurst et al. | Jan 2004 | A1 |
| 20040015205 | Whitehurst et al. | Jan 2004 | A1 |
| 20040024422 | Hill et al. | Feb 2004 | A1 |
| 20040024428 | Barrett et al. | Feb 2004 | A1 |
| 20040024439 | Riso | Feb 2004 | A1 |
| 20040030362 | Hill et al. | Feb 2004 | A1 |
| 20040039427 | Barrett et al. | Feb 2004 | A1 |
| 20040048795 | Ivanova et al. | Mar 2004 | A1 |
| 20040049121 | Yaron | Mar 2004 | A1 |
| 20040049240 | Gerber et al. | Mar 2004 | A1 |
| 20040059383 | Puskas | Mar 2004 | A1 |
| 20040111139 | McCreery et al. | Jun 2004 | A1 |
| 20040138517 | Osorio et al. | Jul 2004 | A1 |
| 20040138518 | Rise et al. | Jul 2004 | A1 |
| 20040138536 | Frei et al. | Jul 2004 | A1 |
| 20040146949 | Tan et al. | Jul 2004 | A1 |
| 20040153127 | Gordon et al. | Aug 2004 | A1 |
| 20040158119 | Osorio et al. | Aug 2004 | A1 |
| 20040162584 | Hill et al. | Aug 2004 | A1 |
| 20040172074 | Yoshihito | Sep 2004 | A1 |
| 20040172085 | Knudson et al. | Sep 2004 | A1 |
| 20040172086 | Knudson et al. | Sep 2004 | A1 |
| 20040172088 | Knudson et al. | Sep 2004 | A1 |
| 20040172094 | Cohen et al. | Sep 2004 | A1 |
| 20040176812 | Knudson et al. | Sep 2004 | A1 |
| 20040178706 | D'Orso | Sep 2004 | A1 |
| 20040193231 | David et al. | Sep 2004 | A1 |
| 20040199209 | Hill et al. | Oct 2004 | A1 |
| 20040199210 | Shelchuk | Oct 2004 | A1 |
| 20040204355 | Tracey et al. | Oct 2004 | A1 |
| 20040215272 | Haubrich et al. | Oct 2004 | A1 |
| 20040215287 | Swoyer et al. | Oct 2004 | A1 |
| 20040236381 | Dinsmoor et al. | Nov 2004 | A1 |
| 20040236382 | Dinsmoor et al. | Nov 2004 | A1 |
| 20040240691 | Grafenberg | Dec 2004 | A1 |
| 20040243182 | Cohen et al. | Dec 2004 | A1 |
| 20040243211 | Colliou et al. | Dec 2004 | A1 |
| 20040254612 | Ezra et al. | Dec 2004 | A1 |
| 20040267152 | Pineda | Dec 2004 | A1 |
| 20050021092 | Yun et al. | Jan 2005 | A1 |
| 20050021101 | Chen et al. | Jan 2005 | A1 |
| 20050027328 | Greenstein | Feb 2005 | A1 |
| 20050043774 | Devlin et al. | Feb 2005 | A1 |
| 20050049655 | Boveja et al. | Mar 2005 | A1 |
| 20050065553 | Ben Ezra et al. | Mar 2005 | A1 |
| 20050065573 | Rezai | Mar 2005 | A1 |
| 20050065575 | Dobak | Mar 2005 | A1 |
| 20050070970 | Knudson et al. | Mar 2005 | A1 |
| 20050070974 | Knudson et al. | Mar 2005 | A1 |
| 20050075701 | Shafer | Apr 2005 | A1 |
| 20050075702 | Shafer | Apr 2005 | A1 |
| 20050095246 | Shafer | May 2005 | A1 |
| 20050096707 | Hill et al. | May 2005 | A1 |
| 20050103351 | Stomberg et al. | May 2005 | A1 |
| 20050113894 | Zilberman et al. | May 2005 | A1 |
| 20050131467 | Boveja | Jun 2005 | A1 |
| 20050131486 | Boveja et al. | Jun 2005 | A1 |
| 20050131487 | Boveja | Jun 2005 | A1 |
| 20050131493 | Boveja et al. | Jun 2005 | A1 |
| 20050137644 | Boveja et al. | Jun 2005 | A1 |
| 20050137645 | Voipio et al. | Jun 2005 | A1 |
| 20050143781 | Carbunaru et al. | Jun 2005 | A1 |
| 20050143787 | Boveja et al. | Jun 2005 | A1 |
| 20050149126 | Libbus | Jul 2005 | A1 |
| 20050149129 | Libbus et al. | Jul 2005 | A1 |
| 20050149131 | Libbus et al. | Jul 2005 | A1 |
| 20050153885 | Yun et al. | Jul 2005 | A1 |
| 20050154425 | Boveja et al. | Jul 2005 | A1 |
| 20050154426 | Boveja et al. | Jul 2005 | A1 |
| 20050165458 | Boveja et al. | Jul 2005 | A1 |
| 20050177200 | George et al. | Aug 2005 | A1 |
| 20050182288 | Zabara | Aug 2005 | A1 |
| 20050182467 | Hunter et al. | Aug 2005 | A1 |
| 20050187584 | Denker et al. | Aug 2005 | A1 |
| 20050187586 | David et al. | Aug 2005 | A1 |
| 20050187590 | Boveja et al. | Aug 2005 | A1 |
| 20050191661 | Gatanaga et al. | Sep 2005 | A1 |
| 20050192644 | Boveja et al. | Sep 2005 | A1 |
| 20050197600 | Schuler et al. | Sep 2005 | A1 |
| 20050197675 | David et al. | Sep 2005 | A1 |
| 20050197678 | Boveja et al. | Sep 2005 | A1 |
| 20050203501 | Aldrich et al. | Sep 2005 | A1 |
| 20050209654 | Boveja et al. | Sep 2005 | A1 |
| 20050216064 | Heruth et al. | Sep 2005 | A1 |
| 20050216070 | Boveja et al. | Sep 2005 | A1 |
| 20050216071 | Devlin et al. | Sep 2005 | A1 |
| 20050240229 | Whitehurst et al. | Oct 2005 | A1 |
| 20050240231 | Aldrich et al. | Oct 2005 | A1 |
| 20050240241 | Yun et al. | Oct 2005 | A1 |
| 20050240242 | DiLorenzo | Oct 2005 | A1 |
| 20050251220 | Barrett et al. | Nov 2005 | A1 |
| 20050251222 | Barrett et al. | Nov 2005 | A1 |
| 20050267542 | David et al. | Dec 2005 | A1 |
| 20050267547 | Knudson et al. | Dec 2005 | A1 |
| 20050277912 | John | Dec 2005 | A1 |
| 20050283198 | Haubrich et al. | Dec 2005 | A1 |
| 20060009815 | Boveja et al. | Jan 2006 | A1 |
| 20060015151 | Aldrich | Jan 2006 | A1 |
| 20060025828 | Armstrong et al. | Feb 2006 | A1 |
| 20060036293 | Whitehurst et al. | Feb 2006 | A1 |
| 20060052657 | Zabara | Mar 2006 | A9 |
| 20060052831 | Fukui | Mar 2006 | A1 |
| 20060052836 | Kim et al. | Mar 2006 | A1 |
| 20060058851 | Cigaina | Mar 2006 | A1 |
| 20060064137 | Stone | Mar 2006 | A1 |
| 20060064139 | Chung et al. | Mar 2006 | A1 |
| 20060074450 | Boveja et al. | Apr 2006 | A1 |
| 20060074473 | Gertner | Apr 2006 | A1 |
| 20060079936 | Boveja et al. | Apr 2006 | A1 |
| 20060085046 | Rezai et al. | Apr 2006 | A1 |
| 20060095081 | Zhou et al. | May 2006 | A1 |
| 20060095090 | De Ridder | May 2006 | A1 |
| 20060100668 | Ben-David et al. | May 2006 | A1 |
| 20060106755 | Stuhec | May 2006 | A1 |
| 20060111644 | Guttag et al. | May 2006 | A1 |
| 20060111754 | Rezal et al. | May 2006 | A1 |
| 20060111755 | Stone et al. | May 2006 | A1 |
| 20060116739 | Betser et al. | Jun 2006 | A1 |
| 20060122675 | Libbus et al. | Jun 2006 | A1 |
| 20060129200 | Kurokawa | Jun 2006 | A1 |
| 20060129202 | Armstrong | Jun 2006 | A1 |
| 20060135998 | Libbus et al. | Jun 2006 | A1 |
| 20060136024 | Cohen et al. | Jun 2006 | A1 |
| 20060142802 | Armstrong | Jun 2006 | A1 |
| 20060142822 | Tulgar | Jun 2006 | A1 |
| 20060149337 | John | Jul 2006 | A1 |
| 20060155495 | Osorio et al. | Jul 2006 | A1 |
| 20060161216 | John et al. | Jul 2006 | A1 |
| 20060161217 | Jaax et al. | Jul 2006 | A1 |
| 20060167497 | Armstrong et al. | Jul 2006 | A1 |
| 20060167498 | DiLorenzo | Jul 2006 | A1 |
| 20060167501 | Ben-David et al. | Jul 2006 | A1 |
| 20060173493 | Armstrong et al. | Aug 2006 | A1 |
| 20060173508 | Stone et al. | Aug 2006 | A1 |
| 20060178691 | Binmoeller | Aug 2006 | A1 |
| 20060178706 | Lisogurski et al. | Aug 2006 | A1 |
| 20060190044 | Libbus et al. | Aug 2006 | A1 |
| 20060200208 | Terry, Jr. et al. | Sep 2006 | A1 |
| 20060200219 | Thrope et al. | Sep 2006 | A1 |
| 20060206155 | Ben-David et al. | Sep 2006 | A1 |
| 20060206158 | Wu et al. | Sep 2006 | A1 |
| 20060229677 | Moffitt et al. | Oct 2006 | A1 |
| 20060229681 | Fischell | Oct 2006 | A1 |
| 20060241697 | Libbus et al. | Oct 2006 | A1 |
| 20060241699 | Libbus et al. | Oct 2006 | A1 |
| 20060247719 | Maschino et al. | Nov 2006 | A1 |
| 20060247721 | Maschino et al. | Nov 2006 | A1 |
| 20060247722 | Maschino et al. | Nov 2006 | A1 |
| 20060259077 | Pardo et al. | Nov 2006 | A1 |
| 20060259084 | Zhang et al. | Nov 2006 | A1 |
| 20060259085 | Zhang et al. | Nov 2006 | A1 |
| 20060259107 | Caparso et al. | Nov 2006 | A1 |
| 20060271115 | Ben-Ezra et al. | Nov 2006 | A1 |
| 20060282121 | Payne et al. | Dec 2006 | A1 |
| 20060282131 | Caparso et al. | Dec 2006 | A1 |
| 20060282145 | Caparso et al. | Dec 2006 | A1 |
| 20060287678 | Shafer | Dec 2006 | A1 |
| 20060287679 | Stone | Dec 2006 | A1 |
| 20060292099 | Milburn et al. | Dec 2006 | A1 |
| 20060293720 | DiLorenzo | Dec 2006 | A1 |
| 20060293721 | Tarver et al. | Dec 2006 | A1 |
| 20060293723 | Whitehurst et al. | Dec 2006 | A1 |
| 20070016262 | Gross et al. | Jan 2007 | A1 |
| 20070016263 | Armstrong et al. | Jan 2007 | A1 |
| 20070021785 | Inman et al. | Jan 2007 | A1 |
| 20070021786 | Paris et al. | Jan 2007 | A1 |
| 20070021814 | Inman et al. | Jan 2007 | A1 |
| 20070025608 | Armstrong | Feb 2007 | A1 |
| 20070027482 | Paris et al. | Feb 2007 | A1 |
| 20070027483 | Maschino et al. | Feb 2007 | A1 |
| 20070027484 | Guzman et al. | Feb 2007 | A1 |
| 20070027486 | Armstrong | Feb 2007 | A1 |
| 20070027492 | Maschino et al. | Feb 2007 | A1 |
| 20070027496 | Parnis et al. | Feb 2007 | A1 |
| 20070027497 | Parnis | Feb 2007 | A1 |
| 20070027498 | Maschino et al. | Feb 2007 | A1 |
| 20070027499 | Maschino et al. | Feb 2007 | A1 |
| 20070027500 | Maschino et al. | Feb 2007 | A1 |
| 20070027504 | Barrett et al. | Feb 2007 | A1 |
| 20070055324 | Thompson et al. | Mar 2007 | A1 |
| 20070067004 | Boveja et al. | Mar 2007 | A1 |
| 20070083242 | Mazgalev et al. | Apr 2007 | A1 |
| 20070093434 | Rossetti et al. | Apr 2007 | A1 |
| 20070093870 | Maschino | Apr 2007 | A1 |
| 20070093875 | Chavan et al. | Apr 2007 | A1 |
| 20070100263 | Merfeld | May 2007 | A1 |
| 20070100377 | Armstrong et al. | May 2007 | A1 |
| 20070100378 | Maschino | May 2007 | A1 |
| 20070100380 | Fukui | May 2007 | A1 |
| 20070100392 | Maschino et al. | May 2007 | A1 |
| 20070106339 | Errico et al. | May 2007 | A1 |
| 20070112404 | Mann et al. | May 2007 | A1 |
| 20070118177 | Libbus et al. | May 2007 | A1 |
| 20070118178 | Fukui | May 2007 | A1 |
| 20070129767 | Wahlstrand | Jun 2007 | A1 |
| 20070129780 | Whitehurst et al. | Jun 2007 | A1 |
| 20070135846 | Knudson et al. | Jun 2007 | A1 |
| 20070135856 | Knudson et al. | Jun 2007 | A1 |
| 20070135857 | Knudson et al. | Jun 2007 | A1 |
| 20070135858 | Knudson et al. | Jun 2007 | A1 |
| 20070136098 | Smythe et al. | Jun 2007 | A1 |
| 20070142870 | Knudson et al. | Jun 2007 | A1 |
| 20070142871 | Libbus et al. | Jun 2007 | A1 |
| 20070142874 | John | Jun 2007 | A1 |
| 20070150006 | Libbus et al. | Jun 2007 | A1 |
| 20070150011 | Meyer et al. | Jun 2007 | A1 |
| 20070150021 | Chen et al. | Jun 2007 | A1 |
| 20070150027 | Rogers | Jun 2007 | A1 |
| 20070156180 | Jaax et al. | Jul 2007 | A1 |
| 20070198063 | Hunter et al. | Aug 2007 | A1 |
| 20070239243 | Moffitt et al. | Oct 2007 | A1 |
| 20070244522 | Overstreet | Oct 2007 | A1 |
| 20070250145 | Kraus et al. | Oct 2007 | A1 |
| 20070255320 | Inman et al. | Nov 2007 | A1 |
| 20070255333 | Giftakis | Nov 2007 | A1 |
| 20070255339 | Torgerson | Nov 2007 | A1 |
| 20080021517 | Dietrich | Jan 2008 | A1 |
| 20080021520 | Dietrich | Jan 2008 | A1 |
| 20080046055 | Durand et al. | Feb 2008 | A1 |
| 20080051852 | Dietrich et al. | Feb 2008 | A1 |
| 20080058871 | Libbus et al. | Mar 2008 | A1 |
| 20080103407 | Bolea et al. | May 2008 | A1 |
| 20080140138 | Ivanova et al. | Jun 2008 | A1 |
| 20080166348 | Kupper et al. | Jul 2008 | A1 |
| 20080183226 | Buras et al. | Jul 2008 | A1 |
| 20080183246 | Patel et al. | Jul 2008 | A1 |
| 20080195171 | Sharma | Aug 2008 | A1 |
| 20080208266 | Lesser et al. | Aug 2008 | A1 |
| 20080213331 | Gelfand et al. | Sep 2008 | A1 |
| 20080234790 | Bayer et al. | Sep 2008 | A1 |
| 20080281197 | Wiley et al. | Nov 2008 | A1 |
| 20080281365 | Tweden et al. | Nov 2008 | A1 |
| 20080281372 | Libbus et al. | Nov 2008 | A1 |
| 20090012590 | Inman et al. | Jan 2009 | A1 |
| 20090048194 | Aerssens et al. | Feb 2009 | A1 |
| 20090076561 | Libbus et al. | Mar 2009 | A1 |
| 20090082832 | Carbunaru et al. | Mar 2009 | A1 |
| 20090088821 | Abrahamson | Apr 2009 | A1 |
| 20090105782 | Mickle et al. | Apr 2009 | A1 |
| 20090112291 | Wahlstrand et al. | Apr 2009 | A1 |
| 20090123521 | Weber et al. | May 2009 | A1 |
| 20090125076 | Shuros et al. | May 2009 | A1 |
| 20090125079 | Armstrong et al. | May 2009 | A1 |
| 20090171405 | Craig | Jul 2009 | A1 |
| 20090177112 | Gharib et al. | Jul 2009 | A1 |
| 20090187231 | Errico et al. | Jul 2009 | A1 |
| 20090210042 | Kowalczewski | Aug 2009 | A1 |
| 20090248097 | Tracey et al. | Oct 2009 | A1 |
| 20090254143 | Tweden et al. | Oct 2009 | A1 |
| 20090275997 | Faltys et al. | Nov 2009 | A1 |
| 20090276019 | Perez et al. | Nov 2009 | A1 |
| 20090281593 | Errico et al. | Nov 2009 | A9 |
| 20090312817 | Hogle et al. | Dec 2009 | A1 |
| 20100003656 | Kilgard et al. | Jan 2010 | A1 |
| 20100010556 | Zhao et al. | Jan 2010 | A1 |
| 20100010571 | Skelton et al. | Jan 2010 | A1 |
| 20100010581 | Goetz et al. | Jan 2010 | A1 |
| 20100010603 | Ben-David et al. | Jan 2010 | A1 |
| 20100016746 | Hampton et al. | Jan 2010 | A1 |
| 20100042186 | Ben-David et al. | Feb 2010 | A1 |
| 20100063563 | Craig | Mar 2010 | A1 |
| 20100074934 | Hunter | Mar 2010 | A1 |
| 20100191304 | Scott | Jul 2010 | A1 |
| 20100204766 | Zdeblick et al. | Aug 2010 | A1 |
| 20100215632 | Boss et al. | Aug 2010 | A1 |
| 20100241183 | DiLorenzo | Sep 2010 | A1 |
| 20100241195 | Meadows et al. | Sep 2010 | A1 |
| 20100241207 | Bluger | Sep 2010 | A1 |
| 20100249859 | DiLorenzo | Sep 2010 | A1 |
| 20100280500 | Skelton et al. | Nov 2010 | A1 |
| 20100280562 | Pi et al. | Nov 2010 | A1 |
| 20100280569 | Bobillier et al. | Nov 2010 | A1 |
| 20110004266 | Sharma | Jan 2011 | A1 |
| 20110009734 | Foley et al. | Jan 2011 | A1 |
| 20110054569 | Zitnik et al. | Mar 2011 | A1 |
| 20110066208 | Pasricha et al. | Mar 2011 | A1 |
| 20110082515 | Libbus et al. | Apr 2011 | A1 |
| 20110092882 | Firlik et al. | Apr 2011 | A1 |
| 20110144717 | Burton et al. | Jun 2011 | A1 |
| 20110145588 | Stubbs et al. | Jun 2011 | A1 |
| 20110152967 | Simon et al. | Jun 2011 | A1 |
| 20110224749 | Ben-David et al. | Sep 2011 | A1 |
| 20110247620 | Armstrong et al. | Oct 2011 | A1 |
| 20110275927 | Wagner et al. | Nov 2011 | A1 |
| 20110301658 | Yoo et al. | Dec 2011 | A1 |
| 20110307027 | Sharma et al. | Dec 2011 | A1 |
| 20120053657 | Parker et al. | Mar 2012 | A1 |
| 20120065706 | Vallapureddy et al. | Mar 2012 | A1 |
| 20120179219 | Kisker et al. | Jul 2012 | A1 |
| 20120185009 | Kornet et al. | Jul 2012 | A1 |
| 20120185020 | Simon et al. | Jul 2012 | A1 |
| 20120296176 | Herbst | Nov 2012 | A1 |
| 20120302821 | Burnett | Nov 2012 | A1 |
| 20130013016 | Diebold | Jan 2013 | A1 |
| 20130018439 | Chow et al. | Jan 2013 | A1 |
| 20130066392 | Simon et al. | Mar 2013 | A1 |
| 20130066395 | Simon et al. | Mar 2013 | A1 |
| 20130071390 | Stadheim et al. | Mar 2013 | A1 |
| 20130150756 | Vitek et al. | Jun 2013 | A1 |
| 20130245718 | Birkholz et al. | Sep 2013 | A1 |
| 20130317580 | Simon et al. | Nov 2013 | A1 |
| 20140046407 | Ben-Ezra et al. | Feb 2014 | A1 |
| 20140206945 | Liao | Jul 2014 | A1 |
| 20140257425 | Arcot-Krishnamurthy et al. | Sep 2014 | A1 |
| 20140277260 | Khalil et al. | Sep 2014 | A1 |
| 20140288551 | Bharmi et al. | Sep 2014 | A1 |
| 20140324118 | Simon et al. | Oct 2014 | A1 |
| 20140330335 | Errico et al. | Nov 2014 | A1 |
| 20150018728 | Gross et al. | Jan 2015 | A1 |
| 20150119956 | Libbus et al. | Apr 2015 | A1 |
| 20150133717 | Ghiron et al. | May 2015 | A1 |
| 20150180271 | Angara et al. | Jun 2015 | A1 |
| 20150196767 | Ahmed | Jul 2015 | A1 |
| 20150233904 | Nayak | Aug 2015 | A1 |
| 20150241447 | Zitnik et al. | Aug 2015 | A1 |
| 20160089540 | Bolea | Mar 2016 | A1 |
| 20160250097 | Tracey et al. | Sep 2016 | A9 |
| 20160331952 | Faltys et al. | Nov 2016 | A1 |
| 20160367808 | Simon et al. | Dec 2016 | A9 |
| 20170202467 | Zitnik et al. | Jul 2017 | A1 |
| 20170245379 | Kang | Aug 2017 | A1 |
| 20170304621 | Malbert et al. | Oct 2017 | A1 |
| 20170361093 | Yoo et al. | Dec 2017 | A1 |
| 20180021580 | Tracey et al. | Jan 2018 | A1 |
| 20180085578 | Rennaker, II et al. | Mar 2018 | A1 |
| 20180117320 | Levine et al. | May 2018 | A1 |
| 20180289970 | Faltys et al. | Oct 2018 | A1 |
| 20190010535 | Pujol Onofre et al. | Jan 2019 | A1 |
| 20190022389 | Leonhardt | Jan 2019 | A1 |
| 20190054295 | Pannu et al. | Feb 2019 | A1 |
| 20190192847 | Faltys et al. | Jun 2019 | A1 |
| 20190290902 | Romero-Ortega et al. | Sep 2019 | A1 |
| 20200330760 | Levine et al. | Oct 2020 | A1 |
| 20210251848 | Tracey et al. | Aug 2021 | A1 |
| 20210315505 | Levine et al. | Oct 2021 | A1 |
| 20210353949 | Faltys et al. | Nov 2021 | A1 |
| 20220040483 | Levine et al. | Feb 2022 | A1 |
| 20220072309 | Levine et al. | Mar 2022 | A9 |
| 20220118257 | Huston et al. | Apr 2022 | A1 |
| 20220193413 | Levine et al. | Jun 2022 | A1 |
| 20220212001 | Faltys et al. | Jul 2022 | A1 |
| 20220212012 | Manogue | Jul 2022 | A1 |
| 20220257941 | Levine et al. | Aug 2022 | A1 |
| 20220280797 | Faltys et al. | Sep 2022 | A1 |
| 20230117074 | Zanos et al. | Apr 2023 | A1 |
| 20230144580 | Manogue | May 2023 | A1 |
| 20230241387 | Levine et al. | Aug 2023 | A1 |
| 20230321445 | Zanos et al. | Oct 2023 | A1 |
| Number | Date | Country |
|---|---|---|
| 201230913 | May 2009 | CN |
| 101528303 | Sep 2009 | CN |
| 101578067 | Nov 2009 | CN |
| 101868280 | Oct 2010 | CN |
| 104220129 | Dec 2014 | CN |
| 2628045 | Jan 1977 | DE |
| 3736664 | May 1989 | DE |
| 20316509 | Apr 2004 | DE |
| 0438510 | Aug 1996 | EP |
| 0726791 | Jun 2000 | EP |
| 1001827 | Jan 2004 | EP |
| 2213330 | Aug 2010 | EP |
| 2073896 | Oct 2011 | EP |
| 3470111 | Apr 2019 | EP |
| 04133 | Feb 1910 | GB |
| 2073428 | Oct 1981 | GB |
| 2017502787 | Jan 2017 | JP |
| 2019517830 | Jun 2019 | JP |
| 20050039445 | Apr 2005 | KR |
| WO9301862 | Feb 1993 | WO |
| WO9730998 | Aug 1997 | WO |
| WO9820868 | May 1998 | WO |
| WO0027381 | May 2000 | WO |
| WO0047104 | Aug 2000 | WO |
| WO0100273 | Jan 2001 | WO |
| WO0108617 | Feb 2001 | WO |
| WO0189526 | Nov 2001 | WO |
| WO0244176 | Jun 2002 | WO |
| WO02057275 | Jul 2002 | WO |
| WO03072135 | Sep 2003 | WO |
| WO2004000413 | Dec 2003 | WO |
| WO2004064918 | Aug 2004 | WO |
| WO2006073484 | Jul 2006 | WO |
| WO2006076681 | Jul 2006 | WO |
| WO2007133718 | Nov 2007 | WO |
| WO2010005482 | Jan 2010 | WO |
| WO2010067360 | Jun 2010 | WO |
| WO2010118035 | Oct 2010 | WO |
| WO2015009907 | Jan 2015 | WO |
| WO2016134197 | Aug 2016 | WO |
| Entry |
|---|
| US 6,184,239 B1, 02/2001, Puskas (withdrawn) |
| Jacob et al.; Detrimental role of granulocyte-colony stimulating factor in neuromyelitis optica: clinical case and histological evidence; Multiple Sclerosis Journal; 18(12); pp. 1801-1803; Dec. 2012. |
| Levine et al.; U.S. Appl. No. 18/151,407 entitled “Control of vagal stimulation,” filed Jan. 6, 2023. |
| De Jonge et al.; Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway; Nature Immunology; 6(8); pp. 844-851; Aug. 2005. |
| Emery et al.; Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: switch-ra, a global, oberservational, comparative effectiveness study; Annals of the Rheumatic Diseases; 4(6); pp. 979-984; Jun. 2015. |
| Gottenberg et al.; Non-TNF-targeted biologic vs a second anti-TNF drug to treat theumatoid arthritis in patients with insufficient response to a first anti TNF drug: a randomized clinical trial; JAMA; 316(11); pp. 1172-1180; Sep. 2016. |
| Monaco et al.; Anti-TNF therapy:past,present, and future; International Immunology; 27(1); pp. 55-62; Jan. 2015. |
| Olofsson et al.; Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia; Bioelectronic Medicine; 2(1); pp. 37-42; Jun. 2015. |
| Rendas-Baum et al.; Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-alpha inhibitors; Arthritis research and therapy; 13; R25; 15 pages; ; Feb. 2011. |
| Rosas-Ballina et al.; Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit Science: 334(6052); pp. 98-101; 10 pages; (Author Manuscript); Oct. 2011. |
| Vida et al.; Aplha 7-cholinergic receptor mediates vagal induction of splenic norepinephrine; Journal of Immunology; 186(7); pp. 4340-4346; 16 pages; (Author Manuscript); Apr. 2011. |
| Yang et al.; Acetylcholine inhibits LPS-induced MMP-9 production and ccell migration via the alpha7 nAChR-JAK2/STAT3 pathway in RAW264.7 cells; Cellular Physiology and Biochemistry: 36(5); pp. 2025-2038; (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue) 2015. |
| Abraham, Coagulation abnormalities in acute lung injury and sepsis, Am. J. Respir. Cell Mol. Biol., vol. 22(4), pp. 401-404, Apr. 2000. |
| Aekerlund et al., Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-Alpha) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats, Clinical & Experimental Immunology, vol. 115, No. 1, pp. 32-41, Jan. 1, 1999. |
| Anderson et al.; Reflex principles of immunological homeostasis; Annu. Rev. Immunol.; 30; pp. 313-335; Apr. 2012. |
| Antonica, A., et al., Vagal control of lymphocyte release from rat thymus, J. Auton. Nerv. Syst., vol. 48(3), pp. 187-197, Aug. 1994. |
| Asakura et al., Non-surgical therapy for ulcerative colitis, Nippon Geka Gakkai Zasshi, vol. 98, No. 4, pp. 431-437, Apr. 1997 (abstract only). |
| Beliavskaia et al., “On the effects of prolonged stimulation of the peripheral segment of the vagus nerve . . . ,” Fiziologicheskii Zhurnal SSSR Imeni I.M. Sechenova., vol. 52(11); p. 1315-1321, Nov. 1966. |
| Ben-Noun et al.; Neck circumference as a simple screening measure for identifying overweight and obese patients; Obesity Research; vol. 9; No. 8; pp. 470-477; Aug. 8, 2001. |
| Benoist, et al., “Mast cells in autoimmune disease” Nature., vol. 420(19): pp. 875-878, Dec. 2002. |
| Benthem et al.; Parasympathetic inhibition of sympathetic neural activity to the pancreas; Am.J.Physiol Endocrinol.Metab; 280(2); pp. E378-E381; Feb. 2001. |
| Bernik et al., Vagus nerve stimulation attenuates cardiac TNF production in endotoxic shock, (supplemental to Shock, vol. 15, 2001, Injury, inflammation and sepsis: laboratory and clinical approaches, Shock, Abstracts, 24th Annual Conference on Shock, Marco Island, FL, Jun. 9-12, 2001), Abstract No. 81. |
| Bernik et al., Vagus nerve stimulation attenuates endotoxic shock and cardiac TNF production, 87th Clinical Congress of the American College of Surgeons, New Orleans, LA, Oct. 9, 2001. |
| Bernik et al., Vagus nerve stimulation attenuates LPS-induced cardiac TNF production and myocardial depression IN shock, New York Surgical Society, New York, NY, Apr. 11, 2001. |
| Bernik, et al., Pharmacological stimulation of the cholinergic anti-inflammatory pathway, The Journal of Experimental Medicine, vol. 195, No. 6, pp. 781-788, Mar. 18, 2002. |
| Besedovsky, H., et al., Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones, Science, vol. 233, No. 4764, pp. 652-654, Aug. 1986. |
| Bhattacharya, S.K. et al., Central muscarinic receptor subtypes and carrageenin-induced paw oedema in rats, Res. Esp. Med. vol. 191(1), pp. 65-76, Dec. 1991. |
| Bianchi et al., Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone, Journal of Experimental Medicine, vol. 183, pp. 927-936, Mar. 1996. |
| Biggio et al.; Chronic vagus nerve stimulation induces neuronal plasticity in the rat hippocampus; Int. J. Neurpsychopharmacol; vol. 12; No. 9; pp. 1209-1221; Oct. 2009. |
| Blackwell, T. S. et al., Sepsis and cytokines: current status, Br. J. Anaesth., vol. 77(1), pp. 110-117, Jul. 1996. |
| Blum, A. et al., Role of cytokines in heart failure, Am. Heart J., vol. 135(2), pp. 181-186, Feb. 1998. |
| Boldyreff, Gastric and intestinal mucus, its properties and physiological importance, Acta Medica Scandinavica (journal), vol. 89, Issue 1-2, pp. 1-14, Jan./Dec. 1936. |
| Borovikova et al., Acetylcholine inhibition of immune response to bacterial endotoxin in human macrophages, Abstracts, Society for Neuroscience, 29th Annual Meeting, Miami Beach, FL, (Abs. No. 624.6); Oct. 23-28, 1999. |
| Borovikova et al., Efferent vagus nerve activity attenuates cytokine-mediated inflammation, Society for Neuroscience Abstracts, vol. 26, No. 102, Nov. 4-9, 2000 (abstract only). |
| Borovikova et al., Intracerebroventricular CNI-1493 prevents LPS-induced hypotension and peak serum TNF at a four-log lower dose than systemic treatment, 21st Annual Conference on Shock, San Antonio, TX, Jun. 14-17, 1998, Abstract No. 86. |
| Borovikova et al., Role of the efferent vagus nerve signaling in the regulation of the innate immune response to LPS, (supplemental to Shock, vol. 13, 2000, Molecular, celular, and systemic pathobiological aspects and therapeutic approaches, abstracts, 5th World Congress on Trauma, Shock inflammation and sepsis-pathophysiology, immune consequences and therapy, Feb. 29, 2000-Mar. 4, 2000, Munich, DE), Abstract No. 166. |
| Borovikova et al., Role of the vagus nerve in the anti-inflammatory effects of CNI-1493, the FASEB journal, vol. 14, No. 4, 2000 (Experimental Biology 2000, San Diego, CA, Apr. 15-18, 2000, Abstract No. 97.9). |
| Borovikova et al., Vagotomy blocks the protective effects of I.C.V. CNI-1493 against LPS-induced shock, (Supplemental to Shock, vol. 11, 1999, Molecular, cellular, and systemic pathobioloigal aspects and therapeutic approaches, abstacts and program, Fourth international Shock Congress and 22nd Annual Conference on Shock, Philadelphia, PA, Jun. 12-16, 1999), Abstract No. 277. |
| Borovikova, L. V., et al., Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation, Autonomic Neuroscience, vol. 85, No. 1-3, pp. 141-147, Dec. 20, 2000. |
| Borovikova, L. V., et al., Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin, Nature, vol. 405, No. 6785: pp. 458-462, May 25, 2000. |
| Bruchfeld et al.; Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis; J. Int. Med .; 268(1); pp. 94-101; Jul. 2010. |
| Bulloch et al.; Characterization of choline O-acetyltransferase (ChAT) in the BALB/C mouse spleen; Int.J.Neurosci.; 76(1-2); pp. 141-149; May 1994. |
| Bumgardner, G. L. et al., Transplantation and cytokines, Seminars in Liver Disease, vol. 19, No. 2, Thieme Medical Publishers; pp. 189-204, © 1999. |
| Burke et al., Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HIV-1) reverse transcriptase, J. Mol. Biol., vol. 264(4); pp. 650-666, Dec. 1996. |
| Bushby et al; Centiles for adult head circumference; Archives of Disease in Childhood; vol. 67(10); pp. 1286-1287; Oct. 1992. |
| Cano et al.; Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing; J.Comp Neurol.; 439(1); pp. 1-18; Oct. 2001. |
| Carteron, N. L., Cytokines in rheumatoid arthritis: trials and tribulations, Mol. Med. Today, vol. 6(8), pp. 315-323, Aug. 2000. |
| Cavaillon et al.; The pro-inflammatory cytokine casade; Immune Response in the Critically Ill; Springer-Verlag Berlin Hiedelberg; pp. 37-66; Jan. 21, 2002. |
| Cheyuo et al.; The parasympathetic nervous system in the quest for stroke therapeutics; J. Cereb. Blood Flow Metab.; 31(5); pp. 1187-1195; May 2011. |
| Cicala et al., “Linkage between inflammation and coagulation: An update on the molecular basis of the crosstalk,” Life Sciences, vol. 62(20); pp. 1817-1824, Apr. 1998. |
| Clark et al.; Enhanced recognition memory following vagus nerve stimulation in human subjects; Nat. Neurosci.; 2(1); pp. 94-98; Jan. 1999. |
| Cohen, “The immunopathogenesis of sepsis,” Nature., vol. 420(6917): pp. 885-891, Dec. 2002. |
| Corcoran, et al., The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in humans: a preliminary report, NeuroImmunoModulation, vol. 12(5), pp. 307-309, Sep. 2005. |
| Crusz et al.; Inflammation and cancer; advances and new agents; Nature reviews Clinical Oncology; 12(10); pp. 584-596; doi: 10.1038/nrclinonc.2015.105; Jun. 30, 2015. |
| Dake; Chronic cerebrospinal venous insufficiency and multiple sclerosis: Hostory and background; Techniques Vasc. Intervent. Radiol.; 15(2); pp. 94-100; Jun. 2012. |
| Das, Critical advances in spticemia and septic shock, Critical Care, vol. 4, pp. 290-296, Sep. 7, 2000. |
| Del Signore et al; Nicotinic acetylcholine receptor subtypes in the rat sympathetic ganglion: pharmacological characterization, subcellular distribution and effect of pre- and postganglionic nerve crush; J.Neuropathol.Exp.Neurol.; 63(2); pp. 138-150; Feb. 2004. |
| Diamond et al.; Mapping the immunological homunculus; Proc. Natl. Acad. Sci. USA; 108(9); pp. 3461-3462; Mar. 1, 2011. |
| Dibbs, Z., et al., Cytokines in heart failure: pathogenetic mechanisms and potential treatment, Proc. Assoc. Am. Physicians, vol. 111, No. 5, pp. 423-428, Sep.-Oct. 1999. |
| Dinarello, C. A., The interleukin-1 family: 10 years of discovery, FASEB J., vol. 8, No. 15, pp. 1314-1325, Dec. 1994. |
| Dorr et al.; Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission; J. Pharmacol. Exp. Ther.; 318(2); pp. 890-898; Aug. 2006. |
| Doshi et al., Evolving role of tissue factor and its pathway inhibitor, Crit. Care Med., vol. 30, suppl. 5, pp. S241-S250, May 2002. |
| Elenkov et al.; Stress, corticotropin-releasing hormone, glucocorticoids, and the immune / inflammatory response: acute and chronic effects; Ann. N.Y. Acad. Sci.; 876; pp. 1-13; Jun. 22, 1999. |
| Ellington et al., In vitro selection of RNA molecules that bind specific ligands, Nature, vol. 346, pp. 818-822, Aug. 30, 1990. |
| Ellrich et al.; Transcutaneous vagus nerve stimulation; Eur. Neurological Rev.; 6(4); pp. 254-256; Winter 2011. |
| Engineer et al.; Directing neural plasticity to understand and treat tinnitus; Hear. Res.; 295; pp. 58-66; Jan. 2013. |
| Engineer et al.; Reversing pathological neural activity using targeted plasticity; Nature; 470(7332); pp. 101-104; Feb. 3, 2011 (Author Manuscript). |
| Esmon, The protein C pathway, Crit. Care Med., vol. 28, suppl. 9, pp. S44-S48, Sep. 2000. |
| Fields; New culprits in chronic pain; Scientific American; pp. 50-57; Nov. 2009. |
| Fleshner, M., et al., Thermogenic and corticosterone responses to intravenous cytokines (IL-1? and TNF-?) are attenuated by subdiaphragmatic vagotomy, J. Neuroimmunol., vol. 86(2), pp. 134-141, Jun. 1998. |
| Fox, D. A., Cytokine blockade as a new strategy to treat rheumatoid arthritis, Arch. Intern. Med., vol. 160, pp. 437-444, Feb. 28, 2000. |
| Fox, et al., Use of muscarinic agonists in the treatment of Sjorgren' syndrome, Clin. Immunol., vol. 101, No. 3; pp. 249-263, Dec. 2001. |
| Fujii et al.; Simvastatin regulates non-neuronal cholinergic activity in T lymphocytes via CD11a-mediated pathways; J. Neuroimmunol.; 179(1-2); pp. 101-107; Oct. 2006. |
| Gao et al.; Investigation of specificity of auricular acupuncture points in regulation of autonomic function in anesthetized rats; Autonomic Neurosc.; 138(1-2); pp. 50-56; Feb. 29, 2008. |
| Gattorno, M., et al., Tumor necrosis factor induced adhesion molecule serum concentrations in henoch-schoenlein purpura and pediatric systemic lupus erythematosus, J. Rheumatol., vol. 27, No. 9, pp. 2251-2255, Sep. 2000. |
| Gaykema, R. P., et al., Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion, Endocrinology, vol. 136, No. 10, pp. 4717-4720, Oct. 1995. |
| Ghelardini et al., S-(-)-ET 126: A potent and selective M1 antagonist in vitro and in vivo, Life Sciences, vol. 58, No. 12, pp. 991-1000, Feb. 1996. |
| Ghia, et al., The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model, Gastroenterology, vol. 131, No. 4, pp. 1122-1130, Oct. 2006. |
| Giebelen, et al., Stimulation of ?7 cholinergic receptors inhibits lipopolysaccharide-induced neutrophil recruitment by a tumor necrosis factor ?-independent mechanism, Shock, vol. 27, No. 4, pp. 443-447, Apr. 2007. |
| Goyal et al., Nature of the vagal inhibitory innervation to the lower esophageal sphincter, Journal of Clinical Investigation, vol. 55, pp. 1119-1126, May 1975. |
| Gracie, J. A., et al., A proinflammatory role for IL-18 in rheumatoid arthritis, J. Clin. Invest., vol. 104, No. 10, pp. 1393-1401, Nov. 1999. |
| Granert et al., Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic haemophilus influenzae infection, Infection and Immunity, vol. 68, No. 9, pp. 5329-5334, Sep. 2000. |
| Green et al., Feedback technique for deep relaxation, Psycophysiology, vol. 6, No. 3, pp. 371-377, Nov. 1969. |
| Gregory et al., Neutrophil-kupffer-cell interaction in host defenses to systemic infections, Immunology Today, vol. 19, No. 11, pp. 507-510, Nov. 1998. |
| Groves et al.; Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat; Neuroscience Letters; 379(3); pp. 174-179; May 13, 2005. |
| Guarente, Leonard, Ph. D.; Sirtuins, Aging, and Medicine; N Engl J Med ; vol. 364:pp. 2235-2244; Jun. 2011. |
| Guslandi, M., Nicotine treatment for ulcerative colitis, Br. J. Clin. Pharmacol., vol. 48(4), pp. 481-484, Oct. 1999. |
| Hansson, E.; Could chronic pain and spread of pain sensation be induced and maintained by glial activation?. Acta Physiologica, vol. 187, Issue 1-2; pp. 321R327, May/Jun. 2006. |
| Harrison's Principles of Internal Medicine, 13th Ed., pp. 511-515 and 1433-1435, Mar. 1994. |
| Hatton et al.; Vagal nerve stimulation: overview and implications for anesthesiologists; Int'l Anesthesia Research Society; vol. 103; No. 5; pp. 1241-1249; Nov. 2006. |
| Hirano, T., Cytokine suppresive agent improves survival rate in rats with acute pancreatitis of closed duodenal loop, J. Surg. Res., vol. 81, No. 2, pp. 224-229, Feb. 1999. |
| Hirao et al., The limits of specificity: an experimental analysis with RNA aptamers to MS2 coat protein variants, Mol. Divers., vol. 4, No. 2, pp. 75-89, 1999 (Accepted Jan. 13, 1999). |
| Hoffer et al.; Implantable electrical and mechanical interfaces with nerve and muscle; Annals of Biomedical Engineering; vol. 8; pp. 351-360; Jul. 1980. |
| Holladay et al., Neuronal nicotinic acetylcholine receptors as targets for drug discovery, Journal of Medicinal Chemistry, 40(26), pp. 4169-4194, Dec. 1997. |
| Hommes, D. W. et al., Anti- and Pro-inflammatory cytokines in the pathogenesis of tissue damage in Crohn's disease, Current Opinion in Clinical Nutrition and Metabolic Care, vol. 3(3), pp. 191-195, May 2000. |
| Housley et al.; Biomarkers in multiple sclerosis; Clinical Immunology; 161(1); pp. 51-58; Nov. 2015. |
| Hsu, et al., Analysis of efficiency of magnetic stimulation, IEEE Trans. Biomed. Eng., vol. 50(11), pp. 1276-1285, Nov. 2003. |
| Hsu, H. Y., et al., Cytokine release of peripheral blood monoculear cells in children with chronic hepatitis B virus infection, J. Pediatr. Gastroenterol., vol. 29, No. 5, pp. 540-545, Nov. 1999. |
| Hu, et al., The effect of norepinephrine on endotoxin-mediated macrophage activation, J. Neuroimmunol., vol. 31(1), pp. 35-42, Jan. 1991. |
| Huston et al.; Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis; J. Exp. Med. 2006; vol. 203, No. 7; pp. 1623-1628; Jun. 19, 2006. |
| Huston et al.; Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis; Crit. Care Med.; 35(12); pp. 2762-2768; Dec. 2007. |
| Hutchinson et al.; Proinflammatory cytokines oppose opioid induced acute and chronic analgesia; Brain Behav Immun.; vol. 22; No. 8; pp. 1178-1189; Nov. 2008. |
| Ilton et al., “Differential expression of neutrophil adhesion molecules during coronary artery surgery with cardiopulmonary bypass” Journal of Thoracic and Cardiovascular Surgery, Mosby-Year Book, inc., St. Louis, Mo, US, pp. 930-937, Nov. 1, 1999. |
| Jaeger et al., The structure of HIV-1 reverse transcriptase complexed with an RNA pseudoknot inhibitor, The EMBO Journal, 17(15), pp. 4535-4542, Aug. 1998. |
| Jander, S. et al., Interleukin-18 is induced in acute inflammatory demyelinating polymeuropathy, J. Neuroimmunol., vol. 114, pp. 253-258, Mar. 2001. |
| Joshi et al., Potent inhibition of human immunodeficiency virus type 1 replection by template analog reverse transcriptase , J. Virol., 76(13), pp. 6545-6557, Jul. 2002. |
| Kalishevskaya et al. “The character of vagotomy-and atropin-induced hypercoagulation,” Sechenov Physiological Journal of the USSR, 65(3): pp. 398-404, Mar. 1979. |
| Kalishevskaya et al.; Nervous regulation of the fluid state of the blood; Usp. Fiziol. Nauk;, vol. 13; No. 2; pp. 93-122; Apr.-Jun. 1982. |
| Kanai, T. et al., Interleukin-18 and Crohn's disease, Digestion, vol. 63, suppl. 1, pp. 37-42; 2001 (year of pub. sufficiently earlier than effective US filing date and any foreign priority date). |
| Katagiri, M., et al., Increased cytokine production by gastric mucosa in patients with helicobacter pylori infection, J. Clin, Gastroenterol., vol. 25, Suppl. 1, pp. S211-S214, 1997. |
| Katsavos et al.; Biomarkers in multiple sclerosis: an up-to-date overview; Multiple Sclerosis International; vol. 2013, Article ID 340508, 20 pages; 2013 (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Kawahara et al.; SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.; Cell. ; vol. 136; No. 1; pp. 62-74; Jan. 2009. |
| Kawashima, et al., Extraneuronal cholinergic system in lymphocytes, Pharmacology & Therapeutics, vol. 86, pp. 29-48, Apr. 2000. |
| Kees et al; Via beta-adrenoceptors, stimulation of extrasplenic sympathetic nerve fibers inhibits lipopolysaccharide-induced TNF secretion in perfused rat spleen; J. Neuroimmunol.; 145(1-2); pp. 77-85; Dec. 2003. |
| Kensch et al., HIV-1 reverse transcriptase-pseudoknot RNA aptamer interaction has a binding affinity in the low picomolar range coupled with high specificity, J. Biol. Chem., 275(24), pp. 18271-18278, Jun. 16, 2000. |
| Khatun, S., et al., “Induction of hypercoagulability condition by chronic localized cold stress in rabbits,” Thromb. and Haemost., 81(3): pp. 449-455, Mar. 1999. |
| Kimball, et al., Levamisole causes differential cytokine expression by elicited mouse peritoneal macrophases, Journal of Leukocyte Biology, vo. 52, No. 3, pp. 349-356, Sep. 1992 (abstract only). |
| Kimmings, A. N., et al., Systemic inflammatory response in acute cholangitis and after subsequent treatment, Eur. J. Surg., vol. 166, pp. 700-705, Sep. 2000. |
| Kirchner et al.; Left vagus nerve stimulation suppresses experimentally induced pain; Neurology; vol. 55; pp. 1167-1171; Oct. 2000. |
| Kokkula, R. et al., Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity, Arthritis Rheum., 48(7), pp. 2052-2058, Jul. 2003. |
| Koopman et al.; Pilot study of stimulation of the cholinergic anti-inflammatory pathway with an implantable vagus nerve stimulation device in patients with rheumatoid arthritis; Arth. Rheum.; 64(10 suppl.); pp. S195; Oct. 2012. |
| Koopman et al.; Pilot study of stimulation of the cholinergic anti-inflammatory pathway with an implantable vagus nerve stimulation device in patients with rheumatoid arthritis; 2012 ACR/ARHP Annual Meeting; Abstract No. 451; 4 pages, retrieved from the intemet (https://acrabstracts.org/abstract/pilot study-of-stimulation -of-the-cholinergic-anti-inflammatory-pathway-with-an-implantable-vagus-nerve stimulation-device-in-patients-with-rheumatoid arthritis); (Abstract Only); on Sep. 24, 2020. |
| Koopman et al.; THU0237 first-in-human study of vagus nerve stimulation for rheumatoid arthritis: clinical and biomarker results through day 84; Annals of the Rheumatic Diseases; 72(Suppl 3):A245; Jun. 1, 2013 (Abstract Only). |
| Koopman et al.; Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis; Proceedings of the National Academy of Sciences; 113(29); pp. 8284-8289; Jul. 19, 2016. |
| Krarup et al.; Conduction studies in peripheral cat nerve using implanted electrodes: I. methods and findings in controls; Muscle & Nerve; vol. 11; pp. 922-932; Sep. 1988. |
| Kudrjashov, et al. “Reflex nature of the physiological anticoagulating system,” Nature, vol. 196(4855): pp. 647-649; Nov. 17, 1962. |
| Kumins, N. H., et al., Partial hepatectomy reduces the endotoxin-induced peak circulating level of tumor necrosis factor in rats, Shock, vol. 5, No. 5, pp. 385-388, May 1996. |
| Kuznik, “Role of the vascular wall in the process of hemostatis,” Usp Sovrem Biol., vol. 75(1): pp. 61-85; 1973 (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Kuznik, et al., “Blood Coagulation in stimulation of the vagus nerve in cats,” Biull. Eskp. Biol. Med., vol. 78(7): pp. 7-9; 1974 (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Kuznik, et al., “Heart as an efferent regulator of the process of blood coagulation and fibrinolysis,” Kardiologiia, vol. 13(3): pp. 10-17; 1973 (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Kuznik, et al., “Role of the heart and vessels in regulating blood coagulation and fibrinolysis,” Kagdiologiia, vol. 13(4): pp. 145-154, Apr. 1973. |
| Kuznik, et al., “Secretion of blood coagulation factors into saliva under conditions of hypo-and hypercoagulation,” Voprosy Meditsinskoi Khimil, vol. 19(1): pp. 54-57; 1973(the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Kuznik, et al., “The dynamics of procoagulatible and fibrinolytic activities during electrical stimulation of peripheral nerves,” Sechenov Physiological Journal of the USSR, vol. 65; No. 3: pp. 414-420, Mar. 1979. |
| Kuznik, et al., “The role of the vascular wall in the mechanism of control of blood coagulation and fibrinolysis on stimulation of the vagus nerve,” Cor Vasa, vol. 17(2): pp. 151-158; 1975 (the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue). |
| Lang, et al., “Neurogenic control of cerebral blood flow,” Experimental Neurology, 43(1): pp. 143-161, Apr. 1974. |
| Lee, H. G., et al., Peritoneal lavage fluids stimulate NIH3T3 fibroblast proliferation and contain increased tumour necrosis factor and IL6 in experimental silica-induced rat peritonitis, Clin. Exp. Immunol., vol. 100, pp. 139-144, Apr. 1995. |
| LeNovere, N. et al., Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells, J. Mol. Evol., 40, pp. 155-172, Feb. 1995. |
| Leonard, S. et al., Neuronal nicotinic receptors: from structure to function, Nicotine & Tobacco Res. 3:203-223, Aug. 2001. |
| Lips et al.; Coexpression and spatial association of nicotinic acetylcholine receptor subunits alpha7 and alpha10 in rat sympathetic neurons; J.Mol.Neurosci.; 30; pp. 15-16; Feb. 2006. |
| Lipton, J. M. et al.; Anti-inflammatory actions of the neuroimmunomodulator ?—MSH, Immunol. Today, vol. 18, pp. 140-145, Mar. 1997. |
| Loeb et al.; Cuff electrodes for chronic stimulation and recording of peripheral nerve activity; Journal of Neuroscience Methods; vol. 64; pp. 95-103; Jan. 1996. |
| Mayo Clinic; The factsheet of vagus nerve stimulation from the Mayo Clinic website: www.mayoclinic.org/tests-procedures/vagus-nerve-sti mulation/about/pac-20384565; retrieved from the internet on Sep. 28, 2021. |
| Madretsma, G. S., et al., Nicotine inhibits the in vitro production of interleukin 2 and tumour necrosis factor-alpha by human monocuclear cells, Immunopharmacology, vol. 35, No. 1, pp. 47-51, Oct. 1996. |
| Manta et al.; Optimization of vagus nerve stimulation parameters using the firing activity of serotonin neurons in the rat dorsal raphe; European Neuropsychopharmacology; vol. 19; pp. 250-255; Jan. 2009 (doi: 10.1016/j.euroneuro.2008.12.001). |
| Martindale: The Extra Pharmacopoeia; 28th Ed. London; The Pharmaceutical Press; pp. 446-485; © 1982. |
| Martiney et al., Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent, Journal of Immunology, vol. 160, No. 11, pp. 5588-5595, Jun. 1, 1998. |
| McGuinness, P. H., et al., Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particulary interleukin 18) in chronic hepatitis C infection, Gut, vol. 46(2), pp. 260-269, Feb. 2000. |
| Miguel-Hidalgo, J.J.; The role of glial cells in drug abuse; Current Drug Abuse Reviews; vol. 2; No. 1; pp. 76-82; Jan. 2009. |
| Milligan et al.; Pathological and protective roles of glia in chronic pain; Nat Rev Neurosci.; vol. 10; No. 1; pp. 23-26; Jan. 2009. |
| Minnich et al.; Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls; Proceedings of the Nutrition Society; vol. 63(3); pp. 437-441; Aug. 2004. |
| Mishchenko, et al., “Coagulation of the blood and fibrinolysos in dogs during vagal stimulation,” Sechenov Physiological Journal of the USSR, vol. 61(1): pp. 101-107, 1975. |
| Mishchenko, “The role of specific adreno-and choline-receptors of the vascular wall in the regulation of blood coagulation in the stimulation of the vagus nerve,” Biull. Eskp. Biol. Med., vol. 78(8): pp. 19-22, 1974. |
| Molina et al., CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS, Shock, vol. 10, No. 5, pp. 329-334, Nov. 1998. |
| Nadol et al., “Surgery of the Ear and Temporal Bone,” Lippinkott Williams & Wilkins, 2nd Ed., 2005, (Publication date: Sep. 21, 2004), p. 580. |
| Nagashima et al., Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life, J. Clin. Invest., 109, pp. 101-110, Jan. 2002. |
| Nathan, C. F., Secretory products of macrophages, J. Clin. Invest., vol. 79 (2), pp. 319-326, Feb. 1987. |
| Navalkar et al.; Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis; Journal of the American College of Cardiology; vol. 37; No. 2; pp. 440-444; Feb. 2001. |
| Navzer et al.; Reversing pathological neural activity using targeted plasticity; Nature; 470(7332); pp. 101-104; Feb. 3, 2011. |
| Neuhaus et al.; P300 is enhanced in responders to vagus nerve stimulation for treatment of major depressive disorder; J. Affect. Disord.; 100(1-3); pp. 123-128; Jun. 2007. |
| Noguchi et al., Increases in Gastric acidity in response to electroacupuncture stimulation of hindlimb of anesthetized rats, Jpn. J. Physiol., 46(1), pp. 53-58, Feb. 1996. |
| Norton, Can ultrasound be used to stimulate nerve tissue, BioMedical Engineering OnLine, 2(1), pp. 6, Mar. 4, 2003. |
| Olofsson et al.; Rethinking inflammation: neural circuits in the regulation of immunity; Immunological Reviews; 248(1); pp. 188-204; Jul. 2012. |
| Oshinsky et al.; Non-invasive vagus nerve stimulation as treatment for trigeminal allodynia; Pain; 155(5); pp. 1037-1042; May 2014. |
| Palmblad et al., Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis: a thereapeutic study unding a macrophage-deactivation compound, American Journal of Pathology, vol. 158, No. 2, pp. 491-500, Feb. 2, 2001. |
| Pateyuk, et al., “Treatment of Botkin's disease with heparin,” Klin. Med., vol. 51(3): pp. 113-117, Mar. 1973. |
| Pavlov et al.; Controlling inflammation: the cholinergic anti-inflammatory pathway; Biochem. Soc. Trans.; 34(Pt 6); pp. 1037-1040; Dec. 2006. |
| Pavlov et al.; The cholinergic anti-inflammatory pathway; Brain, Behavior, and Immunity; 19; p. 493-499; Nov. 2005. |
| Palov et al.; The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation; Molecular Medicine; 9(5); pp. 125-134; May 2003. |
| Payne, J. B. et al., Nicotine effects on PGE2 and IL-1 beta release by LPS-treated human monocytes, J. Perio. Res., vol. 31, No. 2, pp. 99-104, Feb. 1996. |
| Peuker; The nerve supply of the human auricle; Clin. Anat.; 15(1); pp. 35-37; Jan. 2002. |
| Pongratz et al.; The sympathetic nervous response in inflammation; Arthritis Research and Therapy; 16(504); 12 pages; retrieved from the internet (http://arthritis-research.com/content/16/6/504) ; Jan. 2014. |
| Prystowsky, J. B. et al., Interleukin-1 mediates guinea pig gallbladder inflammation in vivo, J. Surg. Res., vol. 71, No. 2, pp. 123-126, Aug. 1997. |
| Pulkki, K. J., Cytokines and cardiomyocyte death, Ann. Med., vol. 29(4), pp. 339-343, Aug. 1997. |
| Pullan, R. D., et al., Transdermal nicotine for active ulcerative colitis, N. Engl. J. Med., vol. 330, No. 12, pp. 811-815, Mar. 24, 1994. |
| Pulvirenti et al; Drug dependence as a disorder of neural plasticity:focus on dopamine and glutamate; Rev Neurosci.; vol. 12; No. 2; pp. 141-158; Apr./Jun. 2001. |
| Rahman et al.; Mammalian Sirt 1: Insights on its biological functions; Cell Communications and Signaling; vol. 9; No. 11; pp. 1-8; May 2011. |
| Rayner, S. A. et al., Local bioactive tumour necrosis factor (TNF) in corneal allotransplantation, Clin. Exp. Immunol., vol. 122, pp. 109-116, Oct. 2000. |
| Reale et al.; Treatment with an acetylcholinesterase inhibitor in alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines; J. Neuroimmunology; 148(1-2); pp. 162-171; Mar. 2004. |
| Rinner et al.; Rat lymphocytes produce and secrete acetylcholine in dependence of differentiation and activation; J.Neuroimmunol.; 81(1-2); pp. 31-37; Jan. 1998. |
| Robinson et al.; Studies with the Electrocardiogram the Action of the Vagus Nerve on the Human Heart; J Exp Med; 14(3):217-234; Sep. 1911. |
| Romanovsky, A. A., et al., The vagus nerve in the thermoregulatory response to systemic inflammation, Am. J. Physiol., vol. 273, No. 1 (part 2), pp. R407-R413, Jul. 1, 1997. |
| Saghizadeh et al.; The expression of TNF? by human muscle; J. Clin. Invest.; vol. 97; No. 4; pp. 1111-1116; Feb. 15, 1996. |
| Saindon et al.; Effect of cervical vagotomy on sympathetic nerve responses to peripheral interleukin-1beta; Auton.Neuroscience Basic and Clinical; 87; pp. 243-248; Mar. 23, 2001. |
| Saito, Involvement of muscarinic M1 receptor in the central pathway of the serotonin-Induced bezold-jarisch reflex in rats, J. Autonomic Nervous System, vol. 49, pp. 61-68, Sep. 1994. |
| Sandborn, W. J., et al., Transdermal nicotine for mildly to moderately active ulcerative colitis, Ann. Intern. Med, vol. 126, No. 5, pp. 364-371, Mar. 1, 1997. |
| Sato, E., et al., Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity, Am. J. Physiol., vol. 274, pp. L970-L979, Jun. 1998. |
| Sato, K.Z., et al., Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukosytes and leukemic cell lines, Neuroscience Letters, vol. 266, pp. 17-20, Apr. 30, 1999. |
| Scheinman, R. I., et al., Role of transcriptional activation of I?B? in mediation of immunosuppression by glucocorticoids, Science, vol. 270, No. 5234, pp. 283-286, Oct. 13, 1995. |
| Schneider et al., High-affinity ssDNA inhibitors of the review transcriptase of type 1 human immunodeficiency virus, Biochemistry, 34(29), pp. 9599-9610, Jul. 1995. |
| Shafer, Genotypic testing for human immunodeficiency virus type 1 drug resistance, Clinical Microbiology Reviews, vol. 15, pp. 247-277, Apr. 2002. |
| Shapiro et al.; Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery; Thromb Haemost; vol. 80(5); pp. 773-778; Nov. 1998. |
| Sher, M. E., et al., The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease, Inflamm. Bowel Dis., vol. 5, No. 2, pp. 73-78, May 1999. |
| Shi et al.; Effects of efferent vagus nerve excitation on inflammatory response in heart tissue in rats with endotoxemia; vol. 15, No. 1; pp. 26-28; Jan. 2003 (Eng. Abstract). |
| Snyder et al., Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors; Nature Medicine, 5(1), pp. 64-70, Jan. 1999. |
| Sokratov, et al. “The role of choline and adrenegic structures in regulation of renal excretion of hemocoagulating compounds into the urine,” Sechenov Physiological Journal of the USSR, vol. 63(12): pp. 1728-1732, 1977. |
| Stalcup et al., Endothelial cell functions in the hemodynamic responses to stress, Annals of the New York Academy of Sciences, vol. 401, pp. 117-131, Dec. 1982. |
| Steinlein, New functions for nicotine acetylcholine receptors?, Behavioural Brain Res., vol. 95(1), pp. 31-35, Sep. 1998. |
| Sternberg, E. M., Perspectives series: cytokines and the brain ‘neural-immune interactions in health and disease,’ J. Clin. Invest., vol. 100, No. 22, pp. 2641-2647, Dec. 1997. |
| Stevens et al.; The anti-inflammatory effect of some immunosuppressive agents; J. Path.; 97(2); pp. 367-373; Feb. 1969. |
| Strojnik et al.; Treatment of drop foot using and implantable peroneal underknee stimulator; Scand. J. Rehab. Med.; vol. 19(1); pp. 37R43; Dec. 1986. |
| Strowig et al.; Inflammasomes in health and disease; Nature; vol. 481; pp. 278-286; doi: 10.1038/nature10759; Jan. 19, 2012. |
| Sugano et al., Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaβ activation, Biochemical and Biophysical Research Communications, vol. 252, No. 1, pp. 25-28, Nov. 9, 1998. |
| Suter et al.; Do glial cells control pain ?; Neuron Glia Biol.; vol. 3; No. 3; pp. 255-268; Aug. 2007. |
| Swick et al.; Locus coeruleus neuronal activity in awake monkeys: relationship to auditory P300-like potentials and spontaneous EEG. Exp. Brain Res.; 101(1); pp. 86-92; Sep. 1994. |
| Sykes, et al., An investigation into the effect and mechanisms of action of nicotine in inflammatory bowel disease, Inflamm. Res., vol. 49, pp. 311-319, Jul. 2000. |
| Takeuchi et al., A comparison between chinese blended medicine “Shoseiryuto” tranilast and ketotifen on the anit-allergic action in the guinea pigs, Allergy, vol. 34, No. 6, pp. 387-393, Jun. 1985 (eng. abstract). |
| Tekdemir et al.; A clinico-anatomic study of the auricular branch of the vagus nerve and arnold's ear-cough reflex; Surg. Radiol. Anat.; 20(4); pp. 253-257; Mar. 1998. |
| Toyabe, et al., Identification of nicotinic acetylcholine receptors on lymphocytes in the periphery as well as thymus in mice, Immunology, vol. 92(2), pp. 201-205, Oct. 1997. |
| Tracey et al., Mind over immunity, Faseb Journal, vol. 15, No. 9, pp. 1575-1576, Jul. 2001. |
| Tracey, K. J. et al., Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia; Nature, 330: pp. 662-664, Dec. 23, 1987. |
| Tracey, K. J. et al., Physiology and immunology of the cholinergic antiinflammatory pathway; J Clin Invest.; vol. 117: No. 2; pp. 289-296; Feb. 2007. |
| Tracey, K. J. et al., Shock and tissue injury induced by recombinant human cachectin, Science, vol. 234, pp. 470-474, Oct. 24, 1986. |
| Tracey, K. J.; Reflex control of immunity; Nat Rev Immunol; 9(6); pp. 418-428; Jun. 2009. |
| Tracey, K.J., The inflammatory reflex, Nature, vol. 420, pp. 853-859, Dec. 19-26, 2002. |
| Tsutsui, H., et al., Pathophysiolocical roles of interleukin-18 in inflammatory liver diseases; Immunol. Rev., 174:192-209, Apr. 2000. |
| Tuerk et al., RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase; Proc. Natl. Acad. Sci. USA, 89, pp. 6988-6992, Aug. 1992. |
| Tuerk et al., Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase; Science, 249(4968), pp. 505-510, Aug. 3, 1990. |
| Van Der Horst et al.; Stressing the role of FoxO proteins in lifespan and disease; Nat Rev Mol Cell Biol.; vol. 8; No. 6; pp. 440-450; Jun. 2007. |
| Van Dijk, A. P., et al., Transdermal nictotine inhibits interleukin 2 synthesis by mononuclear cells derived from healthy volunteers, Eur. J. Clin. Invest, vol. 28, pp. 664-671, Aug. 1998. |
| Vanhoutte, et al., Muscarinic and beta-adrenergic prejunctional modulation of adrenergic neurotransmission in the blood vessel wall, Gen Pharmac., vol. 14(1), pp. 35-37, Jan. 1983. |
| VanWesterloo, et al., The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis, The Journal of Infectious Diseases, vol. 191, pp. 2138-2148, Jun. 15, 2005. |
| Ventureyra, Transcutaneous vagus nerve stimulation for partial onset seizure therapy, Child's Nerv Syst, vol. 16(2), pp. 101-102, Feb. 2000. |
| Vijayaraghavan, S.; Glial-neuronal interactions-implications for plasticity anddrug addictionl AAPS J.; vol. 11; No. 1; pp. 123-132; Mar. 2009. |
| Villa et al., Protection against lethal polymicrobial sepsis by CNI-1493, an inhibitor of pro-inflammatory cytokine synthesis, Journal of Endotoxin Research, vol. 4, No. 3, pp. 197-204, Jun. 1997. |
| Von Känel, et al., Effects of non-specific ?—adrenergic stimulation and blockade on blood coagulation in hypertension, J. Appl. Physiol., vol. 94, pp. 1455-1459, Apr. 2003. |
| Von Känel, et al., Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo, Eur. J. Haematol., vol. 65: pp. 357-369, Dec. 2000. |
| Walland et al., Compensation of muscarinic brochlal effects of talsaclidine by concomitant sympathetic activation in guinea pigs; European Journal of Pharmacology, vol. 330(2-3), pp. 213-219, Jul. 9, 1997. |
| Wang et al.; Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation; Nature; 421; 384-388; Jan. 23, 2003. |
| Wang, H., et al., HMG-1 as a late mediator of endotoxin lethality in mice, Science, vol. 285, pp. 248-251, Jul. 9, 1999. |
| Waserman, S. et al., TNF-? dysregulation in asthma: relationship to ongoing corticosteroid therapy, Can. Respir. J., vol. 7, No. 3, pp. 229-237, May-Jun. 2000. |
| Watanabe, H. et al., The significance of tumor necrosis factor (TNF) levels for rejection of joint allograft, J. Reconstr. Microsurg., vol. 13, No. 3, pp. 193-197, Apr. 1997. |
| Wathey, J.C. et al., Numerical reconstruction of the quantal event at nicotinic synapses; Biophys. J., vol. 27: pp. 145-164, Jul. 1979. |
| Watkins, L.R. et al., Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication, Neurosci. Lett., vol. 183(1-2), pp. 27-31, Jan. 1995. |
| Watkins, L.R. et al., Implications of immune-to-brain communication for sickness and pain, Proc. Natl. Acad. Sci. U.S.A., vol. 96(14), pp. 7710-7713, Jul. 6, 1999. |
| Webster's Dictionary, definition of “intrathecal”, online version accessed Apr. 21, 2009. |
| Weiner, et al., “Inflammation and therapeutic vaccination in CNS diseases,” Nature., vol. 420(6917): pp. 879-884, Dec. 19-26, 2002. |
| Westerheide et al.; Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1.; Science; Vo. 323; No. 5717; pp. 1063-1066; Feb. 2009. |
| Whaley, K. et al., C2 synthesis by human monocytes is modulated by a nicotinic cholinergic receptor, Nature, vol. 293, pp. 580-582, Oct. 15, 1981. |
| Woiciechowsky, C. et al., Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury, Nature Med., vol. 4, No. 7, pp. 808-813, Jul. 1998. |
| Yeh, S.S. et al., Geriatric cachexia: the role of cytokines, Am. J. Clin. Nutr., vol. 70(2), pp. 183-197, Aug. 1999. |
| Yu et al.; Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a non-invasive approach to treat the initial phase of atrial fibrillation; Heart Rhythm; 10(3); pp. 428-435; Mar. 2013. |
| Zamotrinsky et al.; Vagal neurostimulation in patients with coronary artery disease; Auton. Neurosci.; 88(1-2); pp. 109-116; Apr. 2001. |
| Zhang et al., Tumor necrosis factor, The Cytokine Handbook, 3rd ed., Ed. Thompson, Academic Press, pp. 517-548, Jul. 1, 1998. |
| Zhang et al.; Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model; Circulation Heart Fail.; 2; pp. 692-699; Nov. 2009. |
| Zhang et al.; Roles of SIRT1 in the acute and restorative phases following induction of inflammation.; J Biol Chem.; vol. 285; No. 53; pp. 41391-401; Dec. 2010. |
| Zhao et al.; Transcutaneous auricular vagus stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation; Evid. Based Complement Alternat. Med.; vol. 2012; Article ID 627023; 10 pages; Dec. 29, 2012. |
| Zitnik et al.; Treatment of chronic inflammatory diseases with implantable medical devices; Cleveland Clinic Journal of Medicine; 78(Suppl 1); pp. S30-S34; Aug. 2011. |
| Caravaca et al.; A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve; Journal of Neural Engineering: 14(6);066005; Nov. 1, 2017. |
| Huston et al.; U.S. Appl. No. 17/784,805 entitled “Treating bleeding and bleeding disorders via high intensity focused ultrasound stimulation of the spleen,” filed Jun. 13, 2022. |
| Huston et al.; U.S. Appl. No. 18/355,401 entitled “Methods for reducing bleeding in hemophilia by vagus nerve stimualtion to prime platelets,” filed Jul. 19, 2023. |
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